Pre-exercise carbohydrate or protein ingestion influences substrate oxidation but not performance or hunger compared with cycling in the fasted state

Nutritional intake can influence exercise metabolism and performance, but there is a lack of research comparing protein-rich pre-exercise meals with endurance exercise performed both in the fasted state and following a carbohydrate-rich breakfast. The purpose of this study was to determine the effects of three pre-exercise nutrition strategies on metabolism and exercise capacity during cycling. On three occasions, seventeen trained male cyclists (VO2peak 62.2 ± 5.8 mL·kg−1·min−1, 31.2 ± 12.4 years, 74.8 ± 9.6 kg) performed twenty minutes of submaximal cycling (4 × 5 min stages at 60%, 80%, and 100% of ventilatory threshold (VT), and 20% of the difference between power at the VT and peak power), followed by 3 × 3 min intervals at 80% peak aerobic power and 3 × 3 min intervals at maximal effort, 30 min after consuming a carbohydrate-rich meal (CARB; 1 g/kg CHO), a protein-rich meal (PROTEIN; 0.45 g/kg protein + 0.24 g/kg fat), or water (FASTED), in a randomized and counter-balanced order. Fat oxidation was lower for CARB compared with FASTED at and below the VT, and compared with PROTEIN at 60% VT. There were no differences between trials for average power during high-intensity intervals (367 ± 51 W, p = 0.516). Oxidative stress (F2-Isoprostanes), perceived exertion, and hunger were not different between trials. Overall, exercising in the overnight-fasted state increased fat oxidation during submaximal exercise compared with exercise following a CHO-rich breakfast, and pre-exercise protein ingestion allowed similarly high levels of fat oxidation. There were no differences in perceived exertion, hunger, or performance, and we provide novel data showing no influence of pre-exercise nutrition ingestion on exercise-induced oxidative stress

The effect of dietary nitrate supplementation on physiology and performance in trained cyclists

Purpose: To determine the effect of dietary nitrate (NO₃⁻) supplementation on physiology and performance in well-trained cyclists following six to eight-days of NO₃⁻ supplementation. Methods: Eight competitive male cyclists (mean ± SD; age = 26 ± 8 y; body mass = 76.7 ± 6.9 kg; VO2peak = 63 ± 4 ml.kg⁻¹.min⁻¹) participated in a double-blind, placebo-controlled, crossover-design study in which participants ingested 70 ml beetroot juice containing ~4 mmol NO₃⁻ (NIT) or a NO₃⁻ depleted placebo (PLA) , each for 8-days. Replicating pre-treatment measures, participants undertook an incremental ramp assessment to determine VO₂peak, first (VT₁), and second (VT₂) ventilatory thresholds on day 6 (NIT6 and PLA6), moderate-intensity cycling economy on day 7 (NIT7 and PLA7), and a 4-km time-trial on day 8 (NIT8 and PLA8). Results: Relative to PLA, 6 days of NIT supplementation produced unclear effects for VO2peak (mean ±95%CL: 1.8 ±5.5%) and VT1 (3.7 ±12.3%) and trivial effects for both VT2 (-1.0 ±3.0%) and exercise economy on day 7 (-1.0 ±1.6%). However, effects for time-trial performance time (0.7 ±0.9%), and power (2.4 ±2.5%), on day 8 were likely beneficial. Conclusions: Despite mostly unclear outcomes for standard physiological determinants of performance, 8-days of NO₃⁻ supplementation resulted in likely beneficial improvements to 4-km time-trial performance in well trained male endurance cyclists

The Effect of Nitrate Supplementation on Cycling Performance in the Heat in Well-Trained Cyclists

Purpose: The aim of this study was to determine the effect of NO₃⁻ consumption on measures of perception, thermoregulation and cycling performance in hot conditions. Methods: Using a randomised, double-blind, crossover-design, 8 well-trained cyclists (mean ± SD: age: 25 ± 8 y, V̇O2peak: 64 ± 5 ml·kg⁻¹·min⁻¹) performed 2 separate trials, in hot (35°C, 60% relative humidity) environments, having ingested either 140 ml NO3--rich beetroot juice ~8 mmol NO₃⁻ (NIT), or placebo (PLA), daily for 3-days with a 7-day washout period separating trials. Trials consisted of 2 × 10 min bouts at 40 and 60% peak power output (PPO) to determine physiological and perceptual responses in the heat, followed by a 4 km cycling time-trial. Results: Basal [nitrite] was substantially elevated in NIT (2.70 ± 0.98 μM) vs PLA (1.10 ± 0.61 μM) resulting in a most likely (ES = 1.58 ± 0.93) increase after 3-days. There was a very likely trivial increase in rectal temperature [Tᵣₑ] in NIT at 40% (PLA;37.4 ± 0.2°C vs NIT;37.5 ± 0.3°C, 0.1 ± 0.2°C) and 60% (PLA;37.8 ± 0.2°C vs NIT;37.9 ± 0.3°C, 0.1 ± 0.2°C) PPO. Cycling performance was similar between trials (PLA;336 ± 45 W vs NIT;337 ± 50 W, CV±95%CL; 0.2 ± 2.5%). Outcomes for heart rate, and perceptual measures were unclear across the majority of time-points. Conclusions: Three days of NO₃⁻ supplementation, resulted in small increases in Tᵣₑ during low- to moderate-intensity exercise, however this did not appear to influence 4 km cycling time-trial performance in hot climates

Clinical Utility of Random Anti–Tumor Necrosis Factor Drug–Level Testing and Measurement of Antidrug Antibodies on the Long-Term Treatment Response in Rheumatoid Arthritis

Objective: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions.  Methods: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated.  Results: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody–positive patients received lower median dosages of methotrexate compared with antidrug antibody–negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m2 and poor adherence were associated with lower drug levels.  Conclusion: Pharmacologic testing in anti–tumor necrosis factor–treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months

Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis

Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Socioeconomic deprivation is associated with reduced response and lower treatment persistence with TNF inhibitors in rheumatoid arthritis

Objective To investigate the association between socioeconomic deprivation and outcomes following TNF inhibitor (TNFi) treatment. Methods Individuals commencing their first TNFi in the British Society for Rheumatology Biologics Register for RA (BSRBR-RA) and Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS) cohort were included. Socioeconomic deprivation was proxied using the Index of Multiple Deprivation and categorized as 20% most deprived, middle 40% or 40% least deprived. DAS28-derived outcomes at 6 months (BSRBR-RA) and 3 months (BRAGGSS) were compared using regression models with the least deprived as referent. Risks of all-cause and cause-specific drug discontinuation were compared using Cox models in the BSRBR-RA. Additional analyses adjusted for lifestyle factors (e.g. smoking, BMI) as potential mediators. Results 16 085 individuals in the BSRBR-RA were included (mean age 56 years, 76% female), of whom 18%, 41% and 41% were in the most, middle and least deprived groups, respectively. Of 3459 included in BRAGGSS (mean age 57, 77% female), proportions were 22%, 36% and 41%, respectively. The most deprived group had 0.3-unit higher 6-month DAS28 (95% CI 0.22, 0.37) and were less likely to achieve low disease activity (odds ratio [OR] 0.76; 95% CI 0.68, 0.84) in unadjusted models. Results were similar for 3-month DAS28 (β = 0.23; 95% CI 0.11, 0.36) and low disease activity (OR 0.77; 95% CI 0.63, 0.94). The most deprived were more likely to discontinue treatment (hazard ratio 1.18; 95% CI 1.12, 1.25), driven by ineffectiveness rather than adverse events. Adjusted estimates were generally attenuated. Conclusion Socioeconomic deprivation is associated with reduced response to TNFi. Improvements in determinants of health other than lifestyle factors are needed to address socioeconomic inequities

Moderate-domain pulmonary oxygen uptake kinetics and endurance running performance

The aims of this study were to determine if the primary time constant (T) for oxygen uptake (VO2) at the onset of moderate-intensity treadmill exercise is related to endurance running performance, and to establish if T could be considered a determinant of endurance running performance. Thirty-six endurance trained male runners performed a series of laboratory tests, on separate days, to determine maximal oxygen uptake (VO2 max), the ventilatory threshold (VT) and running economy. In addition, runners completed six transitions from walking (4 km . h-1) to moderate-intensity running (80% VT) for the determination of the VO2 primary time constant and mean response time. During all tests, pulmonary gas-exchange was measured breath-by-breath. Endurance running performance was determined using a treadmill 5-km time-trial, after which runners were considered as combined performers (n=36) and, using a ranking system, high performers (n=10) and low performers (n=10). Relationships between T and endurance running performance were quantified using correlation coefficients (r). Stepwise multiple regression was used to determine the primary predictor variables of endurance running performance in combined performers. Moderate correlations were observed between T, mean response time and endurance running performance, but only for the combined performers (r=-0.55, P=0.001 and r=-0.50, P=0.002, respectively). The regression model for predicting 5-km performance did not include T or mean response time. The velocity at VO2 max was strongly correlated to endurance running performance in all groups (r=0.72 - 0.84, P < 0.01) and contributed substantially to the prediction of performance. In conclusion, the results suggest that despite their role in determining the oxygen deficit and having a moderate relationship with endurance running performance, neither T nor mean response time is a primary determinant of endurance running performance.</p

A comparison of pulmonary oxygen uptake kinetics in middle- and long-distance runners

The purpose of this study was two-fold: 1) to compare the on- and off-transient pulmonary oxygen uptake (VO2) kinetics, in the moderate-intensity domain, of middle-distance (MD) and long-distance (LD) runners and 2) to determine the relationship between the volume of training and VO2 kinetics. With institutional ethics approval, 16 competitive male MD (800/1500 m) and 16 competitive male LD runners (5000/10 000 m) participated in the study. Each runner completed a series of tests to assess maximal VO2 (VO2max), ventilatory threshold (VT), and both the on- and off-transient primary time constants (Ton and Toff, respectively) in response to moderate-intensity treadmill exercise. The results showed that Ton was significantly shorter in LD (12.3 ± 0.5 s) than MD runners (16.4 ± 1.0 s, p = 0.002). During recovery from exercise, Toff was shorter in LD than MD runners (Toff, 24.3 ± 0.6 s vs. 26.9 ± 0.8 s, p = 0.017). The volume of training was greater in LD (66.6 ± 3.5 km . wk-1) than MD runners (43.5 ± 3.9 km . wk-1, p on in both groups of runner (MD: r = - 0.63, p = 0.009; LD: r = - 0.68, p = 0.004). Collectively, the results show that MD and LD runners can be differentiated on the basis of their on- and off-transient VO2 kinetics, despite similarities of VO2 max and VT. This is attributable to the greater volume of training performed by LD runners. Further investigations into adaptation(s) to training in muscle in MD and LD runners is required to determine the functional significance of such differences and the response of VO2 kinetic parameters to different training stimuli.</p