The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

New Home, New You: A retrospective mixed-methods evaluation of a health-related behavioural intervention programme supporting social housing tenants.

BACKGROUND: Social housing tenants are at greater risk of engaging in unhealthy behaviours than the general population. Housing association employees are in an ideal position to contribute positively to their tenants' health. 'New Home, New You' (NHNY) is a joint venture between a social housing association, a city council and a community healthcare provider in the South West of England. It was designed with the aim of improving the health and well-being of social housing tenants. OBJECTIVES: The aim of this retrospective evaluation was to establish whether social housing tenants were benefiting from this health-related behavioural intervention in terms of their mental well-being and health-related behaviours. METHODS: This was a mixed-methods evaluation. The outcome evaluation was a secondary analysis of quantitative data collected during the NHNY project. The process of delivering and receiving the intervention was evaluated using qualitative, semi-structured interviews with housing officers and tenants who had participated in the programme. The development of the intervention was evaluated through a focus group and additional semistructured interviews with key stakeholders. Quantitative data were analysed using the Statistical Package for the Social Sciences. Qualitative interviews were analysed using thematic analysis. RESULTS: Six key stakeholders and a total of seven housing officers from several teams and seven tenants were interviewed. Of the 1016 tenants who were invited to participate in NHNY, 226 enroled in the programme. For participating tenants, the scope for health-related behaviour change was greatest in relation to eating and smoking. Small positive statistically significant changes in mental health were found between the 6- and 12-month mean score and between the baseline and the 12-month score. CONCLUSIONS: The findings indicate that NHNY may have been beneficial for some participating tenants. Housing officers can have a significant role in promoting health messages and embedding behaviour change among their tenants. Although the programme was implemented as a service improvement rather than a controlled trial and focused on a particular intervention and geographical area, other housing associations may find this evaluation useful for considering whether to adopt some of the principles applied in NHNY in other settings. PATIENT OR PUBLIC CONTRIBUTION: A social housing tenant representative provided input on the methodology and methods used to evaluate NHNY, as well as the information sheet.

Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer's Disease Patients Carrying the APOE Epsilon 4 Allele.

Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aß) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aß/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not ß-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.

Mitochondrial ß-amyloid in Alzheimer's disease.

It is well established that the intracellular accumulation of Aß (amyloid ß-peptide) is associated with AD (Alzheimer's disease) and that this accumulation is toxic to neurons. The precise mechanism by which this toxicity occurs is not well understood; however, identifying the causes of this toxicity is an essential step towards developing treatments for AD. One intracellular location where the accumulation of Aß can have a major effect is within mitochondria, where mitochondrial proteins have been identified that act as binding sites for Aß, and when binding occurs, a toxic response results. At one of these identified sites, an enzyme known as ABAD (amyloid-binding alcohol dehydrogenase), we have identified changes in gene expression in the brain cortex, following Aß accumulation within mitochondria. Specifically, we have identified two proteins that are up-regulated not only in the brains of transgenic animal models of AD but also in those of human sufferers. The increased expression of these proteins demonstrates the complex and counteracting pathways that are activated in AD. Previous studies have identified approximate contact sites between ABAD and Aß; on basis of these observations, we have shown that by using a modified peptide approach it is possible to reverse the expression of these two proteins in living transgenic animals and also to recover mitochondrial and behavioural deficits. This indicates that the ABAD-Aß interaction is potentially an interesting target for therapeutic intervention. To explore this further we used a fluorescing substrate mimic to measure the activity of ABAD within living cells, and in addition we have identified chemical fragments that bind to ABAD, using a thermal shift assay.

National patterns in paediatric hospital admissions for dental extractions in England.

OBJECTIVES: Paediatric hospital admissions for dental extractions remain a cause for concern, despite decreasing levels of dental diseases in some areas of the country. While local investigations have taken place, little is known about national patterns, and how the relationship between the number of hospital admissions and key independent variables differs across England. The aim of this study was to examine spatial differences in the number of paediatric hospital admissions for extractions in relation to four key independent variables: dental caries, deprivation, units of dental activity and child access to dentists. METHODS: Hospital admissions data (for all dental-related reasons) were taken from the Hospital Episode Statistics (HES) for England (2017/18) for children and adolescents aged up to 19 years. All data were collected at local authority level. Geographically weighted regression was used to examine associations between the number of hospital admissions and the independent variables, as well as the strength of these associations and how they differed spatially. RESULTS: Geographically weighted regression revealed considerable differences in the associations between the number of paediatric hospital admissions and the independent variables across England, with distinct regional clusters identified in the data. Some areas exhibited positive associations between independent variables and the number of hospital admissions, such as in Yorkshire and areas of south-west, south-east and north-west England, where greater mean dmft scores were associated with greater numbers of hospital admissions. Negative associations were also found, such as in south-west, north-west and North East England, where higher deprivation scores were associated with lower admission numbers. Despite the patterns found, a much smaller sample of the associations between the independent variables and the number of hospital admissions was statistically significant. CONCLUSIONS: This analysis allows for a better understanding of the spatial associations between the number of hospital admissions and key independent variables, as well as how changes to these independent variables may affect the number of admissions in each local authority. These findings should be considered in the context of the limitations of HES dataset.

Does suprascapular nerve block reduce shoulder pain following stroke: a double-blind randomised controlled trial with masked outcome assessment.

BACKGROUND: Shoulder pain is a common complication of a stroke which can impede participation in rehabilitation programs and has been associated with poorer outcomes. The evidence base for current medical and therapeutic management options of hemiplegic shoulder pain is limited. This study will evaluate the use of suprascapular nerve block injection as part of an interdisciplinary approach to the treatment of shoulder pain following stroke. The technique has previously been proven safe and effective in the treatment of shoulder pain associated with rheumatoid arthritis and degenerative shoulder conditions but its usefulness in a stroke population is unclear. METHODS/DESIGN: A double blind randomised placebo controlled trial will assess the effect of a suprascapular nerve block compared with placebo in a population of 66 stroke patients. The trial will measure effect of injection on the primary outcome of pain, and secondary outcomes of function and quality of life. Measurements will take place at baseline, and 1, 4 and 12 weeks post intervention. Both groups will continue to receive routine physiotherapy and standard ward care. DISCUSSION: The results of this study could reduce pain symptoms in persons with mechanical shoulder pain post stroke and provide improvement in upper limb function. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12609000621213.

Management of plaque in people experiencing homelessness using 'peer education': a pilot study.

Introduction People who experience homelessness have poor oral health and limited access to dental services.Aim To examine whether 'peer education' could yield improved plaque management among people experiencing homelessness.Methods A quasi-experimental, one-group pre-test-post-test study was conducted, with follow-up at one and two months. Participants were living in temporary accommodation in Plymouth, UK. Plaque levels were assessed using the simplified oral hygiene index. A questionnaire and the oral health impact profile (OHIP-14) were administered. Patient satisfaction and barriers to dental care were explored by interviews.Results The baseline sample included 24 people with a mean age of 36.88 ± 10.26 years. The mean OHIP-14 score was 25.08 ± 19.56; finding it uncomfortable to eat and being embarrassed attracted the highest values (2.46 ± 1.53 and 2.33 ± 1.63, respectively). Plaque levels decreased by month one and month two, though the changes were not statistically significant. Positive changes in confidence in toothbrushing at month two were identified (p = 0.01).Conclusion Experiencing pain and the opportunity to access treatment were key drivers of study participation. The study indicated that it is feasible to conduct oral health promotion projects for people in temporary accommodation. Adequately powered studies examining the impact of peer education on improving homeless people's oral health are warranted.

Determinants of theory of mind performance in Alzheimer's disease: A data-mining study.

Whether theory of mind (ToM) is preserved in Alzheimer's disease (AD) remains a controversial subject. Recent studies have showed that performance on some ToM tests might be altered in AD, though to a lesser extent than in behavioural-variant Frontotemporal Dementia (bvFTD). It is however, unclear if this reflects a genuine impairment of ToM or a deficit secondary to the general cognitive decline observed in AD. Aiming to investigate the cognitive determinants of ToM performance in AD, a data-mining study was conducted in 29 AD patients then replicated in an independent age-matched group of 19 AD patients to perform an independent replication of the results. 44 bvFTD patients were included as a comparison group. All patients had an extensive neuropsychological examination. Hierarchical clustering analyses showed that ToM performance clustered with measures of executive functioning (EF) in AD. ToM performance was also specifically correlated with the executive component extracted from a principal component analysis. In a final step, automated linear modelling conducted to determine the predictors of ToM performance showed that 48.8% of ToM performance was significantly predicted by executive measures. Similar findings across analyses were observed in the independent group of AD patients, thereby replicating our results. Conversely, ToM impairments in bvFTD appeared independent of other cognitive impairments. These results suggest that difficulties of AD patients on ToM tests do not reflect a genuine ToM deficit, rather mediated by general (and particularly executive) cognitive decline. They also suggest that EF has a key role in mental state attribution, which support interacting models of ToM functioning. Finally, our study highlights the relevancy of data-mining statistical approaches in clinical and cognitive neurosciences.