Exact approximation of Rao-Blackwellised particle filters

Particle methods are a category of Monte Carlo algorithms that have become popular for performing inference in non-linear non-Gaussian state-space models. The class of 'Rao-Blackwellised' particle filters exploits the analytic marginalisation that is possible for some state- space models to reduce the variance of the Monte Carlo estimates. Despite being applicable to only a restricted class of state-space models, such as conditionally linear Gaussian models, these algorithms have found numerous applications. In scenarios where no such analytical integration is possible, it has recently been proposed in Chen et al. [2011] to use 'local' particle filters to carry out this integration numerically. We propose here an alternative approach also relying on \local" particle filters which is more broadly applicable and has attractive theoretical properties. Proof-of-concept simulation results are presented

The Alcohol Health Alliance: the emergence of an advocacy coalition to stimulate policy change

This paper provides an account of the emergence and early development of the Alcohol Health Alliance (AHA), a coalition of organizations including medical bodies, charities and alcohol health campaigners. Launched in 2007, the AHA aimed to re-frame awareness of alcohol consumption and related harms, to gain greater policy saliency for health compared to criminal justice priorities, and to shift policy towards adopting a population approach as compared to a targeted approach to intervention. The strategies used by the AHA to mobilize support and re-frame understanding of the alcohol problem, were successful in the short term. The alliance benefited from their links with established powerful institutions that helped them secure a strong presence within the policy arena and in the media, not least by forging relationships with political allies. However, in the longer term, it may be difficult to maintain a position of strength and to combat pre-existing entrenched relationships that favour competing alternative perceptions of the alcohol problem and the appropriate policy response

Identifying promising approaches and initiatives to reducing alcohol related harm

This study aimed to identify promising approaches that could be included in multi-component programmes (MCPs) to reduce alcohol related harm at local level in the UK. MCPs involve the identification of alcohol related problems at the local level and implementation of a programme of co-ordinated projects to tackle a problem. They are based on an integrative design where singular interventions run in combination with each other and/or are sequenced together over time; the identification, coordination and mobilisation of local agencies, stakeholders and community are key elements (Thom and Bayley, 2007). This study was underpinned by the recognition that the voices of practitioners are often marginalised in the debates about ‘what works’ and it set out to include their views. So whilst acknowledging the importance of the international research literature, care was taken not to privilege it over other ‘softer’ sources e.g. knowledge and experience of practitioners

Randomized double-blind placebo-controlled trial of 40 mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial)

Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis. Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization. Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238). Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings. Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517

Protocol for a feasibility study of smoking cessation in the surgical pathway before major lung surgery: Project MURRAY

INTRODUCTION: Smoking prior to major thoracic surgery is the biggest risk factor for development of postoperative pulmonary complications, with one in five patients continuing to smoke before surgery. Current guidance is that all patients should stop smoking before elective surgery yet very few are offered specialist smoking cessation support. Patients would prefer support within the thoracic surgical pathway. No study has addressed the effectiveness of such an intervention in this setting on cessation. The overall aim is to determine in patients who undergo major elective thoracic surgery whether an intervention integrated (INT) into the surgical pathway improves smoking cessation rates compared with usual care (UC) of standard community/hospital based NHS smoking support. This pilot study will evaluate feasibility of a substantive trial. METHODS AND ANALYSIS: Project MURRAY is a trial comparing the effectiveness of INT and UC on smoking cessation. INT is pharmacotherapy and a hybrid of behavioural support delivered by the trained healthcare practitioners (HCPs) in the thoracic surgical pathway and a complimentary web-based application. This pilot study will evaluate the feasibility of a substantive trial and study processes in five adult thoracic centres including the University Hospitals Birmingham NHS Foundation Trust. The primary objective is to establish the proportion of those eligible who agree to participate. Secondary objectives include evaluation of study processes. Analyses of feasibility and patient-reported outcomes will take the form of simple descriptive statistics and where appropriate, point estimates of effects sizes and associated 95% CIs. ETHICS AND DISSEMINATION: The study has obtained ethical approval from NHS Research Ethics Committee (REC number 19/WM/0097). Dissemination plan includes informing patients and HCPs; engaging multidisciplinary professionals to support a proposal of a definitive trial and submission for a full application dependent on the success of the study. TRIAL REGISTRATION NUMBER: NCT04190966

Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D

BACKGROUND: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients.METHODS: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured ( n = 27). RESULTS: Elevated FGF23 (quartile 4 vs. quartiles 1-3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients ( p &lt; 0.001) and long-term (two-year) mortality in oesophagectomy patients ( p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0-14,000), while those who survived had 120.4 pg/mL (range = 15-14,000) ( p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154-77,800), while those who survived had 644 pg/mL (range = 179-54,894) ( p &lt; 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients ( p = 0.4802). CONCLUSIONS: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.</p

11β hydroxysteroid dehydrogenase type 1 transgenic mesenchymal stem cells attenuate inflammation in models of sepsis

Background: Human bone marrow mesenchymal stem cell (MSC) administration reduces inflammation in pre-clinical models of sepsis and sepsis-related lung injury, however clinical efficacy in patients has not yet been demonstrated. We previously showed that Alveolar Macrophage (AM) 11β-hydroxysteroid dehydrogenase type-1 (HSD-1) autocrine signalling is impaired in critically ill sepsis patients, which promotes inflammatory injury. Administration of transgenic MSCs (tMSCs) which overexpress HSD-1 may enhance the anti-inflammatory effects of local glucocorticoids and be more effective at reducing inflammation in sepsis than cellular therapy alone.Methods: MSCs were transfected using a recombinant lentiviral vector containing the HSD-1 and GPF transgenes under the control of a tetracycline promoter. Thin layer chromatography assessed HSD-1 reductase activity in tMSCs. Mesenchymal stem cell phenotype was assessed by flow cytometry and bi-lineage differentiation. HSD-1 tMSCs were co-cultured with LPS-stimulated monocyte-derived macrophages (MDMs) from healthy volunteers prior to assessment of pro-inflammatory cytokine release. HSD-1 tMSCs were administered intravenously to mice undergoing caecal ligation and puncture (CLP).Results: MSCs were transfected with an efficiency of 91.1%, and maintained an MSC phenotype. Functional HSD-1 activity was demonstrated in tMSCs, with predominant reductase cortisol activation (peak 8.23 pM/hour/100,000 cells). HSD-1 tMSC co-culture with LPS-stimulated MDMs suppressed TNFα and IL-6 release. Administration of transgene activated HSD-1 tMSCs in a murine model of CLP attenuated neutrophilic inflammation more effectively than transgene inactive tMSCs (medians 0.403 v 1.36 × 106/ml, p = 0.033).Conclusion: The synergistic impact of HSD-1 transgene expression and MSC therapy attenuated neutrophilic inflammation in a mouse model of peritoneal sepsis more effectively than MSC therapy alone. Future studies investigating the anti-inflammatory capacity of HSD-1 tMSCs in models of sepsis-related direct lung injury and inflammatory diseases are required

Stakeholder ownership: a theoretical framework for cross national understanding and analyses of stakeholder involvement in issues of substance use, problem use and addiction

This project contributes to understanding of the role of different stakeholder groups in the formulation and implementation of policy in the addictions field in Austria, Denmark, Finland, Italy, Poland and the UK. It comprises a number of case studies which draw on a range of theoretical frameworks to examine stakeholder dynamics at international, national and local levels. Mainly qualitative methods were used: interviews, policy and documentation analyses, webcrawler network analysis, and simple surveys; one case study was based on a survey only. The case studies fall into four main categories: three focus on controversial issues in drug treatment policy and practice – opioid substitution treatment, drug consumption rooms, and heroin assisted treatment; three look at stakeholder activity in alcohol control and public health; one pilot case study considers the potential role of researchers in the development of a scientific network around gambling; and one looks at the role of nurses in implementing brief interventions. In addition, themes explored across case studies included the role of evidence and stakeholder activity, drug users as stakeholders, and the role of external stakeholders on national policy. Professional stakeholders at implementation level and families and drug users as stakeholders are also considered. The case studies revealed that, in many instances, the addictions field is characterised by tensions between groups, by entrenched relationships between some addiction-specific stakeholder groups and powerful political stakeholders, and by the dominance of some forms of evidence over other forms of knowledge. Science and scientists are only influential in policy terms if their scientific findings ‘fit’ with the wider political context. Nevertheless, at least within the European context, there are opportunities for new stakeholder groups to emerge and gain policy salience and there are opportunities for stakeholders to challenge prevailing frames of understanding the addictions and prevailing modes of responding to problems of substance misuse and addiction