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Efficacy of Physical Exercise to Offset Anthracycline‐Induced Cardiotoxicity: A Systematic Review and Meta‐Analysis of Clinical and Preclinical Studies

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.

Sustained changes in body composition during 6 months follow-up after combined lifestyle intervention in older adults with obesity and type 2 diabetes

Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.

Physiotherapists Using the Biopsychosocial Model for Chronic Pain: Barriers and Facilitators - A scoping review

The use of the biopsychosocial model in primary care physiotherapy for chronic pain is far from the recommendations given in research and current guidelines. To understand why physiotherapists have difficulty implementing a biopsychosocial approach, more insight is needed on the barriers and facilitators. This scoping review aimed to investigate and map these barriers and facilitators that physiotherapists working in primary care reportedly face when treating patients with chronic musculoskeletal pain from a biopsychosocial perspective. Four electronic databases (PubMed, Embase, CINAHL and ERIC) and the grey literature were searched. Studies were included if they investigated the experiences of physiotherapists in the treatment of chronic pain from a biopsychosocial perspective in primary care. Extracted data were discussed and sub grouped in themes following a qualitative content analysis approach. To align with current use of theories on behavior change, the resulting themes were compared to the Theoretical Domains Framework. After screening, twenty-four studies were included. Eight groups of barriers and facilitators were identified, thematically clustered in six themes: knowledge, skills, and attitudes; environmental context and resources; role clarity; confidence; therapeutic alliance; and patient expectations. The results of this review can be used to inform the development of implementation programs.

Effects of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity

Objective Animal data suggest that exercise during chemotherapy is cardioprotective, but clinical evidence to support this is limited. This study evaluated the effect of exercise during chemotherapy for breast cancer on long-term cardiovascular toxicity. Methods This is a follow-up study of two previously performed randomised trials in patients with breast cancer allocated to exercise during chemotherapy or non-exercise controls. Cardiac imaging parameters, including T1 mapping (native T1, extracellular volume fraction (ECV)), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), cardiorespiratory fitness, and physical activity levels, were acquired 8.5 years post-treatment. Results In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years), of whom 99% and 18% were treated with anthracyclines and trastuzumab, respectively. ECV and Native T1 were 25.3%±2.5% and 1026±51 ms in the control group, and 24.6%±2.8% and 1007±44 ms in the exercise group, respectively. LVEF was borderline normal in both groups, with an LVEF<50% prevalence of 22.5% (n=40/178) in all participants. Compared with control, native T1 was statistically significantly lower in the exercise group (β=-20.16, 95% CI -35.35 to -4.97). We found no effect of exercise on ECV (β=-0.69, 95% CI -1.62 to 0.25), LVEF (β=-1.36, 95% CI -3.45 to 0.73) or GLS (β=0.31, 95% CI -0.76 to 1.37). Higher self-reported physical activity levels during chemotherapy were significantly associated with better native T1 and ECV. Conclusions In long-term breast cancer survivors, exercise and being more physically active during chemotherapy were associated with better structural but not functional cardiac parameters. The high prevalence of cardiac dysfunction calls for additional research on cardioprotective measures, including alternative exercise regimens. Trial registration number NTR7247.

Prediction of carcinogenic potential of chemicals using repeated-dose (13-week) toxicity data

From the article: Abstract Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study.