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Objectives: People with intellectual disabilities are more vulnerable to and experience mental health concerns at a higher incidence than their peers without intellectual disabilities. This may be directly related to the aetiology of their intellectual disability but also occur because of negative psychological and social factors that affect their lives, such as loss of self-esteem or lack of meaningful opportunities. The SOOTHE project, sought to understand the meaning that adults with intellectual disabilities attribute to mental health and wellbeing, the factors influencing good and poor mental health, and the strategies they utilised to maintain good mental health and wellbeing. Using an online anonymous survey, participants were invited to electronically submit an image that represented their perspectives on what mental health and wellbeing meant to them. Methods: This study, which took place in 2020 during the first year of the Covid-19 pandemic, employed an anonymous survey approach which resulted in individual images being received from 329 people with intellectual disabilities living in Spain, the Netherlands, and Ireland. These were analysed thematically and brought together in an electronic quilt/mosaic. Results: Images were classified into seven potential themes: (1) Covid-19 and mental health; (2) maintaining good mental health; (3) activities that promote good mental health; (4) nature and mental health; (5) perspectives on self; (6) the importance of relationships; and (7) home and feeling safe. Conclusions: This paper explores the possible meaning of the images and seeks alignment of those meanings with the rights and freedoms enshrined in the UNCRPD. The project supports the belief that persons with intellectual disabilities have an understanding of mental health and wellbeing and are able to identify ways of maintaining positive mental health.

Spatial transcriptomics measures in situ gene expression at millions of locations within a tissue1, hitherto with some trade-off between transcriptome depth, spatial resolution and sample size2. Although integration of image-based segmentation has enabled impactful work in this context, it is limited by imaging quality and tissue heterogeneity. By contrast, recent array-based technologies offer the ability to measure the entire transcriptome at subcellular resolution across large samples3–6. Presently, there exist no approaches for cell type identification that directly leverage this information to annotate individual cells. Here we propose a multiscale approach to automatically classify cell types at this subcellular level, using both transcriptomic information and spatial context. We showcase this on both targeted and whole-transcriptome spatial platforms, improving cell classification and morphology for human kidney tissue and pinpointing individual sparsely distributed renal mouse immune cells without reliance on image data. By integrating these predictions into a topological pipeline based on multiparameter persistent homology7–9, we identify cell spatial relationships characteristic of a mouse model of lupus nephritis, which we validate experimentally by immunofluorescence. The proposed framework readily generalizes to new platforms, providing a comprehensive pipeline bridging different levels of biological organization from genes through to tissues.

The Covid-19 pandemic provided a research opportunity to explore online group exercise programmes in larger numbers while restrictions on group gatherings were in place. An online survey was conducted with Irish Physiotherapists to ascertain their views on online group exercise programmes and the methods they employed to conduct their online classes in order to guide Physiotherapists with future care delivery. A mixed-methods design was employed using a cross-sectional national online survey of Physiotherapists in Ireland. The survey collected both qualitative and quantitative data. Descriptive statistics were used to summarise the ordinal and continuous data and free-text responses were analysed using conventional content analysis. In total, 81 Physiotherapists completed the surveys. The majority of Physiotherapists (62%) feel a blended or hybrid model is the best option for the future. Convenience and decreased travel were cited as the main advantages of online classes. Physiotherapists cited in-person classes as being of higher teaching quality with improved safety and social interaction. Physiotherapists indicated that very little staff or technological resources were needed for their online classes and serious adverse events during the classes were extremely infrequent. Online group exercise programmes were well received by Physiotherapists, although the majority of those questioned believe a mixture of both online and in person exercise classes should be offered going forward.

To evaluate the differences in the antenatal and neonatal courses of maternal-infant dyads within a homeless population as compared to the general hospital population.

Introduction:Ireland has an ageing population of persons with intellectual disability (ID), autism spectrum disorder (ASD) and both (ID/ASD). Despite this, little is known about the prevalence of ASD and its effect on functional outcomes, psychiatric comorbidity or diagnostic issues in an older population with ID. This article reviews the literature on older adults with ID/ASD and identifies opportunities for future research in this population.Method:The authors searched the Medline, Pubmed, Embase, CINAHL and PsychInfo databases using the search terms using key words: (older adults) AND (ID OR mental retardation OR learning disability) AND (autism OR ASD). After excluding articles for relevance, a scoping review was carried out on the results retrieved.Results:Of the 1227 articles retrieved from the literature on ID and autism/ASD in older adults, 85 articles were relevant to an adult population with ID/ASD. The data were collated and are presented covering domains of diagnosis, prevalence, psychiatric comorbidities and functional outcomes.Conclusions:Despite increased prevalence in childhood ASD in the last 20 years, there is a lack of research regarding adults, especially older adults, with ASD, up to half of whom will have some level of ID. The existing literature suggests that older adults with ID/ASD may have reduced functional independence, increased psychiatric comorbidity and psychotropic prescribing and more behavioural presentations than the older population generally or those with ID only. There is a need for longitudinal data to be collected on this ageing population so that care and management needs can be met in the future.

To determine the involvement of the endocannabinoid (EC) family member in the pathophysiology of endometriosis (EMS).

Objective: A post hoc appraisal of the PDA RCT to assess the relationship between early patent ductus arteriosus (PDA) shunt elimination and chronic lung disease or death (CLD/Death). Study design: Infants <29 weeks were divided into four groups: intervention arm in whom PDA closure was achieved (n= 17); intervention arm in whom PDA closure was not achieved (n= 13); placebo arm (n= 30); low risk infants (n= 13). The main outcome measure was CLD/Death. Results: The rates of CLD/Death were lower in the Intervention Success Group (29%) when compared to the Intervention Failure Group (85%) or the Placebo Group (60%, all p< 0.05). There was no difference in CLD/Death between the Intervention Success and Low Risk Groups (8%, p> 0.05). A persistent PDA beyond Day 8 was associated with CLD/Death (aOR 6.5 [1.7–25.5]). Conclusions: Early shunt elimination in preterm infants with a PDA may reduce respiratory morbidity when compared to infants with prolonged shunt exposure.

Essential thrombocythaemia (ET) is driven by somatic mutations involving the JAK2, CALRand MPLgenes. Approximately 10% of patients lack driver mutations and are referred as ‘triple-negative’ ET (TN-ET). The diagnosis of TN-ET, however, relies on bone marrow examination that is not always performed in routine practice, and thus in the real-world setting, there are a group of cases with suspected TN-myeloproliferativeneoplasm.In this real-world cohort, patients with suspected TN-ET were initially rescreened for JAK2, CALRand MPLand then targeted next-generation sequencing (NGS) was applied.The 35 patients with suspected TN-ET had a median age at diagnosis of 43 years (range 16–79) and a follow-up of 10 years (range 2–28). The median platelet count was 758×109/L (range 479–2903). Thrombosis prior to and following diagnosis was noted in 20% and 17% of patients. Six patients were JAK2V617F and two patients were CALRpositive on repeat screening. NGS results showed that 24 of 27 patients harboured no mutations. Four mutations were noted in three patients.There was no evidence of clonality for the majority of patients with suspected TN-ET with targeted NGS analysis. Detection of driver mutations in those who were previously screened suggests that regular rescreening is required. This study also questions the diagnosis of TN-ET without the existence of a clonal marker.

AbstractThis observational cross-sectional study presents methods employed in designing and undertaking a suite of eight health assessments, purposely named The Health Fair, as part of Wave 2 (2014) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA) study. Overall, 604 persons of all levels of intellectual disability, aged 40 years and above and in different living circumstances, participated. The Health Fair process was mobile and overcame barriers such as communication challenges or access that people with intellectual disability face. This protocol could support researchers and practitioners in clinical practice to guide and improve the health assessment of people with intellectual disability to facilitate a better understanding of their health pathways and improve health care delivery and services.

ABSTRACTOlder adults with Intellectual Disability have been described as among the most medicated groups in society, with rates of polypharmacy significantly exceeding that of the general population. They are at heightened risk of medication-related harm and have high exposure to high-risk medications, for example, anticholinergic ad sedative medicines. There has been significant controversy internationally relating to the inappropriate use of antipsychotics for challenging behavior, often in the absence of a psychiatric diagnosis. Despite this, the evidence base of the safety of use of medicines in this population is lacking, the provision of healthcare is often suboptimal and this population is often excluded from Randomized Controlled Trials. In this editorial, we describe the unique challenges in ensuring safe and appropriate medicines in this population. We describe tools to date that has been used in this population to measure the burden of medicines that increase the risk of adverse outcomes. We outline current and future developments required to improve the quality and safety of medicines use in this population, for example, longitudinal cohort studies.

No examination of a child’s abdomen or gastrointestinal system is complete without an examination of the ’backside' or perineum, however there is often reluctance among paediatricians to perform this examination routinely. This article aims to describe how to use perineal examination in infants and children. It discusses the indications and stepwise approach to performing a per-rectal examination and interpretation of the findings one could expect to encounter. We include four cases encompassing the major conditions, both congenital and acquired, that paediatricians should be aware of and how they were managed in our institution.

We explore the ability of amino acid solutions, of l-Trp, l-Tyr, or l-Val, to solvate pristine graphene flakes in an aqueous environment via atomistic molecular dynamics simulations and experimental characterization. In accord with previous theoretical work, simulations of single amino acid adsorption on graphene predict that l-Trp is most strongly bound, followed by l-Tyr and then l-Val. As the number of amino acids is increased in the simulations, steric hindrance at the graphene interface and amino acid clustering (most pronounced for l-Tyr) reduces the efficiency of interaction with graphene. Using atomic force microscopy and UV–vis absorption spectroscopy, we determine that all three amino acid solutions can exfoliate and suspend pristine graphene flakes in water. However, l-Trp and l-Tyr solutions are considerably more effective than l-Val: l-Trp produces the most stable suspensions and thinnest graphene flakes compared to l-Tyr, with a mean thickness of 6.4 nm, and a narrow distribution of diameter with a mean value of 16 nm, commensurate with the width of cell membranes. At high concentrations of l-Trp and l-Tyr, there was severe instability of the suspensions along with agglomeration and precipitation; this reflects clustering of amino acid molecules observed in molecular dynamics simulations. This study indicates the potential of amino acids to exfoliate and suspend pristine graphene as a step toward developing nontoxic graphene-based vehicles for drug delivery and other in vivoapplications.

d-Stereoselective peptidases that degrade nonribosomal peptides (NRPs) were recently discovered and could have serious implications for the future of NRPs as antibiotics. Herein, we report chemical modifications that can be used to impart resistance to the d-peptidases BogQ and TriF. New tridecaptin A analogues were synthesized that retain strong antimicrobial activity and have significantly enhanced d-peptidase stability. Invitroassays confirmed that synthetic analogues retain the ability to bind to their cellular receptor, peptidoglycan intermediate lipid II.

CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P< .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P= .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.

Memory for music has attracted much recent interest in Alzheimer's disease but the underlying brain mechanisms have not been defined in patients directly. Here we addressed this issue in an Alzheimer's disease cohort using activation fMRI of two core musical memory systems.

Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression.

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1–2%)1–3that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA5–8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4(which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

A comprehensive overview of the γδ T cell literature, focusing on the ways in which their functional heterogeneity contributes to outcomes after transplantation, and reflection upon methods to harness their beneficial properties.γδ T cells are a subpopulation of lymphocytes expressing heterodimeric T-cell receptors composed of γ and δ chains. They are morphologically and functionally heterogeneous, innate yet also adaptive in behavior, and exhibit diverse activities spanning immunosurveillance, immunomodulation, and direct cytotoxicity. The specific responses of γδ T cells to allografts are yet to be fully elucidated with evidence of both detrimental and tolerogenic roles in different settings. Here we present an overview of γδ T-cell literature, consider ways in which their functional heterogeneity contributes to the outcomes after transplantation, and reflect on methods to harness their beneficial properties.

It is known that for all adults, prevalence of potentially inappropriate prescribing (PIP) and polypharmacy increases with advancing age and morbidity. This has been associated with adverse drug reactions and poor outcomes. As a result, screening tools have been developed to identify PIP and to improve prescribing and health outcomes.A growing body of evidence supports the fact that there are even greater concerns among older adults with intellectual disability (ID) who are living longer than before but still have premature mortality and poorer health outcomes compared with the general population. They have different patterns of multimorbidity, with higher rates of epilepsy and mental health conditions. Polypharmacy is prevalent and some prescribing practices may be inappropriate. High exposure to anticholinergic and sedative medicines has additional adverse effects on quality of life. There may also be underutilization of clinically needed therapies. There has been substantial controversy internationally relating to extensive use of psychotropic medicines, particularly off-label use for challenging behaviours.Despite the mounting evidence and concerns about the impact of PIP on quality of life, health and safety for people with ID, appropriate methods to measure PIP are lacking, which represents an important gap in the research literature. Differences in morbidity and medicines use patterns in this population mean instruments used to identify inappropriate medicines in the older population are not suitable. In this perspective article we outline the specific health and medicinal needs for people with ID, the prevalence of polypharmacy and presentation of chronic health conditions in older adults with ID. We provide an overview of the psychotropic medicine classes most frequently used in people with ID which carry substantial risk. We highlight studies to date that have attempted to assess PIP and present research priorities to improve prescribing, health outcomes and quality of life for people with ID.

ABSTRACT:One of postmodernity's hallmarks—the orientation toward greater individualism—has negatively affected the Catholic liturgy. Observations of Sunday liturgies identify liturgical actions that we describe as ritual attunements and dis-attunements. Dis-attunement occurs when a liturgical action causes the worshiper to be self-reflexive, to delve more deeply into the self—a postmodern characteristic. Attunement is evident when aspects of the liturgy orient the worshiper outward toward greater communal participation—uncharacteristic of postmodernity. This paper is a sociological examination of the liturgy in a postmodern context, and makes the argument that the liturgy can provide an antidote to postmodern individualism if the liturgical ritual remains intact, enhancing attuning and obfuscating dis-attuning elements.

A specially commissioned working group produced a report on caregiving, intellectual and developmental disabilities (IDDs), and dementia for the National Institutes of Health–located National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers.

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