Project description:Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events are unclear. This has resulted in ineffective development of sepsis-specific biomarkers and therapies, and suboptimal treatment regimens in preventing and reversing organ damage. Here, we used pharmacoproteomics to score treatment effects in a preclinical Escherichia coli sepsis model based on changes in the organ, cell, and plasma proteome landscapes. A combination of pathophysiological read-outs and time-resolved proteome maps of organs and blood enabled the definition of time-dependent and organotypic proteotypes of dysfunction and damage that was used to guide the administration of several combinations of beta-lactam antibiotic meropenem and immunomodulatory glucocorticoid methylprednisolone. The proteome-based scoring strategy revealed three distinct response patterns defined as intervention-specific reversions, non-reversions, and specific intervention-induced effects, revealing that the intervention effects depended on the underlying proteotype and varied significantly between organs. In the later stages of the disease, administration of glucocorticoids accentuated some of the positive effects exerted by Mem leading to superior reduction of the inflammatory response in the kidneys and partial restoration of the metabolic dysfunction instigated by sepsis. Unexpectedly, antibiotics introduced sepsis-independent perturbations in the mitochondrial proteome that was to some degree counteracted by glucocorticoids. In summary, this study provides a pharmacoproteomic resource describing the time-resolved septic organ failure landscape across organs and the blood compartment, and a novel scoring strategy that captures unintended secondary drug effects as an important criterion to consider while assessing therapeutic efficacy. Such information is critically important to enable a quantitative, objective and organotypic assessment of treatment benefits and unintended effects, drug synergies of candidate treatments as well as the effect of dose and time in murine sepsis models.

Project description:BACKGROUND:Transfer from pediatric to adult care is a crucial period for adolescents with inflammatory bowel disease (IBD). OBJECTIVE:Our aim was to develop a personalized transition-transfer concept including relevant tools in an established eHealth (electronic health) program. METHODS:Required transition skills and validated patient-reported outcome measures (PROMs) were identified via bibliographic search and clinical experience and were implemented into an existing eHealth program. RESULTS:The following skills were identified: disease knowledge, social life, disease management, and making well-informed, health-related decisions. The PROMs included the following: self-efficacy (the IBD Self-Efficacy Scale-Adolescents), resilience (the 10-item Connor-Davidson Resilience Scale), response to stress (the Child Self-Report Responses to Stress-IBD), and self-management and health care transition skills (the Self-Management and Transition to Adulthood with Treatment questionnaire). Starting at age 14, the patient will be offered a 1-hour annual transition consultation with an IBD-specialized nurse. The consultation will be based on the results of the PROMs and will focus on the patient's difficulties. Patients will complete the PROMs on the eHealth program at home, allowing nurses and patients to prepare for the meeting. Symptom scores and medication will be filled out on the eHealth program to support disease self-management. The consultation will be a topic-centered dialogue with practical exercises. During routine outpatient visits with the provider, parents will be left out of half of the consultation when the patient is 16 years old; at 17 years old, the parents will not be present. At the transfer consultation, the pediatric provider, the adult gastroenterologist, the pediatric nurse, the patient, and the parents will be present to ensure a proper transfer. CONCLUSIONS:We have conducted a personalized eHealth transition concept consisting of basic elements that measure, train, and monitor the patients' transition readiness. The concept can be implemented and adjusted to local conditions.

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Staging and Personalized Intervention for Infection and Sepsis.

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