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Exercise training mode effects on myokine expression in healthy adults: A systematic review with meta-analysis.
Bettariga, F, Taaffe, DR, Galvão, DA, Lopez, P, Bishop, C, Markarian, AM, Natalucci, V, Kim, JS, Newton, RU
Journal of sport and health science. 2024
Abstract
BACKGROUND The benefits of exercise are well known; however, many of the underlying molecular mechanisms are not fully understood. Skeletal muscle secretes myokines, which mediate muscle-organ crosstalk. Myokines regulate satellite-cell proliferation and migration, inflammatory cascade, insulin secretion, angiogenesis, fatty oxidation, and cancer suppression. To date, the effects of different exercise modes (namely, aerobic and resistance exercise) on myokine response remain to be elucidated. This is crucial considering the clinical implementation of exercise to enhance general health and wellbeing and as a medical treatment. METHODS A systematic search was undertaken in PubMed, Medline, CINAHL, Embase, SPORTDiscus, and Web of Science in April 2023. Eligible studies examining the effects of a single bout of exercise on IL-15, irisin, SPARC, OSM, and decorin were included. A random-effects meta-analysis was also undertaken to quantify the magnitude of change. RESULTS Sixty-two studies were included (n = 1193). Overall, exercise appeared to induce small to large increases in myokine expression, with effects observed immediately after to 60 min post-exercise, although these were mostly not statistically significant. Both aerobic and resistance exercise resulted in changes in myokine levels, without any significant difference between training modes, and with the magnitude of change differing across myokines. Myokine levels returned to baseline levels within 180 min to 24 h post-exercise. However, owing to potential sources of heterogeneity, most changes were not statistically significant, indicating that precise conclusions cannot be drawn. CONCLUSION Knowledge is limited but expanding with respect to the impact of overall and specific effects of exercise on myokine expression at different time points in the systemic circulation. Further research is required to investigate the effects of different exercise modes at multiple time points on myokine response.
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Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.
Tricou, V, Yu, D, Reynales, H, Biswal, S, Saez-Llorens, X, Sirivichayakul, C, Lopez, P, Borja-Tabora, C, Bravo, L, Kosalaraksa, P, et al
The Lancet. Global health. 2024;(2):e257-e270
Abstract
BACKGROUND About half of the world's population lives in dengue-endemic areas. We aimed to evaluate the long-term efficacy and safety of two doses of the tetravalent dengue vaccine TAK-003 in preventing symptomatic dengue disease of any severity and due to any dengue virus (DENV) serotypes in children and adolescents. METHODS In this ongoing double-blind, randomised, placebo-controlled trial, we enrolled healthy participants aged 4-16 years at 26 medical and research centres across eight dengue-endemic countries (Brazil, Colombia, Dominican Republic, Nicaragua, Panama, Philippines, Sri Lanka, and Thailand). The main exclusion criteria were febrile illness (body temperature ≥38°C) at the time of randomisation, hypersensitivity or allergy to any of the vaccine components, pregnancy or breastfeeding, serious chronic or progressive disease, impaired or altered immune function, and previous receipt of a dengue vaccine. Participants were randomly assigned 2:1 (stratified by age and region) using an interactive web response system and dynamic block assignment to receive two subcutaneous doses of TAK-003 or placebo 3 months apart. Investigators, participants, and their parents or legal guardians were blinded to group assignments. Active febrile illness surveillance and RT-PCR testing of febrile illness episodes were performed for identification of virologically confirmed dengue. Efficacy outcomes were assessed in the safety analysis set (all randomly assigned participants who received ≥1 dose) and the per protocol set (all participants who had no major protocol violations), and included cumulative vaccine efficacy from first vaccination to approximately 4·5 years after the second vaccination. Serious adverse events were monitored throughout. This study is registered with ClinicalTrials.gov, NCT02747927. FINDINGS Between Sept 7, 2016, and March 31, 2017, 20 099 participants were randomly assigned (TAK-003, n=13 401; placebo, n=6698). 20 071 participants (10 142 [50·5%] males; 9929 [49·5%] females; safety set) received TAK-003 or placebo, with 18 257 (91·0%) completing approximately 4·5 years of follow-up after the second vaccination (TAK-003, 12 177/13 380; placebo, 6080/6687). Overall, 1007 (placebo: 560; TAK-003: 447) of 27 684 febrile illnesses reported were virologically confirmed dengue, with 188 cases (placebo: 142; TAK-003: 46) requiring hospitalisation. Cumulative vaccine efficacy was 61·2% (95% CI 56·0-65·8) against virologically confirmed dengue and 84·1% (77·8-88·6) against hospitalised virologically confirmed dengue; corresponding efficacies were 53·5% (41·6-62·9) and 79·3% (63·5-88·2) in baseline seronegative participants (safety set). In an exploratory analysis, vaccine efficacy was shown against all four serotypes in baseline seropositive participants. In baseline seronegative participants, vaccine efficacy was shown against DENV-1 and DENV-2 but was not observed against DENV-3 and low incidence precluded evaluation against DENV-4. During part 3 of the trial (approximately 22-57 months after the first vaccination), serious adverse events were reported for 664 (5·0%) of 13 380 TAK-003 recipients and 396 (5·9%) of 6687 placebo recipients; 17 deaths (6 in the placebo group and 11 in the TAK-003 group) were reported, none were considered study-vaccine related. INTERPRETATION TAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals. FUNDING Takeda Vaccines. TRANSLATIONS For the Portuguese, Spanish translations and plain language summary of the abstract see Supplementary Materials section.
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Effects and moderators of exercise medicine on cardiometabolic outcomes in men with prostate cancer previously or currently undergoing androgen deprivation therapy: An individual patient data meta-analysis.
Lopez, P, Newton, RU, Taaffe, DR, Winters-Stone, K, Buffart, LM, Galvão, DA
Critical reviews in oncology/hematology. 2023;:103995
Abstract
PURPOSE To examine the effects and moderators of exercise effects on cardiometabolic outcomes in men with prostate cancer previously or currently undergoing androgen deprivation therapy (ADT). RESULTS Seven trials including 560 patients were examined. Exercise resulted in significant effects on whole-body and regional fat mass (P ≤ 0.001). For whole-body fat mass, significant exercise effects were observed in patients who were unmarried (-1.4 kg, P < 0.05) and who presented with higher fat mass levels (-1.0 kg, P < 0.05). For diastolic blood pressure and low-density lipoprotein (LDL), younger (-4.7 mmHg, P < 0.05) and older patients (-0.2 mmol.l-1, P < 0.10) achieved greater effects, respectively. Regarding high-density lipoprotein (HDL), patients undertaking ADT + prostatectomy + radiotherapy derived significant exercise effects (0.3 mmol.l-1, P < 0.05). CONCLUSIONS Exercise effectively reduces fat mass across subgroups of men undergoing or following ADT with different characteristics. For diastolic blood pressure, HDL and LDL, groups based on age and treatment history could be specifically targeted with exercise medicine.
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Prehabilitative versus rehabilitative exercise in prostate cancer patients undergoing prostatectomy.
Singh, F, Newton, RU, Taaffe, DR, Lopez, P, Thavaseelan, J, Brown, M, Ooi, E, Nosaka, K, Hayne, D, Galvão, DA
Journal of cancer research and clinical oncology. 2023;(18):16563-16573
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PURPOSE The study compared the efficacy of commencing supervised exercise in men with prostate cancer before and after prostatectomy on objective and patient-reported outcomes, hospital length of stay, and urinary incontinence. METHODS Forty-one men were randomised to a 6-week prehabilitation or rehabilitation exercise programme. Prehabilitation involved resistance and aerobic exercise thrice weekly pre-surgery, while rehabilitation comprised the same commencing 6-weeks post-surgery. Assessments included strength, function (chair rise, stair climb, 400-m, 6-m usual, fast, and backwards walk), body composition, fatigue and quality of life, undertaken at pre-surgery, early post-surgery and late post-surgery phase, with urinary incontinence (24-h pad test) assessed at 2, 6, and 12-weeks post-surgery. Intention-to-treat and sensitivity analyses were undertaken. RESULTS Of thirty-eight men (48-73 years), 29 completed all assessments with most undergoing robotic-assisted laparoscopic prostatectomy (92.1%). In the pre-surgery phase, prehabilitation improved muscle strength (leg press: 17.2 kg; chest press: 2.9 kg; p ≤ 0.001), 400-m, chair rise, 6-m fast and backward walk tests (p ≤ 0.001-0.028). Strength and function declines in the early post-surgery phase were maintained late post-surgery. Rehabilitation showed declines of these outcomes after surgery with improvement late post-surgery (leg press: 14.6 kg, p < 0.001; chest press: 6.8 kg, p < 0.001; 400-m walk: -12.0 s, p = 0.005), resulting in no difference between groups at 12 weeks. There were no significant differences between groups for patient-reported outcomes, hospital length of stay or urinary incontinence. CONCLUSION Pre-surgical exercise enhanced strength and function, protecting against post-surgery declines. Although exercise post-surgery is beneficial for recouping strength and function, where possible men undergoing prostatectomy are encouraged to exercise pre-surgery. TRIAL REGISTRATION ACTRN12617001115325 registered 31 July 2017.
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What are the most effective exercise, physical activity and dietary interventions to improve body composition in women diagnosed with or at high-risk of breast cancer? A systematic review and network meta-analysis.
Kudiarasu, C, Lopez, P, Galvão, DA, Newton, RU, Taaffe, DR, Mansell, L, Fleay, B, Saunders, C, Fox-Harding, C, Singh, F
Cancer. 2023;(23):3697-3712
Abstract
BACKGROUND Obesity has been recognized as a risk factor in the development and recurrence of breast cancer and is also associated with poor prognostic outcomes. This systematic review and network meta-analysis aimed to identify the most effective exercise, physical activity, and dietary interventions to reduce fat mass, body fat percentage and body weight as well as potentially increase lean mass in women diagnosed with or at high risk of breast cancer. METHODS A systematic search of databases was performed up to May 2022. Eligible randomized controlled trials examined the effects of exercise, physical activity and/or dietary interventions on fat mass and lean mass in women diagnosed with or at high risk of breast cancer. A random-effects network meta-analysis was conducted to determine the effects of different interventions across outcomes when sufficient studies were available. RESULTS Eighty-four studies (n = 6428) were included in this review. Caloric restriction and combined exercise + caloric restriction significantly reduced fat mass (range, -3.9 to -3.7 kg) and body weight (range, -5.3 to -4.7 kg), whereas physical activity + caloric restriction significantly reduced body fat percentage (-2.4%; 95% confidence interval [CI], -3.4% to -13%) and body mass index (-2.2 kg × m-2 ; 95% CI, -3.0 to -1.4 kg × m-2 ) in breast cancer patients. Resistance exercise was the most effective intervention to increase lean mass (0.7 kg; 95% CI, 0.5-1.0 kg) in breast cancer patients. CONCLUSION Multimodal exercise and diet programs were the most effective interventions to reduce fat mass, body fat percentage, and body weight and increase and/or preserve lean mass.
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Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.
Sanyal, AJ, Lopez, P, Lawitz, EJ, Lucas, KJ, Loeffler, J, Kim, W, Goh, GBB, Huang, JF, Serra, C, Andreone, P, et al
Nature medicine. 2023;(2):392-400
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The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 μg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-μg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-μg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-μg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-μg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.
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Feasibility of supervised telehealth exercise for patients with advanced melanoma receiving checkpoint inhibitor therapy.
Crosby, BJ, Newton, RU, Galvão, DA, Taaffe, DR, Lopez, P, Meniawy, TM, Khattak, MA, Lam, WS, Gray, ES, Singh, F
Cancer medicine. 2023;(13):14694-14706
Abstract
PURPOSE To determine the feasibility, safety and preliminary efficacy of a telehealth supervised exercise programme in patients with advanced melanoma receiving checkpoint inhibitor therapy. METHODS A 8-week non-randomised feasibility pilot trial utilising a telehealth delivered multimodal exercise programme undertaken thrice weekly with assessments at baseline and post-intervention. The study was considered feasible if there were no severe or life-threatening adverse events as a result of exercise, and three or more of the following criteria were met: the recruitment rate was >50%, completion rate was >80%, median programme attendance was >75%, median exercise compliance >75%, and average tolerance was >70%. Preliminary efficacy was assessed for objective measures of physical function (2-min step test, repeated chair stand test, 30-s push-up test, and a modified static balance test) and quality of life (QoL), fatigue and other patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. RESULTS Eleven patients (32-80 years) were included in the study (6 female, 5 male). The recruitment rate was 48%, completion rate 91%, programme attendance 88%, median exercise compliance 82.1% and 84.9% for resistance and aerobic exercise, respectively, and tolerance 88%, with no severe or life-threatening adverse events as a result of exercise. In terms of preliminary efficacy, physical function significantly improved while QoL was maintained following the intervention. CONCLUSION An 8-week telehealth exercise intervention is feasible and safe for patients with advanced melanoma and appears to improve physical function while preserving QoL during checkpoint inhibitor therapy.
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Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.
Bravo, L, Smolenov, I, Han, HH, Li, P, Hosain, R, Rockhold, F, Clemens, SAC, Roa, C, Borja-Tabora, C, Quinsaat, A, et al
Lancet (London, England). 2022;(10323):461-472
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BACKGROUND A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 μg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.
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Weight loss for overweight and obese patients with prostate cancer: a study protocol of a randomised trial comparing clinic-based versus Telehealth delivered EXercise and nutrition intervention (the TelEX trial).
Galvão, DA, Taaffe, DR, Hayne, D, Lopez, P, Lyons-Wall, P, Tang, CI, Chambers, SK, Devine, A, Spry, N, Jeffery, E, et al
BMJ open. 2022;(6):e058899
Abstract
INTRODUCTION Obese men with prostate cancer have an increased risk of biochemical recurrence, metastatic disease and mortality. For those undergoing androgen deprivation therapy (ADT), substantial increases in fat mass are observed in the first year of treatment. Recently, we showed that a targeted supervised clinic-based exercise and nutrition intervention can result in a substantial reduction in fat mass with muscle mass preserved in ADT-treated patients. However, the intervention needs to be accessible to all patients and not just those who can access a supervised clinic-based programme. The purpose of this study was to evaluate the efficacy of telehealth delivered compared with supervised clinic-based delivered exercise and nutrition intervention in overweight/obese patients with prostate cancer. METHODS AND ANALYSIS A single-blinded, two-arm parallel group, non-inferiority randomised trial will be undertaken with 104 overweight/obese men with prostate cancer (body fat percentage ≥25%) randomly allocated in a ratio of 1:1 to a telehealth-delivered, virtually supervised exercise and nutrition programme or a clinic-based, face-to-face supervised exercise and nutrition programme. Exercise will consist of supervised resistance and aerobic exercise performed three times a week plus additional self-directed aerobic exercise performed 4 days/week for the first 6 months. Thereafter, for months 7-12, the programmes will be self-managed. The primary endpoint will be fat mass. Secondary endpoints include lean mass and abdominal aortic calcification, anthropometric measures and blood pressure assessment, objective measures of physical function and physical activity levels, patient-reported outcomes and blood markers. Measurements will be undertaken at baseline, 6 months (post intervention), and at 12 months of follow-up. Data will be analysed using intention-to-treat and per protocol approaches. ETHICS AND DISSEMINATION Ethics approval has been obtained from the Edith Cowan University Human Research Ethics Committee (ID: 2021-02157-GALVAO). Outcomes from the study will be published in academic journals and presented in scientific and consumer meetings. TRIAL REGISTRATION NUMBER ACTRN12621001312831.
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Association between Energy Balance-Related Factors and Clinical Outcomes in Patients with Ovarian Cancer: A Systematic Review and Meta-Analysis.
Stelten, S, Schofield, C, Hartman, YAW, Lopez, P, Kenter, GG, Newton, RU, Galvão, DA, Hoedjes, M, Taaffe, DR, van Lonkhuijzen, LRCW, et al
Cancers. 2022;(19)
Abstract
Background: This systematic review and meta-analysis synthesized evidence in patients with ovarian cancer at diagnosis and/or during first-line treatment on; (i) the association of body weight, body composition, diet, exercise, sedentary behavior, or physical fitness with clinical outcomes; and (ii) the effect of exercise and/or dietary interventions. Methods: Risk of bias assessments and best-evidence syntheses were completed. Meta-analyses were performed when ≥3 papers presented point estimates and variability measures of associations or effects. Results: Body mass index (BMI) at diagnosis was not significantly associated with survival. Although the following trends were not supported by the best-evidence syntheses, the meta-analyses revealed that a higher BMI was associated with a higher risk of post-surgical complications (n = 5, HR: 1.63, 95% CI: 1.06−2.51, p = 0.030), a higher muscle mass was associated with a better progression-free survival (n = 3, HR: 1.41, 95% CI: 1.04−1.91, p = 0.030) and a higher muscle density was associated with a better overall survival (n = 3, HR: 2.12, 95% CI: 1.62−2.79, p < 0.001). Muscle measures were not significantly associated with surgical or chemotherapy-related outcomes. Conclusions: The prognostic value of baseline BMI for clinical outcomes is limited, but muscle mass and density may have more prognostic potential. High-quality studies with comprehensive reporting of results are required to improve our understanding of the prognostic value of body composition measures for clinical outcomes. Systematic review registration number: PROSPERO identifier CRD42020163058.