Prevalence and differences in the co-administration of drugs known to interact: an analysis of three distinct and large populations.

BACKGROUND: The co-administration of drugs known to interact greatly impacts morbidity, mortality, and health economics. This study aims to examine the drug-drug interaction (DDI) phenomenon with a large-scale longitudinal analysis of age and gender differences found in drug administration data from three distinct healthcare systems. METHODS: This study analyzes drug administrations from population-wide electronic health records in Blumenau (Brazil; 133 K individuals), Catalonia (Spain; 5.5 M individuals), and Indianapolis (USA; 264 K individuals). The stratified prevalences of DDI for multiple severity levels per patient gender and age at the time of administration are computed, and null models are used to estimate the expected impact of polypharmacy on DDI prevalence. Finally, to study actionable strategies to reduce DDI prevalence, alternative polypharmacy regimens using drugs with fewer known interactions are simulated. RESULTS: A large prevalence of co-administration of drugs known to interact is found in all populations, affecting 12.51%, 12.12%, and 10.06% of individuals in Blumenau, Indianapolis, and Catalonia, respectively. Despite very different healthcare systems and drug availability, the increasing prevalence of DDI as patients age is very similar across all three populations and is not explained solely by higher co-administration rates in the elderly. In general, the prevalence of DDI is significantly higher in women - with the exception of men over 50 years old in Indianapolis. Finally, we show that using proton pump inhibitor alternatives to omeprazole (the drug involved in more co-administrations in Catalonia and Blumenau), the proportion of patients that are administered known DDI can be reduced by up to 21% in both Blumenau and Catalonia and 2% in Indianapolis. CONCLUSIONS: DDI administration has a high incidence in society, regardless of geographic, population, and healthcare management differences. Although DDI prevalence increases with age, our analysis points to a complex phenomenon that is much more prevalent than expected, suggesting comorbidities as key drivers of the increase. Furthermore, the gender differences observed in most age groups across populations are concerning in regard to gender equity in healthcare. Finally, our study exemplifies how electronic health records' analysis can lead to actionable interventions that significantly reduce the administration of known DDI and its associated human and economic costs.

The ultrametric backbone is the union of all minimum spanning forests.

Minimum spanning trees and forests are powerful sparsification techniques that remove cycles from weighted graphs to minimize total edge weight while preserving node reachability, with applications in computer science, network science, and graph theory. Despite their utility and ubiquity, they have several limitations, including that they are only defined for undirected networks, they significantly alter dynamics on networks, and they do not generally preserve important network features such as shortest distances, shortest path distribution, and community structure. In contrast, distance backbones, which are subgraphs formed by all edges that obey a generalized triangle inequality, are well defined in directed and undirected graphs and preserve those and other important network features. The backbone of a graph is defined with respect to a specified path-length operator that aggregates weights along a path to define its length, thereby associating a cost to indirect connections. The backbone is the union of all shortest paths between each pair of nodes according to the specified operator. One such operator, the max function, computes the length of a path as the largest weight of the edges that compose it (a weakest link criterion). It is the only operator that yields an algebraic structure for computing shortest paths that is consistent with De Morgan's laws. Applying this operator yields the ultrametric backbone of a graph in that (semi-triangular) edges whose weights are larger than the length of an indirect path connecting the same nodes (i.e. those that break the generalized triangle inequality based on max as a path-length operator) are removed. We show that the ultrametric backbone is the union of minimum spanning forests in undirected graphs and provides a new generalization of minimum spanning trees to directed graphs that, unlike minimum equivalent graphs and minimum spanning arborescences, preserves all max - min shortest paths and De Morgan's law consistency.

Models of Cell Processes are Far from the Edge of Chaos.

Complex living systems are thought to exist at the "edge of chaos" separating the ordered dynamics of robust function from the disordered dynamics of rapid environmental adaptation. Here, a deeper inspection of 72 experimentally supported discrete dynamical models of cell processes reveals previously unobserved order on long time scales, suggesting greater rigidity in these systems than was previously conjectured. We find that propagation of internal perturbations is transient in most cases, and that even when large perturbation cascades persist, their phenotypic effects are often minimal. Moreover, we find evidence that stochasticity and desynchronization can lead to increased recovery from regulatory perturbation cascades. Our analysis relies on new measures that quantify the tendency of perturbations to spread through a discrete dynamical system. Computing these measures was not feasible using current methodology; thus, we developed a multipurpose CUDA-based simulation tool, which we have made available as the open-source Python library cubewalkers. Based on novel measures and simulations, our results suggest that-contrary to current theory-cell processes are ordered and far from the edge of chaos.

The distance backbone of complex networks.

Redundancy needs more precise characterization as it is a major factor in the evolution and robustness of networks of multivariate interactions. We investigate the complexity of such interactions by inferring a connection transitivity that includes all possible measures of path length for weighted graphs. The result, without breaking the graph into smaller components, is a distance backbone subgraph sufficient to compute all shortest paths. This is important for understanding the dynamics of spread and communication phenomena in real-world networks. The general methodology we formally derive yields a principled graph reduction technique and provides a finer characterization of the triangular geometry of all edges-those that contribute to shortest paths and those that do not but are involved in other network phenomena. We demonstrate that the distance backbone is very small in large networks across domains ranging from air traffic to the human brain connectome, revealing that network robustness to attacks and failures seems to stem from surprisingly vast amounts of redundancy.