Building a biopsychosocial model of cancer-related fatigue: the BIOCARE FActory cohort study protocol.

BACKGROUND: Cancer-related fatigue (CRF) is the most common side effect of cancer and cancer treatment. CRF prevalence is up to 50% in breast cancer patients and can continue several years after cancer remission. This persistent subjective sense of exhaustion is multifactorial. Numerous parameters have been evidenced to be related to CRF across biological, physical, psychological, social and/or behavioral dimensions. Although CRF has been studied for many years, the majority of previous studies focused on only one dimension, i.e., physical function. Moreover, few studies investigated CRF longitudinally with repeated measures. These are the two main obstacles that limit the understanding of CRF mechanisms. The purpose of this study is to create a biopsychosocial model of CRF with simultaneous and longitudinal anthropometric, clinical, biological, physical, psychological and sociological parameters. METHODS: BIOCARE FActory is a multicentric prospective study that will consist of an 18-month follow-up of 200 women diagnosed with breast cancer. Four visits will be scheduled at diagnosis, after treatments, and 12 and 18 months after diagnosis. The same procedure will be followed for each visit. Each session will be composed of anthropometric data collection, a semi-structured interview, cognitive tests, postural control tests, neuromuscular fatigability tests and a cardiorespiratory fitness test. Clinical and biological data will be collected during medical follow-ups. Participants will also complete questionnaires to assess psychological aspects and quality of life and wear an actigraphy device. Using a structural equation modeling analysis (SEM), collected data will build a biopsychosocial model of CRF, including the physiological, biological, psychological, behavioral and social dimensions of CRF. DISCUSSION: This study aims to highlight the dynamics of CRF and its correlates from diagnosis to post treatment. SEM analysis could examine some relations between potential mechanisms and CRF. Thus, the biopsychosocial model will contribute to a better understanding of CRF and its underlying mechanisms from diagnosis to the aftermaths of cancer and its treatments. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov ( NCT04391543 ), May 2020.

Exposure to hypobaric hypoxia results in higher oxidative stress compared to normobaric hypoxia.

Sixteen healthy exercise trained participants underwent the following three, 10-h exposures in a randomized manner: (1) Hypobaric hypoxia (HH; 3450m terrestrial altitude) (2) Normobaric hypoxia (NH; 3450m simulated altitude) and (3) Normobaric normoxia (NN). Plasma oxidative stress (malondialdehyde, MDA; advanced oxidation protein products, AOPP) and antioxidant markers (superoxide dismutase, SOD; glutathione peroxidase, GPX; catalase; ferric reducing antioxidant power, FRAP) were measured before and after each exposure. MDA was significantly higher after HH compared to NN condition (+24%). SOD and GPX activities were increased (vs. before; +29% and +54%) while FRAP was decreased (vs. before; -34%) only after 10h of HH. AOPP significantly increased after 10h for NH (vs. before; +83%), and HH (vs. before; +99%) whereas it remained stable in NN. These results provide evidence that prooxidant/antioxidant balance was impaired to a greater degree following acute exposure to terrestrial (HH) vs. simulated altitude (NH) and that the chamber confinement (NN) did likely not explain these differences.

Effect of α-thalassaemia on exercise-induced oxidative stress in sickle cell trait.

AIM: Alpha-thalassaemia is known to reduce intra-erythrocyte HbS (sickle haemoglobin) concentration in sickle cell trait (SCT) subjects. Because HbS was shown to increase oxidative stress, the purpose of this study was to assess the effects of the coexistence of α-thalassaemia and SCT on oxidative stress markers and nitric oxide (NO) metabolism after an acute physical exercise. METHODS: Forty subjects (age: 23.5 ± 2.21 years), SCT carriers (HbAS) or healthy subjects (HbAA), with (-αT) or without (-NαT) an associated α-thalassaemia took part in the study. Plasma markers of oxidative stress [advanced oxidation protein products (AOPP), protein carbonyl, malondialdehyde (MDA) and nitrotyrosine], anti-oxidant defences and NO metabolism (NOx) were measured at rest (T(rest)), immediately following an incremental maximal exercise test (T(ex)) and during recovery (T(1h), T(2h) and T(24h)). RESULTS: Malondialdehyde expressed as the percentage of changes from baseline was significantly higher in the HbAS-NαT compared with HbAS-αT during recovery (+36.3 ± 14.1% vs. -1.8 ± 13.2% at T(1h), P = 0.02; +36.6 ± 13.4% vs. -11.4 ± 12.5% at T(2h), P = 0.004 and +24.1 ± 12.3% vs. -14.4 ± 11.5% at T(24h), P = 0.02 in HbAS-NαT vs. HbAS-αT). Compared with HbAS-NαT, HbAS-αT had a higher NOx change from baseline at T(ex) (-23.4 ± 20.6% vs. +57.7 ± 19.3%, respectively; P = 0.005) and lower nitrotyrosine change from baseline at T(1h) (+7.2 ± 22.2% vs. +93.5%±29.3%, respectively; P = 0.04). CONCLUSION: All these data suggest that the presence of α-thalassaemia may blunt the higher level of oxidative stress and the impaired bioavailability of NO observed in the SCT carriers.

Effects of intermittent hypoxia on erythropoietin, soluble erythropoietin receptor and ventilation in humans.

Erythropoietin (EPO) and soluble EPO receptors (sEPOR) have been proposed to play a central role in the ventilatory acclimatisation to continuous hypoxia in mice. In this study, we demonstrated for the first time in humans (n = 9) that sEPOR is downregulated upon daytime exposure to 4 days of intermittent hypoxia (IH; 6 h·day⁻¹, cycles of 2 min of hypoxia followed by 2 min of reoxygenation; peak end-tidal oxygen tension (P(ET,O2)) 88 Torr, nadir P(ET,O2)) 45 Torr), thereby allowing EPO concentration to rise. We also determined the strength of the association between these haematological adaptations and alterations in the acute hypoxic ventilatory response (AHVR). We observed a nadir in sEPOR on day 2 (-70%), concomitant with the peak in EPO concentration (+50%). Following exposure to IH, tidal volume (V(T)) increased, respiratory frequency remained unchanged, and minute ventilation (V'(E)) was increased. There was a negative correlation between EPO and sEPOR (r = -0.261; p = 0.05), and between sEPOR and V(T) (r = -0.331; p = 0.02). EPO was positively correlated with V'(E) (r = 0.458; p = 0.001). In conclusion, the downregulation of sEPOR by IH modulates the subsequent EPO response. Furthermore, the alterations in AHVR and breathing pattern following IH appear to be mediated, at least in part, by the increase in EPO.

Influence of the Numbers of Players in the Heart Rate Responses of Youth Soccer Players Within 2 vs. 2, 3 vs. 3 and 4 vs. 4 Small-sided Games.

The purpose of this study was to compare heart rate (HR) responses within and between small-sided games (SSG) training methods in elite young soccer players. Twenty-seven youth soccer players (age: 16.5 ± 0.5 years, height: 174.5 ± 5.5 cm, weight: 62.9 ± 8.3, velocity at maximal aerobic speed (MAS): 15.9 ± 0.9 km.h(-1)) performed 3 different SSG (2 vs. 2, 3 vs. 3, 4 vs. 4 without goalkeeper). In each SSG, HR was continuously measured and expressed as a mean percentage of HR reserve (%HRreserve). The mean %HRreserve calculated during the SSG was significantly lower during 4 vs. 4 (70.6 ± 5.9 %) compared to 2 vs. 2 (80.1 ± 3.6 %, p<0.001) and 3 vs. 3 (81.5 ± 4.3 %, p<0.001) SSG. Regardless of the time spent above 60, 65, 70, 75, 80, 85 and 90 % of HRreserve, 4 vs. 4 solicited lower percentage of time than 3 vs. 3 and 2 vs. 2. Intersubject coefficients of variation were significantly higher during 4 vs. 4 compared to 2 vs.2 and 3 vs. 3. The %HRreserve after 30s of recovery was significantly higher for 3 vs. 3 (70.6 ± 5.3 %) compared to 2 vs. 2 (65.2 ± 4.8 %, p<0.05) and 4 vs. 4 (61.6 ± 9.3 %, p<0.05). In conclusion, this study demonstrates that the physiological demands is higher during 2 vs. 2 and 3 vs. 3 compared to 4 vs. 4 in youth soccer players. This difference could be due to that young soccer players do not have the same technical ability and experience as adult players and thus, their activity during the 2 vs. 2 and 3 vs. 3 induces a greater physical demand due to their lack of experience. The age of the players could be linked with the physical demands within small-sided games.

Effects of acute hypoxic exposure on prooxidant/antioxidant balance in elite endurance athletes.

We investigated whether acute hypoxic exposures could modify the pro-oxidant/antioxidant balance in elite endurance athletes, known to have efficient antioxidant status. Forty-one elite athletes were subjected to two hypoxic tests: one at an altitude of 4 800 m during 10-min of mild exercise (4 800 m test) and the second at rest for 3 h at an altitude of 3 000 m (3 000 m test). Plasma levels of advanced oxidation protein products (AOPP), malondialdehydes (MDA), ferric reducing antioxidant power (FRAP) and lipid-soluble antioxidants were measured before and immediately after the 4 800 m test and at the end of the 3 000 m test. The 4 800 m and the 3 000 m tests induced a significant increase in the level of MDA and AOPP (+7.1% and +71.7% for 4 800 m test and +8.6% and +40.9% for 3 000 m test). The changes in plasma MDA and arterial oxygen saturations were significantly correlated (r=0.35) during the 3 000 m test. FRAP values (-13%) and alpha-tocopherol (-21%) were decreased following the 3 000 m test. However, following the 4 800 m test, only alpha-tocopherol was decreased (-16%). These results provide evidence that the highly-trained athletes do not have the antioxidant buffering capacity to counterbalance free radical over-production generated by acute hypoxic exposure, with or without mild exercise.

Effects of the 'live high-train low' method on prooxidant/antioxidant balance on elite athletes.

BACKGROUND/OBJECTIVES: We previously demonstrated that acute exposure to hypoxia (3 h at 3000 m) increased oxidative stress markers. Thus, by using the 'living high-training low' (LHTL) method, we further hypothesized that intermittent hypoxia associated with endurance training alters the prooxidant/antioxidant balance. SUBJECTS/METHODS: Twelve elite athletes from the Athletic French Federation were subjected to 18-day endurance training. They were divided into two groups: one group (control group) trained at 1200 m and lived in hypoxia (2500-3000 m simulated altitude) and the second group trained and lived at 1200 m. The subjects performed an acute hypoxic test (10 min at 4800 m) before and immediately after the training. Plasma levels of advanced oxidation protein products (AOPP), malondialdehydes (MDA), ferric-reducing antioxidant power (FRAP), lipid-soluble antioxidants normalized for triacylglycerols, and cholesterol and retinol were measured before and after the 4800 m tests. RESULTS: After the training, MDA and AOPP concentrations were decreased in response to the 4800 m test only for the control group. Eighteen days of LHTL induced a significant decrease of all antioxidant markers (FRAP, P=0.01; alpha-tocopherol, P=0.04; beta-carotene, P=0.01 and lycopene, P=0.02) for the runners. This imbalance between antioxidant and prooxidant might result from insufficient intakes in vitamins A and E. CONCLUSIONS: The LHTL model characterized by the association of aerobic exercises and intermittent resting hypoxia exposures decreased the antioxidant status whereas the normoxic endurance training induced preconditioning mechanisms in response to the 4800 m test.

Energy expenditure of submaximal running does not increase after cycle-run transition.

AIM: This study was performed to determine the relationship between increased fat oxidation and decreased running efficiency following intense cycling exercise. METHODS: Twenty-two middle-level triathletes were studied during submaximal running before and after submaximal cycling exercise. All subjects completed a 13-min run on a track at a velocity corresponding to 75% of their maximal aerobic speed (MAS) before (T1) and after (T2) submaximal cycling exercise at 75 % of maximal aerobic power (MAP). The energy cost of running (Cr) was quantified using the O(2) uptake (.VO(2)) and energy expenditure (EE) using the respiratory exchange ratio (RER). Gas exchange was measured over 30 s during the 3(rd) min and last 30 s of each run. RESULTS: The results show that after cardiorespiratory equilibration (12 min 30 s), Cr (calculated in mL(O(2))*kg(-1)*m(-1)) during T2 was higher than during T1 (+ 8.2+/-4.3%; P = 0.03). Similar observations were made for .VO(2) (+ 8.2+/-4.3%; P = 0.03) and pulmonary ventilation (+ 7.0+/-12.3%; P = 0.04). RER decreased between T1 and T2 (- 8.6+/-9.2 %; p = 0.01). EE and Cr expressed in kJ.kg(-1).m(-1) did not vary significantly between T1 and T2. CONCLUSION: We suggest that the decrease in RER drop may be a result of greater lipid oxidation as metabolic substrate after cycling exercise.

Effects of exercise and training in hypoxia on antioxidant/pro-oxidant balance.

OBJECTIVE: The aim was to investigate the effects of acute exercise under hypoxic condition and the repetition of such exercise in a 'living low-training high' training on the antioxidant/prooxidant balance. DESIGN: Randomized, repeated measures design. SETTING: Faculté de Médecine, Clermont-Ferrand, France. SUBJECTS: Fourteen runners were randomly divided into two groups. A 6-week endurance training protocol integrated two running sessions per week at the second ventilatory threshold into the usual training. INTERVENTION: A 6-week endurance training protocol integrated two running sessions per week at the second ventilatory threshold into the usual training. The first hypoxic group (HG, n=8) carried out these sessions under hypoxia (3000 m simulated altitude) and the second normoxic group (NG, n=6) in normoxia. In control period, the runners were submitted to two incremental cycling tests performed in normoxia and under hypoxia (simulated altitude of 3000 m). Plasma levels of advanced oxidation protein products (AOPP), malondialdehydes (MDA) and lipid oxidizability, ferric-reducing antioxidant power (FRAP), lipid-soluble antioxidants (alpha-tocopherol and beta-carotene) normalized for triacyglycerols and cholesterol were measured before and after the two incremental tests and at rest before and after training. RESULTS: No significant changes of MDA and AOPP level were observed after normoxic exercise, whereas hypoxic exercise induced a 56% rise of MDA and a 44% rise of AOPP. Plasma level of MDA and arterial oxygen hemoglobin desaturations after the acute both exercises were highly correlated (r=0.73). alpha-Tocopherol normalized for cholesterol and triacyglycerols increased only after hypoxic exercise (10-12%, P<0.01). After training, FRAP resting values (-21%, P<0.05) and alpha-tocopherol/triacyglycerols ratio (-24%, P<0.05) were diminished for HG, whereas NG values remained unchanged. CONCLUSIONS: Intense exercise and hypoxia exposure may have a cumulative effect on oxidative stress. As a consequence, the repetition of such exercise characterizing the 'living low-training high' model has weakened the antioxidant capacities of the athletes. SPONSORSHIP: International Olympic Committee and the Direction Régionale de la Jeunesse et des Sports de la Région Auvergne.

Effect of hypervolemia on heart rate during 4 days of prolonged exercises.

The aim was to evaluate the cardiodynamic adjustment during 4 days of prolonged exercises and to check if the plasma volume (PV) expansion which is observed generally during such events plays a role in this adaptation. Thirteen subjects exercised 5 hours per day on a cycle ergometer alternately with a treadmill for 4 days (D1 to D4) (6 x 50 min sessions per day). The individual cycle ergometer load and the treadmill speed were unchanged during each exercise session and throughout all the sessions, and corresponded to a moderate exercise intensity: 58 - 63 % of peak oxygen uptake (VO (2)peak). Heart rate (HR) was recorded every 15 s during each exercise session and VO (2) was measured from the expired air at the beginning and the end of each exercise session. Relative PV changes were measured from haematocrit and haemoglobin changes in the morning before the exercise bouts. No significant changes of VO (2) were observed between the first and the last exercise session i. e. for cycling: 2.1 +/- 0.2 l/min and for running: 2.4 +/- 0.3 l/min. Between the first and the last day, HR decreased from 143 to 129 bpm for cycle (p < 0.0001) and from 147 to 137 bpm (p = 0.01) for treadmill. As compared to D1, PV increased gradually from D2 (+ 1.8 % +/- 4.7 %) to D4 (+ 8.5 % +/- 4.7 %). The individual PV increases were significantly correlated with cycling HR decreases from D1 to D4 (r (2) = 0.40, p = 0.02). In conclusion, the 4 days' prolonged exercise induced a HR decrease during submaximal exercise without VO (2) drift. Here we suggested that this HR decline could be in part linked to the transient PV expansion.