Temporal changes in the epidemiology, management, and outcome from acute respiratory distress syndrome in European intensive care units: a comparison of two large cohorts

Background: Mortality rates for patients with ARDS remain high. We assessed temporal changes in the epidemiology and management of ARDS patients requiring invasive mechanical ventilation in European ICUs. We also investigated the association between ventilatory settings and outcome in these patients. Methods: This was a post hoc analysis of two cohorts of adult ICU patients admitted between May 1–15, 2002 (SOAP study, n = 3147), and May 8–18, 2012 (ICON audit, n = 4601 admitted to ICUs in the same 24 countries as the SOAP study). ARDS was defined retrospectively using the Berlin definitions. Values of tidal volume, PEEP, plateau pressure, and FiO2 corresponding to the most abnormal value of arterial PO2 were recorded prospectively every 24 h. In both studies, patients were followed for outcome until death, hospital discharge or for 60 days. Results: The frequency of ARDS requiring mechanical ventilation during the ICU stay was similar in SOAP and ICON (327[10.4%] vs. 494[10.7%], p = 0.793). The diagnosis of ARDS was established at a median of 3 (IQ: 1–7) days after admission in SOAP and 2 (1–6) days in ICON. Within 24 h of diagnosis, ARDS was mild in 244 (29.7%), moderate in 388 (47.3%), and severe in 189 (23.0%) patients. In patients with ARDS, tidal volumes were lower in the later (ICON) than in the earlier (SOAP) cohort. Plateau and driving pressures were also lower in ICON than in SOAP. ICU (134[41.1%] vs 179[36.9%]) and hospital (151[46.2%] vs 212[44.4%]) mortality rates in patients with ARDS were similar in SOAP and ICON. High plateau pressure (> 29 cmH2O) and driving pressure (> 14 cmH2O) on the first day of mechanical ventilation but not tidal volume (> 8 ml/kg predicted body weight [PBW]) were independently associated with a higher risk of in-hospital death. Conclusion: The frequency of and outcome from ARDS remained relatively stable between 2002 and 2012. Plateau pressure > 29 cmH2O and driving pressure > 14 cmH2O on the first day of mechanical ventilation but not tidal volume > 8 ml/kg PBW were independently associated with a higher risk of death. These data highlight the continued burden of ARDS and provide hypothesis-generating data for the design of future studies

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

Characterising dynamical systems models of tumour-immune interactions

Despite clinical successes, data from trials of cancer immunotherapies continue to highlight non-responders. A better understanding of tumour-immune interactions is needed to explain outcome variability. In this thesis, we investigate whether tumour-immune interaction models can explain variation in mouse tumour volume time series data, focusing on a well-known mathematical model by Kuznetsov et al. (1994). Exploiting a separation of timescales in the original model, and using matched asymptotics, we derive a new long-timescale approximation of the model, which differs from the quasi-steady-state approximation (QSSA) introduced by Kuznetsov et al. (1994), but is in good agreement with numerical solutions of the original model. As well as exhibiting the three stages of immunoediting – elimination, equilibrium and escape, together with complex bifurcations and bistability, our reduced model highlights excitability, a feature not traditionally associated with tumour-immune models. We also identify different biophysical parameters that could be targeted with immunotherapy in order to control tumour size. As the QSSA model is simpler, but still exhibits immunoediting, we use it for case studies investigating parameter identifiability for complex bifurcating and bistable models using in silico data, generated from the model with variable parameters, observables and noise levels. Using profile likelihoods, we show that identifiability varies across dynamically different datasets. Parameters related to the immune system are highly correlated, and can result in large parameter confidence intervals and bimodal likelihood surfaces. We then explore a population approach, where the model is simultaneously calibrated to dichotomous data from two individuals, noting that variation in tumour outcomes can arise from bistability or bifurcations, representing distinct hypotheses for heterogeneous tumour responses. We demonstrate the hypotheses can be distinguished for most synthetic datasets considered, except for highly noisy tumour data, by comparing Bayesian population fits under each hypothesis. This thesis provides a new perspective on how qualitative differences between tumour growth dynamics of responders and non-responders may be explained by bifurcating and/or bistable models. At the same time, it illustrates how integration of mathematical and statistical methods can facilitate development of simplified models, their analysis and calibration.</p

Data for paper 'Identifying and characterising the impact of excitability in a mathematical model of tumour-immune interactions'

Please see included 'README.md' for details on the dataset. Data were produced using Python and Mathematica

Trace Element Analysis of Steels and Nickel Alloys by Atomic Spectrometry

The determination of arsenic and antimony in electrical steel sheets and nickel-base alloys at low concentration levels using graphite furnace atomic absorption spectrometry was investigated. The analytical and instrumental parameters were optimized. The influence of various modifiers on sensitivity and reproducibility of analytical signal was studied. The selection of optimal temperature program with regard to volatilization of the elements under investigation, background, matrix interferences, sensitivity and reproducibility of analytical signal and the life time of graphite tube was made. Some characteristic data, such as detection limit, characteristic mass and reproducibility of results were determined. The accuracy of the method was tested with certified standard reference materials of steels and nickel alloys. The experimental results agreed closely with the certified values for the both elements

Quantifying the intersexual and interspecific morphometric variation in two resembling sympatric lacertids: Iberolacerta horvathi and Podarcis muralis

Podarcis muralis and Iberolacerta horvathi are sympatric, frequently syntopic, lacertids through the entire range of I. horvathi and very similar in their general body size and shape, as well as in most ecological traits. We morphologically compared adults from the area of sympatry using biometric measurements and performed analyses to investigate their sexual size and shape dimorphism. A total of 34 males and 24 females of I. horvathi, and 25 males and 23 females of P. muralis, all adult individuals, were measured. Both species showed sexual size dimorphism with females being longer (snout-vent length, SVL) than males. After SVL correction (ANCOVA), head width, length and height and mass showed to be sexually dimorphic in both species. Males carry relatively wider, longer and higher heads and were heavier than conspecific females. I. horvathi heads were more flattened than those of P. muralis and P. muralis were heavier than I. horvathi. Both species displayed the same pattern of sexual dimorphism regarding body size, head size and shape not only in direction but also in magnitude. All results confirm that both species are very similar in studied biometric characters and, together with their ecological similarities, these suggest in absence of other factors they are likely to interact when living together

Quantifying the intersexual and interspecific morphometric variation in two resembling sympatric lacertids

Podarcis muralis and Iberolacerta horvathi are sympatric, frequently syntopic,lacertids through the entire range of I. horvathi and very similar intheir general body size and shape, as well as in most ecological traits. We morphologically compared adults from the area of sympatry using biometric measurements and performed analyses to investigate their sexual size and shapedimorphism. A total of 34 males and 24 females of I. horvathi, and 25 males and 23 females of P. muralis, all adult individuals, were measured. Bothspecies showed sexual size dimorphism with females being longer (snout-vent length, SVL) than males. After SVL correction (ANCOVA), head width, length and height and mass showed to be sexually dimorphic in both species. Males carry relatively wider, longer and higher heads and were heavier than conspecific females. I. horvathi heads were more flattened than those of P. muralis and P. muralis were heavier than I. horvathi. Both speciesdisplayed the same pattern of sexual dimorphism regarding body size, head size and shape not only in direction but also in magnitude. All results confirm that both species are very similar in studied biometric characters and, together with their ecological similarities, these suggest in absence of other factors they are likely to interact when living together

Identifying and characterising the impact of excitability in a mathematical model of tumour-immune interactions

We study a five-compartment mathematical model originally proposed by Kuznetsov et al. (1994) to investigate the effect of nonlinear interactions between tumour and immune cells in the tumour microenvironment, whereby immune cells may induce tumour cell death, and tumour cells may inactivate immune cells. Exploiting a separation of timescales in the model, we use the method of matched asymptotics to derive a new two-dimensional, long-timescale, approximation of the full model, which differs from the quasi-steady-state approximation introduced by Kuznetsov et al. (1994), but is validated against numerical solutions of the full model. Through a phase-plane analysis, we show that our reduced model is excitable, a feature not traditionally associated with tumour-immune dynamics. Through a systematic parameter sensitivity analysis, we demonstrate that excitability generates complex bifurcating dynamics in the model. These are consistent with a variety of clinically observed phenomena, and suggest that excitability may underpin tumour-immune interactions. The model exhibits the three stages of immunoediting - elimination, equilibrium, and escape, via stable steady states with different tumour cell concentrations. Such heterogeneity in tumour cell numbers can stem from variability in initial conditions and/or model parameters that control the properties of the immune system and its response to the tumour. We identify different biophysical parameter targets that could be manipulated with immunotherapy in order to control tumour size, and we find that preferred strategies may differ between patients depending on the strength of their immune systems, as determined by patient-specific values of associated model parameters

Ecophysiological dissimilarities of two sympatric lizards

The lizards Podarcis muralis and Iberolacerta horvathi display an overall similarity in morphology and ecology. Although they are widely sympatric in part of their distribution range of Slovenia, areas of altitudinal segregation have been observed. Ecophysiological traits such as preferred body temperatures (T p ) and rates of evaporative water loss (EWL) are some of the factors likely to be subjacent to this pattern. We expect the species that is more abundant in higher altitudes to have lower T p and higher EWL (due to lower environmental temperatures at higher elevations) than the species that is more abundant in lowlands. We conducted lab experiments to determine whether intra- and interspecific variation in these two physiological traits exists. Contrary to expectations, the means of T p were similar between the species, but their seasonal dynamics differed, which indicates that thermal accuracy might be more important. Species differed in seasonal (and daily) variation of T p , rising from spring to summer more in P. muralis than in I. horvathi. Comparing instantaneous EWL, our results showed interspecific differences with higher values in P. muralis than in I. horvathi. Throughout a 12-h period, the accumulative EWL was also always higher for P. muralis than for I. horvathi, with the greatest differences occurring after 9–12 h of the experiment. Further studies should focus on investigating if these divergent physiological characteristics of both species are associated with their habitat use (in terms of thermal and water environment) and species interaction.Funding for research was provided by a PTDC/BIA–BEC/101256/2008 project award from Fundação para a Ciência e a Tecnologia (FCT, Portugal). EG-M was supported by a postdoctoral grant from FCT (SFRH/BPD/72806/2010), and AZ was supported by Ph.D. grant from FCT (SFRH/BD/81324/ 2011). We thank L. Kastelic, M. Kavšček, B. Rakar, T. Delié, T. Romih, P. Raspor, D. Osojnik, and A. Kastelic, who helped during sampling, and Z. Žagar for constructing the terraria for photogradient experiments. Lizards were collected under two special licenses 35601–32/2010– 6 and 35601–47/2011–6 issued by the Slovenian Environment Agency. We thank J. Harris for the English language review.publishe