Remdesivir and dexamethasone as tools to relieve hospital care systems stressed by COVID-19: A modelling study on bed resources and budget impact.
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ABSTRACT:
SUBMITTER: Beraud G
PROVIDER: S-EPMC8754316 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThe objective of this study was to assess the impact of treatment with dexamethasone, remdesivir or both on neurological complications in acute coronavirus diease 2019 (COVID-19).MethodsWe used observational data from the International Severe Acute and emerging Respiratory Infection Consortium World Health Organization (WHO) Clinical Characterization Protocol, United Kingdom. Hospital inpatients aged ≥18 years with laboratory-confirmed severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection admitted between January 31, 2020, and June 29, 2021, were included. Treatment allocation was non-blinded and performed by reporting clinicians. A propensity scoring methodology was used to minimize confounding. Treatment with remdesivir, dexamethasone, or both was assessed against the standard of care. The primary outcome was a neurological complication occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode.ResultsOut of 89,297 hospital inpatients, 64,088 had severe COVID-19 and 25,209 had non-hypoxic COVID-19. Neurological complications developed in 4.8% and 4.5%, respectively. In both groups, neurological complications were associated with increased mortality, intensive care unit (ICU) admission, worse self-care on discharge, and time to recovery. In patients with severe COVID-19, treatment with dexamethasone (n = 21,129), remdesivir (n = 1,428), and both combined (n = 10,846) were associated with a lower frequency of neurological complications: OR = 0.76 (95% confidence interval [CI] = 0.69-0.83), OR = 0.69 (95% CI = 0.51-0.90), and OR = 0.54 (95% CI = 0.47-0.61), respectively. In patients with non-hypoxic COVID-19, dexamethasone (n = 2,580) was associated with less neurological complications (OR = 0.78, 95% CI = 0.62-0.97), whereas the dexamethasone/remdesivir combination (n = 460) showed a similar trend (OR = 0.63, 95% CI = 0.31-1.15).InterpretationTreatment with dexamethasone, remdesivir, or both in patients hospitalized with COVID-19 was associated with a lower frequency of neurological complications in an additive manner, such that the greatest benefit was observed in patients who received both drugs together. ANN NEUROL 2023;93:88-102.
| S-EPMC9874556 | biostudies-literature
Project description:BackgroundOveruse of proton pump inhibitors (PPIs) - frequently used for relieving symptoms of gastroesophageal reflux disease (GORD) - raises long-term safety concerns, warranting evidence-based non-drug interventions. We conducted a systematic review to evaluate the effect of head-of-bed elevation on relieving symptoms of GORD in adults.MethodsWe included controlled trials comparing the effect of head-of-bed elevation interventions to control in adults with GORD. Two independent reviewers screened articles, extracted data, and assessed quality of included studies. Primary outcomes were changes in GORD symptoms and use of PPIs.ResultsWe screened 1206 records; and included five trials (four cross-over and one factorial) comprising 228 patients. All five included trials were judged to be at high-risk of performance bias and four of selection bias. Of five included trials, two used 'bed blocks' under the bed legs; one used 'sleeping on a wedge' pillow, and two used both. High heterogeneity in outcome measures and reported outcomes data precluded meta-analyses. The four studies that reported on GORD symptoms found an improvement among participants in the head-of-bed elevation; a high-quality crossover trial showed a clinical important reduction in symptom scores at 6 weeks (risk ratio of 2.1; 95% CI 1.2 to 3.6). These results are supported by the observed improvement in physiological intra-oesophageal pH measurements.ConclusionsMethodological and reporting limitations in available literature preclude definitive recommendations. However, head-of-bed elevation could be still considered as a cheap and safe alternative to drug interventions with unfavourable safety profiles.Protocol registrationOpen Science Framework: http://osf.io/2hz3j.
| S-EPMC7816499 | biostudies-literature
Project description:Remdesivir (REM) is the first antiviral drug (Veklury™) approved by the Food and Drug Administration for the therapy of COVID-19. Due to its poor water solubility, the preparation of Veklury™ requires a suitable solubilizing excipient at pH 2 conditions. For this purpose, the final formulation contains the randomly substituted sulfobutylether-β-cyclodextrin (SBEβCD) as a complexing agent. Herein, extensive NMR spectroscopic study with various cyclodextrin (CD) derivatives were conducted to understand the interactions in SBEβCD - REM systems at the molecular level. The pKa value of REM has been determined experimentally for the first time, as the protonation state of the aminopyrrolo-triazine moiety can play a key role in CD-REM inclusion complex formation as SBEβCD has permanent negative charges. The UV-pH titration experiments yielded a pKa of 3.56, thus the majority of REM bears a positive charge at pH 2.0. NMR experiments were performed on β- and γCD derivatives to determine complex stabilities, stoichiometries and structures. The stability constants were determined by nonlinear curve fitting based on 1H NMR titrations at pH 2.0, while Job's method was used to determine the stoichiometries. βCD complexes were one order of magnitude more stable than their γCD counterparts. Sulfobutylation resulted in a significant increase in stability and the single isomer derivatives showed unexpectedly high stability values (logK = 4.35 for REM - per-6-SBEβCD). In the case of βCDs, the ethylbutyl-moiety plays a key role in complexation immersing into the βCD cavity, while the phenoxy-moiety overtakes and drives the inclusion of REM in the case of γCDs. This is the first comprehensive study of REM-CD complexation, allowing the design of new CD derivatives with tailored stabilities, thereby aiding the formulation or production and even the analytical characterization of REM.
| S-EPMC8609759 | biostudies-literature
Project description:BackgroundInequities of health outcomes persist in rural populations globally. This is strongly associated with there being less health coverage in rural and underserviced areas. Increasing health care coverage in rural area requires rural health system strengthening, which subsequently necessitates having tools to guide action.ObjectiveThis mapping review aimed to describe the range of tools, frameworks and resources (hereafter called tools) available globally for rural health system capacity building.MethodsThis study collected peer-reviewed materials published in 15-year period (2005-2020). A systematic mapping review process identified 149 articles for inclusion, related to 144 tools that had been developed, implemented, and/or evaluated (some tools reported over multiple articles) which were mapped against the World Health Organization's (WHO's) six health system building blocks (agreed as the elements that need to be addressed to strengthen health systems).ResultsThe majority of tools were from high- and middle-income countries (n = 85, 59% and n = 43, 29%, respectively), and only 17 tools (12%) from low-income countries. Most tools related to the health service building block (n = 57, 39%), or workforce (n = 33, 23%). There were a few tools related to information and leadership and governance (n = 8, 5% each). Very few tools related to infrastructure (n = 3, 2%) and financing (n = 4, 3%). This mapping review also provided broad quality appraisal, showing that the majority of the tools had been evaluated or validated, or both (n = 106, 74%).ConclusionThis mapping review provides evidence that there is a breadth of tools available for health system strengthening globally along with some gaps where no tools were identified for specific health system building blocks. Furthermore, most tools were developed and applied in HIC/MIC and it is important to consider factors that influence their utility in LMIC settings. It may be important to develop new tools related to infrastructure and financing. Tools that have been positively evaluated should be made available to all rural communities, to ensure comprehensive global action on rural health system strengthening.
| S-EPMC10694960 | biostudies-literature
Project description:ObjectivesInternationally, healthcare systems are confronted by an ever-increasing scarcity of medical resources due to the ongoing novel coronavirus disease 2019 (COVID-19) pandemic. The aim of this study was to investigate the impact of remdesivir on the demand of hospital bed capacities for hospitalized COVID-19 patients and to evaluate the potentially created capacities for treating additional COVID-19 patients or elective treatments at the hospital.MethodsAn epidemiological model was developed that utilized the population of Cologne (Germany) during the first COVID-19 wave (first hospitalized patient-30 September 2020) to compare two scenarios: no administration of remdesivir (A) and the administration of remdesivir according to the EMA label (B). The results of the Adaptive COVID-19 Treatment Trial were used to evaluate the potential impact of remdesivir on hospital capacity.ResultsWith the first recorded patient on 2 March 2020, a total of 576 COVID-19 hospitalized patients were detected during the first wave in Cologne. Comparing both scenarios (A versus B) of the model, the administration of remdesivir increased the number of discharges from 259 to 293 (+5.8%) and fewer patients needed ICU admission [214 versus 178 (-6.3%)]. In addition, the model estimated 20 fewer deaths (scenario B). Based on a reduced length of stay, 31.4 hospital beds (57.0 versus 25.6) could have been freed by administering remdesivir to eligible patients. This would have allowed either the treatment of an additional 730 COVID-19 patients or 660 elective treatments.ConclusionsIn our model, remdesivir administration profoundly contributed to free hospital capacities in the metropolitan city Cologne in Germany.
| S-EPMC8690174 | biostudies-literature
Project description:Lipid droplets (LDs) are intracellular storage organelles composed of neutral lipids, such as triacylglycerol (TG), surrounded by a phospholipid (PL) monolayer decorated with specific proteins. Herein, we investigate the mechanism of protein association during LD and bilayer membrane expansion. We find that the neutral lipids play a dynamic role in LD expansion by further intercalating with the PL monolayer to create more surface-oriented TG molecules (SURF-TG). This interplay both reduces high surface tension incurred during LD budding or growth and also creates expansion-specific surface features for protein recognition. We then show that the autoinhibitory (AI) helix of CTP:phosphocholine cytidylyltransferase, a protein known to target expanding monolayers and bilayers, preferentially associates with large packing defects in a sequence-specific manner. Despite the presence of three phenylalanines, the initial binding with bilayers is predominantly mediated by the sole tryptophan due to its preference for membrane interfaces. Subsequent association is dependent on the availability of large, neighboring defects that can accommodate the phenylalanines, which are more probable in the stressed systems. Tryptophan, once fully associated, preferentially interacts with the glycerol moiety of SURF-TG in LDs. The calculation of AI binding free energy, hydrogen bonding and depth analysis, and in silico mutation experiments support the findings. Hence, SURF-TG can both reduce surface tension and mediate protein association, facilitating class II protein recruitment during LD expansion.
| S-EPMC8796793 | biostudies-literature
Project description:BACKGROUND:Increasing the number of vaccine doses may potentially improve overall efficacy. Decision-makers need information about choosing the most efficient dose schedule to maximise the total health gain of a population when operating under a constrained budget. The objective of this study is to identify the most efficient vaccine dosing schedule within a fixed vaccination budget from a healthcare payer perspective. METHODS:An optimisation model is developed in which maximizing the disease reduction is the functional objective and the constraint is the vaccination budget. The model allows variation in vaccination dosing numbers, in cost difference per dose, in vaccine coverage rate, and in vaccine efficacy. We apply the model using the monovalent rotavirus vaccine as an example. RESULTS:With a fixed budget, a 2-dose schedule for vaccination against rotavirus infection with the monovalent vaccine results in a larger reduction in disease episodes than a 3-dose scheme with the same vaccine under most circumstances. A 3-dose schedule would only be better under certain conditions: a cost reduction of >26% per dose, combined with vaccine efficacy improvement of ?5% and a target coverage rate of 75%. Substantial interaction is observed between cost reduction per dose, vaccine coverage rate, and increased vaccine efficacy. Sensitivity analysis shows that the conditions required for a 3-dose strategy to be better than a 2-dose strategy may seldom occur when the budget is fixed. The model does not consider vaccine herd effect, precise timing for additional doses, or the effect of natural immunity development. CONCLUSIONS:Under budget constraint, optimisation modelling is a helpful tool for a decision-maker selecting the most efficient vaccination dosing schedule. The low dosing scheme could be the optimal option to consider under the many scenarios tested. The model can be applied under many different circumstances of changing dosing schemes with single or multiple vaccines.
| S-EPMC3904011 | biostudies-literature
Project description:Databases and computational tools for mimotopes have been an important part of phage display study. Five special databases and eighteen algorithms, programs and web servers and their applications are reviewed in this paper. Although these bioinformatics resources have been widely used to exclude target-unrelated peptides, characterize small molecules-protein interactions and map protein-protein interactions, a lot of problems are still waiting to be solved. With the improvement of these tools, they are expected to serve the phage display community better.
| S-EPMC6259106 | biostudies-literature
Project description:Pseudokinases regulate diverse cellular processes associated with normal cellular functions and disease. They are defined bioinformatically based on the absence of one or more catalytic residues that are required for canonical protein kinase functions. The ability to define pseudokinases based on primary sequence comparison has enabled the systematic mapping and cataloging of pseudokinase orthologs across the tree of life. While these sequences contain critical information regarding pseudokinase evolution and functional specialization, extracting this information and generating testable hypotheses based on integrative mining of sequence and structural data requires specialized computational tools and resources. In this chapter, we review recent advances in the development and application of open-source tools and resources for pseudokinase research. Specifically, we describe the application of an interactive data analytics framework, KinView, for visualizing the patterns of conservation and variation in the catalytic domain motifs of pseudokinases and evolutionarily related canonical kinases using a consistent set of curated alignments organized based on the widely used kinome evolutionary hierarchy. We also demonstrate the application of an integrated Protein Kinase Ontology (ProKinO) and an interactive viewer, ProtVista, for mapping and analyzing primary sequence motifs and annotations in the context of 3D structures and AlphaFold2 models. We provide examples and protocols for generating testable hypotheses on pseudokinase functions both for bench biologists and advanced users.
| S-EPMC9733567 | biostudies-literature
Project description:Data science and informatics tools are developing at a blistering rate, but their users often lack the educational background or resources to efficiently apply the methods to their research. Training resources and vignettes that accompany these tools often deprecate because their maintenance is not prioritized by funding, giving teams little time to devote to such endeavors. Our group has developed Open-source Tools for Training Resources (OTTR) to offer greater efficiency and flexibility for creating and maintaining these training resources. OTTR empowers creators to customize their work and allows for a simple workflow to publish using multiple platforms. OTTR allows content creators to publish training material to multiple massive online learner communities using familiar rendering mechanics. OTTR allows the incorporation of pedagogical practices like formative and summative assessments in the form of multiple choice questions and fill in the blank problems that are automatically graded. No local installation of any software is required to begin creating content with OTTR. Thus far, 15 training courses have been created with OTTR repository template. By using the OTTR system, the maintenance workload for updating these courses across platforms has been drastically reduced. For more information about OTTR and how to get started, go to ottrproject.org.
| S-EPMC10193921 | biostudies-literature