A Phenomenological Exploration of Families' Experiences of the Mental Health System of Care in the Monadnock Region.

Accessing mental health treatment in rural locations is a unique challenge for families with youth experiencing adverse mental health conditions. Families often experience a variety of difficulties accessing and negotiating changes within the system of care. This study aimed to understand the experiences of families and their youth in navigating the mental health system in a rural community. Interpretative phenomenological analysis was used to examine how participants interpret their experiences within the local system of care. Qualitative interviews were conducted with eight families. Results included five main themes: youth experience, family experience, access to a system of care, relationships between stakeholders, and larger societal beliefs. Families highlighted their experiences accessing the local care system and their hope for strengthening community access and partnerships. Findings indicate that prioritizing family voices should be encouraged by local systems.

Structural Basis of Human Dimeric α-Amino-ß-Carboxymuconate-ε-Semialdehyde Decarboxylase Inhibition With TES-1025.

Human α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) stands at a branch point of the de novo NAD+ synthesis pathway and plays an important role in maintaining NAD+ homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a K i value of 0.85 ± 0.22 nM and binds in the catalytic site, interacting with the Zn2+ metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.

Conducting community rehabilitation review sessions via videoconference: A feasibility study.

OBJECTIVE: To determine the feasibility of conducting a single videoconferencing session (telerehabilitation) instead of a face-to-face home visit for a review appointment in a community rehabilitation program. DESIGN: A feasibility study based on Bowen's framework was used to determine demand, acceptability, limited efficacy and practicality of telerehabilitation. The study involved qualitative and quantitative data analysis. SETTING: Two Victorian community rehabilitation programs providing services to large geographical catchment zones in the outer fringe of a metropolitan area. PARTICIPANTS: Ten adult clients receiving home-based therapy and 5 allied health clinicians working in the program. INTERVENTIONS: Clients participated in a single review therapy appointment (telerehabilitation) from physiotherapy, dietetics or speech pathology using the health network's videoconferencing platfrom and the client's own electronic device. MAIN OUTCOME MEASURES: Demand was assessed by calculating the percentage of eligible clients able to participate compared to total number of home-based clients. Acceptability, practicality and limited efficacy were explored through qualitative analysis of semi-structured interviews. RESULTS: Nearly one quarter of clients screened met eligibility criteria, indicating a large potential demand for telerehabilitation. Telerehabilitation was highly acceptable for clinicians and clients participating in speech pathology and dietitian sessions as these contain targeted education and talking-based therapy. It was less accepted in physiotherapy, where there is a more hands-on approach. Telerehabilitation was practical and efficient for both clinicians and clients, especially when time was allowed for training and initial troubleshooting. CONCLUSION: Telerehabilitation is a feasible modality for review sessions in community rehabilitation and helps improve efficient use of clinician and client time. It is more appropriate for disciplines that use education and talking-based therapy compared with hands-on therapy. Older clients are accepting of new technology with support and education.

Synthetic Lethality in Pancreatic Cancer: Discovery of a New RAD51-BRCA2 Small Molecule Disruptor That Inhibits Homologous Recombination and Synergizes with Olaparib.

Synthetic lethality is an innovative framework for discovering novel anticancer drug candidates. One example is the use of PARP inhibitors (PARPi) in oncology patients with BRCA mutations. Here, we exploit a new paradigm based on the possibility of triggering synthetic lethality using only small organic molecules (dubbed "fully small-molecule-induced synthetic lethality"). We exploited this paradigm to target pancreatic cancer, one of the major unmet needs in oncology. We discovered a dihydroquinolone pyrazoline-based molecule (35d) that disrupts the RAD51-BRCA2 protein-protein interaction, thus mimicking the effect of BRCA2 mutation. 35d inhibits the homologous recombination in a human pancreatic adenocarcinoma cell line. In addition, it synergizes with olaparib (a PARPi) to trigger synthetic lethality. This strategy aims to widen the use of PARPi in BRCA-competent and olaparib-resistant cancers, making fully small-molecule-induced synthetic lethality an innovative approach toward unmet oncological needs.

What do we know about the health and health care of people with intellectual disabilities from minority ethnic groups in the United Kingdom? A systematic review.

BACKGROUND: People with from minority ethnic communities face inequalities in health and health care. This systematic review considers the question of what we know about the health and health care of children and adults with intellectual disabilities from ethnic minority communities in the UK. METHOD: Studies published from 1990 to 2018 were identified via electronic literature databases, email requests and cross-citations. Studies were reviewed narratively in relation to identified themes. RESULTS: Twenty-three studies were identified, most commonly focusing on South Asian communities. Very little information was identified on physical health or physical health care, with the identified evidence tending to focus on mental health care, access to specialist intellectual disability services, and inpatient services. CONCLUSION: Little is known about the health status of people with intellectual disabilities from minority ethnic groups in the UK. It is clear that they may experience barriers to accessing specialist intellectual disability services and other forms of health care.

Vaccine Coverage among Children with and without Intellectual Disabilities in the UK: Cross Sectional Study.

BACKGROUND: Universal childhood vaccination programmes form a core component of child health policies in most countries, including the UK. Achieving high coverage rates of vaccines is critical for establishing 'herd immunity' and preventing disease outbreaks. Evidence from the UK has identified several groups of children who are at risk of not being fully immunised. Our aim was to determine whether children with intellectual disabilities constitute one such group. METHODS: Secondary analysis of parental report data on child vaccination collected in the UK's Millennium Cohort Study when the children were 9 months, 3 years, 5 years and 14 years old. RESULTS: With one exception (MMR coverage at age 5) vaccination coverage rates were lower for children with intellectual disabilities (when compared to children without intellectual disability) for all vaccinations at all ages. Complete coverage rates were significantly lower for children with intellectual disabilities at ages 9 months (unadjusted PRR non-vaccination = 2.03 (1.14-3.60), p < 0.05) and 3 years (unadjusted PRR = 2.16 (1.06-4.43), p < 0.05), but not at age 5 years (unadjusted PRR = 1.91 (0.67-5.49)). HPV vaccination was lower (but not significantly so) at age 14 (PRR = 1.83 (0.99-3.37), p = 0.054). Adjusting PRRs for between group differences in family socio-economic position and other factors associated with coverage reduced the strength of association between intellectual disability and coverage at all ages. However, incomplete vaccination remained significantly elevated for children with intellectual disabilities at ages 9 months and 3 years. There were no statistically significant differences between parents of children with/without intellectual disability regarding the reasons given for non-vaccination. CONCLUSIONS: Children with intellectual disabilities in the UK are at increased risk of vaccine preventable diseases. This may jeopardise their own health, the health of younger siblings and may also compromise herd immunity.

The association between employment and the health of people with intellectual disabilities: A systematic review.

BACKGROUND: There is strong evidence indicating that paid employment is generally good for the physical and mental health of the general population. This systematic review considers the association between employment and the health of people with intellectual disabilities. METHODS: Studies published from 1990 to 2018 were identified via electronic literature databases, email requests and cross-citations. Identified studies were reviewed narratively. RESULTS: Twelve studies were identified. Studies were generally consistent in reporting an association between being in paid employment and better physical or mental health status. CONCLUSIONS: This review supports the view that the well-established association between employment and better health is similar for adults with and without intellectual disabilities. However, evidence establishing causality is lacking and further research to determine specific health benefits attributable to employment for people with intellectual disabilities and the causal pathways that operate is required.

Rad51/BRCA2 disruptors inhibit homologous recombination and synergize with olaparib in pancreatic cancer cells.

Olaparib is a PARP inhibitor (PARPi). For patients bearing BRCA1 or BRCA2 mutations, olaparib is approved to treat ovarian cancer and in clinical trials to treat breast and pancreatic cancers. In BRCA2-defective patients, PARPi inhibits DNA single-strand break repair, while BRCA2 mutations hamper double-strand break repair. Recently, we identified a series of triazole derivatives that mimic BRCA2 mutations by disrupting the Rad51-BRCA2 interaction and thus double-strand break repair. Here, we have computationally designed, synthesized, and tested over 40 novel derivatives. Additionally, we designed and conducted novel biological assays to characterize how they disrupt the Rad51-BRCA2 interaction and inhibit double-strand break repair. These compounds synergized with olaparib to target pancreatic cancer cells with functional BRCA2. This supports the idea that small organic molecules can mimic genetic mutations to improve the profile of anticancer drugs for precision medicine. Moreover, this paradigm could be exploited in other genetic pathways to discover innovative anticancer targets and drug candidates.

Sexual activity and sexual health among young adults with and without mild/moderate intellectual disability.

BACKGROUND: There is widespread concern about the sexual 'vulnerability' of young people with intellectual disabilities, but little evidence relating to sexual activity and sexual health. METHOD: This paper describes a secondary analysis of the nationally representative longitudinal Next Steps study (formerly the Longitudinal Survey of Young People in England), investigating sexual activity and sexual health amongst young people with mild/moderate intellectual disabilities. This analysis investigated family socio-economic position, young person socio-economic position, household composition, area deprivation, peer victimisation, friendships, sexual activity, unsafe sex, STIs, pregnancy outcomes and parenting. RESULTS: Most young people with mild/moderate intellectual disabilities have had sexual intercourse by age 19/20, although young women were less likely to have sex prior to 16 than their peers and both men and women with intellectual disabilities were more likely to have unsafe sex 50% or more of the time than their peers. Women with intellectual disabilities were likely to have been pregnant and more likely to be a mother. CONCLUSION: Most young people with mild/moderate intellectual disabilities have sex and are more likely to have unsafe sex than their peers. Education and health services need to operate on the assumption that most young people with mild/moderate intellectual disabilities will have sex.

The association between employment status and health among British adults with and without intellectual impairments: cross-sectional analyses of a cohort study.

BACKGROUND: There exists a well established link between employment status and health, with unemployment being associated with poorer health. Much less is known about the association between economic inactivity and health, especially among people with disabilities. Our aim is to determine whether the association between employment status and health is similar for adults with and adults without intellectual impairment. METHODS: Using nationally representative data from the 1970 British Cohort Study, we undertook a series of cross sectional analyses of the association between employment status and health (self-reported general health, mental health) among British adults with and without intellectual impairments at ages 26, 30, 34, 38 and 42. RESULTS: People with intellectual disability and borderline intellectual functioning had markedly lower employment rates and poorer health than other participants at all waves of data collection. When compared with participants in full-time employment the prevalence of poorer self rated health and mental health was higher among participants with and without intellectual impairment who were in either part-time employment or were economically inactive at all ages. When compared with participants in employment the prevalence of poorer self rated health and mental health was higher among participants with and without intellectual impairment who were in the economically inactive categories of unemployment, education/training and ill/disabled at all ages. Intellectual disability status appeared to moderate the strength of the relationship between economic activity and self-rated health and, to a much lesser extent, the relationship between economic activity and mental health. In all instances the moderation indicated a stronger association among participants without intellectual impairment. CONCLUSIONS: The results provide substantive evidence to suggest that the nature of the well-established association between employment and better health is similar for British adults with and without intellectual impairments. The results do, however, indicate that the magnitude of the effect involved differed. Further research is needed to identify mechanisms that may underlie this difference.

The association between non-standard employment, job insecurity and health among British adults with and without intellectual impairments: Cohort study.

We sought to investigate the association between employment conditions and health among working age British adults with and without intellectual impairments. Using data from the 1970 British Cohort Study, we undertook a series of cross sectional analyses of the association between employment conditions and health (self-reported general health, mental health) among British adults with and without intellectual impairments at ages 30, 34 and 42. Our results indicated that: (1) British adults with intellectual impairments were more likely than their peers to be exposed to non-standard employment conditions and experience job insecurity; (2) in both groups exposure was typically associated with poorer health; (3) British adults with intellectual impairments in non-standard employment conditions were more likely than their peers to transition to economic inactivity; (4) among both groups, transitioning into employment was associated with positive health status and transitioning out of employment was associated with poorer health status. British adults with intellectual impairments are significantly more likely than their peers to be exposed to non-standard and more precarious working conditions. The association between employment conditions and health was similar for British adults with and without intellectual impairments. As such, the study found no evidence to suggest that research on causal pathways between employment and health derived from studies of the general population should not generalize to the population of people with intellectual impairments.

α-Amino-ß-carboxymuconate-ε-semialdehyde Decarboxylase (ACMSD) Inhibitors as Novel Modulators of De Novo Nicotinamide Adenine Dinucleotide (NAD+) Biosynthesis.

NAD+ has a central function in linking cellular metabolism to major cell-signaling and gene-regulation pathways. Defects in NAD+ homeostasis underpin a wide range of diseases, including cancer, metabolic disorders, and aging. Although the beneficial effects of boosting NAD+ on mitochondrial fitness, metabolism, and lifespan are well established, to date, no therapeutic enhancers of de novo NAD+ biosynthesis have been reported. Herein we report the discovery of 3-[[[5-cyano-1,6-dihydro-6-oxo-4-(2-thienyl)-2-pyrimidinyl]thio]methyl]phenylacetic acid (TES-1025, 22), the first potent and selective inhibitor of human ACMSD (IC50 = 0.013 µM) that increases NAD+ levels in cellular systems. The results of physicochemical-property, ADME, and safety profiling, coupled with in vivo target-engagement studies, support the hypothesis that ACMSD inhibition increases de novo NAD+ biosynthesis and position 22 as a first-class molecule for the evaluation of the therapeutic potential of ACMSD inhibition in treating disorders with perturbed NAD+ supply or homeostasis.

Self-Reported Participation in Sport/Exercise Among Adolescents and Young Adults With and Without Mild to Moderate Intellectual Disability.

BACKGROUND: Physical inactivity is a leading risk factor for mortality. Adults with intellectual disability are extremely inactive, but less is known about physical activity levels in children and youth with intellectual disability. This paper examines the participation by adolescents and young adults with and without mild to moderate intellectual disability in sport/exercise. METHODS: Secondary analysis was undertaken of Next Steps, an annual panel study that followed a cohort from early adolescence into adulthood. Participants with mild to moderate intellectual disability were identified through data linkage with educational records. RESULTS: Sport/exercise participation rates were consistently lower for adolescents and young people with mild to moderate intellectual disability than for their peers without intellectual disability. Matching participants on between-group differences in exposure to extraneous risk factors did not impact on these between-group differences in participation in sport/exercise. CONCLUSION: The results support limited existing evidence regarding the low level of participation of children and young people with intellectual disability in sport/exercise compared with their peers. Future work on promoting sport/exercise and physical activity in children and young people with intellectual disability may play a role in helping to reduce the health inequalities experienced by people with intellectual disability.

Constipation management in people with intellectual disability: A systematic review.

BACKGROUND: Constipation can lead to serious health issues and death. This systematic review summarizes international research pertaining to the management of constipation in people with intellectual disability. METHOD: Studies published from 1990 to 2017 were identified using Medline, Cinahl, PsycINFO, Web of Science, email requests and cross-citations. Studies were reviewed narratively in relation to identified themes. RESULTS: Eighteen studies were reviewed in relation to three themes: laxative receipt; interventions (dietary fibre, abdominal massage and macrogol); and staff issues (knowledge and training). Laxative polypharmacy was common. Studies report positive results for dietary fibre and abdominal massage although study quality was limited. CONCLUSION: The main management response to constipation in people with intellectual disability is laxative use despite limited effectiveness. An improved evidence base is required to support the suggestion that an individualized, integrated bowel management programme may reduce constipation and associated health conditions in people with intellectual disability.

The mental health of adolescents with and without mild/moderate intellectual disabilities in England: Secondary analysis of a longitudinal cohort study.

BACKGROUND: Children with mild/moderate intellectual disabilities are at greater risk for mental health problems, with socio-economic factors and adversity partly accounting for this. Fewer data are available for adolescents. METHODS: Secondary analysis was undertaken of the Next Steps annual panel study following a cohort through adolescence into adulthood containing self-report mental health data up to age 16/17. Participants with mild/moderate intellectual disabilities were identified through data linkage with educational records. RESULTS: Adolescents with mild/moderate intellectual disabilities were more likely than non-disabled peers to experience socio-economic disadvantage and bullying. Incidence rates of mental health problems were generally not significantly different between adolescents with and without intellectual disabilities. CONCLUSIONS: These findings are consistent with higher rates of persistent mental health problems beginning earlier among children with intellectual disabilities. Greater attention needs to be paid to the timecourse of mental health problems, and the impact of socio-economic factors, family and peers on mental health.

Postural care for people with intellectual disabilities and severely impaired motor function: A scoping review.

BACKGROUND: Poor postural care can have severe and life-threatening complications. This scoping review aims to map and summarize existing evidence regarding postural care for people with intellectual disabilities and severely impaired motor function. METHOD: Studies were identified via electronic database searches (MEDLINE, CINAHL, PsycINFO and Web of Science) covering January 1990 to March 2016, and email requests to researcher networks. Results were collated via descriptive numerical summary of studies and thematic analysis. RESULTS: Twenty-three studies were identified and summarized narratively in relation to three themes: characteristics and prevalence, interventions and service related issues. The evidence base is small with significant gaps. Lack of evidence for night-time positioning equipment and 24-hr postural care needs to be addressed urgently. CONCLUSION: Future research should be clearly directed towards ascertaining how best postural care interventions can be employed to help improve the health and quality of life of people with intellectual disabilities.

People with intellectual disabilities and dysphagia.

PURPOSE: Dysphagia (difficulties in eating, drinking or swallowing) is associated with serious health complications and psychosocial sequelae. This review aims to summarise the state of the evidence regarding dysphagia in people with intellectual disabilities (excluding prevalence), identify gaps in the evidence base and highlight future research priorities. METHOD: Studies published from 1 January 1990 to 19 July 2016 were identified using Medline, Cinahl, PsycINFO, Web of Science, email requests and cross citations. Studies were reviewed narratively in relation to identified themes. RESULTS: A total of 35 studies were included in the review. Themes identified were as follows: health conditions associated with dysphagia; mortality; health service use; practice and knowledge in supporting people with intellectual disabilities and dysphagia; intervention effectiveness and quality of life. Dysphagia is associated with respiratory infections and choking and may be under-recognised. Silent aspiration is common and may go unnoticed. Management practices exist, but there are few intervention studies and no randomised controlled trials (RCTs), and hence, the effectiveness of these is currently unclear. CONCLUSION: Dysphagia is a key concern in relation to people with intellectual disabilities. There is urgent need for research on the management of dysphagia in people with intellectual disabilities, including mealtime support offered, positioning, dietary modification and impact on wellbeing. Implications for Rehabilitation Dysphagia is common in people with intellectual disabilities, associated with serious health risks and may be under-recognised. Caregivers of people with intellectual disabilities should be educated about dysphagia. There is an urgent need for research on improving the management of dysphagia in people with intellectual disabilities. Improved recognition and management of dysphagia may reduce the occurrence of associated health conditions and reduce hospital admissions and premature death in people with intellectual disabilities.

Prevalence of Dysphagia in People With Intellectual Disability: A Systematic Review.

Dysphagia (feeding and swallowing disorder) is associated with serious health complications and psychosocial sequelae. This review summarizes international research relating to the prevalence of dysphagia in people with intellectual disability. Studies published from 1990 to July 2016 were identified using Medline, Cinahl, PsycINFO, Web of Science, email requests, and cross-citations. Twenty studies were identified. Dysphagia in people with intellectual disability appears to be associated with more severe levels of intellectual disability, comorbid cerebral palsy, and motor impairments. However, further research with representative samples of people with intellectual disability using adequate methods of assessment are required in order to provide more precise prevalence estimates and clarify factors that may be associated with dysphagia in this population.

Synthetic Lethality Triggered by Combining Olaparib with BRCA2-Rad51 Disruptors.

In BRCA2-defective cells, poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors can trigger synthetic lethality, as two independent DNA-repairing mechanisms are simultaneously impaired. Here, we have pharmacologically induced synthetic lethality, which was triggered by combining two different small organic molecules. When administered with a BRCA2-Rad51 disruptor in nonmutant cells, Olaparib showed anticancer activity comparable to that shown when administered alone in BRCA2-defective cells. This strategy could represent an innovative approach to anticancer drug discovery and could be extended to other synthetic lethality pathways.

Service Responses to People with Intellectual Disabilities and Epilepsy: A Systematic Review.

BACKGROUND: Epilepsy is highly prevalent in people with intellectual disabilities and is associated with increased mortality and high healthcare usage. This systematic review summarizes research on service responses to people with intellectual disabilities and epilepsy. METHOD: Studies published from 1990 were identified via electronic searches using Medline, Cinahl, PsycINFO and Web of Science, email requests to researcher networks, and cross-citations. Information extracted from studies was reviewed narratively in relation to identified themes. RESULTS: Thirty-five studies met the inclusion criteria. Overall study quality was low, with no RCTs or similarly robust intervention study designs. Access to specialists was inconsistent. The importance of proxies and the need for education regarding epilepsy for staff, carers and people with intellectual disabilities were highlighted. CONCLUSION: There are no methodologically robust studies on service-related interventions for people with intellectual disabilities and epilepsy. Further research on improving service delivery is required to substantiate findings reported here.