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ABSTRACT: Leahy, MG, Kipp, S, and Sheel, AW. The effect of waistbands on intra-abdominal pressure and respiratory mechanics during bodyweight exercise. J Strength Cond Res XX(X): 000-000, 2024-Athletic apparel is often designed with high-waisted, elastic bands around the abdomen to provide comfort and support during functional exercises. The abdominal musculature aids in both active respiration and trunk stability during the exercise, but whether high-waistband athletic garments affect pulmonary function and respiratory mechanics is unknown. Ten healthy women participated in a single-visit study. Subjects were fitted with esophageal and gastric balloon-tipped catheters and completed three bouts of isometric and dynamic bodyweight squats, lunges, and planks, during which ventilation and pulmonary pressures were continuously recorded. Resting pulmonary function was unchanged by high-waistband garments. During isometric squatting exercise, peak abdominal pressure was significantly greater while wearing high-waistband garments (17 ± 6 cmH2O), relative to low-waistband garments (15 ± 6 cmH2O, p = 0.032). The work of breathing was reduced when completing dynamic squat exercise in a high-waistband garment (16.2 ± 3.9 J·min-1), relative to a low-waistband garment (18.6 ± 5.7 J·min-1, p = 0.026). High waistbands had no effect on abdominal pressures or pulmonary mechanics during lunge or plank exercises. We believe our findings indicate that high-waistband garments have the capacity to alter abdominal and ventilatory mechanics during bodyweight squatting exercises but are unlikely to have an effect during other exercise movements.
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Cardiac output (QÌC) and leg blood flow (QÌLEG) can be measured simultaneously with high accuracy using transpulmonary and femoral vein thermodilution with a single-bolus injection. The invasive measure has offered important insight into leg hemodynamics and blood flow distribution during exercise. Despite being the natural modality of exercise in humans, there has been no direct measure of QÌLEG while running in humans. We sought to determine the feasibility of the thermodilution technique for measuring QÌLEG and conductance during high-intensity running, in an exploratory case study. A trained runner (30 years male) completed two maximal incremental tests on a cycle ergometer and motorized treadmill. QÌLEG and QÌC were determined using the single-bolus thermodilution technique. Arterial and venous blood were sampled throughout exercise, with continuous monitoring of metabolism, intra-arterial and venous pressure, and temperature. The participant reached a greater peak oxygen uptake (VÌO2peak) during running relative to cycling (74 vs. 68 mL/kg/min) with comparable QÌLEG (19.0 vs. 19.5 L/min) and QÌC (27.4 vs. 26.2 L/min). Leg vascular conductance was greater during high-intensity running relative to cycling (82 vs. 70 mL/min/mmHg @ ~80% VÌO2peak). The "beat phenomenon" was apparent in femoral flow while running, producing large gradients in conductance (62-90 mL/min/mmHg @ 70% VÌO2peak). In summary, we present the first direct measure of QÌLEG and conductance in a running human. Our findings corroborate several assumptions about QÌLEG during running compared with cycling. Importantly, we demonstrate that using thermodilution in running exercise can be completed effectively and safely.
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Gasto Cardíaco , Pierna , Consumo de Oxígeno , Flujo Sanguíneo Regional , Carrera , Termodilución , Humanos , Termodilución/métodos , Gasto Cardíaco/fisiología , Carrera/fisiología , Masculino , Pierna/irrigación sanguínea , Pierna/fisiología , Adulto , Consumo de Oxígeno/fisiología , Flujo Sanguíneo Regional/fisiología , Prueba de Esfuerzo/métodosRESUMEN
Given that 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 (VÌo2RM) for exercise ventilations in healthy younger and older males and females. Forty healthy participants (10 young males 24 ± 3 yr; 10 young females 24 ± 3 yr; 10 older males 63 ± 3 yr, 10 older females 63 ± 6 yr) mimicked their exercise breathing patterns (voluntary hyperpnea) in the absence of exercise across a range of exercise intensities. At peak exercise, VÌo2RM represented a significantly greater fraction of peak oxygen consumption (VÌo2peak) in young females, 12.7 ± 4.0%, compared with young males, 10.7 ± 3.0% (P = 0.027), whereas VÌo2RM represented 13.5 ± 2.3% of VÌo2peak 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 VÌo2RM (6.6 ± 1.9%) than the younger males (4.4 ± 1.3%; P = 0.012), and older females consuming a significantly greater fraction of VÌo2RM (6.9 ± 2.5%) than the younger females (5.1 ± 1.4%; P = 0.004) at 65% VÌemax. 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). Normal age-related changes in respiratory function, in addition to sex-based differences in airway anatomy, appear to influence the ventilatory responses and the cost incurred to breathe during exercise.NEW & NOTEWORTHY Here we show that at moderate and high-intensity exercise, older individuals incur a higher cost to breathe than their younger counterparts. However, as individuals age, the sex difference in the cost of breathing narrows. Collectively, our findings suggest that the normative age-related changes in respiratory structure and function, and sex differences in airway anatomy, appear to influence the ventilatory responses to exercise and the oxygen cost to breathe.
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Ejercicio Físico , Consumo de Oxígeno , Respiración , Humanos , Masculino , Femenino , Ejercicio Físico/fisiología , Persona de Mediana Edad , Consumo de Oxígeno/fisiología , Adulto , Adulto Joven , Anciano , Envejecimiento/fisiología , Factores de Edad , Factores Sexuales , Metabolismo Energético/fisiologíaRESUMEN
ABSTRACT: In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).
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Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Ciclofosfamida , Dexametasona , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Anciano , Masculino , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
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.
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Inhalación , Reflejo , Músculos Respiratorios , Sistema Nervioso Simpático , Humanos , Masculino , Femenino , Sistema Nervioso Simpático/fisiología , Adulto , Músculos Respiratorios/inervación , Músculos Respiratorios/fisiología , Adulto Joven , Factores Sexuales , Presión Arterial , Presión Sanguínea , Trabajo RespiratorioRESUMEN
INTRODUCTION: The demand for resources to support emotional and behavioural development in early childhood is ever increasing. However, conventional interventions are lacking in resources and have significant barriers. The Embers the Dragon programme helps address the growing unmet need of children requiring support. The delivery of the current project seeks to help support parents, reduce the burden placed on pressed services (eg, Child and Adolescent Mental Health Services) and to help improve the emotional and behavioural development of children. METHODS AND ANALYSIS: This project aims to investigate the efficacy and acceptability of Embers on parenting and children's psychosocial outcomes. 364 parents/guardians of children aged between 4 and 7 will be recruited via the internet, schools and general practitioners (GPs). This is an online waitlist-controlled trial with three arms: (1) control arm, (2) access to Embers arm and (3) access to Embers+school. Participants will be randomised (1:1) into (1) or (2) to evaluate the use of Embers at home. To evaluate scalability in schools, (3) will be compared with (2), and (1) to test efficacy against treatment as usual (not receiving the intervention). Qualitative interviews will also be conducted. Primary outcomes are the Parental Self-efficacy Scale, Strengths and Difficulties Questionnaire and qualitative interviews. Outcomes will be compared between the three groups at baseline, 8, 16 and 24 weeks. ETHICS AND DISSEMINATION: Ethical approval has been granted by the London South Bank University ethics panel (ETH2324-0004). To recruit via GPs, NHS ethical approval has been applied for, and the IRAS (331410) application is under consideration by the Central Bristol REC. The results of the project will be submitted for publication in a peer-reviewed journal. Parents/guardians will provide informed consent online prior to taking part in the study. For the interviews, assent will be taken from children by the researchers on the day. TRIAL REGISTRATION NUMBER: ISRCTN58327872.
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Servicios de Salud del Adolescente , Intervención basada en la Internet , Preescolar , Adolescente , Niño , Humanos , Emociones , Internet , Padres , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.
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Mielofibrosis Primaria , Pirimidinas , Calidad de Vida , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Pirimidinas/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Estudios Retrospectivos , Pirazoles/uso terapéutico , Benzamidas/uso terapéutico , Nitrilos/uso terapéuticoRESUMEN
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.
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Mecánica Respiratoria , Carrera , Humanos , Femenino , Carrera/fisiología , Mecánica Respiratoria/fisiología , Adulto , Trabajo Respiratorio/fisiología , Adulto Joven , Equipo Deportivo , Consumo de Oxígeno/fisiología , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
Transcription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical "MF-like" morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.
What is the context? We investigated TCF3 (transcription factor 3), a gene that regulates megakaryocyte development, for genomic and proteomic changes in myelofibrosis.Myelofibrosis is the aggressive phase of a group of blood cancers called myeloproliferative neoplasms, and abnormalities in development and maturation of megakaryocytes is thought to drive the development of myelofibrosis.What is new? We report detection of three novel TCF3 mutations in megakaryocytes and decreases in TCF3 protein and gene expression in primary megakaryocytes and platelets from patients with myelofibrosis.This is the first association between loss of TCF3 in megakaryocytes from patients and myelofibrosis.What is the impact? TCF3 dysregulation may be a novel mechanism that is responsible for the development of myelofibrosis and better understanding of this pathway could identify new drug targets.
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Megacariocitos , Mielofibrosis Primaria , Factor de Transcripción 3 , Humanos , Médula Ósea/patología , Megacariocitos/metabolismo , Policitemia Vera/genética , Policitemia Vera/metabolismo , Policitemia Vera/patología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Proteómica , Trombocitemia Esencial/patología , Factor de Transcripción 3/metabolismoRESUMEN
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% VÌO2peak). 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.
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Sistema Cardiovascular , Músculo Esquelético , Femenino , Humanos , Masculino , Presión Sanguínea/fisiología , Ejercicio Físico/fisiología , Terapia por Ejercicio , Fuerza de la Mano/fisiología , Frecuencia Cardíaca/fisiología , Músculo Esquelético/fisiología , Reflejo , Adulto Joven , AdultoRESUMEN
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.
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Platelets are small circulating fragments of cells that play important roles in thrombosis, haemostasis, immune response, inflammation and cancer growth. Although anucleate, they contain a rich RNA repertoire which offers an opportunity to characterise changes in platelet gene expression in health and disease. Whilst this can be achieved with conventional RNA sequencing, a large input of high-quality RNA, and hence blood volume, is required (unless a pre-amplification step is added), along with specialist bioinformatic skills for data analysis and interpretation. We have developed a transcriptomics next-generation sequencing-based approach that overcomes these limitations. Termed PlateletSeq, this method requires very low levels of RNA input and does not require specialist bioinformatic analytical skills. Here we describe the methodology, from sample collection to processing and data analysis. Specifically, blood samples can be stored for up to 8 days at 4 °C prior to analysis. Platelets are isolated using multi-step centrifugation and a purity of ≤ 1 leucocyte per 0.26x106 platelets is optimal for gene expression analysis. We have applied PlateletSeq to normal adult blood samples and show there are no age-associated variations and only minor gender-associated differences. In contrast, platelets from patients with myeloproliferative neoplasms show differences in platelet transcript profiles from normal and between disease subtypes. This illustrates the potential applicability of PlateletSeq for biomarker discovery and studying platelet biology in patient samples. It also opens avenues for assessing platelet quality in other fields such as transfusion research.
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Plaquetas , Neoplasias , Adulto , Humanos , Plaquetas/metabolismo , ARN/metabolismo , Biomarcadores/metabolismo , Leucocitos , Neoplasias/metabolismoRESUMEN
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 (VÌO2maxâ¡ = 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).
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Hipoxia , Consumo de Oxígeno , Humanos , Femenino , Ejercicio Físico , Oxígeno , AtletasRESUMEN
BACKGROUND: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. METHODS: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. RESULTS: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. CONCLUSIONS: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings.
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Inhibidores de las Cinasas Janus , Mielofibrosis Primaria , Humanos , Benzamidas , Inhibidores de las Cinasas Janus/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/diagnóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de VidaRESUMEN
BACKGROUND: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. METHODS: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). RESULTS: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54-5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19-3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42-3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01-4.68, P = 0.04). CONCLUSIONS: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.
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Sarcoma , Hipoxia Tumoral , Humanos , Reproducibilidad de los Resultados , Pronóstico , Biomarcadores de Tumor/genética , Sarcoma/genética , Sarcoma/patología , Hipoxia , Microambiente TumoralRESUMEN
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.
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Presión Arterial , Músculos Respiratorios , Masculino , Humanos , Femenino , Anciano , Músculos Respiratorios/fisiología , Presión Sanguínea/fisiología , Presión Arterial/fisiología , Reflejo/fisiología , Envejecimiento , Músculo Esquelético/fisiologíaRESUMEN
BACKGROUND: Predicting red cell transfusion may assist in identifying those most likely to benefit from patient blood management strategies. Our objective was to identify a simple statistical model to predict transfusion in elective surgery from routinely available data. MATERIALS AND METHODS: Our final multicentre cohort consisted of 42,546 patients and contained the following potential predictors of red cell transfusion known prior to admission: patient age, sex, pre-admission hemoglobin, surgical procedure, and comorbidities. Missing data were handled by multiple imputation methods. The outcome measure of interest was administration of a red cell transfusion. We used multivariable logistic regression models to predict transfusion, and evaluated the performance by applying a 10-fold cross-validation. Model accuracy was assessed by comparing the area under the receiver operating characteristics curve. After applying an optimal probability cut-off we measured model accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: 7.0% (n=2,993) of the study population received a red cell transfusion. Our most simple model predicted red cell transfusion based on admission hemoglobin and surgical procedure with a multiply imputed estimated area under the curve of 0.862 (0.856, 0.864). The estimated accuracy, sensitivity, specificity, positive predictive, and negative predictive values at the probability cut-off of 0.4 were 0.934, 0.257, 0.986, 0.573, and 0.946 respectively. DISCUSSION: A small number of variables available prior to admission can predict red cell transfusion with very good accuracy. Our model can be used to flag high-risk patients most likely to benefit from pre-operative patient blood management measures.
Asunto(s)
Transfusión Sanguínea , Transfusión de Eritrocitos , Humanos , Transfusión Sanguínea/métodos , Modelos Estadísticos , Modelos Logísticos , Hemoglobinas/análisis , Estudios Retrospectivos , Factores de RiesgoRESUMEN
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.