Gene networks and liar paradoxes

Network motifs are small patterns of connections, found over-represented in gene regulatory networks. An example is the negative feedback loop (e.g. factor A represses itself). This opposes its own state so that when ‘on’ it tends towards ‘off’ – and vice versa. Here, we argue that such self-opposition, if considered dimensionlessly, is analogous to the liar paradox: ‘This statement is false’. When ‘true’ it implies ‘false’ – and vice versa. Such logical constructs have provided philosophical consternation for over 2000 years. Extending the analogy, other network topologies give strikingly varying outputs over different dimensions. For example, the motif ‘A activates B and A. B inhibits A’ can give switches or oscillators with time only, or can lead to Turing-type patterns with both space and time (spots, stripes or waves). It is argued here that the dimensionless form reduces to a variant of ‘The following statement is true. The preceding statement is false’. Thus, merely having a static topological description of a gene network can lead to a liar paradox. Network diagrams are only snapshots of dynamic biological processes and apparent paradoxes can reveal important biological mechanisms that are far from paradoxical when considered explicitly in time and space

Physiological parameters for Prognosis in Abdominal Sepsis (PIPAS) Study : a WSES observational study

BackgroundTiming and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted.MethodsThis worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018.ResultsA total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47years (interquartile range [IQR] 28-66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6days (IQR 4-10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate >= 22 breaths/min, systolic blood pressure 4mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0-1, 22.7% for those who had scores of 2-3, 46.8% for those who had scores of 4-5, and 86.7% for those who have scores of 7-8.ConclusionsThe simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.Peer reviewe

Remote Auscultation of Heart and Lungs as an Acceptable Alternative to Legacy Measures in Quarantined COVID-19 Patients—Prospective Evaluation of 250 Examinations

The COVID-19 pandemic accelerated the assimilation of telemedicine platforms into medical practice. Nevertheless, research-based evidence in this field is still accumulating. This was a prospective, cross-sectional comparative assessment of a remote physical examination device used mainly for heart and lung digital auscultation. We analyzed usage patterns, user (physician) subjective appreciation and compared it to legacy measures. Eighteen physicians (median age 36 years (IQR 32–45): two interns, seven residents and nine senior physicians; eleven internists, five geriatricians and two pediatricians) executed over 250 remote physical examinations. Their median work duration with quarantined patients was 60 days (IQR 45–60). The median number of patients examined by a single physician was 17 (IQR 10–34). Regarding overall estimation, all participants tended to prefer the remote examination in the setting of quarantined patients (median 6, IQR 3.75–8), while no statistically significant difference was demonstrated compared to the indifference value (p = 0.122). Internists preferred tele-medical examination over non-internists, with significant differences between groups regarding heart auscultation, (median 7, (IQR 3–7) vs. median 2, (IQR 1–5, respectively)), p = 0.044. In the setting of quarantined patients, from the physicians’ perspective, a digital platform for remote auscultation of heart and lungs was considered as an acceptable alternative to legacy measures

Harmonic Oscillations in Homeostatic Controllers: Dynamics of the p53 Regulatory System

Homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Previously, we have described molecular mechanisms that lead to robust homeostasis/adaptation under inflow or outflow perturbations. Here we report that harmonic oscillations occur in models of such homeostatic controllers and that a close relationship exists between the control of the p53/Mdm2 system and that of a homeostatic inflow controller. This homeostatic control model of the p53 system provides an explanation why large fluctuations in the amplitude of p53/Mdm2 oscillations may arise as part of the homeostatic regulation of p53 by Mdm2 under DNA-damaging conditions. In the presence of DNA damage p53 is upregulated, but is subject to a tight control by Mdm2 and other factors to avoid a premature apoptotic response of the cell at low DNA damage levels. One of the regulatory steps is the Mdm2-mediated degradation of p53 by the proteasome. Oscillations in the p53/Mdm2 system are considered to be part of a mechanism by which a cell decides between cell cycle arrest/DNA repair and apoptosis. In the homeostatic inflow control model, harmonic oscillations in p53/Mdm2 levels arise when the binding strength of p53 to degradation complexes increases. Due to the harmonic character of the oscillations rapid fluctuating noise can lead, as experimentally observed, to large variations in the amplitude of the oscillation but not in their period, a behavior which has been difficult to simulate by deterministic limit-cycle models. In conclusion, the oscillatory response of homeostatic controllers may provide new insights into the origin and role of oscillations observed in homeostatically controlled molecular networks