An Approach to Relate Viewpoints and Modeling Languages

The architectural design of distributed enterprise applications from the viewpoints of different stakeholders has been proposed for some time, for example, as part of RM-ODP and IEEE 1471, and seems now-a-days to gain acceptance in practice. However, much work remains to be done on the relationships between different viewpoints. Failing to relate viewpoints may lead to a collection of viewpoint models that is inconsistent, and may therefore lead to an incorrect implementation. This paper defines an approach that helps designers to relate different viewpoints to each other. Thereby, it helps to enforce the consistency of the overall design. The results of this paper are expected to be particularly interesting for Model Driven Architecture (MDA) projects, since the proposed models can be used for the explicit definition of the models and relationships between models in an MDA trajectory

Spatial distribution of micrometre‐scale porosity and permeability across the damage zone of a reverse‐reactivated normal fault in a tight sandstone : Insights from the Otway Basin, SE Australia

This research forms part of a PhD project supported by the Australian Research Council [Discovery Project DP160101158] and through an Australian Government Research Training Program Scholarship. Dave Healy acknowledges the support of the Natural Environment Research Council (NERC, UK) through the award NE/N003063/1 ‘Quantifying the Anisotropy of Permeability in Stressed Rock’. This study was also funded by scholarships from the Petroleum Exploration Society of Australia and the Australian Petroleum Production and Exploration Association. We thank Gordon Holm for preparing thin sections and Colin Taylor for carrying out particle size measurements and mercury injection capillary pressure analyses. Aoife McFadden and David Kelsey from Adelaide Microscopy, Braden Morgan, and Sophie Harland are acknowledged for their assistance with laboratory work. Field assistants James Hall, Rowan Hansberry, and Lachlan Furness are also gratefully acknowledged for their assistance with sample collection. Discussions with Ian Duddy on the mineralogy of the Eumeralla Formation are also greatly appreciated. This forms TRaX record 416.Peer reviewedPublisher PD

Molecular and Cellular Mechanisms Affected in ALS

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways

Integrating palliative care and heart failure: a systematic realist synthesis (PalliatHeartSynthesis)

Objectives (1) Develop a programme theory of why, for whom and in what contexts integrated palliative care (PC) and heart failure (HF) services work/do not work; (2) use the programme theory to co-produce with stakeholders, intervention strategies to inform best practice and future research. Methods A systematic review of all published articles and grey literature using a realist logic of analysis. The search strategy combined terms significant to the review questions: HF, PC and end of life. Documents were included if they were in English and provided data relevant to integration of PC and HF services. Searches were conducted in November 2021 in EMBASE, MEDLINE, PsycINFO, AMED, HMIC and CINAHL. Further relevant documents were identified via monthly alerts (up until April 2023) and the project stakeholder group (patient/carers, content experts and multidisciplinary practitioners). Results 130 documents were included (86 research, 22 literature reviews, 22 grey literature). The programme theory identified intervention strategies most likely to support integration of PC and HF services. These included protected time for evidence-based PC and HF education from undergraduate/postgraduate level and continuing professional practice; choice of educational setting (eg, online, face-to-face or hybrid); increased awareness and seeing benefits of PC for HF management; conveying the emotive and intellectual need for integrating PC and HF via credible champions; and prioritising PC and HF guidelines in practice. Conclusions The review findings outline the required steps to take to increase the likelihood that all key players have the capacity, opportunity and motivation to integrate PC into HF management. PROSPERO registration number CRD42021240185

RIPK3-mediated cell death is involved in DUX4-mediated toxicity in facioscapulohumeral dystrophy

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is caused by mutations leading to the aberrant expression of the DUX4 transcription factor in muscles. DUX4 was proposed to induce cell death, but the involvement of different death pathways is still discussed. A possible pro-apoptotic role of DUX4 was proposed, but as FSHD muscles are characterized by necrosis and inflammatory infiltrates, non-apoptotic pathways may be also involved. METHODS: We explored DUX4-mediated cell death by focusing on the role of one regulated necrosis pathway called necroptosis, which is regulated by RIPK3. We investigated the effect of necroptosis on cell death in vitro and in vivo experiments using RIPK3 inhibitors and a RIPK3-deficient transgenic mouse model. RESULTS: We showed in vitro that DUX4 expression causes a caspase-independent and RIPK3-mediated cell death in both myoblasts and myotubes. In vivo, RIPK3-deficient animals present improved body and muscle weights, a reduction of the aberrant activation of the DUX4 network genes, and an improvement of muscle histology. CONCLUSIONS: These results provide evidence for a role of RIPK3 in DUX4-mediated cell death and open new avenues of research

The role of trust and hope in antipsychotic medication reviews between GPs and service users a realist review

Abstract Background Increasing number of service users diagnosed with schizophrenia and psychosis are being discharged from specialist secondary care services to primary care, many of whom are prescribed long-term antipsychotics. It is unclear if General Practitioners (GPs) have the confidence and experience to appropriately review and adjust doses of antipsychotic medication without secondary care support. Aim To explore barriers and facilitators of conducting antipsychotic medication reviews in primary care for individuals with no specialist mental health input. Design &amp; setting Realist review in general practice settings. Method A realist review has been conducted to synthesise evidence on antipsychotic medication reviews conducted in primary care with service users diagnosed with schizophrenia or psychosis. Following initial scoping searches and discussions with stakeholders, a systematic search and iterative secondary searches were conducted. Articles were systematically screened and analysed to develop a realist programme theory explaining the contexts (C) and mechanisms (M) which facilitate or prevent antipsychotic medication reviews (O) in primary care settings, and the potential outcomes of medication reviews. Results Meaningful Antipsychotic medication reviews may not occur for individuals with only primary care medical input. Several, often mutually reinforcing, mechanisms have been identified as potential barriers to conducting such reviews, including low expectations of recovery for people with severe mental illness, a perceived lack of capability to understand and participate in medication reviews, linked with a lack of information shared in appointments between GPs and Service Users, perceived risk and uncertainty regarding antipsychotic medication and illness trajectory. Conclusions The review identified reciprocal and reinforcing stereotypes affecting both GPs and service users. Possible mechanisms to counteract these barriers are discussed, including realistic expectations of medication, and the need for increased information sharing and trust between GPs and service users. </jats:sec

Evaluation of expression and function of the H+/myo-inositol transporter HMIT;

BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control

Evaluation of expression and function of the H+/myo-inositol transporter HMIT;

BACKGROUND: The phosphoinositide (PIns) signalling pathway regulates a series of neuronal processes, such as neurotransmitter release, that are thought to be altered in mood disorders. Furthermore, mood-stabilising drugs have been shown to inhibit key enzymes that regulate PIns production and alter neuronal growth cone morphology in an inositol-reversible manner. Here, we describe analyses of expression and function of the recently identified H+/myo-inositol transporter (HMIT) investigated as a potential regulator of PIns signalling. RESULTS: We show that HMIT is primarily a neuronal transporter widely expressed in the rat and human brain, with particularly high levels in the hippocampus and cortex, as shown by immunohistochemistry. The transporter is localised at the Golgi apparatus in primary cultured neurones. No HMIT-mediated electrophysiological responses were detected in rat brain neurones or slices; in addition, inositol transport and homeostasis were unaffected in HMIT targeted null-mutant mice. CONCLUSION: Together, these data do not support a role for HMIT as a neuronal plasma membrane inositol transporter, as previously proposed. However, we observed that HMIT can transport inositol triphosphate, indicating unanticipated intracellular functions for this transporter that may be relevant to mood control

A realist review of medication optimisation of community dwelling service users with serious mental illness

Background: Severe mental illness (SMI) incorporates schizophrenia, bipolar disorder, non-organic psychosis, personality disorder or any other severe and enduring mental health illness. Medication, particularly antipsychotics and mood stabilisers are the main treatment options. Medication optimisation is a hallmark of medication safety, characterised by the use of collaborative, person-centred approaches. There is very little published research describing medication optimisation with people living with SMI. Objective: Published literature and two stakeholder groups were employed to answer: What works for whom and in what circumstances to optimise medication use with people living with SMI in the community? Methods: A five-stage realist review was co-conducted with a lived experience group of individuals living with SMI and a practitioner group caring for individuals with SMI. An initial programme theory was developed. A formal literature search was conducted across eight bibliographic databases, and literature were screened for relevance to programme theory refinement. In total 60 papers contributed to the review. 42 papers were from the original database search with 18 papers identified from additional database searches and citation searches conducted based on stakeholder recommendations. Results: Our programme theory represents a continuum from a service user’s initial diagnosis of SMI to therapeutic alliance development with practitioners, followed by mutual exchange of information, shared decision-making and medication optimisation. Accompanying the programme theory are 11 context-mechanism-outcome configurations that propose evidence-informed contextual factors and mechanisms that either facilitate or impede medication optimisation. Two mid-range theories highlighted in this review are supported decision-making and trust formation. Conclusions: Supported decision-making and trust are foundational to overcoming stigma and establishing ‘safety’ and comfort between service users and practitioners. Avenues for future research include the influence of stigma and equity across cultural and ethnic groups with individuals with SMI; and use of trained supports, such as peer support workers. PROSPERO registration number: CRD42021280980