THE METABOLIC COST OF BREATHING FOR EXERCISE VENTILATIONS: EFFECTS OF AGE AND SEX.

Given there are both sex-based structural differences in the respiratory system and age-associated declines in pulmonary function, the purpose of this study was to assess the effects of age and sex on the metabolic cost of breathing (VO2RM) for exercise ventilations in healthy younger and older, males and females. METHODS: Forty healthy participants (10 young males 23±3yrs; 10 young females 23±3yrs; 10 older males 63±3yrs, 10 older females 63±6yrs) mimicked their exercise breathing patterns in the absence of exercise across a range of exercise intensities. RESULTS: At peak exercise, VO2RM represented a significantly greater fraction of peak oxygen consumption (VO2peak) in young females, 12.8±3.9%, compared to young males, 10.7±3.0% (P=0.027), while VO2RM represented 13.5±2.3% of VO2peak in older females and 13.2±3.3% in older males. At relative ventilations, there was a main effect of age, with older males consuming a significantly greater fraction of VO2RM (6.6%±1.9)than younger males (4.4%±1.3;P=0.012), and older females consuming a significantly greater fraction of VO2RM (6.9%±2.5)than younger females (5.1%±1.4;P=0.004) at 65% max. Furthermore, both younger and older males had significantly better respiratory muscle efficiency than their female counterparts at peak exercise (P=0.011;P=0.015). Similarly younger participants were significantly more efficient than older participants (6.5%±1.5% vs. 5.5±2.0%;P=0.001). CONCLUSION: Age-related changes in respiratory function, and sex-based differences in airway anatomy, influence the cost to breathe during exercise. It is possible the higher fraction of VO2RM during peak exercise predispose young females and older individuals to divert more blood flow to respiratory muscles at the expense of other muscles.

Reflex sympathetic activation to inspiratory muscle loading is attenuated in females relative to males.

Intense inspiratory muscle work can evoke a metabolite-stimulated pressor reflex, commonly referred to as the respiratory muscle metaboreflex. When completing similar relative and absolute levels of inspiratory work, females have an attenuated blood pressure response. We sought to test the hypothesis that the lower blood pressure response to the respiratory muscle metaboreflex in females is associated with a reduced sympathetic response. Healthy young (26 ± 4 yr) males (n = 9) and females (n = 7) completed two experimental days. On day 1, participants completed pulmonary function testing and became familiarized with an inspiratory pressure-threshold loading (PTL) task. On the second day, balloon-tipped catheters were placed in the esophagus and stomach to measure pleural and gastric pressures, and transdiaphragmatic pressure was calculated. A microelectrode was inserted into the fibular nerve to quantify muscle sympathetic nerve activity (MSNA), and participants then completed isocapnic PTL to task failure. There was a significant sex-by-time interaction in the mean arterial pressure (MAP, P = 0.015) and burst frequency (P = 0.039) response to PTL. Males had a greater rise in MAP (Δ21 ± 9 mmHg) than females (Δ13 ± 5 mmHg, P = 0.026). Males also demonstrated a greater rise in MSNA burst frequency (Δ18 ± 7 bursts/min) than females (Δ10 ± 5 bursts/min, P = 0.015). The effect of sex was observed despite females and males completing the same magnitude of diaphragm work throughout the task (P = 0.755). Our findings provide novel evidence that the lower blood pressure response to similar relative and absolute inspiratory muscle work in females is associated with lower sympathetic activation.NEW & NOTEWORTHY The blood pressure response to high levels of inspiratory muscle work is lower in females and occurs alongside a reduced sympathetic response. The reduced blood pressure and sympathetic response occur despite males and females performing similar levels of absolute inspiratory work. Our findings provide evidence that sex differences in the respiratory muscle metaboreflex are, in part, sympathetically mediated.

Sports Bra Restriction on Respiratory Mechanics during Exercise.

PURPOSE: We set out to understand how underband tightness or pressure of a sports bra relates to respiratory function and the mechanical work of breathing ( during exercise. Our secondary purpose was to quantify the effects of underband pressure on O 2 during submaximal running. METHODS: Nine highly trained female runners with normal pulmonary function completed maximal and submaximal running in three levels of underband restriction: loose, self-selected, and tight. RESULTS: During maximal exercise, we observed a significantly greater during the tight condition (350 ± 78 J·min -1 ) compared with the loose condition (301 ± 78 J·min -1 ; P < 0.05), and a 5% increase in minute ventilation ( ) during the tight condition compared with the loose condition ( P < 0.05). The pattern of breathing also differed between the two conditions; the greater maximal during the tight condition was achieved by a higher breathing frequency (57 ± 6 vs. 52 ± 7 breaths·min -1 ; P < 0.05), despite tidal volume being significantly lower in the tight condition compared with the loose condition (1.97 ± 0.20 vs. 2.05 ± 0.23 L; P < 0.05). During steady-state submaximal running, O 2 increased 1.3 ± 1.1% (range: -0.3 to 3.2%, P < 0.05) in the tight condition compared with the loose condition. CONCLUSIONS: Respiratory function may become compromised by the pressure exerted by the underband of a sports bra when women self-select their bra size. In the current study, loosening the underband pressure resulted in a decreased work of breathing, changed the ventilatory breathing pattern to deeper, less frequent breaths, and decreased submaximal oxygen uptake (improved running economy). Our findings suggest sports bra underbands can impair breathing mechanics during exercise and influence whole-body metabolic rate.

The human skeletal muscle metaboreflex contribution to cardiorespiratory control in males and females in dynamic exercise.

There is a significant effect of sex and muscle mass on the cardiorespiratory response to the skeletal muscle metaboreflex during isometric exercise. We therefore tested the hypothesis that sex differences would be present when isolated following dynamic exercise. We also tested the hypothesis that single and double leg post-exercise circulatory occlusion (PECO) following heavy exercise would elicit a cardiorespiratory response proportional to the absolute muscle mass. Healthy (24 ± 4 years) males (n = 10) and females (n = 10) completed pulmonary function and an incremental cycle test to exhaustion. Participants completed two randomized, 6 min bouts of intense cycle exercise (84 ± 7% V̇O2peak). One exercise bout was immediately followed by 3 min PECO (220 mmHg) of the legs while the other exercise bout was followed by passive recovery. Males completed an additional session of testing with single leg PECO. The mean arterial pressure during PECO and control was greater in males compared to females (p = 0.004). The was a significant time by condition by sex interaction in the heart rate response to PECO (p = 0.027). There was also a significant condition by sex interaction in the ventilatory response to PECO (p = 0.026). In males, we observed a dose-dependent cardiovascular, but not ventilatory, response to muscle mass occluded (all p < 0.05). Our findings suggest the metaboreflex contribution to cardiorespiratory control during dynamic exercise is greater in males compared to females. The ventilatory response induced by double-leg occlusion but not single-leg occlusion, suggests that the ventilatory influence of the metaboreflex is less sensitive than the cardiovascular response and may be linked to the greater afferent activation induced by double-leg occlusion.

Exercise-induced arterial hypoxemia in female masters athletes.

The purpose of the study was to characterize exercise induced arterial hypoxemia (EIAH) in female masters athletes (FMA). We hypothesized that FMA would experience EIAH during treadmill running. Eight FMA (48-57 years) completed pulmonary function testing and an incremental exercise test until exhaustion (V̇O2max⁡ = 45.7 ± 6.5, range:35-54 ml/kg/min). On a separate day, the participants were instrumented with a radial arterial catheter and an esophageal temperature probe. Participants performed three to four constant load exercise tests at 60-70 %, 75 %, 90 %, 95 %, and 100 % of maximal oxygen uptake while sampling arterial blood and recording esophageal temperature. We found that FMA decrease their partial pressure of oxygen (86.0 ± 7.6, range:73-108 mmHg), arterial saturation (96.2 ± 1.2, range:93-98 %), and widen their alveolar to arterial oxygen difference (23.2 ± 8.8, range:5-42 mmHg) during all exercise intensities however, with variability in terms of severity and pattern. Our findings suggest that FMA experience EIAH however aerobic fitness appears unrelated to occurrence or severity (r = 0.13, p = 0.756).

Effects of sex and ageing on the human respiratory muscle metaboreflex.

Intense inspiratory muscle work evokes a sympathetically mediated pressor reflex, termed the respiratory muscle metaboreflex, in which young females demonstrate an attenuated response relative to males. However, the effects of ageing and female sex hormones on the respiratory muscle metaboreflex are unclear. We tested the hypothesis that the pressor response to inspiratory work would be similar between older males and females, and higher relative to their younger counterparts. Healthy, normotensive young (26 ± 3 years) males (YM; n = 10) and females (YF; n = 10), as well as older (64 ± 5 years) males (OM; n = 10) and females (OF; n = 10), performed inspiratory pressure threshold loading (PTL) to task failure. Older adults had a greater mean arterial pressure (MAP) response to PTL than young (P < 0.001). YF had a lower MAP compared to YM (+10 ± 6 vs. +19 ± 15 mmHg, P = 0.026); however, there was no difference observed between OF and OM (+26 ± 11 vs. +27 ± 11 mmHg, P = 0.162). Older adults had a lower heart rate response to PTL than young (P = 0.002). There was no effect of sex between young females and males (+19 ± 9 and +27 ± 11 bpm, P = 0.186) or older females and males (+17 ± 7 and +20 ± 7 bpm, P = 0.753). We conclude the respiratory muscle metaboreflex response is heightened in older adults, and the sex effect between older males and post-menopause females is absent, suggesting an effect of circulating sex hormones. KEY POINTS: The arterial blood pressure response to the respiratory muscle metaboreflex is greater in older males and females. Compared to sex-matched young individuals, there is no sex differences in the blood pressure response between older males and post-menopause females. Our results suggest the differences between males and females in the cardiovascular response to high levels of inspiratory muscle work is abolished with reduced circulating female sex hormones.

The effect of proportional assist ventilation on the electrical activity of the human diaphragm during exercise.

NEW FINDINGS: What is the central question of this study? What is the effect of lowering the normally occurring work of breathing on the electrical activity and pressure generated by the diaphragm during submaximal exercise in healthy humans? What is the main finding and its importance? Ventilatory assist during exercise elicits a proportional lowering of both the work performed by the diaphragm and diaphragm electrical activity. These findings have implications for exercise training studies using proportional assist ventilation to reduce diaphragm work in patients with cardiopulmonary disease. ABSTRACT: We hypothesized that when a proportional assist ventilator (PAV) is applied in order to reduce the pressure generated by the diaphragm, there would be a corresponding reduction in electrical activity of the diaphragm. Healthy participants (five male and four female) completed an incremental cycle exercise test to exhaustion in order to calculate workloads for subsequent trials. On the experimental day, participants performed submaximal cycling, and three levels of assisted ventilation were applied (low, medium and high). Ventilatory parameters, pulmonary pressures and EMG of the diaphragm (EMGdi ) were obtained. To compare the PAV conditions with spontaneous breathing intervals, ANOVA procedures were used, and significant effects were evaluated with a Tukey-Kramer test. Significance was set at P < 0.05. The work of breathing was not different between the lowest level of unloading and spontaneous breathing (P = 0.151) but was significantly lower during medium (25%, P = 0.02) and high (36%, P < 0.001) levels of PAV. The pressure-time product of the diaphragm (PTPdi ) was lower across PAV unloading conditions (P < 0.05). The EMGdi was significantly lower in medium and high PAV conditions (P = 0.035 and P < 0.001, respectively). The mean reductions of EMGdi with PAV unloading were 14, 22 and 39%, respectively. The change in EMGdi for a given lowering of PTPdi with the PAV was significantly correlated (r = 0.61, P = 0.01). Ventilatory assist during exercise elicits a reduction in the electrical activity of the diaphragm, and there is a proportional lowering of the work of breathing. Our findings have implications for exercise training studies using assisted ventilation to reduce diaphragm work in patients with cardiopulmonary disease.

Perceived exertion and dyspnea while cycling during a hypoxic and hyperoxic placebo.

Rating of perceived exertion (RPE) is used to subjectively quantify the perception of physical activity, breathlessness or dyspnea, and leg discomfort (RPElegs) during exercise. However, it is unknown how dyspnea or RPElegs can be influenced by expectations. Thirty healthy, active participants (19 males, 11 females) completed five, 5-minute submaximal cycling trials at 60% peak work rate. We deceived participants by telling them they were inspiring different hypoxic and hyperoxic gases, when in fact they breathed room air. Cardiorespiratory variables were similar between the trials, however, dyspnea and RPElegs evaluated with a Borg scale changed in a dose-response manner. When participants believed they were breathing 15% O2, they significantly increased dyspnea +0.70 ± 0.2 units (p = 0.03) compared to room air, whereas RPElegs was unchanged +0.35 ± 0.1 units (p = 0.70). When participants believed they were breathing 15% O2, they significantly increased dyspnea +1.05 ± 0.4 units (p = 0.003) compared to 23% hyperoxic condition, whereas RPElegs was unchanged +0.35 ± 0.1 units (p = 0.70). We found that dyspnea during exercise is susceptible to expectancy, without any accompanying physiological changes. Given coaches and clinicians use perceived exertion to prescribe exercise intensity and evaluate treatments, our findings show that the effect of expectations must be considered when interpreting sensations of breathlessness.

Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 "CREATE" Trial.

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 "CREATE" phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan-Meier estimates, Cox regression, and the Fisher's exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.

Airway luminal area and the resistive work of breathing during exercise in healthy young females and males.

We examined the relationship between the work of breathing (Wb) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive Wb during exercise in females. Healthy participants (n = 11 females and n = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where Wb was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm2 vs. females: 27.5 ± 7.4 mm2) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm2 vs. females: 1,594 ± 389 mm2) were significantly larger in males (both P = 0.003). When minute ventilation was greater than ∼60 L·min-1, the resistive Wb was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size (r = 0.524, P = 0.012) and Weibel area (r = 0.525, P = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive Wb during exercise in females compared with males.NEW & NOTEWORTHY We hypothesized that the higher resistive work of breathing in females compared with males during high-intensity exercise is due to smaller airways. In vivo measures of the fourth to eighth airway generations made using optical coherence tomography show that females tend to have smaller airway luminal areas of the fourth to sixth airway generations. Sex differences in airway luminal area result in a greater resistive work of breathing during exercise in females compared with males.

Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE.

PURPOSE: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. PATIENTS/METHODS: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. RESULTS: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. CONCLUSION: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. CLINICAL TRIAL NUMBER: EORTC 90101, NCT01524926.

Respiratory modulation of sympathetic vasomotor outflow during graded leg cycling.

Respiratory modulation of sympathetic vasomotor outflow to skeletal muscles (muscle sympathetic nerve activity; MSNA) occurs in resting humans. Specifically, MSNA is highest at end-expiration and lowest at end-inspiration during quiet, resting breathing. We tested the hypothesis that within-breath modulation of MSNA would be amplified during graded leg cycling. Thirteen (n = 3 females) healthy young (age: 25.2 ± 4.7 yr) individuals completed all testing. MSNA (right median nerve) was measured at rest (baseline) and during semirecumbent cycle exercise at 40%, 60%, and 80% of maximal workload (Wmax). MSNA burst frequency (BF) was 20.0 ± 4.0 bursts/min at baseline and was not different during exercise at 40%Wmax (21.3 ± 3.7 bursts/min; P = 0.292). Thereafter, MSNA BF increased significantly compared with baseline (60%Wmax: 31.6 ± 5.8 bursts/min; P < 0.001, 80%Wmax: 44.7 ± 5.3 bursts/min; P < 0.001). At baseline and all exercise intensities, MSNA BF was lowest at end-inspiration and greatest at mid-to-end expiration. The within-breath change in MSNA BF (ΔMSNA BF; end-expiration minus end-inspiration) gradually increased from baseline to 60%Wmax leg cycling, but no further increase appeared at 80%Wmax exercise. Our results indicate that within-breath modulation of MSNA is amplified from baseline to moderate intensity during dynamic exercise in young healthy individuals, and that no further potentiation occurs at higher exercise intensities. Our findings provide an important extension of our understanding of respiratory influences on sympathetic vasomotor control.NEW & NOTEWORTHY Within-breath modulation of sympathetic vasomotor outflow to skeletal muscle (muscle sympathetic nerve activity; MSNA) occurs in spontaneously breathing humans at rest. It is unknown if respiratory modulation persists during dynamic whole body exercise. We found that MSNA burst frequency was lowest at end-inspiration and highest at mid-to-end expiration during rest and graded leg cycling. Respiratory modulation of sympathetic vasomotor outflow remains intact and is amplified during dynamic whole body exercise.

An integrative approach to the pulmonary physiology of exercise: when does biological sex matter?

Historically, many studies investigating the pulmonary physiology of exercise (and biomedical research in general) were performed exclusively or predominantly with male research participants. This has led to an incomplete understanding of the pulmonary response to exercise. More recently, important sex-based differences with respect to the human respiratory system have been identified. The purpose of this review is to summarize current findings related to sex-based differences in the pulmonary physiology of exercise. To that end, we will discuss how morphological sex-based differences of the respiratory system affect the respiratory response to exercise. Moreover, we will discuss sex-based differences of the physiological integrative responses to exercise, and how all these differences can influence the regulation of breathing. We end with a brief discussion of pregnancy and menopause and the accompanying ventilatory changes observed during exercise.

Partitioning the work of breathing during running and cycling using optoelectronic plethysmography.

Work of breathing ([Formula: see text]) derived from a single lung volume and pleural pressure is limited and does not fully characterize the mechanical work done by the respiratory musculature. It has long been known that abdominal activation increases with increasing exercise intensity, yet the mechanical work done by these muscles is not reflected in [Formula: see text]. Using optoelectronic plethysmography (OEP), we sought to show first that the volumes obtained from OEP (VCW) were comparable to volumes obtained from flow integration (Vt) during cycling and running, and second, to show that partitioned volume from OEP could be utilized to quantify the mechanical work done by the rib cage ([Formula: see text]RC) and abdomen ([Formula: see text]AB) during exercise. We fit 11 subjects (6 males/5 females) with reflective markers and balloon catheters. Subjects completed an incremental ramp cycling test to exhaustion and a series of submaximal running trials. We found good agreement between VCW versus Vt during cycling (bias = 0.002; P > 0.05) and running (bias = 0.016; P > 0.05). From rest to maximal exercise,[Formula: see text]AB increased by 84% (range: 30%-99%; [Formula: see text]AB: 1 ± 1 J/min to 61 ± 52 J/min). The relative contribution of the abdomen increased from 17 ± 9% at rest to 26 ± 16% during maximal exercise. Our study highlights and provides a quantitative measure of the role of the abdominal muscles during exercise. Incorporating the work done by the abdomen allows for a greater understanding of the mechanical tasks required by the respiratory muscles and could provide further insight into how the respiratory system functions during disease and injury.NEW & NOTEWORTHY We demonstrated that optoelectronic plethysmography (OEP) is a reliable tool to determine ventilatory volume changes during cycling and running, without restricting natural upper arm movements. Second, using OEP volumes coupled with pressure-derived measures, we calculated the work done by the rib cage and abdomen, respectively, during exercise. Collectively, our findings indicate that pulmonary mechanics can be accurately quantified using OEP, and abdominal work performed during ventilation contributes substantially to the overall work of the respiratory musculature.

Near-infrared spectroscopy measures of sternocleidomastoid blood flow during exercise and hyperpnoea.

NEW FINDINGS: What is the central question of this study? How does sternocleidomastoid blood flow change in response to increasing ventilation and whole-body exercise intensity? What is the main finding and its importance? Sternocleidomastoid blood flow increased with increasing ventilation. For a given ventilation, sternocleidomastoid blood flow was lower during whole-body exercise compared to resting hyperpnoea. These findings suggest that locomotor muscle work exerts an effect on respiratory muscle blood flow that can be observed in the sternocleidomastoid. ABSTRACT: Respiratory muscle work influences the distribution of blood flow during exercise. Most studies have focused on blood flow to the locomotor musculature rather than the respiratory muscles, owing to the complex anatomical arrangement of respiratory muscles. The purpose of this study was to examine how accessory respiratory (i.e. sternocleidomastoid, and muscles in the intercostal space) muscle blood flow changes in response to locomotor muscle work. Seven men performed 5 min bouts of constant load cycling exercise trials at 30%, 60% and 90% of peak work rate in a randomized order, followed by 5 min bouts of voluntary hyperpnoea (VH) matching the ventilation achieved during each exercise (EX) trial. Blood-flow index (BFI) of the vastus lateralis, sternocleidomastoid (SCM) and seventh intercostal space (IC) were estimated using near-infrared spectroscopy and indocyanine green and expressed relative to resting levels. BFISCM was greater during VH compared to EX (P = 0.002) and increased with increasing exercise intensity (P = 0.036). BFISCM reached 493 ± 219% and 301 ± 215% rest during VH and EX at 90% peak work rate, respectively. BFIIC increased to 242 ± 178% and 210 ± 117% rest at 30% peak work rate during VH and EX, respectively. No statistically significant differences in BFIIC were observed with increased work rate during VH or EX (both P > 0.05). Moreover, there was no observed difference in BFIIC between conditions (P > 0.05). BFISCM was lower for a given minute ventilation during EX compared to VH, suggesting that accessory respiratory muscle blood flow is influenced by whole-body exercise.

Diaphragm fatigue and inspiratory muscle metaboreflex in men and women matched for absolute diaphragmatic work during pressure-threshold loading.

KEY POINTS: The female diaphragm fatigues at a slower rate compared to that of males, with blunted cardiovascular consequences (i.e. inspiratory muscle metaboreflex). It is unclear if these findings are a function of relative or absolute diaphragmatic work. We asked if sex differences in diaphragm fatigue and the inspiratory muscle metaboreflex persisted during inspiratory loading performed at equal absolute intensities. We found that matching men and women for absolute diaphragmatic work resulted in an equal degree of diaphragm fatigue, despite women performing significantly greater work relative to body mass. Metabolite-induced reflex influences in sympathetic outflow originating from the diaphragm are attenuated in women, with potential implications for blood flow distribution during exercise. ABSTRACT: In response to inspiratory pressure-threshold loading (PTL), women have greater inspiratory muscle endurance time, slower rate of diaphragm fatigue development, and a blunted pressor response compared to men. It is unclear if these differences are due to discrepancies in absolute diaphragm force output. We tested the hypothesis that following inspirations performed at equal absolute intensities, females would develop a similar level of diaphragm fatigue and an attenuated cardiovascular response relative to men. Healthy young men (n = 8, age = 24 ± 3 years) and women (n = 8, age = 23 ± 3 years) performed PTL whilst targeting a transdiaphragmatic pressure (Pdi ) of 92 cmH2 O for 5 min. Diaphragm fatigue was assessed via twitch Pdi (Pdi,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial blood pressure were monitored continuously. During PTL, the absolute amount of diaphragm work was not different between men (13,399 ± 2019 cmH2 O s) and women (12,986 ± 1846 cmH2 O s; P > 0.05); however, women performed the PTL task at a higher relative P¯di /Pdi,max . Following inspiratory PTL, the magnitude of reduction in Pdi,tw was similar between men (-27.1 ± 7.2%) and women (-23.8 ± 13.8%; P > 0.05). There were significant increases in HR over time (P < 0.05), but this did not differ on the basis of sex (P > 0.05). Mean arterial blood pressure increased significantly over time in both men and women (P < 0.05); however, the rate of change was higher in men (6.24 ± 2.54 mmHg min-1 ) than in women (4.15 ± 2.52 mmHg min-1 ) (P < 0.05). We conclude that the female diaphragm is protected against severe fatigue when inspiratory work is excessive and as a result does not evoke overt sympathoexcitation.

The Mechanics of Breathing during Swimming.

The thorax undergoes unique conditions while swimming. Hydrostatic pressure from water immersion places an external load on the thorax and increases airway resistance, and the horizontal body position results in central venous engorgement and an associated reduction in lung compliance. The aforementioned factors likely increase the work of breathing (Wb); however, this hypothesis remains untested. PURPOSE: This study aimed to compare Wb during freestyle swimming relative to cycling and to characterize the differences in the cardiorespiratory responses to swimming relative to cycling in the same individuals. METHODS: Eight collegiate swimmers (four men and four women, age = 22 ± 2 yr) performed an incremental swim test while tethered to a resistance apparatus. On a separate day, subjects performed an incremental cycle test. During swimming and cycling, metabolic and ventilatory parameters were measured using a customized metabolic cart, and inspired Wb was quantified using an esophageal balloon catheter. RESULTS: Swimming and cycling elicited statistically similar levels of peak oxygen uptake (3.87 ± 0.92 vs 4.20 ± 0.83 L·min, P = 0.143). However, peak minute ventilation (V˙E) (118 ± 3 vs 154 ± 25 L·min) and heart rate (164 ± 19 vs 183 ± 8 bpm) were significantly lower during swimming relative to cycling (both P < 0.05). Inspired Wb was higher at a V˙E of 50 L·min (+27 ± 16 J·min), 75 L·min (+56 ± 23 J·min), and 100 L·min (+53 ± 22 J·min) during swimming compared with cycling (all P < 0.05). Periods of interbreath apnea were observed while swimming (duration = 0.13-2.07 s). CONCLUSION: We interpret our findings to mean that the horizontal body position and hydrostatic pressure on the chest wall requires swimmers to generate greater inspiratory pressures to sustain adequate V˙E during exercise.

Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.

BACKGROUND: An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. METHODS: We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926. FINDINGS: Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358-1304). Six of 12 ALK-positive patients (50%, 95% CI 21·1-78·9) and one of seven ALK-negative patients (14%, 0·0-57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. INTERPRETATION: With 50% of participants with ALK-positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK-positive IMFT who do not qualify for curative surgery. FUNDING: The European Organisation for Research and Treatment of Cancer and Pfizer.

The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 'CREATE'.

BACKGROUND: Alveolar rhabdomyosarcomas (ARMSs) can harbour MET and anaplastic lymphoma kinase (ALK) alterations. We prospectively assessed crizotinib in patients with advanced/metastatic ARMS. METHODS: Eligible patients with a central diagnosis of ARMS received oral crizotinib 250 mg twice daily. Patients were attributed to MET/ALK+ or MET/ALK- subcohorts by assessing the presence or absence of the forkhead box O1 (FOXO1; a marker of MET upregulation) and/or ALK gene rearrangement. The primary end-point was the objective response rate (ORR). Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS) and safety. FINDINGS: Nineteen of 20 consenting patients had centrally confirmed ARMS. Molecular assessment revealed rearrangement of FOXO1 in 17 tumours and ALK in none. Thirteen eligible patients were treated, but only eight were evaluable for the primary end-point because of the observed aggressiveness of the disease. Among seven evaluable MET+/ALK- patients, only one achieved a confirmed partial response (ORR: 14.3%; 95% confidence interval [CI]: 0.3-57.8) with a DOR of 52 d. Further MET+/ALK- efficacy end-points were DCR: 14.3% (95% CI: 0.3-57.8), median PFS: 1.3 months (95% CI: 0.5-1.5) and median OS: 5.6 months (95% CI: 0.7-7.0). The remaining MET+/ALK- and MET-/ALK- patients had early progression as best response. Common treatment-related adverse events were fatigue (5/13 [38.5%]), nausea (4/13 [30.8%]), anorexia (4/13 [30.8%]), vomiting (2/13 [15.4%]) and constipation (2/13 [15.4%]). All 13 treated patients died early because of progressive disease. INTERPRETATION: Crizotinib is well tolerated but lacks clinically meaningful activity as a single agent in patients with advanced metastatic ARMS. Assessing single agents in aggressive, chemotherapy-refractory ARMS is challenging, and future trials should explore established chemotherapy ± investigational compounds in earlier lines of treatment. CLINICAL TRIAL NUMBER: EORTC 90101, ClinicalTrials.gov NCT01524926.