Alarm Management in Provisional COVID-19 Intensive Care Units: Retrospective Analysis and Recommendations for Future Pandemics.

Background: In response to the high patient admission rates during the COVID-19 pandemic, provisional intensive care units (ICUs) were set up, equipped with temporary monitoring and alarm systems. We sought to find out whether the provisional ICU setting led to a higher alarm burden and more staff with alarm fatigue.

Objective: We aimed to compare alarm situations between provisional COVID-19 ICUs and non-COVID-19 ICUs during the second COVID-19 wave in Berlin, Germany.

InterAgent on FHIR - Lessons Learned from Implementing an Intelligent Tutoring System with the Help of HL7 FHIR.

Introduction: For an interoperable Intelligent Tutoring System (ITS), we used resources from Fast Healthcare Interoperability Resources (FHIR) and mapped learning content with Unified Medical Language System (UMLS) codes to enhance healthcare education. This study addresses the need to enhance the interoperability and effectiveness of ITS in healthcare education.

State Of The Art: The current state of the art in ITS involves advanced personalized learning and adaptability techniques, integrating technologies such as machine learning to personalize the learning experience and to create systems that dynamically respond to individual learner needs.

Factors Influencing the Strategic Governance of EHR Interoperability: A Rapid Literature Review.

While the importance of Electronic Health Records (EHR) interoperability is widely recognised in the healthcare digitalisation context, its optimal governance structure remains controversial, requiring further research. Through the rapid literature review of 32 articles retrieved from PubMed and EBSCO, 47 distinct factors under ten categories were established. The three most cited factors in the reviewed 32 articles were "Robust inter-institutional connections, trust, and the technologies to ensure security", "Legal adaptations to the evolving digitalisation needs", and "Standardisation of terminologies and codes, and harmonised data structure".

Integrating FHIR and UMLS in an Intelligent Tutoring System.

Our novel Intelligent Tutoring System (ITS) architecture integrates HL7 Fast Healthcare Interoperability Resources (FHIR) for data exchange and Unified Medical Language System (UMLS) codes for content mapping.

Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.

Background And Objective: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (Evrysdi) increases SMN protein and is approved for the treatment of SMA. Risdiplam has high oral bioavailability and is primarily eliminated through hepatic metabolism by flavin-containing monooxygenase3 (FMO3) and cytochrome P450 (CYP) 3A, by 75% and 20%, respectively.

Artificial Intelligence Competencies in Postgraduate Medical Training in Germany.

Routine medical care is to be transformed by the introduction of artificial intelligence (AI), requiring medical professionals to acquire a novel set of skills. We assessed the density of AI learning objectives and the availability of courses containing AI content in postgraduate medical education in Germany. The results reveal general paucity in AI learning objectives and content across (sub-)specialty training and continuing medical education (CME) in Germany.

Disease Modeling and Model-Based Meta-Analyses to Define a New Direction for a Phase III Program of Gantenerumab in Alzheimer's Disease.

Selecting the right dose is a significant challenge in designing clinical development programs, especially for slowly progressing diseases lacking predictive biomarkers of efficacy that may require long-term treatment to assess clinical benefit. Gantenerumab, a fully human monoclonal antibody (mAb) that binds to aggregated amyloid-beta, was tested in two 24-month phase III studies (NCT01224106, NCT02051608) in participants with prodromal and mild Alzheimer's disease (AD), respectively. Dosing in the first phase III study was suspended after a preplanned interim futility analysis in 2014.

Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer.

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate.

Population pharmacokinetic analysis of entrectinib in pediatric and adult patients with advanced/metastatic solid tumors: support of new drug application submission.

Purpose: Entrectinib (ROZLYTREK) is a CNS-active, potent, and selective inhibitor of ROS1, TRK A/B/C, and ALK kinase activity. It was recently approved for the treatment of ROS1-positive non-small cell lung cancer and NTRK gene fusion-positive solid tumors. The main objective of this analysis was to characterize the pharmacokinetics (PK) of entrectinib and its main active metabolite, M5.

Physiologically-Based Pharmacokinetic Modelling of Entrectinib Parent and Active Metabolite to Support Regulatory Decision-Making.

Background And Objective: Entrectinib is a selective inhibitor of ROS1/TRK/ALK kinases, recently approved for oncology indications. Entrectinib is predominantly cleared by cytochrome P450 (CYP) 3A4, and modulation of CYP3A enzyme activity profoundly alters the pharmacokinetics of both entrectinib and its active metabolite M5. We describe development of a combined physiologically based pharmacokinetic (PBPK) model for entrectinib and M5 to support dosing recommendations when entrectinib is co-administered with CYP3A4 inhibitors or inducers.

A Baseline Score to Predict Response to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration.

Purpose: What are the patient characteristics predictive of response to ranibizumab treatment?

Methods: Model-based characterization of best-corrected visual acuity (BCVA) time profiles of patients with neovascular age-related macular degeneration under ranibizumab or sham treatment based on 24-month observations of BCVA in 2419 patients from randomized multicenter phase 3 trials of ranibizumab: ANCHOR, MARINA, PIER, and HARBOR. Goodness-of-fit plots and precision of parameter estimates were used for measure of accuracy.

Results: The model incorporates a long-term effect on disease progression and an additive and more potent short-term effect of ranibizumab.

Population pharmacokinetic and exposure-response analyses of intravenous and subcutaneous rituximab in patients with chronic lymphocytic leukemia.

A subcutaneous formulation of the anti-CD20 antibody rituximab has been developed. Fixed-dose subcutaneous rituximab delivers noninferior serum trough concentrations (C ), ensuring similar target saturation and comparable efficacy/safety, to intravenous rituximab, but with simplified and shortened preparation and administration. We aimed to characterize the pharmacokinetic (PK) and exposure-response properties of subcutaneous rituximab.

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B-Cell Hematological Malignancies.

A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.

Exposure-Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII.

Background And Objective: Emicizumab is a monoclonal antibody that bridges activated coagulation factor IX and factor X to restore effective hemostasis in persons with hemophilia A. It is indicated for routine prophylaxis of bleeding episodes in persons with hemophilia A. The aim of the present study is to describe the exposure-response relationship between emicizumab concentrations and bleeding frequency, and to confirm adequate bleeding control of the investigated dosing regimens 1.

cLRT-Mod: An efficient methodology for pharmacometric model-based analysis of longitudinal phase II dose finding studies under model uncertainty.

Within the challenging context of phase II dose-finding trials, longitudinal analyses may increase drug effect detection power compared to an end-of-treatment analysis. This work proposes cLRT-Mod, a pharmacometric adaptation of the MCP-Mod methodology, which allows the use of nonlinear mixed effect models to first detect a dose-response signal and then identify the doses for the confirmatory phase while accounting for model structure uncertainty. The method was evaluated through extensive clinical trial simulations of a hypothetical phase II dose-finding trial using different scenarios and comparing different methods such as MCP-Mod.

Population Pharmacokinetic Analysis and Exploratory Exposure-Bleeding Rate Relationship of Emicizumab in Adult and Pediatric Persons with Hemophilia A.

Background: Emicizumab is a bispecific monoclonal antibody developed for routine prophylaxis of bleeding in people with hemophilia A (PwHA). This work characterizes the pharmacokinetics of emicizumab in adult and pediatric PwHA, identifies factors contributing to its between-person variabilities, compares the pharmacokinetics following different dosing regimens, and makes a descriptive assessment of the exposure-bleeding events relationship.

Methods: A population pharmacokinetic model was developed, using a database of 389 PwHA from five clinical studies.

Model-based approach for methoxy polyethylene glycol-epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease.

Aims: Methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator, C.E.R.

Laccaria bicolor MiSSP8 is a small-secreted protein decisive for the establishment of the ectomycorrhizal symbiosis.

The ectomycorrhizal symbiosis is a predominant tree-microbe interaction in forest ecosystems sustaining tree growth and health. Its establishment and functioning implies a long-term and intimate relationship between the soil-borne fungi and the roots of trees. Mycorrhiza-induced Small-Secreted Proteins (MiSSPs) are hypothesized as keystone symbiotic proteins, required to set up the symbiosis by modifying the host metabolism and/or building the symbiotic interfaces.

Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab-refractory follicular lymphoma patients in the GADOLIN phase III study.

Aims: Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.

From waterfall plots to spaghetti plots in early oncology clinical development.

Waterfall plots are used to describe changes in tumor size observed in clinical studies. They are frequently used to illustrate the overall drug response in oncology clinical trials because of its simple representation of results. Unfortunately, this visual display suffers a number of limitations including (1) potential misguidance by masking the time dynamics of tumor size, (2) ambiguous labelling of the y-axis, and (3) low data-to-ink ratio.

Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy.

Aims: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (C ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.

Methods: Individual exposures (C ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data.