Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: A randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine

Background: Skeletal metastases present a major challenge for clinicians, representing an advanced and typically incurable stage of cancer. Bone is also the most common location for metastatic breast carcinoma, with skeletal lesions identified in over 80% of patients with advanced breast cancer. Preclinical models have demonstrated the ability of mechanical stimulation to suppress tumour formation and promote skeletal preservation at bone sites with osteolytic lesions, generating modulatory interference of tumour-driven bone remodelling. Preclinical studies have also demonstrated anti-cancer effects through exercise by minimising tumour hypoxia, normalising tumour vasculature and increasing tumoural blood perfusion. This study proposes to explore the promising role of targeted exercise to suppress tumour growth while concomitantly delivering broader health benefits in patients with advanced breast cancer with osteolytic bone metastases. Methods: This single-blinded, two-armed, randomised and controlled pilot study aims to establish the safety, feasibility and efficacy of an individually tailored, modular multi-modal exercise programme incorporating spinal isometric training (targeted muscle contraction) in 40 women with advanced breast cancer and stable osteolytic spinal metastases. Participants will be randomly assigned to exercise or usual medical care. The intervention arm will receive a 3-month clinically supervised exercise programme, which if proven to be safe and efficacious will be offered to the control-arm patients following study completion. Primary endpoints (programme feasibility, safety, tolerance and adherence) and secondary endpoints (tumour morphology, serum tumour biomarkers, bone metabolism, inflammation, anthropometry, body composition, bone pain, physical function and patient-reported outcomes) will be measured at baseline and following the intervention. Discussion: Exercise medicine may positively alter tumour biology through numerous mechanical and nonmechanical mechanisms. This randomised controlled pilot trial will explore the preliminary effects of targeted exercise on tumour morphology and circulating metastatic tumour biomarkers using an osteolytic skeletal metastases model in patients with breast cancer. The study is principally aimed at establishing feasibility and safety. If proven to be safe and feasible, results from this study could have important implications for the delivery of this exercise programme to patients with advanced cancer and sclerotic skeletal metastases or with skeletal lesions present in haematological cancers (such as osteolytic lesions in multiple myeloma), for which future research is recommended. Trial registration: anzctr.org.au, ACTRN-12616001368426. Registered on 4 October 2016

Perceptions of diagnosis and management of patients with acute respiratory distress syndrome: a survey of United Kingdom intensive care physicians

BackgroundAcute respiratory distress syndrome (ARDS) is a potentially devastating refractory hypoxemic illness with multi-organ involvement. Although several randomised controlled trials into ventilator and fluid management strategies have provided level 1 evidence to guide supportive therapy, there are few, established guidelines on how to manage patients with ARDS. In addition, and despite their continued use, pharmacotherapies for ARDS disease modulation have no proven benefit in improving mortality. Little is known however about the variability in diagnostic and treatment practices across the United Kingdom (UK). The aim of this survey, therefore, was to assess the use of diagnostic criteria and treatment strategies for ARDS in critical care units across the UK.MethodsThe survey questionnaire was developed and internally piloted at University Hospital Southampton NHS Foundation Trust. Following ethical approval from University of Southampton Ethics and Research Committee, a link to an online survey engine (Survey Monkey) was then placed on the Intensive Care Society (UK) website. Fellows of The Intensive Care Society were subsequently personally approached via e-mail to encourage participation. The survey was conducted over a period of 3 months.ResultsThe survey received 191 responses from 125 critical care units, accounting for 11% of all registered intensive care physicians at The Intensive Care Society. The majority of the responses were from physicians managing general intensive care units (82%) and 34% of respondents preferred the American European Consensus Criteria for ARDS. There was a perceived decline in both incidence and mortality in ARDS. Primary ventilation strategies were based on ARDSnet protocols, though frequent deviations from ARDSnet positive end expiratory pressure (PEEP) recommendations (51%) were described. The majority of respondents set permissive blood gas targets (hypoxia (92%), hypercapnia (58%) and pH (90%)). The routine use of pharmacological agents is rare. Neuromuscular blockers and corticosteroids are considered occasionally and on a case-by-case basis. Routine (58%) or late (64%) tracheostomy was preferred to early tracheostomy insertion. Few centres offered routine follow-up or dedicated rehabilitation programmes following hospital discharge.ConclusionsThere is substantial variation in the diagnostic and management strategies employed for patients with ARDS across the UK. National and/or international guidelines may help to improve standardisation in the management of ARDS

Effects of exercise during radiotherapy on physical function and treatment-related side effects in men with prostate cancer: A systematic review and meta-analysis

Purpose Radiation therapy is a commonly used treatment for prostate cancer; however, the side effects may negatively affect quality of life and cause patients to be less physically active. Although exercise has been shown to mitigate radiation therapy–related fatigue in men with prostate cancer during radiation therapy, other adverse effects of treatment such as physical deconditioning, urinary symptoms, or sexual dysfunction have not been systematically reviewed in this patient population. Thus, the purpose of this review was to investigate the effect of exercise on physical function and treatment-related side effects in men with prostate cancer undergoing radiation therapy. Methods A systematic literature search was conducted in the PubMed, Embase, CINAHL Plus, SPORTDiscus, and Web of Science databases in December 2020. Included studies were randomized controlled trials examining the effects of aerobic and/or resistance exercise interventions on measures of physical function and treatment-related side effects in prostate cancer patients undergoing radiation therapy. Meta-analysis was performed on outcomes that were reported in 2 or more studies. Results Seven publications from 6 randomized controlled trials involving 391 prostate cancer patients were included. Patients had stage I to IV cancer with a Gleason score of ≤ 6 to 10. Exercise resulted in consistent significant benefits for physical function in terms of cardiovascular fitness (standardized mean difference [SMD], 0.83; 95% confidence interval [CI], 0.31-1.36; P \u3c .01) and muscle function (SMD, 1.30; 95% CI, 0.53-2.07; P \u3c .01). Furthermore, there was a significant positive effect of exercise on urinary toxicity (SMD, –0.71; 95% CI, –1.25 to –0.18; P \u3c .01), but not on intestinal (P = .21) or hormonal toxicity (P = .41), depression (P = .45), or sleep symptoms (P = .88). Conclusion Based on the current evidence, exercise in men with prostate cancer undergoing radiation therapy improves physical function and mitigates urinary toxicity. The effect of exercise on other treatment-related side effects are less clear and require further investigation

Effect of exercise adjunct to radiation and androgen deprivation therapy on patient-reported treatment toxicity in men with prostate cancer: A secondary analysis of 2 randomized controlled trials

Purpose: Physical inactivity, in addition to clinical factors, has been associated with higher levels of late pelvic symptoms in patients with prostate cancer (PCa) after radiation therapy. The aim of this study was to investigate the effect of a structured multicomponent exercise program comprised of aerobic and resistance training as well as impact loading on the prevalence and severity of symptoms commonly resulting from androgen deprivation therapy (ADT) and pelvic radiation therapy. Methods and Materials: We performed a secondary analysis of pooled data from 2 randomized controlled trials that investigated the role of exercise on treatment-related side effects in patients with PCa receiving ADT. Patients were included in the analysis if they had undergone radiation therapy during the intervention in addition to ADT. Patient-reported quality of life and functional and symptom scales were assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and PR25 before and after 6 months of exercise or usual care (UC). Results: One-hundred and fifteen patients with PCa receiving ADT, aged 47 to 84 years, who also underwent radiation therapy were included in the analysis (exercise, n = 72; UC, n = 43). There was a significant reduction in physical functioning (P = .019) and increased fatigue (P = .007) in the control group, with no change observed in the exercise group. Similarly, there was a trend toward reduced sexual activity in the control group (P = .064), with a mean adjusted change of -7.1 points. Furthermore, the prevalence of clinically important pain at 6 months was lower in the exercise group compared with UC (18.1 vs 37.2%, P = .022). No between-group differences were found for urinary (P = .473) or hormonal treatment-related symptoms (P = .552). Conclusions: Exercise during concomitant hormone and radiation treatment for men with PCa may mitigate some adverse changes in patient-reported fatigue, physical functioning, and possibly sexual activity. The promotion and provision of exercise to counter a range of treatment-related adverse effects in patients with PCa undergoing radiation therapy and ADT should be actively encouraged

Nationwide industry-led community exercise program for men with locally advanced, relapsed, or metastatic prostate cancer on androgen-deprivation therapy

Purpose Androgen-deprivation therapy in patients with prostate cancer (PCa) is associated with considerable side effects and secondary comorbidities such as overweight/obesity and cardiovascular disease. The aim of thisstudy was to investigate the effectiveness of an industry-led, treatment-integrated, community-based exercise program on outcomes of body weight, cardiovascular health, and physical function. Patients and Methods PCa patients with locally advanced, relapsed, or metastatic disease receiving leuprorelin acetate were enrolled across multiple sites in Australia and assigned supervised group exercise undertaken weekly or biweekly (ie, 16 exercise sessions in total) for 10-18 weeks, consisting of aerobic and resistance training performed at moderate-to-vigorous intensity. Results Between 2014 and 2020, 760 participants completed the baseline and follow-up assessment. Participants were age 48-94 years, and most were either overweight (42.1%) or obese (38.1%). Program compliance was high, with 90% of participants completing all 16 exercise sessions. There was a small but significant reduction in waist circumference (–0.9 cm; 95% CI [–1.2 to –0.5]; P \u3c .001) and no change in weight or body mass index. Systolic (–3.7 mmHg; 95% CI [–4.8 to –2.6]; P \u3c .001) and diastolic (–1.7 mmHg; 95% CI [–2.3 to –1.0]; P \u3c .001) blood pressure were significantly lower after the program. Furthermore, significant improvements were seen in cardiorespiratory fitness and muscle strength (P \u3c .001). For most of the investigated outcomes, participants with poorer initial measures had the greatest benefit from participating in the program. Conclusion The community exercise program was feasible and effective in preventing weight gain, reducing blood pressure, and improving physical function in patients with PCa on androgen-deprivation therapy

Validation of a new patient-reported outcome measure of balance recovery confidence (BRC) for community-dwelling older adults: A study protocol

From Crossref journal articles via Jisc Publications RouterBackground: Patient-reported outcome measures (PROMs) provide clinicians a greater understanding of patients’ perceived ability in their physical performance. Existing PROMs on falls efficacy provide meaningful information about the perceived ability in older people to perform common activities of daily living without falling. However, the perceived ability to recover balance from a slip, a trip, or volitional movements has been inadequately assessed. Balance recovery confidence relates to the judgment of self-reactive ability. The scale of balance recovery confidence (BRC) is a new PROM that measures perceived balance recovery self-efficacy. The purpose of the study protocol is to describe the first psychometric evaluation of BRC’s measurement properties.Objective: This study is a validation phase of a newly developed PROM conducted in Singapore.Methods: Two hundred community-dwelling older adults, aged 65 years and older, will complete five self-reported instruments (BRC, Activities-specific Balance Confidence Scale, Falls Efficacy Scale-International, Late-Life Function and Disability Instrument-Function and Global Perceived Effect) and three performance measures (Hand strength dynamometer, 30-second Chair Stand, Mini BESTest). Classical test theory methods will assess acceptability, data completeness, targeting of the items, scaling assumptions, internal consistency reliability and construct validity. Factor analysis will establish unidimensionality. Rasch analysis will evaluate item fit, differential item functioning, response scale ordering, targeting of persons and items and the reliability.Results: The findings from this study will be published in peer-reviewed journals and presented at national and international conferences in rehabilitation-specific context.Conclusions: This is the first validation study of BRC. The study will give confidence among clinicians and researchers to use the BRC in fall management research and clinical practice.https://doi.org/10.1080/10833196.2021.193886726pubpub

Performance of a Homemade Vanadium-Manganese Redox Flow Battery using Electrospun Carbon Electrode Catalyst and its Preliminary System Integration

In this study, the possibility of enhancing the performance of the all-vanadium redox flow battery (VRFB) and a vanadium/manganese redox flow battery (V/Mn RFB) using carbonized catalyst layers (CCLs) prepared via electrospinning is considered. To display performance enhancement caused by such catalysts, a home-made reactor with non-optimized compression and serpentine flow fields was employed. This reactor was manufactured using a combination of recycled metals, graphite and chemically resistant plastic, with serpentine flow fields engraved using in-house computer aided manufacture employing SolidWorks software. The surface morphologies of the graphite and carbon-based electrodes used during electrochemical tests were characterized by SEM and XRD analyses. For such a non-optimized reactor, the application of the CCL as an additional material to an as-received graphite felt electrode shows improvements for both vanadium-based RFB technologies. For instance, the enhancements in power densities of VRFBs were achieved by 30% improvement in peak power density using CCL. V/Mn flow batteries showed 50% improvement in capacity utilization when using CCL. It is also postulated that because the CCL needs to be placed between the flow fields and the felt electrodes to prevent fiber protrusion into the flow channels when compressed in the reactor, the peak power densities and cycling efficiencies were lower than those reported for optimized RFBs in the literature. The need to improve the power density is a critical consideration for RFBs. A high-power density translates into lower capital costs for V/Mn RFBs, which translates into an effective system integration for grid-scale load levelling, water desalination or renewable energy storage

Falls efficacy instruments for community-dwelling older adults: A COSMIN-based systematic review

From Springer Nature via Jisc Publications RouterBackground: Falls efficacy is a widely-studied latent construct in community-dwelling older adults. Various self-reported instruments have been used to measure falls efficacy. In order to be informed of the choice of the best measurement instrument for a specific purpose, empirical evidence of the development and measurement properties of falls efficacy related instruments is needed. Methods: The Consensus-based Standards for the Selection of Health Measurement Intruments (COSMIN) checklist was used to summarise evidence on the development, content validity, and structural validity of instruments measuring falls efficacy in community-dwelling older adults. Databases including MEDLINE, Web of Science, PsychINFO, SCOPUS, CINAHL were searched (May 2019). Records on the development of instruments and studies assessing content validity or structural validity of falls efficacy related scales were included. COSMIN methodology was used to guide the review of eligible studies and in the assessment of their methodological quality. Evidence of content validity: relevance, comprehensiveness and comprehensibility and unidimensionality for structural validity were synthesised. A modified GRADE approach was applied to evidence synthesis. Results: Thirty-five studies, of which 18 instruments had been identified, were included in the review. High-quality evidence showed that the Modified Falls Efficacy Scale (FES)-13 items (MFES-13) has sufficient relevance, yet insufficient comprehensiveness for measuring falls efficacy. Moderate quality evidence supported that the FES-10 has sufficient relevance, and MFES-14 has sufficient comprehensibility. Activities-specific Balance Confidence (ABC) Scale–Simplified (ABC-15) has sufficient relevance in measuring balance confidence supported by moderate-quality evidence. Low to very low-quality evidence underpinned the content validity of other instruments. High-quality evidence supported sufficient unidimensionality for eight instruments (FES-10, MFES-14, ABC-6, ABC-15, ABC-16, Iconographical FES (Icon-FES), FES–International (FES-I) and Perceived Ability to Prevent and Manage Fall Risks (PAPMFR)). Conclusion: Content validity of instruments to measure falls efficacy is understudied. Structural validity is sufficient for a number of widely-used instruments. Measuring balance confidence is a subset of falls efficacy. Further work is needed to investigate a broader construct for falls efficacy.21pubpu

Does exercise impact gut microbiota composition in men receiving androgen deprivation therapy for prostate cancer? A single-blinded, two-armed randomised controlled trial

Introduction: A potential link exists between prostate cancer (PCa) disease and treatment and increased inflammatory levels from gut dysbiosis. This study aims to examine if exercise favourably alters gut microbiota in men receiving androgen deprivation therapy (ADT) for PCa. Specifically, this study will explore whether: (1) exercise improves the composition of gut microbiota and increases the abundance of bacteria associated with health promotion and (2) whether gut health correlates with favourable inflammatory status, bowel function, continence and nausea among patients participating in the exercise intervention. Methods and analysis: A single-blinded, two-armed, randomised controlled trial will explore the influence of a 3-month exercise programme (3 days/week) for men with high-risk localised PCa receiving ADT. Sixty patients will be randomly assigned to either exercise intervention or usual care. The primary endpoint (gut health and function assessed via feacal samples) and secondary endpoints (self-reported quality of life via standardised questionnaires, blood biomarkers, body composition and physical fitness) will be measured at baseline and following the intervention. A variety of statistical methods will be used to understand the covariance between microbial diversity and metabolomics profile across time and intervention. An intention-to-treat approach will be utilised for the analyses with multiple imputations followed by a secondary sensitivity analysis to ensure data robustness using a complete cases approach. Ethics and dissemination: Ethics approval was obtained from the Human Research Ethics Committee of Edith Cowan University (ID: 19827 NEWTON). Findings will be reported in peer-reviewed publications and scientific conferences in addition to working with national support groups to translate findings for the broader community. If exercise is shown to result in favourable changes in gut microbial diversity, composition and metabolic profile, and reduce gastrointestinal complications in PCa patients receiving ADT, this study will form the basis of a future phase III trial. Trial registration number: ANZCTR12618000280202

Sphingosine kinase 1 regulates the survival of breast cancer stem cells and non-stem breast cancer cells by suppression of STAT1

Cancer stem cells (CSCs) represent rare tumour cell populations capable of self-renewal, differentiation and tumour initiation, and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches which can effectively target CSCs and tumour cells could be the key towards efficient tumour treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibits cell proliferation and induces apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhances breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signalling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrate that SPHK1 inhibitors, FTY720 and PF543 synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies