Providing holistic end-of-life care for people with a history of problem substance use: a mixed methods cohort study of interdisciplinary service provision and integrated care.

Harmful use of illicit drugs and/or alcohol is linked to life-limiting illness and complex health and social care needs, but people who use substances and have complex needs do not receive timely palliative care and fail to achieve quality standards for a good death. They and their families often require support from multiple health and social care services which are shown to be poorly integrated and fail to deliver interdisciplinary care. This study aimed to identify the existing barriers and facilitators within and between services in providing this population with a good death. Using a mixed methods approach of survey, focus groups and semi-structured interviews, we explored the perspectives of practitioner and management staff across a range of health and social disciplines and organisations in one combined authority in a large city in the north west of England. Our findings indicate that practitioners want to provide better care for this client group, but face structural, organisational and professional boundary barriers to delivering integrated and shared care. Differences in philosophy of care, piecemeal commissioning and funding of services, and regulatory frameworks for different services, lead to poor and inequitable access to health and social care services. Ways forward for improving care are suggested as bespoke hostel-based accommodation for palliative care for this client group, and specialist link workers who can transcend professional and organisational boundaries to support co-ordination of services and support. We conclude that it is no longer adequate to call for more training, better communication and improved joint working. Complex care at the end of life requires creative and cohesive systemic responses that enable multi-disciplinary practitioners to provide the care they wish to give and enables individuals using substances to get the respect and quality service they deserve.

Psychosocial functioning in individuals with advanced oesophago-gastric cancer: a mixed methods systematic review.

BACKGROUND: Oesophago-gastric cancer is an aggressive disease with a high rate of recurrence and mortality across the disease trajectory. Reduced psychosocial functioning has been evidenced amongst those with advanced disease, however little is known about the contributing factors. Determining these factors is an important clinical consideration to inform assessment and intervention. This review aimed to synthesise the available evidence on the psychosocial functioning of individuals with advanced oesophago-gastric cancer and their carers. METHODS: A JBI mixed-methods systematic review. Four bibliographic databases, MEDLINE, Embase, PsycINFO, and CINAHL, were searched. Quantitative and qualitative studies were screened for inclusion and critically appraised for methodological quality. Both types of data were extracted using JBI tools for mixed-methods systematic reviews. A convergent segregated approach to synthesis and integration was used. The findings of the synthesis have been configured according to JBI methodology. RESULTS: A total of 12 studies were included in this review, including 6 quantitative studies and 6 qualitative studies. The quantitative results provide preliminary indication of several physical, biological, psychological and macro-level contextual factors associated with psychosocial functioning in this clinical population. The qualitative findings shed light on a range of physical, psychosocial, and existential challenges faced by advanced oesophago-gastric cancer patients. These multiple and often persistent challenges appear to cause considerable distress; however, patients describe the importance of maintaining a sense of normality and control over their illness and its effects. Patients value continuity and structure, however many report shortcomings when accessing care. No findings reporting the experiences from the perspective of carers were found, therefore all findings represent the perspective of the patient. CONCLUSIONS: Further high-quality research is needed to understand how best to support and manage the palliative care needs of individuals living with advanced oesophago-gastric cancer. Implications for practice are discussed, suggesting that psychosocial interventions, complex symptom management and continuity of care could improve the psychosocial functioning of individuals in this setting. PRE-REGISTRATION: The systematic review was pre-registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020181273) and the protocol can be viewed on the OSF ( http://osf.io/exuzf ).

Towards a Dignified Death: A New Approach to Care for People Using Substances Who Are at, or Near, the End of Their Lives.

There are no effective intervention studies for people using substances who are at, or near, the end of their lives. The needs of this group of people have been consistently overlooked even within the literature that identifies marginalised groups of people in need of greater recognition in palliative and end-of-life care. The aims of the project were to: (i) determine what a new, co-produced, model of care should look like for people using substances needing palliative and end-of-life care, and (ii) establish whether the new model had the potential to improve people's access to, and experience of, end-of-life care. This paper presents the development of the new approach to care. It was developed using participatory action research principles over a course of online workshops during the COVID-19 pandemic lockdown period in the UK. A theory of change that aims to inform future policy and practice development is presented. While the ambition of the research was stunted by the pandemic, the process of its development and dissemination of the model and its resources has continued. Response from participants highlighted the importance of this work, however, in this new field of policy and practice, preparatory work that engages a wide range of stakeholders is crucial to its success. This relationship building and topic engagement are major parts of implementation before more substantial and sustainable development goals can be met.

An ethical exploration of the narratives surrounding substance use and pain management at the end of life: a discussion paper.

This discussion article examines narrative positioning related to pain management for people who use substances at the end of life. We explore how dominant narrative genres associated with biomedicine, such as 'restitution' and narratives common within the context of drug services such as 'recovery' can hinder effective pain management within this population. We argue that these discourses can marginalise the ethical self-identity of patients who use substances at the end of life. It can also trouble health and social care professionals in supporting patients and generating counter-narratives that challenge those often associated with substance use. Stigma is a common experience for this population with stereotyping as 'junkies' and associated with criminality. They are positioned as drug-seeking, and this requires more surveillance at the end of life when opioid therapy is potentially more available and authorised. This can make it challenging to generate 'companion' stories that are positive and maintain moral adequacy. Dominant biomedical narrative genres often prevent the recognition of the fractured stories that people using substances can often present with. This can lead to narrative silencing and to the under treatment of pain. The person's self-identity is invested in narratives of recovery, and opioid use symbolises their addicted past because for practitioners, this population is at clinical risk with the potential for drug seeking behaviours. Whilst not requiring formal ethical review this discussion paper was constructed in accordance with good scientific practice with the work of other researchers respected and cited appropriately.

The C-terminal priming domain is strongly associated with the main body of bacteriophage ϕ6 RNA-dependent RNA polymerase.

Double-stranded RNA viruses encode a single protein species containing RNA-dependent RNA polymerase (RdRP) motifs. This protein is responsible for RNA transcription and replication. The architecture of viral RdRPs resembles that of a cupped right hand with fingers, palm and thumb domains. Those using de novo initiation have a flexible structural elaboration that constitutes the priming platform. Here we investigate the properties of the C-terminal priming domain of bacteriophage ϕ6 to get insights into the role of an extended loop connecting this domain to the main body of the polymerase. Proteolyzed ϕ6 RdRP that possesses a nick in the hinge region of this loop was better suited for de novo initiation. The clipped C-terminus remained associated with the main body of the polymerase via the anchor helix. The structurally flexible hinge region appeared to be involved in the control of priming platform movement. Moreover, we detected abortive initiation products for a bacteriophage RdRP.

Noncatalytic ions direct the RNA-dependent RNA polymerase of bacterial double-stranded RNA virus ϕ6 from de novo initiation to elongation.

RNA-dependent RNA polymerases (RdRps) are key to the replication of RNA viruses. A common divalent cation binding site, distinct from the positions of catalytic ions, has been identified in many viral RdRps. We have applied biochemical, biophysical, and structural approaches to show how the RdRp from bacteriophage ϕ6 uses the bound noncatalytic Mn(2+) to facilitate the displacement of the C-terminal domain during the transition from initiation to elongation. We find that this displacement releases the noncatalytic Mn(2+), which must be replaced for elongation to occur. By inserting a dysfunctional Mg(2+) at this site, we captured two nucleoside triphosphates within the active site in the absence of Watson-Crick base pairing with template and mapped movements of divalent cations during preinitiation. These structures refine the pathway from preinitiation through initiation to elongation for the RNA-dependent RNA polymerization reaction, explain the role of the noncatalytic divalent cation in 6 RdRp, and pinpoint the previously unresolved Mn(2+)-dependent step in replication.

Structural explanation for the role of Mn2+ in the activity of phi6 RNA-dependent RNA polymerase.

The biological role of manganese (Mn(2+)) has been a long-standing puzzle, since at low concentrations it activates several polymerases whilst at higher concentrations it inhibits. Viral RNA polymerases possess a common architecture, reminiscent of a closed right hand. The RNA-dependent RNA polymerase (RdRp) of bacteriophage 6 is one of the best understood examples of this important class of polymerases. We have probed the role of Mn(2+) by biochemical, biophysical and structural analyses of the wild-type enzyme and of a mutant form with an altered Mn(2+)-binding site (E491 to Q). The E491Q mutant has much reduced affinity for Mn(2+), reduced RNA binding and a compromised elongation rate. Loss of Mn(2+) binding structurally stabilizes the enzyme. These data and a re-examination of the structures of other viral RNA polymerases clarify the role of manganese in the activation of polymerization: Mn(2+) coordination of a catalytic aspartate is necessary to allow the active site to properly engage with the triphosphates of the incoming NTPs. The structural flexibility caused by Mn(2+) is also important for the enzyme dynamics, explaining the requirement for manganese throughout RNA polymerization.

Experiences of anabolic steroid use: in-depth interviews with men and women body builders.

This study was designed to investigate anabolic steroid users' experiences of, and motivations for, use. Five men and six women users took part in in-depth interviews. Four themes emerged: Steroid Use vs Abuse; Side-effects; Trusted Information Sources; and Social Pressure. Many users believed that steroids used in moderation were safe. Serious side-effects (liver and kidney damage, hypertension) were not significant disincentives. Information from health professionals tended to be mistrusted because it was not based on first-hand experience of use. Social support, especially from within the body building community, was an important motivator. It is concluded that intervention programmes need the support of the body building community in order to be effective.

Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice.

Several clinical and angiographic intervention trials have shown that fibrate treatment leads to a reduction of the coronary events associated to atherosclerosis. Fibrates are ligands for peroxisome proliferator-activated receptor alpha (PPARalpha) that modulate risk factors related to atherosclerosis by acting at both systemic and vascular levels. Here, we investigated the effect of treatment with the PPARalpha agonist fenofibrate (FF) on the development of atherosclerotic lesions in apolipoprotein (apo) E-deficient mice and human apoA-I transgenic apoE-deficient (hapoA-I Tg x apoE-deficient) mice fed a Western diet. In apoE-deficient mice, plasma lipid levels were increased by FF treatment with no alteration in the cholesterol distribution profile. FF treatment did not reduce atherosclerotic lesion surface area in the aortic sinus of 5-month-old apoE-deficient mice. By contrast, FF treatment decreased total cholesterol and esterified cholesterol contents in descending aortas of these mice, an effect that was more pronounced in older mice exhibiting more advanced lesions. Furthermore, FF treatment reduced MCP-1 mRNA levels in the descending aortas of apoE-deficient mice, whereas ABCA-1 expression levels were maintained despite a significant reduction of aortic cholesterol content. In apoE-deficient mice expressing a human apoA-I transgene, FF increased human apoA-I plasma and hepatic mRNA levels without affecting plasma lipid levels. This increase in human apoA-I expression was accompanied by a significant reduction in the lesion surface area in the aortic sinus. These data indicate that the PPARalpha agonist fenofibrate reduces atherosclerosis in these animal models of atherosclerosis.