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

Is vitamin D deficiency a mechanistic driver of acute lung injury?

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the critically ill patient. There are no effective strategies for identifying those most at risk or therapeutic interventions proven to prevent its occurrence. Vitamin D deficiency is common and has important functions besides calcium homeostasis with profound effects on human immunity. Preliminary data suggests in the high-risk sepsis and oesophagectomy groups that vitamin D deficiency may be a pre-existing risk factor and mechanistic driver of ARDS. This thesis investigated in an animal model and in-vitro studies whether vitamin D influences the innate immune response to sepsis and resolution of neutrophilic injury. In addition, it reports a proof of concept phase II study to determine if vitamin D therapy in patients undergoing oesophagectomy is anti-inflammatory and protective of markers of lung injury. Vitamin D deficiency significantly increased the bacterial load, bacteraemia and translocation to the lung in a murine model of peritonitis. This was associated with a rise in tissue permeability locally and within the lung, reduced antimicrobial peptide and defective peritoneal macrophage phagocytosis. These data support pre-existing vitamin D deficiency as a determinant of the severity of bacteraemic sepsis. In-vivo high dose vitamin D supplementation was a safe, well-tolerated preoperative intervention with reduced biomarkers of alveolar oedema, capillary leak and macrophage efferocytosis. In-vitro culture with vitamin D increased macrophage efferocytosis and promoted monocyte differentiation to a pro-resolution phenotype. This suggests a potential mechanism for vitamin D on protecting barrier integrity and resolution of neutrophilic inflammation, a hallmark of ARDS. This body of work demonstrates that vitamin D deficiency is a potential modifiable risk factor and should be identified and treated in patients at risk of sepsis and ARDS. Larger trials powered to evaluate the effect of vitamin D on preventing and improving clinical outcomes in sepsis and ARDS are warranted

Post-Operative Complications Following Emergency Laparotomy are Common and Associated with increased Late Mortality - A Retrospective Multi-Centre study

Emergency abdominal surgery, often termed emergency laparotomy, is a common surgical procedure undertaken in the United Kingdom (U.K), with approximately 30000 procedures annually. Patients presenting for emergency abdominal surgery are heterogeneous and present with diverse pathology, resulting in challenges for the surgical, anaesthetic and critical care team that manage them. Emergency laparotomy, by its very nature is high-risk surgery, with an estimated 30-day mortality in the U.K of 11%, which is over 10 times greater than the mortality of patients undergoing major elective surgery (e.g. cardiac, vascular and oncological surgery) and a median hospital length of stay (LOS) of 12-days. Risk factors associated with poorer outcomes from emergency laparotomy have been identified by the National Emergency Laparotomy Audit (NELA) and include advancing age, with each decade above the age of 50 being associated with increasing risk. Additional risk factors include an American Society of Anaesthesia (ASA) status of 3 or more and Portsmouth- Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (P-POSSUM) risk of death of greater than 5%. The development of post-operative pulmonary complications (PPCs) is a composite definition for a variety of respiratory complications that occur following surgery. They range from clinically significant bronchospasm and atelectasis, through to the development of pneumonia and the acute respiratory distress syndrome (ARDS). The incidence following elective major abdominal surgery has been estimated at 11.9% and is associated poorer outcomes with increased length of hospital stay, increased re-admissions and a higher mortality. Although emergency surgery is well established as a significant risk factor for the development of PPCs, the incidence is not well established. This study aimed to establish the incidence of PPCs in a cohort of patients undergoing emergency laparoto

Management of Non-Ventilated hospital acquired pneumonia

Non-ventilated hospital acquired pneumonia (NV-HAP) is defined as pneumonia that develops at least 48 h after hospital admission in the non-invasively ventilated patient. Guidance in the management of NV-HAP has historically used extrapolated research from the wider field of HAP, which includes patients with the separate clinical entity of ventilator associated pneumonia (VAP), or the field of community acquired pneumonia (CAP). However, NV-HAP is being increasingly recognised as a subtype of HAP owing to its high incidence, mortality, morbidity and health-economic burden. With a wide range of underlying causative organisms, the management approach focuses on initial broad-spectrum coverage of common bacterial pathogens. If microbiological results are available, targeted treatment can be started. Throughout all phases of treatment, supportive measures must also be considered. This includes the use of physiotherapy, oxygen and ventilatory support, fluid therapy and nutritional support. Research is ongoing into novel treatments, including new antimicrobials, nebulised therapies and monoclonal antibodies. Future research would benefit from a focussed approach that aims to standardise clinical and research definitions and treats NV-HAP as a separate entity to VAP. Collection of specific data would allow for the development of risk-stratification or severity tools which have been fundamental in improving the management of other pneumonia patients, for example, the use of CURB-65 in CAP. Review of commonplace supportive measures in the NV-HAP population would also be beneficial in view of the mostly frail co-morbid population affected

Sepsis induces a dysregulated neutrophil phenotype that is associated with increased mortality

Background. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods. This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA) using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman’s rho. Results. Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p=0.002). PMA NETosis from patients with septic shock was reduced further (p<0.001) compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p<0.001), and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p=0.002) and 90-day mortality (p=0.014) in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions. Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced immunosuppression. For the first time, we demonstrate that reduced ex vivo NETosis is associated with poorer outcomes from sepsis

Vitamin D and critical illness:what endocrinology can learn from intensive care and vice versa.

The prevalence of vitamin D deficiency in intensive care units ranges typically between 40 and 70%. There are many reasons for being or becoming deficient in the ICU. Hepatic, parathyroid and renal dysfunction additionally increases the risk for developing vitamin D deficiency. Moreover, therapeutic interventions like fluid resuscitation, dialysis, surgery, extracorporeal membrane oxygenation, cardiopulmonary bypass and plasma exchange may significantly reduce vitamin D levels. Many observational studies have consistently shown an association between low vitamin D levels and poor clinical outcomes in critically ill adults and children, including excess mortality and morbidity such as acute kidney injury, acute respiratory failure, duration of mechanical ventilation and sepsis. It is biologically plausible that vitamin D deficiency is an important and modifiable contributor to poor prognosis during and after critical illness. Although vitamin D supplementation is inexpensive, simple and has an excellent safety profile, testing for and treating vitamin D deficiency is currently not routinely performed. Overall, less than 800 patients have been included in RCTs worldwide, but the available data suggest that high-dose vitamin D supplementation could be beneficial. Two large RCTs in Europe and the United States, together aiming to recruit >5000 patients, have started in 2017, and will greatly improve our knowledge in this field. This review aims to summarize current knowledge in this interdisciplinary topic and give an outlook on its highly dynamic future

Towards personalised anti-microbial and immune approaches to infections in acute care. Can real-time genomic-informed diagnosis of pathogens, and immune-focused therapies improve outcomes for patients? An observational, experimental study protocol

Introduction: Infection causes a vast burden of disease, with significant mortality, morbidity and costs to health-care systems. However, identifying the pathogen causative infection can be challenging, resulting in high use of broad-spectrum antibiotics, much of which may be inappropriate. Novel metagenomic methods have potential to rapidly identify pathogens, however their clinical utility for many infections is currently unclear. Outcome from infection is also impacted by the effectiveness of immune responses, which can be impaired by age, co-morbidity and the infection itself. The aims of this study are twofold: 1. To compare diversity of organisms identified and time-to-result using metagenomic methods versus traditional culture -based techniques, to explore the potential clinical role of metagenomic approaches to pathogen identification in a range of infections.2. To characterise the ex vivo function of immune cells from patients with acute infection, exploring host and pathogen-specific factors which may affect immune function and overall outcomes. Methods: This is a prospective observational study of patients with acute infection. Patients with symptoms suggestive of an acute infection will be recruited, and blood and bodily fluid relevant to the site of infection collected (for example, sputum and naso-oropharyngeal swabs for respiratory tract infections, or urine for a suspected urinary tract infection). Metagenomic analysis of samples will be compared to traditional microbiology, alongside the antimicrobials received. Blood and respiratory samples such as bronchoalveolar lavage will be used to isolate immune cells and interrogate immune cell function. Where possible, similar samples will be collected from matched participants without a suspected infection to determine the impact of infection on both microbiome and immune cell function.</p

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