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JN was funded by a fellowship from the French MENESR.Peer reviewedPeer Reviewe

Effect of heavy-intensity 'priming' exercise on oxygen uptake and muscle deoxygenation kinetics during moderate-intensity step-transitions initiated from an elevated work rate

We examined the effect of heavy-intensity ‘priming’ exercise on the rate of adjustment of pulmonary O2 uptake (τ 2p) initiated from elevated intensities. Fourteen men (separated into two groups: τ 2p≤25s [Fast] or τ 2p>25s [Slow]) completed step-transitions from 20W-to- 45%lactate threshold (LT; lower-step, LS) and 45%-to-90%LT (upper-step, US) performed (i) without; and (ii) with US preceded by heavy-intensity exercise (HUS). Breath-by-breath 2p and near-infrared spectroscopy-derived muscle deoxygenation ([HHb+Mb]) were measured. Compared to LS, τ 2p was greater (p0.05) from LS or Fast group US. In Slow, τ[HHb+Mb] increased (p<0.05) in US relative to HUS; this finding coupled with a reduced τ 2p indicates a priming-induced improvement in matching of muscle O2 delivery-to-O2 utilization during transitions from elevated intensities in those with Slow but not Fast 2p kinetics

The influence of metabolic and circulatory heterogeneity on the expression of pulmonary oxygen uptake kinetics in humans

New Findings What is the central question of this study? The finding that pulmonary oxygen uptake (inline image) kinetics on transition to moderate exercise is invariant and exponential is consistent with a first-order reaction controlling inline image. However, slowed inline image kinetics when initiating exercise from raised baseline intensities challenges this notion. What is the main finding and its importance? Here, we demonstrate how a first-order system can respond with non-first-order response dynamics. Data suggest that progressive recruitment of muscle fibre populations having progressively lower mitochondrial density and slower microvascular blood flow kinetics can unify the seemingly contradictory evidence for the control of inline image on transition to exercise. We examined the relationship amongst baseline work rate (WR), phase II pulmonary oxygen uptake (inline image) time constant (inline image) and functional gain inline image during moderate-intensity exercise. Transitions were initiated from a constant or variable baseline WR. A validated circulatory model was used to examine the role of heterogeneity in muscle metabolism (inline image) and blood flow (inline image) in determining inline image kinetics. We hypothesized that inline image and GP would be invariant in the constant baseline condition but would increase linearly with increased baseline WR. Fourteen men completed three to five repetitions of ∆40 W step transitions initiated from 20, 40, 60, 80, 100 and 120 W on a cycle ergometer. The ∆40 W step transitions from 60, 80, 100 and 120 W were preceded by 6 min of 20 W cycling, from which the progressive ΔWR transitions (constant baseline condition) were examined. The inline image was measured breath by breath using mass spectrometry and a volume turbine. For a given ΔWR, both inline image (22–35 s) and GP (8.7–10.5 ml min−1 W−1) increased (P < 0.05) linearly as a function of baseline WR (20–120 W). The inline image was invariant (P < 0.05) in transitions initiated from 20 W, but GP increased with ΔWR (P < 0.05). Modelling the summed influence of multiple muscle compartments revealed that inline image could appear fast (24 s), and similar to in vivo measurements (22 ± 6 s), despite being derived from inline image values with a range of 15–40 s and inline image with a range of 20–45 s, suggesting that within the moderate-intensity domain phase II inline image kinetics are slowed dependent on the pretransition WR and are strongly influenced by muscle metabolic and circulatory heterogeneity

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy

BackgroundThough metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT.Patients and methodsWe assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases.ResultsA database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and &gt; 1 (0, 1, and 2); 0, 1, and &gt; 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung).ConclusionThis pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT

Speeding of V̇o2 kinetics with endurance training in old and young men is associated with improved matching of local O2 delivery to muscle O2 utilization

The time course and mechanisms of adjustment of pulmonary oxygen uptake (V̇o2) kinetics (time constant τV̇o2p) were examined during step transitions from 20 W to moderate-intensity cycling in eight older men (O; 68 ± 7 yr) and eight young men (Y; 23 ± 5 yr) before training and at 3, 6, 9, and 12 wk of endurance training. V̇o2p was measured breath by breath with a volume turbine and a mass spectrometer. Changes in deoxygenated hemoglobin concentration (Δ[HHb]) were measured by near-infrared spectroscopy. V̇o2p and Δ[HHb] were modeled with a monoexponential model. Training was performed on a cycle ergometer three times per week for 45 min at ∼70% of peak V̇o2. Pretraining τV̇o2p was greater (P < 0.05) in O (43 ± 10 s) than Y (34 ± 8 s). τV̇o2p decreased (P < 0.05) by 3 wk of training in both O (35 ± 9 s) and Y (22 ± 8 s), with no further changes thereafter. The pretraining overall adjustment of Δ[HHb] was faster than τV̇o2p in both O and Y, resulting in Δ[HHb]/V̇o2p displaying an “overshoot” during the transient relative to the subsequent steady-state level. After 3 wk of training the Δ[HHb]/V̇o2p overshoot was attenuated in both O and Y. With further training, this overshoot persisted in O but was eliminated after 6 wk in Y. The training-induced speeding of V̇o2p kinetics in O and Y at 3 wk of training was associated with an improved matching of local O2 delivery to muscle V̇o2 (as represented by a lower Δ[HHb]/V̇o2p). The continued overshoot in Δ[HHb]/V̇o2p in O may reflect a reduced vasodilatory responsiveness that may limit muscle blood flow distribution during the on-transient of exercise