SO2 and copper tolerance exhibit an evolutionary trade-off in Saccharomyces cerevisiae.

Copper tolerance and SO2 tolerance are two well-studied phenotypic traits of Saccharomyces cerevisiae. The genetic bases of these traits are the allelic expansion at the CUP1 locus and reciprocal translocation at the SSU1 locus, respectively. Previous work identified a negative association between SO2 and copper tolerance in S. cerevisiae wine yeasts. Here we probe the relationship between SO2 and copper tolerance and show that an increase in CUP1 copy number does not always impart copper tolerance in S. cerevisiae wine yeast. Bulk-segregant QTL analysis was used to identify variance at SSU1 as a causative factor in copper sensitivity, which was verified by reciprocal hemizygosity analysis in a strain carrying 20 copies of CUP1. Transcriptional and proteomic analysis demonstrated that SSU1 over-expression did not suppress CUP1 transcription or constrain protein production and provided evidence that SSU1 over-expression induced sulfur limitation during exposure to copper. Finally, an SSU1 over-expressing strain exhibited increased sensitivity to moderately elevated copper concentrations in sulfur-limited medium, demonstrating that SSU1 over-expression burdens the sulfate assimilation pathway. Over-expression of MET 3/14/16, genes upstream of H2S production in the sulfate assimilation pathway increased the production of SO2 and H2S but did not improve copper sensitivity in an SSU1 over-expressing background. We conclude that copper and SO2 tolerance are conditional traits in S. cerevisiae and provide evidence of the metabolic basis for their mutual exclusivity. These findings suggest an evolutionary driver for the extreme amplification of CUP1 observed in some yeasts.

Identification and support of autistic individuals within the UK Criminal Justice System: a practical approach based upon professional consensus with input from lived experience.

BACKGROUND: Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual's journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes. METHODS: This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS. RESULTS: The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS. CONCLUSION: Greater attention needs to be given to this population as they navigate the CJS.

The potential unintended consequences of Mental Health Act reforms in England and Wales on people with intellectual disability and/or autism.

The draft Mental Health Bill, which amends the Mental Health Act 1983 for England and Wales, proposes protections for people with intellectual disability and/or autism (ID/A) to prevent detention in hospital in the absence of mental illness. This editorial critically appraises the positive impact and unintended consequences of the proposed reforms for people with ID/A.

Perceived burden and need for support among caregivers of cancer patients.

BACKGROUND: The aims of this study were to examine (1) the perceived burden among caregivers and identify those in risk of high burden and (2) the need for support among caregivers and identify associated factors. MATERIALS AND METHODS: Cancer patients who participated in an educational program at the Montebello Center (MBC) in Norway between May 2021 and February 2022 were asked to invite a caregiver to answer a questionnaire. The caregiving burden was assessed with the Caregivers Reaction Assessment (CRA) that consists of 24 questions scored from 1 (strongly disagree) to 5 (strongly agree), covering five domains. A mean sum score was calculated for each domain. Higher subscale scores indicate higher levels of burden, except for caregiver esteem where a high score indicates a low burden. Need for support was assessed with 13 questions. RESULTS: Of 464 invitations, 185 caregivers responded (response 40%), median age was 58.0 years and 58% were male. Caregiver burden mean scores were: 2.6 (SD 1.03) for Impact on schedule, 2.1 (SD 0.79) for Lack of family support, 2.1 (SD 0.76) for Impact on health, 2.0 (SD 0.86) for Impact on finances, and 4.2 (SD 0.47) for Caregiver esteem. Female caregivers, younger, higher education, having comorbidities, caring for patients having recurrence of cancer, and shorter time since diagnosis were associated with higher burden measured on individual subscales of the CRA. Most reported needs were information about: cancer, late effects and rehabilitation services and support from peers and professionals to cope with the new situation. Younger, caregiver comorbidity and recurrence of cancer of the patient were associated with more needs. CONCLUSIONS: The results indicate that caregivers of cancer patients participating at the MBC report moderate caregiver burden, however, numerous caregivers reported need for support within several areas. Our findings need to be confirmed in a larger unselected group.

A realist evaluation of an enhanced court-based liaison and diversion service for defendants with neurodevelopmental disorders.

BACKGROUND: In England, court-based mental health liaison and diversion (L&D) services work across courts and police stations to support those with severe mental illness and other vulnerabilities. However, the evidence around how such services support those with neurodevelopmental disorders (NDs) is limited. AIMS: This study aimed to evaluate, through the lens of court and clinical staff, the introduction of a L&D service for defendants with NDs, designed to complement the existing L&D service. METHODS: A realist evaluation was undertaken involving multiple agencies based within an inner-city Magistrates' Court in London, England. We developed a logic model based on the initial programme theory focusing on component parts of the new enhanced service, specifically training, screening, signposting and interventions. We conducted semi-structured interviews with the court staff, judiciary and clinicians from the L&D service. RESULTS: The L&D service for defendants with NDs was successful in identifying and supporting the needs of those defendants. Benefits of this service included knowledge sharing, awareness raising and promoting good practice such as making reasonable adjustments. However, there were challenges for the court practitioners and clinicians in finding and accessing local specialist community services. CONCLUSION: A L&D service developed for defendants with NDs is feasible and beneficial to staff and clinicians who worked in the court setting leading to good practice being in place for the defendants. Going forward, a local care pathway would need to be agreed between commissioners and stakeholders including the judiciary to ensure timely and equitable access to local services by both defendants and practitioners working across diversion services for individuals with NDs.

DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids.

DNA sensor pathways can initiate inflammasome, cell death, and type I interferon (IFN) signaling in immune-mediated inflammatory diseases (IMIDs), including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC) by analyzing the expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n = 31), inactive UC (n = 31), active UC (n = 33), and a UC single-cell RNA-Seq dataset. The effects of type I IFN (IFN-ß), IFN-γ, and TNF-α on gene expression, cytokine production, and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLR family pyrin domain-containing 3 (NLRP3), caspase, or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1ß/IL-18/CXCL10. The expression of DNA sensor pathway genes-PYHIN family members [absent in melanoma 2 (AIM2), IFI16, myeloid cell nuclear differentiation antigen (MNDA), and pyrin and HIN domain family member 1 (PYHIN1)- as well as Z-DNA-binding protein 1 (ZBP1), cyclic GMP-AMP synthase (cGAS), and DDX41 was increased in active UC and expressed in a cell type-restricted pattern. Inflammasome genes (CASP1, IL1B, and IL18), type I IFN inducers [stimulator of interferon response cGAMP interactor 1 (STING), TBK1, and IRF3), IFNB1, and type I IFN biomarker genes (OAS2, IFIT2, and MX2) were also increased in active UC. Cotreatment of organoids with IFN-ß or IFN-γ in combination with TNFα increased expression of IFI16, ZBP1, CASP1, cGAS, and STING induced cell death and IL-1ß/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.NEW & NOTEWORTHY This study found that patients with active UC have significantly increased colonic gene expression of cytosolic DNA sensor, inflammasome, STING, and type I IFN signaling pathways. The type I IFN, IFN-ß, in combination with TNF-α induced JAK-dependent but NLRP3 and inflammasome-independent inflammatory cell death of colonic organoids. This novel inflammatory cell death phenotype is relevant to UC immunopathology and may partially explain the efficacy of the JAKinibs tofacitinib and upadacitinib in patients with UC.

Severe mental illness, common mental disorders, and neurodevelopmental conditions amongst 9088 lower court attendees in London, UK.

BACKGROUND: Court Mental Health Liaison and Diversion Services (CMHLDS) have developed in some countries as a response to the over-representation of mental illness and other vulnerabilities amongst defendants presenting to criminal justice (or correctional) systems. This study examined the characteristics and rates of mental disorder of 9088 defendants referred to CMHLDS. METHOD: The study analysed service level data, obtained from the National Health Service's mental health data set, to examine characteristics relating to gender, ethnicity and comorbidity of common mental and neurodevelopmental disorders at five CMHLDS across London between September 2015 and April 2017. RESULTS: The sample included 7186 males (79.1%) and 1719 females (18.9%), the gender of 183 (2%) were not recorded. Of those referred, 6616 (72.8%) presented with an identifiable mental disorder and 503 (5.5%) with a neurodevelopmental disorder (NDD). Significantly higher rates of schizophrenia were reported amongst Black defendants (n = 681; 37.2%) and Asian defendants (n = 315; 29%), while higher rates of depression were found amongst White defendants (n = 1007; 22.1%). Substance misuse was reported amongst 2813 defendants (31%), and alcohol misuse amongst 2111 (23.2%), with significantly high rates of substance and alcohol misuse amongst defendants presenting with schizophrenia or personality disorder. CONCLUSIONS: This is one of the largest studies to examine mental health needs and vulnerabilities amongst defendants presenting to CMHLDS. It will enable an improved understanding of the required service designs and resources required to manage the healthcare pathways for people attending CMHLDS.

Transatlantic Collaborations: Baccalaureate Nursing Students' Experiences of Participating in a Semester-Long Study Abroad Program.

AIM: The aim of this study was to describe students' experiences during a 15-week semester involving clinical placement in an Irish university. BACKGROUND: Internationalization is promoted and facilitated through study abroad initiatives within nurse education. Collaborations were developed between one university in the United States, an Irish university, and service partners. This study abroad initiative involved planning logistics, curriculum learning opportunities, and negotiating clinical placement in meeting state professional requirements. METHOD: A qualitative descriptive approach was used. Following ethical approval, 19 fourth-year students participated in focus group and individual semistructured interviews. Data analysis followed a thematic approach. RESULTS: Connecting our worlds details a process of acclimatizing, navigating learning, and using person-centered practices, illustrating meaningful learning in a journey of personal and professional development. CONCLUSION: Moving beyond the rhetoric of globalization is critical in future proofing initiatives in developing nursing practitioners while balancing potential safety risks in a post-COVID-19 era.

Defendants with intellectual disability and autism spectrum conditions: the perspective of clinicians working across three jurisdictions.

The treatment of vulnerable defendants by criminal justice systems or correctional systems varies within and between countries. The purpose of this paper is to examine three legal jurisdictions - New South Wales in Australia; Norway; England and Wales - to understand the extent of variation in practice within the court systems for defendants with intellectual disabilities (ID) and/or autism spectrum conditions (ASC). Two of the jurisdictions had a process for screening in place, either in police custody or at court, but this was not universally implemented across each jurisdiction. All three jurisdictions had a process for supporting vulnerable defendants through the legal system. Across the three jurisdictions, there was variation in disposal options from a mandatory care setting to hospital treatment to a custodial sentence for serious offences. This variation requires further international exploration to ensure the rights of defendants with ID or ASC are understood and safeguarded.

Irish data on the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease.

SUMMARY: This study reviews the safety and efficacy of treatment with vedolizumab for patients with inflammatory bowel disease across 9 Irish hospitals. It generates valuable and timely real-world data on treatment outcomes to add to the existing evidence base. Our population represents a refractory cohort with most patients previously exposed to at least one anti-TNFa agent and expressing an inflammatory phenotype. Results are reassuringly similar to larger international studies with additional insights into potential predictors of treatment response. This study further supports the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease. Key SummaryVedolizumab has growing real world data on its safety and efficacy in the treatment of IBD. Data on predictors of response are lacking. Studies such as VARSITY require new real-world data to help identify the place VDZ will occupy in the treatment algorithm for IBDThis study provides national Irish data on the safety and efficacy of VDZ in the treatment of IBD. It gives insight into various predictors of response for both UC and CD. It strengthens the available body of evidence on the use of VDZ and helps us determine its position on the treatment algorithm.

Making Sense of Family Deaths in Urban Senegal: Diversities, Contexts, and Comparisons.

Despite calls for cross-cultural research, Minority world perspectives still dominate death and bereavement studies, emphasizing individualized emotions and neglecting contextual diversities. In research concerned with contemporary African societies, on the other hand, death and loss are generally subsumed within concerns about AIDS or poverty, with little attention paid to the emotional and personal significance of a death. Here, we draw on interactionist sociology to present major themes from a qualitative study of family deaths in urban Senegal, theoretically framed through the duality of meanings-in-context. Such themes included family and community as support and motivation; religious beliefs and practices as frameworks for solace and (regulatory) meaning; and material circumstances as these are intrinsically bound up with emotions. Although we identify the experience of (embodied, emotional) pain as a common response across Minority and Majority worlds, we also explore significant divergencies, varying according to localized contexts and broader power dynamics.

Prisoners with neurodevelopmental difficulties: Vulnerabilities for mental illness and self-harm.

BACKGROUND: Research into neurodevelopmental disorders in adult offenders has tended to be disorder specific, so hindering service planning for a group of offenders with similar vulnerabilities. AIM: To examine vulnerabilities for mental illness and self-harming behaviours among male prisoners screening positive for a range of neurodevelopmental difficulties-including but not confined to disorders of intellectual ability, attention deficit hyperactivity, and in the autistic spectrum. METHOD: In a cross-sectional study, prisoners who screened positive for neurodevelopmental difficulties were compared to prisoners who screened negative for the same on indicators of suicide-related and self-harm behaviours, mental illness, and substance misuse using the Mini International Neuropsychiatric Interview (MINI). RESULTS: Of 87 prisoners who screened positive for neurodevelopmental difficulties, 69 had full MINI mental health data. In comparison with 69 neurotypical men in the same prison, the neurodevelopmental difficulties group was significantly more likely to have thought about self-harm and suicide in the last month and to have significantly higher rates of concurrent mental disorders including psychosis, anxiety, depression, personality disorder, and substance dependency disorders. CONCLUSIONS: This is one of the first studies to examine the mental health of adults with neurodevelopmental difficulties in a prison setting. This group, unlike those who meet diagnostic threshold, is not routinely considered by mental health or correctional services. The study found prisoners with neurodevelopmental difficulties showed greater vulnerability to mental disorder and thoughts of suicide and suicide-related behaviours than other prisoners. Accordingly, we recommend routine early screening across the criminal justice system for any neurodevelopmental difficulties to inform decision-making on the most appropriate disposal and support.

Impact of cholinesterase inhibitors or memantine on survival in adults with Down syndrome and dementia: clinical cohort study.

BACKGROUND: There is little evidence to guide pharmacological treatment in adults with Down syndrome and Alzheimer's disease. Aims To investigate the effect of cholinesterase inhibitors or memantine on survival and function in adults with Down syndrome and Alzheimer's disease. METHOD: This was a naturalistic longitudinal follow-up of a clinical cohort of 310 people with Down syndrome diagnosed with Alzheimer's disease collected from specialist community services in England. RESULTS: Median survival time (5.59 years, 95% CI 4.67-6.67) for those on medication (n = 145, mainly cholinesterase inhibitors) was significantly greater than for those not prescribed medication (n = 165) (3.45 years, 95% CI 2.91-4.13, log-rank test P<0.001). Sequential assessments demonstrated an early effect in maintaining cognitive function. CONCLUSIONS: Cholinesterase inhibitors appear to offer benefit for people with Down syndrome and Alzheimer's disease that is comparable with sporadic Alzheimer's disease; a trial to test the effect of earlier treatment (prodromal Alzheimer's disease) in Down syndrome may be indicated. Declaration of interest A.S. has undertaken consulting for Ono Pharmaceuticals, outside the submitted work. Z.W. has received a consultancy fee and grant from GE Healthcare, outside the submitted work.

Recommendations for the transition of patients with ADHD from child to adult healthcare services: a consensus statement from the UK adult ADHD network.

The aim of this consensus statement was to discuss transition of patients with ADHD from child to adult healthcare services, and formulate recommendations to facilitate successful transition. An expert workshop was convened in June 2012 by the UK Adult ADHD Network (UKAAN), attended by a multidisciplinary team of mental health professionals, allied professionals and patients. It was concluded that transitions must be planned through joint meetings involving referring/receiving services, patients and their families. Negotiation may be required to balance parental desire for continued involvement in their child's care, and the child's growing autonomy. Clear transition protocols can maintain standards of care, detailing relevant timeframes, responsibilities of agencies and preparing contingencies. Transition should be viewed as a process not an event, and should normally occur by the age of 18, however flexibility is required to accommodate individual needs. Transition is often poorly experienced, and adherence to clear recommendations is necessary to ensure effective transition and prevent drop-out from services.

Dementia diagnostic criteria in Down syndrome.

OBJECTIVE: Dementia is a common clinical presentation among older adults with Down syndrome. The presentation of dementia in Down syndrome differs compared with typical Alzheimer's disease. The performance of manualised dementia criteria in the International Classification of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (DSM-IV-TR) is uncertain in this population.We aimed to determine the concurrent validity and reliability of clinicians' diagnoses of dementia against ICD-10 and DSM-IV-TR diagnoses. Validity of clinical diagnoses were also explored by establishing the stability of diagnoses over time. METHODS: We used clinical data from memory assessments of 85 people with Down syndrome, of whom 64 (75.3%) had a diagnosis of dementia. The cases of dementia were presented to expert raters who rated the case as dementia or no dementia using ICD-10 and DSM-IV-TR criteria and their own clinical judgement. RESULTS: We found that clinician's judgement corresponded best with clinically diagnosed cases of dementia, identifying 84.4% cases of clinically diagnosed dementia at the time of diagnosis. ICD-10 criteria identified 70.3% cases, and DSM-IV-TR criteria identified 56.3% cases at the time of clinically diagnosed dementia. Over time, the proportion of cases meeting ICD-10 or DSM-IV-TR diagnoses increased, suggesting that experienced clinicians used their clinical knowledge of dementia presentation in Down syndrome to diagnose the disorder at an earlier stage than would have been possible had they relied on the classic description contained in the diagnostic systems. CONCLUSIONS: Clinical diagnosis of dementia in Down syndrome is valid and reliable and can be used as the standard against which new criteria such as the DSM-5 are measured.

Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn's disease.

Although epidemiological findings support a role for vitamin K status in the improvement of bone indices in adult patients with Crohn's disease (CD), this needs to be confirmed in double-blind, randomised controlled trials (RCT) with phylloquinone (vitamin K1). By conducting two RCT, the present study aimed to first establish whether supplementation with 1000 µg of phylloquinone daily near-maximally suppresses the percentage of undercarboxylated osteocalcin in serum (%ucOC; marker of vitamin K status) in adult patients with CD currently in remission as it does in healthy adults and second determine the effect of supplementation with phylloquinone at this dose for 12 months on the indices of bone turnover and bone mass. The initial dose-ranging RCT was conducted in adult patients with CD (n 10 per group) using 0 (placebo), 1000 or 2000 µg of phylloquinone daily for 2 weeks. In the main RCT, the effect of placebo v. 1000 µg vitamin K/d (both co-administered with Ca (500 mg/d) and vitamin D3 (10 µg/d)) for 12 months (n 43 per group) on the biochemical indices of bone turnover (determined by enzyme immunoassay) and bone mass (determined by dual-energy X-ray absorptiometry) were investigated. At baseline, the mean %ucOC was 47 %, and this was suppressed upon supplementation with 1000 µg of phylloquinone daily ( - 81 %; P< 0·01) and not suppressed further by 2000 µg of phylloquinone daily. Compared with the placebo, supplementation with 1000 µg of phylloquinone daily for 12 months had no significant effect (P>0·1) on bone turnover markers or on the bone mass of the lumbar spine or femur, but modestly increased (P< 0·05) the bone mass of the total radius. Despite near maximal suppression of serum %ucOC, supplementation with 1000 µg of phylloquinone daily (with Ca and vitamin D3) had no effect on the indices of bone health in adult CD patients with likely vitamin K insufficiency.

Student nurses' views of participating in an intergenerational café with older people.

BACKGROUND: Within the context of global ageing, older people will require health care during times in their later lives. As most nurses will care for older people across a variety of care settings, it is crucial that older people and nurses can work together in partnership. In preparation for this, it is important to develop intergenerational learning innovations for student nurses and older people. An online intergenerational discussion café was developed to provide an opportunity for older people and student nurses to meet and get to know each other. OBJECTIVES: 1) Evaluate the effectiveness of an intergenerational discussion café as a way of facilitating intergenerational learning, 2) Elicit participants' views on whether intergenerational learning had occurred. DESIGN: Ethically approved survey research. SETTINGS: Tertiary education institution. PARTICIPANTS: Third year student nurses (n = 50) across three BSc Nursing pre-registration degree programmes enrolled on a shared community care module. METHODS: Post-café, student nurses were invited via email to voluntarily participate in the research and to complete an anonymous online survey. Questionnaire return implied consent. Fifty student nurses (n = 50) participated in the post café survey. Descriptive statistical analysis of Likert scale quantitative data and thematic analysis of open-ended questions was undertaken. RESULTS: Participants reported that the intergenerational cafés were well organised, worked well and strongly agreed that the cafés were helpful in facilitating student nurses and older people to connect socially and share views. Results also showed that participants felt they got to know a lot about older people and that they were in many ways quite similar to older people. CONCLUSIONS: This study provides valuable information on the use of intergenerational cafés as a means of facilitating intergenerational learning. Findings indicate that it was a positive learning experience for participants.

Conversations through barriers of language and interpretation.

Ireland has become a multicultural society in just over a decade, with non-Irish nationals comprising 12% of the population. The challenge for nurses working in the Irish healthcare system is to provide culturally appropriate care to this diverse population. This paper reports on a qualitative descriptive study exploring nurses' experiences of communicating with people from diverse cultures, and focuses on language barriers and the use of interpreters. The findings indicate that communicating with people who do not share the same first language is challenging, in particular the participants (nurses) were concerned about their ability to make a comprehensive assessment that ultimately forms the basis for quality care provision. The use of interpreters can inform the assessment process, but there are challenges in accessing and utilising these services. Further continuing education is required to promote culturally appropriate care. There is a need for increased discussion between nurses and interpreters to maximise communication with patients.