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Conscious of the careful balance stemming from the Rights, Safeguards and Equality of Opportunity provisions of the Belfast/Good Friday Agreement 1998, it was clear that human rights guarantees underpinned by European Union (EU) law would be a pivotal aspect of the Protocol on Ireland/Northern Ireland within the Withdrawal Agreement. The commitment is particularly prominent in respect of equality law, as a guarantee that no diminution of rights and equality protections would result from withdrawal from the EU was built into article 2(1) of the Protocol providing for non-diminution of rights in Northern Ireland post-Brexit. The purpose of this article is to identify and analyse recent developments in EU equality case law which may trigger the non-diminution obligation from the entry into force of the Protocol to the date of writing (ie between 1 January 2021 and 1 September 2022). This analysis is underpinned by a systematic case law review to provide an evidence-based analysis of: a) where divergence of equality protection standards is occurring presently; and b) where these concerns are likely to present in the future. The article identifies four substantive areas, namely religious discrimination, disability discrimination, gender equality in the field of pensions and social security, and migration law, which raise significant and complex questions about the practical feasibility of the non-diminution obligation. In light of the thematic case law analysis, the article offers broader reflections on the future direction of article 2 obligations, which could be used to approach the non-diminution commitment prospectively.

Because many young adults do not consistently give and receive explicit consent in their sexual relationships, it is important to identify factors associated with sexual consent attitudes and behaviour. In this study, we assessed the extent to which sexual health education, sexual consent education, sexual attitudes, and perceptions of social norms were associated with sexual consent attitudes and behaviour. Participants were 196 undergraduate students between the ages of 18 and 25 enrolled at an eastern Canadian university. At the bivariate level, we found evidence for the importance of sexual consent education by parents, sexual attitudes, and perceptions of social norms with respect to sexual consent attitudes and behaviour. Multiple regression analyses showed that more positive perceptions of social norms, more liberal sexual attitudes, and more sexual consent education from parents were uniquely associated with lower negative attitudes towards sexual consent and more consistent use of explicit sexual consent. More positive perceptions of social norms and less sexual experience were uniquely associated with more positive sexual consent attitudes. Only perception of social norms was uniquely associated with less use of an indirect behavioural approach to establishing consent. The results are interpreted in terms of their implications for enhancing sexual consent attitudes and behaviour among young people.

Purpose:Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.Experimental Design:We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.Results:We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.Conclusions:This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

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People with intellectual disability mostly require life-long care that in many countries is provided by parents. The increased risk of marital breakdown in these families has been a focus of attent...

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Aim Inflammatory bowel disease represents a significant healthcare burden. Management requires a multi-disciplinary approach and a combination of both surgical and medical considerations. The aim of this study was to compare current practice within our colorectal unit for pre-operative optimisation of IBD patients with ACPGBI recommendations, with the view of introducing a proforma for these patients to ensure pre-operative optimisation standards are met. Methods This was a retrospective study identifying patients undergoing elective surgery for IBD in our unit between January 2019-October 2020. Data was collected on pre-operative management and compared to the broad principles of optimisation outlined by ACPGBI in their 2018 guidelines. Clavien-Dindo classification was used to define post-operative complications. Results 94 patients were identified, 67 in 2019 and 27 patients in 2020. 4.3% had active intra-abdominal sepsis. No patients had a clearly documented comprehensive nutritional assessment. 15.6% patients were on oral steroids pre-operatively (Dose ≤30mg). 43.8% were on biologic therapy. Mean length of stay was 11.3days. 39.7% of patients experienced post-operative complications. However, only 12.8% of patients had a Clavien-Dindo score of ≥3. There was no mortality. Conclusion ACPGBI guidelines highlight key areas for adequate pre-operative optimisation. Our study highlighted that our morbidity following IBD surgery was comparable to those in literature. However, key areas of improvement were identified including comprehensive nutritional assessment. Current work involves creating a pre-operative proforma to encompass this and will be followed by a re-audit.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP), released postprandially from K-cells, has established actions on adipocytes and lipid metabolism. In addition, xenin, a related peptide hormone also secreted from K-cells after a meal, has postulated effects on energy regulation and lipid turnover. The current study has probed direct individual and combined effects of GIP and xenin on adipocyte function in 3T3-L1 adipocytes, using enzyme-resistant peptide analogues, (d-Ala2)GIP and xenin-25-Gln, and knockdown (KD) of receptors for both peptides. (d-Ala2)GIP stimulated adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes over 96 h, with xenin-25-Gln evoking similar effects. Combined treatment significantly countered these individual adipogenic effects. Individual receptor KD impaired lipid accumulation and adipocyte differentiation, with combined receptor KD preventing differentiation. (d-Ala2)GIP and xenin-25-Gln increased glycerol release from 3T3-L1 adipocytes, but this lipolytic effect was significantly less apparent with combined treatment. Key adipogenic and lipolytic genes were upregulated by (d-Ala2)GIP or xenin-25-Gln, but not by dual peptide culture. Similarly, both (d-Ala2)GIP and xenin-25-Gln stimulated insulin-induced glucose uptake in 3T3-L1 adipocytes, but this effect was annulled by dual treatment. In conclusion, GIP and xenin possess direct, comparable, lipogenic and lipolytic actions in 3T3-L1 adipocytes. However, effects on lipid metabolism are significantly diminished by combined administration.

Little is known about young people’s perceptions of and attitudes toward the coverage of sexual consent or their perceptions of the extent to which they have learned about sexual consent from various sources. Participants were undergraduate men ( n = 73) and women ( n = 128) between the ages of 18 and 29 ( M = 19.62, SD = 1.75) who completed a survey assessing perceived coverage of sexual consent in school and by parents, attitudes toward university and media coverage of sexual consent, and the amount they perceived they had learned about sexual consent from five sources (mothers, fathers, friends, school-based sexual health education, the Internet). On average, participants reported poor coverage of sexual consent. Participants more strongly agreed that there was extensive coverage and that they had learned a lot from coverage in the media than at university but did not strongly endorse either source. Participants thought they learned significantly more from the media and Internet and peers than from school and parents. Participants who received limited sexual consent education at school/home responded to an open-ended question regarding the perceived impact of limited education from this source. Although some participants reported no impact, others attributed negative experiences to their limited sexual consent education including experiencing non-consensual sexual activities and detrimental effects on their romantic relationships. The results point to the need for parents and schools to do more to educate youth about sexual consent and indicate that young adults are receptive to sexual consent education at university and in the media.

Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinu...

Much has been written about the history of the Queensland Native Mounted Police, mostly focussing on its development, its white officers, how much the Colonial Government genuinely knew about the actions of the Force, and how many people were killed during the frontier wars. Far less attention has been given to the Aboriginal men of the force, the nature of their recruitment, and the long-term traumatic impacts on Aboriginal peoples’ and communities’ psyches rather than broadscale changes to Aboriginal culture per se. This article examines the historical and ongoing psychological impacts of dispossession and frontier violence on Aboriginal people. Specifically, we argue that massacres, frontier violence, displacement, and the ultimate dispossession of land and destruction of traditional cultural practices resulted in both individual and collective inter-generational trauma for Aboriginal peoples. We posit that, despite the Australian frontier wars taking place over a century ago, their impacts continue to reverberate today in a range of different ways, many of which are as yet only partially understood.

Xenin bioactivity and its role in normal physiology has been investigated by several research groups since its discovery in 1992. The 25 amino acid peptide hormone is secreted from the same enteroendocrine K-cells as the incretin hormone glucose-dependent insulinotropic polypeptide (GIP), with early studies highlighting the biological significance of xenin in the gastrointestinal tract, along with effects on satiety. Recently there has been more focus directed towards the role of xenin in insulin secretion and potential for diabetes therapies, especially through its ability to potentiate the insulinotropic actions of GIP as well as utilisation in dual/triple acting gut hormone therapeutic approaches. Currently, there is a lack of clinically approved therapies aimed at restoring GIP bioactivity in type 2 diabetes mellitus, thus xenin could hold real promise as a diabetes therapy. The biological actions of xenin, including its ability to augment insulin secretion, induce satiety effects, as well as restoring GIP sensitivity, earmark this peptide as an attractive antidiabetic candidate. This minireview will focus on the multiple biological actions of xenin, together with its proposed mechanism of action and potential benefits for the treatment of metabolic diseases such as diabetes.

Neurotensin and xenin possess antidiabetic potential, mediated in part through augmentation of incretin hormone, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), action. In the present study, fragment peptides of neurotensin and xenin, acetyl-neurotensin and xenin-8-Gln, were fused together to create Ac-NT/XN-8-Gln. Following assessment of enzymatic stability, effects of Ac-NT/XN-8-Gln on in vitro β-cell function were studied. Subchronic antidiabetic efficacy of Ac-NT/XN-8-Gln alone, and in combination with the clinically approved GLP-1 receptor agonist exendin-4, was assessed in high-fat fed (HFF) mice. Ac-NT/XN-8-Gln was highly resistant to plasma enzyme degradation and induced dose-dependent insulin-releasing actions (P

Summary The extra strains experienced by families who care for a relative with intellectual disabilities are well documented. The provision of overnight (respite) breaks or supports in the home are common ways of supporting family carers. Often demand exceeds supply. Using data from a national register in Ireland, child and adults who received overnight breaks and in-home support were identified along with the characteristics that distinguished them from families that did not have these services. Moreover, changes in provision over a 10-year period were monitored and variations in provision across the country were ascertained. Findings Overnight breaks were the dominant form of family support in Ireland. However, they were available to fewer persons in 2017 compared to 2007, whereas the provision of home supports remained constant. Persons with severe and profound disabilities were those most likely to receive home supports or overnight breaks as were persons aged 30 years and over. There were persistent marked differences across the country in the provision of home supports, although the variation in the usage of overnight breaks had contracted somewhat in 2017. Applications Additional investment is needed to provide supports for families, given the increasing numbers of persons with intellectual disabilities living at home. A wider range of support options would provide greater choice and arguably improve the cost-effectiveness of current resources. Frontline professionals, such as social workers, need to be to the fore in persuading service commissioners of these needs based on empirical data as well as their personal experiences.

Purpose This study aimed to assess how healthcare professionals (HCPs) use social media to determine how it influences the quality of patient care. Materials and methods This is a cross-sectional study conducted over eight months, between August 2020 and March 2021 using a questionnaire and checked amongst investigators. Results One hundred fifty-eight participants had electronic devices and 145 (91.9%) used social media at work. 26.6% of these HCPs said they spent less than an hour on social media forums, 31% said they spent one to two hours, 28.5% said two to three hours, and 13.9% said they spent more than four hours. As compared to nurses (46%), consultants and pharmacists use social media at a much lower rate (1% for each group). Compared to junior doctors, a higher percentage of nurses (40%) said they were aware of a social media policy at their hospital (8%). A quarter of healthcare employees (20%) were unaware of their workplace policy, potentially exposing sensitive medical details to the public. More research is needed to assess the particular effects of these results on patient care quality and can help in providing literature informing applications encrypted and secure patient data. Conclusion According to our results, a large percentage of healthcare quality professionals used social media networks. A significant proportion of doctors and nurses use it to visit online medical forums for improving education. A large portion of surveyed sample was unaware of hospital policy on social media usage. Further education is required to improve the right use of social media in the hospital setting.

Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma1–4. The ageing, sun-exposed dermis accumulates UVR damage5, and older patients develop more melanomas at UVR-exposed sites4,6,7. As fibroblasts are functionally heterogeneous and play key roles in the stromal contribution to cancer8,9, we asked whether UVR modifies dermal fibroblast function. Here we confirmed the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) by UVR-damaged fibroblasts was persistently upregulated to reduce local levels of collagen 1 (COL1A1), and found dermal COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, we show inhibiting extracellular matrix degradation and MMP1 expression restored melanoma invasion to UVR damaged dermis. We confirmed in vitro findings in a cohort of primary cutaneous melanomas of aged humans, showing more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen. We found collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. These data indicate melanomas arising over UVR-damaged, collagen-poor skin of the elderly are less invasive, and this reduced invasion improves survival. Consequently, although UVR increases tumour incidence, it delays primary melanoma invasion by degrading collagen. However, we show melanoma-associated fibroblasts can restore invasion in low-collagen primary tumours by increasing collagen synthesis. Finally, we demonstrate high COL1A1 gene expression is a biomarker of poor outcome across a broad range of primary cancers.

Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P 0.05) the insulinotropic actions of both hormones, as well as enhancing (P 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P 0.05-P 0.001) food intake in overnight fasted lean mice, and enhanced (P 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

Purpose Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. Methods We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. Results We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. Conclusions This work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity. Translational relevance Sex bias affects cancer incidence, mortality and therapy response; and the molecular landscape of cancer differs by sex. However, it is not known if the sex discrepancy is due to a difference in behaviour and exposure to carcinogens, or due to sex-linked susceptibility. This work reveals men are inherently more susceptible to cutaneous aggressive squamous cell carcinoma, in contrast to women who activate stronger immune responses when challenged with the same carcinogens. The loss of immunity particularly affects women. Personalised medicine approaches stratify cancer patients by genotype; however, to date, the potential for cancer stratification, prevention strategies and therapy by sex and immune competency has not been explored. These data indicate men require targeted prevention programs and increased monitoring. Furthermore, we provide a rationale to prioritise men and immunosuppressed women for adjuvant therapy and immunotherapy.

This paper presents findings of a research project undertaken to assess four national health information systems in Ireland and their compliance with nationally agreed health information standards. The review was undertaken in the Health Research Board (HRB) which is a State-funded agency with responsibility for the collection, analysis and reporting of national health data. The aim of the review was to identify the extent to which the HRB was compliant with the national standards for health information agreed by Ireland’s health information regulatory body, the Health Information and Quality Authority (HIQA). The methods used focused on the application of a self-assessment tool (SAT) to the HRB’s health information systems. This involved documentary analysis of written materials about the systems from both primary and secondary data sources. The findings show high levels of compliance with the standards identified but that some areas need to be addressed to ensure that all aspects of the standards are met. The research shows the value of having nationally agreed standards for health information that can be applied to a diverse range of health data sources and systems.

Background People with intellectual disability die younger than their non‐disabled peers. In recent years, greater attention has been paid to closing the gap. However, evidence that this is being achieved is limited by the dearth of longitudinal, national data. Method Over 4,000 decedents identified in the Irish National Intellectual Disability Database from 2001 to 2016 were compared to deaths in the general population based on age and gender profiles using death rates and standardised mortality ratios. A binary logistic regression analysis also identified the characteristics of persons who had a higher risk of dying. Results Irish people with intellectual disability die younger and have a higher rate of death than their non‐disabled peers. Nor has the gap between their mortality and that of the general population closed in recent years. Conclusions More concentrated effort is needed in Ireland on promoting equitable access to health services for people with intellectual disability.

This chapter takes the theme of asylum procedures and reveals how access to a full, fair and effective asylum determination process in the UK is likely to be eroded further, thanks to recently agreed legislation at European Community level. It identifies and critiques some of the deflection mechanisms used in the Procedures Directive. All Member States are signatories to the European Convention on Human Rights and Fundamental Freedoms and are subject to the jurisdiction of the European Court of Human Rights. On 29 April 2004 the Justice and Home Affairs Council in Luxembourg reached political agreement on the ‘general approach’ of the Procedures Directive. The Directive also allows decisions to be made without an interview if applicants fail to turn up for an interview appointment without a reasonable excuse, fail to respond to requests for information or fail to comply with duties to report to the authorities.

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND Ireland has a growing population of adult persons living with family carers, thereby increasing the demand for residential places. Simultaneously, government policy aimed to reprovision residents living in congregated settings but at a time when funding was curtailed due to the economic crisis. This study examines the movements of people into and among three types of residential options between 2009 and 2014. METHOD A cohort of 20,163 persons recorded on the National Intellectual Disability Database in 2009 was identified and tracked to the 2014 database. RESULTS An estimated 200 persons per annum (@1.6% of those living with families) moved from family care although the number of places available nationally fell by 9%. Moreover, transfers of existing residents into vacated places tended to exceed those from families. CONCLUSIONS More people will have to continue living with their families and for longer if funding for new places remains curtailed.

Purpose The purpose of this paper is to document the impact of major policy changes and reductions in government funding on residential provision for people with intellectual disabilities (ID) in Ireland. Design/methodology/approach Ireland is unique in having a national database of people in receipt of services from specialist ID providers. Information on persons in residential settings from 2005 to 2016 was examined in terms of changes in the types of provision over time and broken down by age groups. Findings From 2011 onwards, cuts in government funding coincided with a continuing reduction in the overall provision of residential accommodation for adults with ID. There was a parallel increase in the number of people living with family carers, especially persons aged 55 years and over. The greatest reduction was in residential centres which was in line with recent policy but this was not matched by an increase in alternative options, with fewer people aged 20-34 living in residential accommodation of any kind. Compared to Great Britain, Ireland has proportionately more residential places with fewer people living independently. Social implications More Irish families have to continue caring for their adult relatives into their old age. Likewise, those resident in group homes and living independently are growing older which means there is an increased likelihood they will require additional support. Originality/value This national data set is a valuable tool for monitoring changes in service provision over time and for determining the impact of government policy and funding decisions.

Accessible summary In Ireland school leavers with intellectual disabilities were tracked over a 10-year period from 2004 to 2014. Nearly half were no longer known to services after 10 years. In the 5 years after leaving school, most young adults went to either training centres or to care centres. After 10 years, most were placed in care centres. Few were getting help to obtain paid work or were receiving support in the community. New models of day supports are being promoted by the Government but they are not widely available. Shortage of money and pressure to provide places for school leavers may have contributed to the growth of attendances in care centres. AbstractBackground In recent years, efforts have been made to improve the transition of pupils with intellectual disabilities to adult services and to offer a wider range of choices. However, there have been few longitudinal studies to monitor the services provided to young adults post-school. This case study in the Republic of Ireland identified the services provided 5 and 10 years after pupils had left school. Method Using records from the National Intellectual Disability Database (NIDD), a cohort of 3,206 young people aged 14 to 21 years in 2004 were followed up in 2009 and again in 2014. The pathways to different types of services were identified. Results Upwards of 50% of school leavers were no longer in receipt of services 10 years later. Most had mild intellectual disabilities. Of those who were still involved with services, after 5 years most attended either training centres or care centres with small proportions in sheltered workshops or employment schemes. By 2014, most students leaving training centres had transferred to care centres; including those with mild disabilities. There had been little increase in the numbers receiving other types of day support. Conclusions Care centres remain the most common form of day services provided to school leavers in the Republic of Ireland. The economic recession may have contributed to this. Recent government policies aim to promote more innovative day supports with a focus on employment but further cohort studies should monitor the success of these initiatives.

Summary Background The updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high‐risk stage I tumour subsets. Objectives To determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma. Methods Peritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas. Results Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7‐year disease‐free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi‐quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low‐risk group (n = 239) vs. 85·4% in the AMLo high‐risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69–9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93–9·56; P = 0·068) in stage IB patients. Conclusions Loss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high‐risk tumour subsets independently of Breslow depth. What's already known about this topic? There is an unmet clinical need for biomarkers of early‐stage melanoma.Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor.Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation.The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow‐up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs., https://doi.org/10.1111/bjd.18658 available online Linked Editorial: https://doi.org/10.1111/bjd.18555

Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weight-reducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial in vitro studies revealed that the GIPR agonists, human (h) GIP(1-42), hGIP(1-30) and mouse (m) GIP(1-30), stimulated ( P < 0.01 to P < 0.001) insulin secretion from rat BRIN-BD11 cells. Analysis of insulin secretory effects of the N- and C-terminally cleaved GIP peptides, including hGIP(3-30), mGIP(3-30), h(Pro3)GIP(3-30), hGIP(5-30), hGIP(3-42) and hGIP(5-42), revealed that these peptides did not modulate insulin secretion. More pertinently, only hGIP(3-30), mGIP(3-30) and h(Pro3)GIP(3-30) were able to significantly ( P < 0.01 to P < 0.001) inhibit hGIP(1-42)-stimulated insulin secretion. The human-derived GIPR agonist sequences, hGIP(1-42) and hGIP(1-30), reduced ( P < 0.05) glucose levels in mice following conjoint injection with glucose, but mGIP(1-30) was ineffective. None of the N- and C-terminally cleaved GIP peptides affected glucose homeostasis when injected alone with glucose. However, hGIP(5-30) and mGIP(3-30) significantly ( P < 0.05 to P < 0.01) impaired the glucose-lowering action of hGIP(1-42). Further evaluation of these most effective sequences demonstrated that mGIP(3-30), but not hGIP(5-30), effectively prevented GIP-induced elevations of plasma insulin concentrations. These data highlight, for the first time, that mGIP(3-30) represents an effective molecule to inhibit GIPR activity in mice.

Data were obtained on nearly 20,000 Irish children and adults living in various family care arrangements in 2007, 2012, and 2017. Over 10 years, the percentage increase in adult persons living with family carers was three times higher than the rise in the general population, with people aged 50 years and over having the highest proportional increase. Also a greater number of persons aged 40–49 group continued to live with both parents in 2017 (47%) compared to 2007 (33%). However, there was marked variation across the nine Community Health Organization areas in the proportions of adults living with family carers (from 49% to 62%). In the coming decades, increased provision will be required in both the quantum and type of supports provided to families so as to sustain their caring role but ensuring equity of provision nationally will be a major challenge.

The present study has examined the antidiabetic effects of 21 days co-administration of xenin-8-Gln with the dual-acting fusion peptide, exendin-4/gastrin, as well as persistence of beneficial metabolic benefits, in high fat fed (HFF) mice. Xenin-8-Gln, exendin-4 and gastrin represent compounds that activate receptors of the gut-derived hormones, xenin, glucagon-like peptide-1 (GLP-1) and gastrin, respectively. Twice-daily administration of exendin-4/gastrin, xenin-8-Gln or a combination of both peptides significantly reduced circulating glucose, HbA1c and cumulative energy intake. Combination therapy with xenin-8-Gln and exendin-4/gastrin increased circulating insulin. All HFF mice treated with exendin-4/gastrin presented with body weight similar to lean control mice on day 21. Each treatment improved glucose tolerance and the glucose-lowering actions of glucose dependent insulinotropic polypeptide (GIP), as well as augmenting glucose- and GIP-induced insulin secretion, with benefits being most prominent in the combination group. Administration of exendin-4/gastrin alone, and in combination with xenin-8-Gln, increased pancreatic insulin content and improved the insulin sensitivity index. Pancreatic beta-cell area was significantly increased, and alpha cell area decreased, by all treatments, with the combination group also displaying enhanced overall islet area. Notably, metabolic benefits were generally retained in all groups of HFF mice, and especially in the combination group, following discontinuation of the treatment regimens for 21 days. This was associated with maintenance of increased islet and beta-cell areas. Together, these data confirm the antidiabetic effects of co-activation of GLP-1, gastrin and xenin cell signalling pathways, and highlight the sustainable benefits this type of treatment paradigm can offer in T2DM.

Xenin-25 undergoes rapid enzyme metabolism following secretion. Early studies demonstrated bioactivity of a C-terminal hexapeptide fragment of xenin-25, namely xenin-6, which were enhanced through introduction of a reduced N-terminal peptide bond, to yield Ψ-xenin-6. The present study was undertaken to define the biological actions and potential antidiabetic properties of Ψ-xenin-6. In vitro enzymatic stability, insulin and glucagon secretory activity, as well as effects on beta-cell survival were determined. Studies in mice were used to assess the impact of Ψ-xenin-6 on glucose homeostasis and satiety. Ψ-xenin-6 was resistant to murine plasma degradation. In BRIN-BD11 cells and isolated murine islets, Ψ-xenin-6 significantly stimulated insulin secretion, and prominently enhanced the insulinotropic actions of GIP. Xenin-6 and Ψ-xenin-6 had no impact on glucagon secretion, although xenin-6 partially reversed the glucagonotropic action of GIP. Further in vitro investigations revealed that, similar to GLP-1, Ψ-xenin-6 significantly augmented proliferation of human and rodent clonal beta-cells, whilst also fully protecting against cytokine-induced beta-cell cytotoxicity, with greater potency than xenin-25 and xenin-6. When administered to mice in combination with glucose, Ψ-xenin-6 significantly reduced glucose levels and enhanced glucose-induced insulin release, with a duration of biological action beyond 8 h. Ψ-xenin-6 also significantly enhanced the glucose-lowering action of GIP in vivo. In overnight fasted mice, Ψ-xenin-6 exhibited satiety actions at both 25 and 250 nmol/kg. These data demonstrates that Ψ-xenin-6 is a metabolically stable C-terminal fragment analogue of xenin-25, with a metabolic action profile that merits further study as a potential antidiabetic compound.

The therapeutic mechanism of action of methionine aminopeptidase 2 (MetAP2) inhibitors for obesity-diabetes has not yet been fully defined. Xenin, a K-cell derived peptide hormone, possesses an N-terminal Met amino acid residue. Thus, elevated xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting xenin analogues have been shown to improve obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor, TNP-470, to augment the antidiabetic utility of the incretin-enhancer drug, sitagliptin, in high fat fed (HFF) mice. TNP-470 (1 mg/kg) and sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual therapy with TNP-470 or sitagliptin resulted in numerous metabolic benefits including reduced blood glucose, increased circulating and pancreatic insulin and improved glucose tolerance, insulin sensitivity, pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with TNP-470 alone, or in combination with sitagliptin, reduced food intake and body weight, as well as elevating plasma and intestinal xenin. Importantly, combined sitagliptin and TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that TNP-470 increases plasma and intestinal xenin levels, and augments the antidiabetic advantages of sitagliptin.

Background: International prevalence rates for intellectual disability vary widely with estimates often based on samples. In Ireland people with an intellectual disability are identified in the national census. Moreover, a national register of people receiving or requiring intellectual disability services is maintained and updated annually. Aims: The prevalence rates from the census were contrasted with those from the register along with variations in prevalence across the 26 counties of Ireland. Methods: 2011 and 2016 Census of Population prevalence per 1000 for children (aged 5–19 years) and adults (20 years and over) stratified by the 26 countries were contrasted with similar prevalence in the national register. Publically available data from the 2011 census in Northern Ireland and Scotland were obtained. Results: The Irish census identified nearly twice as many children and adults than were on the national register. Prevalence rates also varied across the 26 counties; more so on the register than the census. The Irish census had lower prevalence rates than Northern Ireland but higher than Scotland. Conclusions: Determining the prevalence of intellectual disability is challenging due to variations in terminology. A national register has advantages over reliance on census data for service planning.

Common rules on most aspects of the asylum process are now in force in the European Union e.g. to determine which State is responsible for determining a claim; on asylum seekers’ entitlements and obligations as regards their reception in Member States; to regulate the asylum procedure itself; and to determine who qualifies for international protection. The so-called EU asylum acquis which resulted in a Common European Asylum System (CEAS) does not stand on its own, but builds on the international refugee protection regime. EU legislation states that the CEAS is to be based on a full and inclusive application of the Geneva Convention relating to the Status of Refugees. In asylum cases the burden of proof is placed on the asylum seeker. Usually states expect asylum seekers to adduce evidence in order to substantiate their asylum claim.