BackgroundPhysical exercise is an intervention that might protect against doxorubicin‐induced cardiotoxicity. In this meta‐analysis and systematic review, we aimed to estimate the effect of exercise on doxorubicin‐induced cardiotoxicity and to evaluate mechanisms underlying exercise‐mediated cardioprotection using (pre)clinical evidence.Methods and ResultsWe conducted a systematic search in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Cochrane's and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk‐of‐bias tools were used to assess the validity of human and animal studies, respectively. Cardiotoxicity outcomes reported by ≥3 studies were pooled and structured around the type of exercise intervention. Forty articles were included, of which 3 were clinical studies. Overall, in humans (sample sizes ranging from 24 to 61), results were indicative of exercise‐mediated cardioprotection, yet they were not sufficient to establish whether physical exercise protects against doxorubicin‐induced cardiotoxicity. In animal studies (n=37), a pooled analysis demonstrated that forced exercise interventions significantly mitigated in vivo and ex vivo doxorubicin‐induced cardiotoxicity compared with nonexercised controls. Similar yet slightly smaller effects were found for voluntary exercise interventions. We identified oxidative stress and related pathways, and less doxorubicin accumulation as mechanisms underlying exercise‐induced cardioprotection, of which the latter could act as an overarching mechanism.ConclusionsAnimal studies indicate that various exercise interventions can protect against doxorubicin‐induced cardiotoxicity in rodents. Less doxorubicin accumulation in cardiac tissue could be a key underlying mechanism. Given the preclinical evidence and limited availability of clinical data, larger and methodologically rigorous clinical studies are needed to clarify the role of physical exercise in preventing cardiotoxicity in patients with cancer.RegistrationURL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42019118218.
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Background:In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19.Objective:Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19.Methods:This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand.Results:As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024.Conclusions:This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment.Trial Registration:ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359International Registered Report Identifier (IRRID):DERR1-10.2196/48183
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Study goal: This study was carried out to answer the following research question: which motivation do healthy volunteers have to participate in phase I clinical trials? - Methods: A literature search was done through Google Scholar and Academic Search Premier, followed by three interviews with volunteers who had recently concluded their participation in a (non-commercial) phase I trial. - Results: Our literature search revealed mainly commercial motives for volunteers to participate in phase I clinical trials. The interviews (with volunteers in a non-commercial trial) showed that other factors may also play a decisive role, such as: (1) wish to support the investigator (2) wish to contribute to science, (3) access to more/better health care (4) sociability: possibility to relax and to communicate with other participants (5) general curiosity. Precondition is that risks and burden are deemed acceptable. - Conclusions: financial remuneration appears to be the predominant motive to participate voluntarily in a clinical trial. Other reasons were also mentioned however, such as general curiosity, the drive to contribute to science and the willingness to help the investigator. In addition, social reasons were given such as possibility to relax and to meet other people. Potential subjects state that they adequately assess the (safety) risks of participating in a trial as part of their decision process.
