Resolving Differences between MLSS and CP by Considering Rates of Change of Blood Lactate during Endurance Exercise.

PURPOSE: To develop a new method that more closely represents the heavy-to-severe exercise domain boundary by evaluating the rates of blood lactate accumulation during the constant power output exercise bouts that are employed in the assessment of the maximal lactate steady state (MLSS). METHODS: Eight well-trained male cyclists completed five exercise tests of up to 30 min for determination of the traditional MLSS (MLSSTRAD) and a further four maximal tests for determination of critical power (CP). The rates of change of blood [lactate] between 10 min and the end of exercise in the MLSS tests were plotted against the corresponding power outputs and a two-segment linear regression model was used to identify individualised breakpoints in lactate accumulation vs. power output (MLSSMOD). RESULTS: MLSSMOD was significantly higher than MLSSTRAD (297 ± 41 vs. 278 ± 41 W; P < 0.001) but was not significantly different from CP (297 ± 41 W; P > 0.05); MLSSMOD and CP were closely aligned (r: 0.97; Bias: -0.52 W; SEE: 10 W; Limits of Agreement: -20 to 19 W). The rates of change of both blood [lactate] and V̇O2 were significantly greater, and exercise intolerance occurred before 30 min, at a power output slightly above MLSSMOD. CONCLUSIONS: A novel method for evaluating blood lactate kinetics during a traditional MLSS protocol produces a modified MLSS that is not different from CP and better represents the heavy-to-severe exercise domain boundary.

Critical Power and Maximal Lactate Steady State in Cycling: "Watts" the Difference?

From a physiological perspective, the delineation between steady-state and non-steady-state exercise, also referred to as the maximal metabolic steady state, holds paramount importance for evaluating athletic performance and designing and monitoring training programs. The critical power and the maximal lactate steady state are two widely used indices to estimate this threshold, yet previous studies consistently reported significant discrepancies between their associated power outputs. These findings have fueled the debate regarding the interchangeability of critical power and the maximal lactate steady state in practice. This paper reviews the methodological intricacies intrinsic to the determination of these thresholds, and elucidates how inappropriate determination methods and methodological inconsistencies between studies have contributed to the documented differences in the literature. Through a critical examination of relevant literature and by integration of our laboratory data, we demonstrate that differences between critical power and the maximal lactate steady state may be reconciled to only a few Watts when applying appropriate and strict determination criteria, so that both indices may be used to estimate the maximal metabolic steady-state threshold in practice. To this end, we have defined a set of good practice guidelines to assist scientists and coaches in obtaining the most valid critical power and maximal lactate steady state estimates.

Effect of Supplemental Oxygen on Physiological Responses to Exercise in Fibrotic Interstitial Lung Disease.

PURPOSE: We studied the effect of O2 supplementation on physiological response to exercise in patients with moderate to severe interstitial lung disease (ILD). METHODS: 13 patients (age 66 ± 10 yrs., 7 males) with ILD (TLC 71 ± 22% predicted, carbon monoxide diffusion capacity (DLCO) 44 ± 16% predicted) and 13 healthy individuals (age 50 ± 17 yrs., 7 males) were tested. ILD patients performed symptom-limited cardiopulmonary exercise tests and constant work-rate tests (CWRTs) at 80% of the work-rate (WR) at the gas exchange threshold (GET). Tests breathing room air (RA, 21% O2) were compared to tests performed breathing 30% O2. Oxygen-uptake (V̇O2) kinetics were calculated from the CWRT results. RESULTS: In the ILD group, peak WR, peak V̇O2 and V̇O2 at the GET improved significantly when breathing 30% O2 compared to RA (mean ± SD 66 ± 23 vs 75 ± 26 watts, 15 ± 2 vs 17 ± 4 ml/kg/min and 854 ± 232 vs 932 ± 245 ml/min; p = 0.004, p = 0.001 and p = 0.01, respectively). O2 saturation (SPO2%) at peak exercise was higher with 30% O2 (97 ± 4% vs 88 ± 9%, p = 0.002). The time constant (tau) of V̇O2 kinetics was faster in ILD patients while breathing 30% O2 (41 ± 10 sec) compared to RA (52 ± 14 sec, p = 0.003). There was a negative linear relation between tau and SPO2% with RA (r = -0.76, p = 0.006) and while breathing 30% O2 (r = -0.68, p = 0.02). CONCLUSIONS: Using a clinically applicable level of O2 supplementation (30%) improved maximal, aerobic exercise capacity and V̇O2 kinetics in ILD patients, likely due to increased blood O2 content subsequently increasing the O2 delivery to the working muscles.

Inequality of opportunity in the double burden of malnutrition in Mexico.

This paper proposes a pseudo-birth-cohort approach to deal with a lack of longitudinal data to measure health inequities over time. Using Roemer's framework for inequality of opportunity, this study measures ex-ante and ex-post inequalities in malnutrition, a concept that spans both sides of the nutrition continuum. The total contribution of observed circumstances and the direct contribution of observed efforts to the variation of malnutrition are disentangled for people born between 1983 and 1988 in Mexico. Results indicate that inequality of opportunity has been persistent across this 30-year lifespan for that cohort. Some evidence suggests that a lack of opportunities has been transmitted from parents to children and that people's circumstances account for most of the explained variation in the double burden of malnutrition. However, stratifying the analysis by sex shows that efforts account for more of the explained variation of inequality of opportunity for women in their middle adulthood than for men in most of the outcomes analyzed.

Relationships between nitric oxide biomarkers and physiological outcomes following dietary nitrate supplementation.

Dietary nitrate (NO3-) supplementation can increase nitric oxide (NO) bioavailability, reduce blood pressure (BP) and improve muscle contractile function in humans. Plasma nitrite concentration (plasma [NO2-]) is the most oft-used biomarker of NO bioavailability. However, it is unclear which of several NO biomarkers (NO3-, NO2-, S-nitrosothiols (RSNOs)) in plasma, whole blood (WB), red blood cells (RBC) and skeletal muscle correlate with the physiological effects of acute and chronic dietary NO3- supplementation. Using a randomized, double-blind, crossover design, 12 participants (9 males) consumed NO3--rich beetroot juice (BR) (∼12.8 mmol NO3-) and NO3--depleted placebo beetroot juice (PL) acutely and then chronically (for two weeks). Biological samples were collected, resting BP was assessed, and 10 maximal voluntary isometric contractions of the knee extensors were performed at 2.5-3.5 h following supplement ingestion on day 1 and day 14. Diastolic BP was significantly lower in BR (-2 ± 3 mmHg, P = 0.03) compared to PL following acute supplementation, while the absolute rate of torque development (RTD) was significantly greater in BR at 0-30 ms (39 ± 57 N m s-1, P = 0.03) and 0-50 ms (79 ± 99 N m s-1, P = 0.02) compared to PL following two weeks supplementation. Greater WB [RSNOs] rather than plasma [NO2-] was correlated with lower diastolic BP (r = -0.68, P = 0.02) in BR compared to PL following acute supplementation, while greater skeletal muscle [NO3-] was correlated with greater RTD at 0-30 ms (r = 0.64, P=0.03) in BR compared to PL following chronic supplementation. We conclude that [RSNOs] in blood, and [NO3-] in skeletal muscle, are relevant biomarkers of NO bioavailability which are related to the reduction of BP and the enhanced muscle contractile function following dietary NO3- ingestion in humans.

Neurovascular complications post bronchial artery embolisation in patients with cystic fibrosis. A 7-year single centre retrospective review.

Bronchial artery embolisation (BAE) is a treatment used to manage haemoptysis. We performed a 7-year review of BAE procedures for haemoptysis at our CF centre aiming to evaluate the incidence and outcomes of patients with neurovascular complications post-BAE. Our review suggests that whilst BAE is an effective method for controlling life-threatening haemoptysis, patients are at risk of developing neurovascular complications with long term residual symptoms, and therefore careful consideration should be given in offering BAE, especially to otherwise well patients with chronic small volume haemoptysis and managing teams should have a low threshold to image symptomatic patients.

When is Burkholderia cepacia complex truly eradicated in adults with cystic fibrosis? A 20-year follow up study.

BACKGROUND: Burkholderia cepacia complex (BCC) infection in cystic fibrosis (CF) is associated with increased morbidity and mortality. Current UK guidance recommends segregation of people with CF according to infection status. To date there is no universally agreed consensus on the number of negative samples or time interval since last isolation of BCC for eradication to be deemed successful. METHODS: All cases of new BCC isolation at Manchester Adult Cystic Fibrosis Centre were followed-up between May 2002-May 2022. The number of subsequent positive and negative sputum samples for BCC were recorded, as well as eradication treatment received. Eradication was deemed successful if there were ≥3 negative sputum samples and no further positive sputum samples for the same species and strain ≥12 months until the end of follow-up. RESULTS: Of 46 new BCC isolation, 25 were successfully eradicated and 21 resulted in chronic infection. 5 (16.7%) cases with exclusively negative sputum samples 6-12 months after initial isolation had subsequent samples that were culture-positive for BCC and 3 (10.7%) cases with exclusively negative sputum samples after 12-24 months had subsequent culture-positive samples. Cases where BCC was eradicated had a greater median number of days of eradication treatment (42, IQR 21-63) compared to those in whom BCC isolation resulted in chronic infection (28, IQR 14-42), p = 0.04. CONCLUSIONS: A cautious approach to segregation should be maintained after new isolation of BCC in CF, as some individuals with ≥3 negative samples 12-24 months after initial isolation had subsequent sputum samples culture-positive for BCC.

Evolution of 1500-m Olympic Running Performance.

PURPOSE: This study determined the evolution of performance and pacing for each winner of the men's Olympic 1500-m running track final from 1924 to 2020. METHODS: Data were obtained from publicly available sources. When official splits were unavailable, times from sources such as YouTube were included and interpolated from video records. Final times, lap splits, and position in the peloton were included. The data are presented relative to 0 to 400 m, 400 to 800 m, 800 to 1200 m, and 1200 to 1500 m. Critical speed and D' were calculated using athletes' season's best times. RESULTS: Performance improved ∼25 seconds from 1924 to 2020, with most improvement (∼19 s) occurring in the first 10 finals. However, only 2 performances were world records, and only one runner won the event twice. Pacing evolved from a fast start-slow middle-fast finish pattern (reverse J-shaped) to a slower start with steady acceleration in the second half (J-shaped). The coefficient of variation for lap speeds ranged from 1.4% to 15.3%, consistent with a highly tactical pacing pattern. With few exceptions, the eventual winners were near the front throughout, although rarely in the leading position. There is evidence of a general increase in both critical speed and D' that parallels performance. CONCLUSIONS: An evolution in the pacing pattern occurred across several "eras" in the history of Olympic 1500-m racing, consistent with better trained athletes and improved technology. There has been a consistent tactical approach of following opponents until the latter stages, and athletes should develop tactical flexibility, related to their critical speed and D', in planning prerace strategy.

Improving detection of cystic fibrosis related liver disease using liver fibrosis assessment tools.

Background & aims: Cystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may underdiagnose liver fibrosis, particularly in its early stages. Newer modalities for the assessment of fibrosis may provide a more accurate assessment. FibroScan is validated in assessing fibrosis for several aetiologies including alcohol and fatty liver, the CFLD cohort have an entirely different phenotype so the cut off values are not transferrable. We appraised fibrosis assessment tools to improve diagnosis of CFLD. Methods: A prospective cohort (n = 114) of patients from the Manchester Adult Cystic Fibrosis Centre, UK were identified at annual assessment. Demographic data including co-morbidity, CFTR genotyping, biochemistry and imaging were used alongside current guidelines to group into CFLD and CF without evidence of liver disease. All patients underwent liver stiffness measurement (LSM) and assessment of serum-based fibrosis biomarker panels. A new diagnostic criterion was created and validated in a second, independent cohort. Results: 12 of 114 patient classified as CFLD according to the European Cystic Fibrosis Society best practice guidelines. No specific risk factors for development of CFLD were identified. Liver enzymes were elevated in patients with CFLD. Serum biomarker panels did not improve diagnostic criteria. LSM accurately predicted CFLD. A new diagnostic criterion was proposed and validated in a separate cohort, accurately predicating CFLD in 10 of 32 patients (31 %). Conclusion: We present a cohort of patients with CF assessed for the presence of liver fibrosis using blood biomarkers and LSM based platforms. We propose a new, simplified diagnostic criteria, capable of accurately predicting liver disease in patients with CF.Clinical trials number: NCT04277819.

Low Carbohydrate, High Fat Diet Alters the Oral Microbiome without Negating the Nitrite Response to Beetroot Juice Supplementation.

A low carbohydrate, high fat (LCHF) diet in athletes increases fat oxidation but impairs sports performance, potentially due to impaired exercise economy. Dietary nitrate supplementation can improve exercise economy via an increase in nitric oxide production, which is initiated by the reduction of nitrate to nitrite within the oral cavity. This reaction is dependent on the presence of nitrate-reducing oral bacteria, which can potentially be altered by dietary changes, including a LCHF diet. This study explored the effect of a LCHF diet on the oral microbiome and subsequent changes to plasma nitrite concentration following nitrate supplementation. Following five days of LCHF or high carbohydrate (HCHO) control dietary intervention, highly trained male race walkers consumed 140 mL beetroot juice containing 8.4 mmol nitrate; they then provided (a) blood samples for plasma nitrate and nitrite analysis and (b) saliva samples for 16S rRNA sequencing of the oral microbiome. The LCHF diet (n = 13) reduced oral bacterial diversity and changed the relative abundance of the genera Neisseria (+10%), Fusobacteria (+3%), Prevotella (-9%), and Veillonella (-4%), with no significant changes observed following the HCHO diet (n = 11). Following beetroot juice ingestion, plasma nitrite concentrations were higher for the LCHF diet compared to the HCHO diet (p = 0.04). However, the absence of an interaction with the trial (pre-post) (p = 0.71) suggests that this difference was not due to the dietary intervention. In summary, we found an increase in plasma nitrate and nitrite concentrations in response to nitrate supplementation independent of diet. This suggests the oral microbiome is adaptive to dietary changes and can maintain a nitrate reduction capacity despite a decrease in bacterial diversity following the LCHF diet.

Localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity.

The nitrate (NO3-) reducing bacteria resident in the oral cavity have been implicated as key mediators of nitric oxide (NO) homeostasis and human health. NO3--reducing oral bacteria reduce inorganic dietary NO3- to nitrite (NO2-) via the NO3--NO2--NO pathway. Studies of oral NO3--reducing bacteria have typically sampled from either the tongue surface or saliva. The aim of this study was to assess whether other areas in the mouth could contain a physiologically relevant abundance of NO3- reducing bacteria, which may be important for sampling in clinical studies. The bacterial composition of seven oral sample types from 300 individuals were compared using a meta-analysis of the Human Microbiome Project data. This analysis revealed significant differences in the proportions of 20 well-established oral bacteria and highly abundant NO3--reducing bacteria across each oral site. The genera included Actinomyces, Brevibacillus, Campylobacter, Capnocytophaga, Corynebacterium, Eikenella, Fusobacterium, Granulicatella, Haemophilus, Leptotrichia, Microbacterium, Neisseria, Porphyromonas, Prevotella, Propionibacterium, Rothia, Selenomonas, Staphylococcus, Streptococcus and Veillonella. The highest proportion of NO3--reducing bacteria was observed in saliva, where eight of the bacterial genera were found in higher proportion than on the tongue dorsum, whilst the lowest proportions were found in the hard oral surfaces. Saliva also demonstrated higher intra-individual variability and bacterial diversity. This study provides new information on where samples should be taken in the oral cavity to assess the abundance of NO3--reducing bacteria. Taking saliva samples may benefit physiological studies, as saliva contained the highest abundance of NO3- reducing bacteria and is less invasive than other sampling methods. These results inform future studies coupling oral NO3--reducing bacteria research with physiological outcomes affecting human health.

Association Between Elevated Blood Eosinophils and Chronic Kidney Disease Progression: Analyses of a Large United States Electronic Health Records Database.

Background: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting. Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] <60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3-4. The primary outcomes were CKD progression and all-cause mortality. Results: We found that high eosinophilic levels (bEOS ≥300 cells/µL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥300 cells/µL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with <300 cells/µL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression. Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.

Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis.

BACKGROUND: There have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF. METHODS: Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry. RESULTS: Post-ETI, mean FEV1 % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged. CONCLUSIONS: Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.

Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. OBJECTIVE: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. METHODS: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. RESULTS: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. CONCLUSIONS: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.

A Perspective on High-Intensity Interval Training for Performance and Health.

Interval training is a simple concept that refers to repeated bouts of relatively hard work interspersed with recovery periods of easier work or rest. The method has been used by high-level athletes for over a century to improve performance in endurance-type sports and events such as middle- and long-distance running. The concept of interval training to improve health, including in a rehabilitative context or when practiced by individuals who are relatively inactive or deconditioned, has also been advanced for decades. An important issue that affects the interpretation and application of interval training is the lack of standardized terminology. This particularly relates to the classification of intensity. There is no common definition of the term "high-intensity interval training" (HIIT) despite its widespread use. We contend that in a performance context, HIIT can be characterized as intermittent exercise bouts performed above the heavy-intensity domain. This categorization of HIIT is primarily encompassed by the severe-intensity domain. It is demarcated by indicators that principally include the critical power or critical speed, or other indices, including the second lactate threshold, maximal lactate steady state, or lactate turnpoint. In a health context, we contend that HIIT can be characterized as intermittent exercise bouts performed above moderate intensity. This categorization of HIIT is primarily encompassed by the classification of vigorous intensity. It is demarcated by various indicators related to perceived exertion, oxygen uptake, or heart rate as defined in authoritative public health and exercise prescription guidelines. A particularly intense variant of HIIT commonly termed "sprint interval training" can be distinguished as repeated bouts performed with near-maximal to "all out" effort. This characterization coincides with the highest intensity classification identified in training zone models or exercise prescription guidelines, including the extreme-intensity domain, anaerobic speed reserve, or near-maximal to maximal intensity classification. HIIT is considered an essential training component for the enhancement of athletic performance, but the optimal intensity distribution and specific HIIT prescription for endurance athletes is unclear. HIIT is also a viable method to improve cardiorespiratory fitness and other health-related indices in people who are insufficiently active, including those with cardiometabolic diseases. Research is needed to clarify responses to different HIIT strategies using robust study designs that employ best practices. We offer a perspective on the topic of HIIT for performance and health, including a conceptual framework that builds on the work of others and outlines how the method can be defined and operationalized within each context.

Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

The fourth dimension: physiological resilience as an independent determinant of endurance exercise performance.

Endurance exercise performance is known to be closely associated with the three physiological pillars of maximal O2 uptake ( V ̇ O 2 max $\dot{V}_{{\rm O}_{2}{\rm max}}$ ), economy or efficiency during submaximal exercise, and the fractional utilisation of V ̇ O 2 max $\dot{V}_{{\rm O}_{2}{\rm max}}$ (linked to metabolic/lactate threshold phenomena). However, while 'start line' values of these variables are collectively useful in predicting performance in endurance events such as the marathon, it is not widely appreciated that these variables are not static but are prone to significant deterioration as fatiguing endurance exercise proceeds. For example, the 'critical power' (CP), which is a composite of the highest achievable steady-state oxidative metabolic rate and efficiency (O2 cost per watt), may fall by an average of 10% following 2 h of heavy intensity cycle exercise. Even more striking is that the extent of this deterioration displays appreciable inter-individual variability, with changes in CP ranging from <1% to ∼32%. The mechanistic basis for such differences in fatigue resistance or 'physiological resilience' are not resolved. However, resilience may be important in explaining superlative endurance performance and it has implications for the physiological evaluation of athletes and the design of interventions to enhance performance. This article presents new information concerning the dynamic plasticity of the three 'traditional' physiological variables and argues that physiological resilience should be considered as an additional component, or fourth dimension, in models of endurance exercise performance.

Multitissue responses to exercise: a MoTrPAC feasibility study.

We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25 ± 2 yr, 12 M, 8 W) completed an endurance exercise bout (n = 8, 40 min cycling at 70% V̇o2max), a resistance exercise bout (n = 6, ∼45 min, 3 sets of ∼10 repetition maximum, 8 exercises), or a resting control period (n = 6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2 h, and 3.5 h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (periumbilical) biopsies were taken before and ∼4 h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) was reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, whereas skeletal muscle was transcriptionally more responsive than adipose 4 h postexercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.NEW & NOTEWORTHY This study highlights the feasibility of key aspects of the MoTrPAC adult human clinical protocols. This initial preview of what can be expected from acute exercise trial data from MoTrPAC provides an impetus for scientists to design exercise studies to interlace with the rich phenotypic and -omics data that will populate the MoTrPAC DataHub at the completion of the parent protocol.

Reduction in blood pressure following acute dietary nitrate ingestion is correlated with increased red blood cell S-nitrosothiol concentrations.

Dietary nitrate (NO3-) supplementation can enhance nitric oxide (NO) bioavailability and lower blood pressure (BP) in humans. The nitrite concentration ([NO2-]) in the plasma is the most commonly used biomarker of increased NO availability. However, it is unknown to what extent changes in other NO congeners, such as S-nitrosothiols (RSNOs), and in other blood components, such as red blood cells (RBC), also contribute to the BP lowering effects of dietary NO3-. We investigated the correlations between changes in NO biomarkers in different blood compartments and changes in BP variables following acute NO3- ingestion. Resting BP was measured and blood samples were collected at baseline, and at 1, 2, 3, 4 and 24 h following acute beetroot juice (∼12.8 mmol NO3-, ∼11 mg NO3-/kg) ingestion in 20 healthy volunteers. Spearman rank correlation coefficients were determined between the peak individual increases in NO biomarkers (NO3-, NO2-, RSNOs) in plasma, RBC and whole blood, and corresponding decreases in resting BP variables. No significant correlation was observed between increased plasma [NO2-] and reduced BP, but increased RBC [NO2-] was correlated with decreased systolic BP (rs = -0.50, P = 0.03). Notably, increased RBC [RSNOs] was significantly correlated with decreases in systolic (rs = -0.68, P = 0.001), diastolic (rs = -0.59, P = 0.008) and mean arterial pressure (rs = -0.64, P = 0.003). Fisher's z transformation indicated no difference in the strength of the correlations between increases in RBC [NO2-] or [RSNOs] and decreased systolic blood pressure. In conclusion, increased RBC [RSNOs] may be an important mediator of the reduction in resting BP observed following dietary NO3- supplementation.