Optimal positive end-expiratory pressure in mechanically ventilated patients: a clinical study

The optimal level of positive end-expiratory pressure (PEEP) is still widely debated in treating acute respiratory distress syndrome (ARDS) patients. Current methods of selecting PEEP only provide a range of values and do not provide unique patient-specific solutions. Model-based methods offer a novel way of using non-invasive pressure-volume (PV) measurements to estimate patient recruitability. This paper examines the clinical viability of such models in pilot clinical trials to assist therapy, optimise patient-specific PEEP, assess the disease state and response over time

Model-based cardiovascular monitoring of acute pulmonary embolism in porcine trials

Introduction: Diagnosis and treatment of cardiac and circulatory dysfunction can be error-prone and relies heavily on clinical intuition and experience. Model-based approaches utilising measurements available in the Intensive care unit (ICU) can provide a clearer physiological picture of a patient’s cardiovascular status to assist medical staff with diagnosis and therapy decisions. This research tests a subject-specific cardiovascular system (CVS) modelling technique on measurements from a porcine model of acute pulmonary embolism (APE). Methods: Measurements were recorded in 5 pig trials, where autologous blood clots were inserted every two hours into the jugular vein to simulate pulmonary emboli. Of these measurements only a minimal set of clinically available or inferable data were used in the identification process (aortic and pulmonary artery pressure, stroke volume, heart rate, global end diastolic volume, and mitral and tricuspid valve closure times). The CVS model was fitted to 46 sets of data taken at 30 minute intervals (t=0, 30, 60, …, 270) during the induction of APE to identify physiological model parameters and their change over time in APE. Model parameters and outputs were compared to experimentally derived metrics and measurements not used in the identification method to validate the accuracy of the model and assess its diagnostic capability. Results: Modelled mean ventricular volumes and maximum ventricular pressures matched measured values with median absolute errors of 4.3% and 4.4%, which are less than experimental measurement noise (~10%). An increase in pulmonary vascular resistance, the main hemodynamic consequence of APE, was identified in all the pigs and related well to experimental values (R=0.68). Detrimental changes in reflex responses, such as decreased right ventricular contractility, were noticed in two pigs that died during the trial, diagnosing the loss of autonomous control. Increases in the ratio of the modelled right to left ventricular end diastolic volumes, signifying the leftward shift of the intra-ventricular septum seen in APE, compared well to the clinically measured index (R=0.88). Conclusions: Subject-specific CVS models can accurately and continuously diagnose and track acute disease dependent cardiovascular changes resulting from APE using readily available measurements. Human trials are underway to clinically validate these animal trial results

Computer-based monitoring of global cardiovascular dynamics during acute pulmonary embolism and septic shock in swine

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Pulmonary embolism diagnostics from the driver function

Ventricular driver functions are not readily measured in the ICU, but can clearly indicate the development of pulmonary embolism (PE) otherwise difficult to diagnose. Recent work has developed accurate methods of measuring these driver functions from readily available ICU measurements. This research tests those methods by assessing the ability of these driver functions to diagnose the evolution of PE

Model-based diagnosis of acute pulmonary embolism and septic shock in porcine trials

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Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis. METHODS: Samples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS. RESULTS: There were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10-5, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097). CONCLUSIONS: People with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias

Are there gender differences in the geography of alcohol-related mortality in Scotland? An ecological study

<b>Background</b> There is growing concern about alcohol-related harm, particularly within Scotland which has some of the highest rates of alcohol-related death in western Europe. There are large gender differences in alcohol-related mortality rates in Scotland and in other countries, but the reasons for these differences are not clearly understood. In this paper, we aimed to address calls in the literature for further research on gender differences in the causes, contexts and consequences of alcohol-related harm. Our primary research question was whether the kind of social environment which tends to produce higher or lower rates of alcohol-related mortality is the same for both men and women across Scotland. <b>Methods</b> Cross-sectional, ecological design. A comparison was made between spatial variation in men's and women's age-standardised alcohol-related mortality rates in Scotland using maps, Moran's Index, linear regression and spatial analyses of residuals. Directly standardised mortality rates were derived from individual level records of death registration, 2000–2005 (n = 8685). <b>Results</b> As expected, men's alcohol-related mortality rate substantially exceeded women's and there was substantial spatial variation in these rates for both men and women within Scotland. However, there was little spatial variation in the relationship between men's and women's alcohol-mortality rates (r2 = 0.73); areas with relatively high rates of alcohol-related mortality for men tended also to have relatively high rates for women. In a small number of areas (8 out of 144) the relationship between men's and women's alcohol-related mortality rates was significantly different. <b>Conclusion</b> In as far as geographic location captures exposure to social and economic environment, our results suggest that the relationship between social and economic environment and alcohol-related harm is very similar for men and women. The existence of a small number of areas in which men's and women's alcohol-related mortality had an different relationship suggests that some places may have unusual drinking cultures. These might prove useful for further investigations into the factors which influence drinking behaviour in men and women

Model-based cardiovascular monitoring of large pore hemofiltration during endotoxic shock in pigs

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Using fractional exhaled nitric oxide (FeNO) to diagnose steroid-responsive disease and guide asthma management in routine care

Acknowledgements We thank Robin Taylor for his informative thinking and publications on FeNO, which have helped to influence and direct the thinking of the authors. Funding Extraction of the real-life dataset was funded by Research in Real Life Limited, the analysis of the dataset and the writing of this manuscript were co-funded (50:50) by Research in Real Life Limited and Aerocrine.Peer reviewedPublisher PD