A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research.

Background/Objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods: We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), differential expression with moderated t-test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results: Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene (p < 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions: Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression.

Early detection of new pandemic waves. Control chart and a new surveillance index.

The COVID-19 pandemic highlights the pressing need for constant surveillance, updating of the response plan in post-peak periods and readiness for the possibility of new waves of the pandemic. A short initial period of steady rise in the number of new cases is sometimes followed by one of exponential growth. Systematic public health surveillance of the pandemic should signal an alert in the event of change in epidemic activity within the community to inform public health policy makers of the need to control a potential outbreak. The goal of this study is to improve infectious disease surveillance by complementing standardized metrics with a new surveillance metric to overcome some of their difficulties in capturing the changing dynamics of the pandemic. At statistically-founded threshold values, the new measure will trigger alert signals giving early warning of the onset of a new pandemic wave. We define a new index, the weighted cumulative incidence index, based on the daily new-case count. We model the infection spread rate at two levels, inside and outside homes, which explains the overdispersion observed in the data. The seasonal component of real data, due to the public surveillance system, is incorporated into the statistical analysis. Probabilistic analysis enables the construction of a Control Chart for monitoring index variability and setting automatic alert thresholds for new pandemic waves. Both the new index and the control chart have been implemented with the aid of a computational tool developed in R, and used daily by the Navarre Government (Spain) for virus propagation surveillance during post-peak periods. Automated monitoring generates daily reports showing the areas whose control charts issue an alert. The new index reacts sooner to data trend changes preluding new pandemic waves, than the standard surveillance index based on the 14-day notification rate of reported COVID-19 cases per 100,000 population.

Optimal control of ICU patient discharge: from theory to implementation.

This paper deals with the management of scarce health care resources. We consider a control problem in which the objective is to minimize the rate of patient rejection due to service saturation. The scope of decisions is limited, in terms both of the amount of resources to be used, which are supposed to be fixed, and of the patient arrival pattern, which is assumed to be uncontrollable. This means that the only potential areas of control are speed or completeness of service. By means of queuing theory and optimization techniques, we provide a theoretical solution expressed in terms of service rates. In order to make this theoretical analysis useful for the effective control of the healthcare system, however, further steps in the analysis of the solution are required: physicians need flexible and medically-meaningful operative rules for shortening patient length of service to the degree needed to give the service rates dictated by the theoretical analysis. The main contribution of this paper is to discuss how the theoretical solutions can be transformed into effective management rules to guide doctors' decisions. The study examines three types of rules based on intuitive interpretations of the theoretical solution. Rules are evaluated through implementation in a simulation model. We compare the service rates provided by the different policies with those dictated by the theoretical solution. Probabilistic analysis is also included to support rule validity. An Intensive Care Unit is used to illustrate this control problem. The study focuses on the Markovian case before moving on to consider more realistic LoS distributions (Weibull, Lognormal and Phase-type distribution).