GLPG1205 for idiopathic pulmonary fibrosis: a phase 2 randomised placebo-controlled trial.

BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed the efficacy, safety and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF). METHODS: PINTA (ClinicalTrials.gov: NCT03725852) was a phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once-daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary end-point was change from baseline in forced vital capacity (FVC); other end-points were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance. RESULTS: In total, 68 patients received study medication. Least squares mean change from baseline in FVC at week 26 was -33.68 (95% CI -112.0-44.68) mL with GLPG1205 and -76.00 (95% CI -170.7-18.71) mL with placebo (least squares mean difference 42.33 (95% CI -81.84-166.5) mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib. CONCLUSIONS: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.

Accelerometery and Heart Rate Responses of Professional Fast-Medium Bowlers in One-Day and Multi-Day Cricket.

The physical demands of fast-medium bowling are increasingly being recognised, yet comparative exploration of the differing demands between competitive formats (i.e. one-day [OD] versus multi-day [MD] matches) remain minimal. The aim of this study was to describe in-match physiological profiles of professional fast-medium bowlers from England across different versions of competitive matches using a multivariable wearable monitoring device. Seven professional cricket fast-medium bowlers wore the BioharnessTM monitoring device during matches, over three seasons (>80 hours in-match). Heart Rate (HR) and Acceleromety (ACC) was compared across match types (OD, MD) and different in-match activity states (Bowling, Between over bowling, Fielding). Peak acceleration during OD bowling was significantly higher in comparison to MD cricket ([OD vs. MD] 234.1 ± 57.9 vs 226.6 ± 32.9 ct·episode-1, p < 0.05, ES = 0.11-0.30). Data for ACC were also higher during OD than MD fielding activities (p < 0.01, ES = 0.11-.30). OD bowling stimulated higher mean HR responses (143 ± 14 vs 137 ± 16 beats·min-1, p < 0.05, ES = 0.21) when compared to MD matches. This increase in OD cricket was evident for both between over (129 ± 9 vs 120 ± 13 beats·min-1,p < 0.01, ES = 0.11-0.50) and during fielding (115 ± 12 vs 106 ± 12 beats·min-1, p < 0.01, ES = 0.36) activity. The increased HR and ACC evident in OD matches suggest greater acute physical loads than MD formats. Therefore, use of wearable technology and the findings provided give a valuable appreciation of the differences in match loads, and thus required physiological preparation and recovery in fast-medium bowlers.

The athletic profile of fast bowling in cricket: a review.

Cricket is a global sport played in over 100 countries with elite performers attracting multimillion dollar contracts. Therefore, performers maintaining optimum physical fitness and remaining injury free is important. Fast bowlers have a vital position in a cricket team, and there is an increasing body of scientific literature that has reviewed this role over the past decade. Previous research on fast bowlers has tended to focus on biomechanical analysis and injury prevention in performers. However, this review aims to critically analyze the emerging contribution of physiological-based literature linked to fast bowling in cricket, highlight the current evidence related to simulated and competitive in-match performance, and relate this practically to the conditioning coach. Furthermore, the review considers limitations with past research and possible avenues for future investigation. It is clear with the advent of new applied mobile monitoring technology that there is scope for more ecologically valid and longitudinal exploration capturing in-match data, providing quantification of physiological workloads, and analysis of the physical demands across the differing formats of the game. Currently, strength and conditioning specialists do not have a critical academic resource with which to shape professional practice, and this review aims to provide a starting point for evidence in the specific area.

Effects of a 15-week accumulated brisk walking programme on the body composition of primary school children.

The purpose of this study was to establish whether an accumulated brisk walking programme, performed during the school day, is effective in changing body composition in primary school children aged 5-11 years. Altogether, 152 participants (79 boys and 73 girls) took part in this repeated-measures intervention study, divided into groups of walkers and controls. The walkers took part in the intervention during school time, which involved brisk walking around the school grounds for 15 min in the morning and afternoon, at least three times a week for 15 weeks. This represented an additional 90 min of moderate physical activity per week. The controls undertook their usual school day activities. Pre- and post-intervention anthropometric and body composition measures were taken. Body fat (-1.95 ± 2.6%) and fat mass (-0.49 ± 1.0 kg) were significantly reduced in the walkers after the intervention, whereas the controls showed no significant changes in these measures. Our results show that regular accumulated bouts of brisk walking during the school day can positively affect body composition in primary school children.

Bioharness(™) multivariable monitoring device: part. I: validity.

The Bioharness(™) monitoring system may provide physiological information on human performance but there is limited information on its validity. The objective of this study was to assess the validity of all 5 Bioharness(™) variables using a laboratory based treadmill protocol. 22 healthy males participated. Heart rate (HR), Breathing Frequency (BF) and Accelerometry (ACC) precision were assessed during a discontinuous incremental (0-12 km·h(-1)) treadmill protocol. Infra-red skin temperature (ST) was assessed during a 45 min(-1) sub-maximal cycle ergometer test, completed twice, with environmental temperature controlled at 20 ± 0.1 °C and 30 ± 0.1 °C. Posture (P) was assessed using a tilt table moved through 160°. Adopted precision of measurement devices were; HR: Polar T31 (Polar Electro), BF: Spirometer (Cortex Metalyser), ACC: Oxygen expenditure (Cortex Metalyser), ST: Skin thermistors (Grant Instruments), P:Goniometer (Leighton Flexometer). Strong relationships (r = .89 to .99, p < 0.01) were reported for HR, BF, ACC and P. Limits of agreement identified differences in HR (-3.05 ± 32.20 b·min(-1)), BF (-3.46 ± 43.70 br·min(-1)) and P (0.20 ± 2.62°). ST established a moderate relationships (-0.61 ± 1.98 °C; r = 0.76, p < 0.01). Higher velocities on the treadmill decreased the precision of measurement, especially HR and BF. Global results suggest that the BioharressTM is a valid multivariable monitoring device within the laboratory environment. Key pointsDifferent levels of precision exist for each variable in the Bioharness(™) (Version 1) multi-variable monitoring deviceAccelerometry and posture variables presented the most precise dataData from the heart rate and breathing frequency variable decrease in precision at velocities ≥ 10 km·h(-1)Clear understanding of the limitations of new applied monitoring technology is required before it is used by the exercise scientist.

Bioharness(™) Multivariable Monitoring Device: Part. II: Reliability.

The Bioharness(™) monitoring system may provide physiological information on human performance but the reliability of this data is fundamental for confidence in the equipment being used. The objective of this study was to assess the reliability of each of the 5 Bioharness(™) variables using a treadmill based protocol. 10 healthy males participated. A between and within subject design to assess the reliability of Heart rate (HR), Breathing Frequency (BF), Accelerometry (ACC) and Infra-red skin temperature (ST) was completed via a repeated, discontinuous, incremental treadmill protocol. Posture (P) was assessed by a tilt table, moved through 160°. Between subject data reported low Coefficient of Variation (CV) and strong correlations(r) for ACC and P (CV< 7.6; r = 0.99, p < 0.01). In contrast, HR and BF (CV~19.4; r~0.70, p < 0.01) and ST (CV 3.7; r = 0.61, p < 0.01), present more variable data. Intra and inter device data presented strong relationships (r > 0.89, p < 0.01) and low CV (<10.1) for HR, ACC, P and ST. BF produced weaker relationships (r < 0.72) and higher CV (<17.4). In comparison to the other variables BF variable consistently presents less reliability. Global results suggest that the Bioharness(™) is a reliable multivariable monitoring device during laboratory testing within the limits presented. Key pointsHeart rate and breathing frequency data increased in variance at higher velocities (i.e. ≥ 10 km.h(-1))In comparison to the between subject testing, the intra and inter reliability presented good reliability in data suggesting placement or position of device relative to performer could be important for data collectionUnderstanding a devices variability in measurement is important before it can be used within an exercise testing or monitoring setting.

Field based reliability and validity of the bioharness™ multivariable monitoring device.

The Bioharness™ device is designed for monitoring physiological variables in free-living situations but has only been proven to be reliable and valid in a laboratory environment. Therefore, this study aimed to determine the reliability and validity of the Bioharness™ using a field based protocol. Twenty healthy males participated. Heart rate (HR), breathing frequency (BF) and accelerometry (ACC) were assessed by simultaneous measurement of two Bioharness™ devices and a test-retest of a discontinuous incremental walk-jog-run protocol (4 - 11 km·h(-1)) completed in a sports hall. Adopted precision of measurement devices were; HR: Polar T31 (Polar Electro), BF: Spirometer (Cortex Metalyser), ACC: Oxygen expenditure (Cortex Metalyser). For all data, precision of measurement reported good relationships (r = 0.61 to 0.67, p < 0.01) and large Limits of Agreement for HR (>79.2 b·min(-1)) and BF (>54.7 br·min(-1)). ACC presented excellent precision (r = 0.94, p < 0.01). Results for HR (r= ~0.91, p < 0.01: CV <7.6) and ACC (r > 0.97, p < 0.01; CV <14.7) suggested these variables are reliable. BF presented more variable data (r = 0.46-0.61, p < 0.01; CV < 23.7). As velocity of movement increased (>8 km·h(-1)) data became more erroneous. A data cleaning protocol removed gross errors in the data analysis and subsequent reliability and validity statistics improved across all variables. In conclusion, the Bioharness™ HR and ACC variables have demonstrated reliability and validity in a field setting, though data collected at higher velocities should be treated with caution. Measuring human physiological responses in a field based environment allows for more ecologically valid data to be collected and devices such as the Bioharness™ could be used by exercise professionals to begin to further investigate this area.

Physiologic profile of professional cricketers.

This study aims to provide a physiologic profile of professional cricketers and note positional differences at the start of the 2007/08 competitive season. Fifteen participants (9 bowlers, 6 batsmen) aged 25.0 ± 5.0 years (mean ± SD) took part in this study. Participants (bowlers and batsmen) completed a series of field-based fitness assessments: body composition (sum of 7 skinfolds, 72.5 ± 16.5 and 65.5 ± 19.3 mm, respectively), flexibility (sit and reach 8.1 ± 10.3 and 6.0 ± 6.2 cm, respectively), predicted maximal oxygen uptake (multistage shuttle run, 54.1 ± 2.8 and 56.1 ± 4.5 ml-1·kg-1·min-1, respectively), upper- (medicine ball throw, 7.7 ± 0.6 and 7.0 ± 0.1 m, respectively) and lower-body strength (countermovement jump, 45.7 ± 5.8 and 43.9 ± 4.1 cm, respectively), speed (sprint 17.7 m, 2.76 ± 0.6 and 2.77 ± 0.1 s, respectively), and explosive power (repeated jump, 31.0 ± 2.0 and 34.1 ± 4.8 cm, respectively). The data provided the physical fitness profile for each player, which, compared with normative data, identified that this cohort of professional cricketers had some superior fitness parameters compared with the general population, and where applicable, were comparable with other professional athletes. In addition, after effect size calculations, the results showed that some physical fitness differences existed between playing positions. Cricket professionals possess a superior level of physical fitness and strength, and conditioning coaches should seek to progress these physical parameters and further identify position-specific physical requirements to progress the modern game.

Rewards and challenges of community health center practice.

BACKGROUND: More than 1100 community health centers (CHCs) in the United States provide primary care to 20 million underserved patients annually. CHCs have struggled to recruit and retain qualified physicians. OBJECTIVE: To understand physicians' work experiences in CHCs and identify major sources of satisfaction and dissatisfaction. METHODS: Using purposeful sampling, we conducted semistructured interviews with 12 family physicians practicing in CHCs. Interview questions assessed physicians' experiences in CHCs and sources of satisfaction and dissatisfaction. Interview notes were coded and analyzed by 2 investigators using a grounded theory approach to identify key themes. RESULTS: Though family physicians feel tremendous satisfaction from care of underserved patients, they are frustrated with the overwhelming workload they experience. Family physicians also report poor administrative management while working in CHCs. CONCLUSIONS: Implementation of the Affordable Care Act, which relies on expansion of CHC services, may be adversely affected by family physicians' frustrations with CHC practice. Further research to explore and potentially improve the CHC work environment may be needed.

Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD.

BACKGROUND: Inhaled corticosteroids (ICS) have proved disappointing at reducing airway inflammation in COPD. However, previous studies indicate that low doses of theophylline enhance the activity of a key corticosteroid-associated corepressor protein, histone deacetylase (HDAC)2, which is reduced in COPD. This may account, at least in part, for the relative corticosteroid resistance. Thus, combination therapy with an ICS and low-dose theophylline may be of benefit in the treatment of COPD. METHODS: To test the hypothesis that ICS and theophylline have a greater therapeutic effect than theophylline alone, 30 patients with COPD were treated with placebo theophylline capsules and either inhaled fluticasone propionate (FP) (500 microg bid) or inhaled placebo for 4 weeks in a double-dummy, randomized, double-blind, parallel study. After a 2-week washout, patients were given active theophylline capsules (plasma level of 8.8-12.4 mg/L). RESULTS: In an across-arm comparison, combination treatment with FP and theophylline did not reduce total sputum neutrophils but significantly reduced total sputum eosinophils (P < .05). Additional across-arm comparisons suggest a further reduction in percentage sputum neutrophils and sputum chemokine (C-X-C motif) ligand 8/IL-8 (P < .05). Furthermore, within-arm observational data also demonstrated increases in forced midexpiratory flow rate and FEV(1)% predicted (P < .05) following combination treatment only. In an open-label study, low-dose theophylline when added to inhaled FP increased total HDAC activity in peripheral blood monocytes ninefold (P < .01) compared with FP alone from the same patients with COPD. CONCLUSIONS: Combination therapy with an inhaled corticosteroid and low-dose theophylline may attenuate airway inflammation in patients with COPD. TRIAL REGISTRATION: clinicaltrials.gov; Identifier NCT00241631.

Steroid resistance in asthma: mechanisms and treatment options.

Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies are not effective. Glucocorticoids, acting through the glucocorticoid receptor (GR), are able to selectively repress inflammatory gene expression by utilizing several distinct mechanisms targeting nuclear factor-varphiB and activator protein-1 activation complexes and by effects on mitogen-activated protein kinases. Different model systems often activate distinct sets of signaling molecules and different glucocorticoid responsiveness may result from differences in concentrations and timing of steroid treatment of cells, GR expression levels, and the precise inflammatory stimulus used. Thus, abnormal activation of many signaling pathways may affect corticosteroid responsiveness in patients with corticosteroid-resistant asthma. Understanding the molecular mechanisms of GR action and inaction may lead to the development of new anti-inflammatory drugs or enable clinicians to reverse the relative steroid-insensitivity that is characteristic of some patients with severe asthma.

Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type II epithelial cells and macrophages.

Bacterial colonization is a secondary feature of many lung disorders associated with elevated cytokine levels and increased leukocyte recruitment. We hypothesized that, alongside macrophages, the epithelium would be an important source of these mediators. We investigated the effect of LPS (0, 10, 100, and 1000 ng/ml LPS, up to 24 h) on primary human lung macrophages and alveolar type II epithelial cells (ATII; isolated from resected lung tissue). Although macrophages produced higher levels of the cytokines TNF-alpha and IL-1beta (p < 0.0001), ATII cells produced higher levels of chemokines MCP-1, IL-8, and growth-related oncogene alpha (p < 0.001), in a time- and concentration-dependent manner. Macrophage (but not ATII cell) responses to LPS required activation of ERK1/2 and p38 MAPK signaling cascades; phosphorylated ERK1/2 was constitutively up-regulated in ATII cells. Blocking Abs to TNF-alpha and IL-1beta during LPS exposure showed that ATII cell (not macrophage) MCP-1 release depended on the autocrine effects of IL-1beta and TNF-alpha (p < 0.003, 24 h). ATII cell release of IL-6 depended on autocrine effects of TNF-alpha (p < 0.006, 24 h). Macrophage IL-6 release was most effectively inhibited when both TNF-alpha and IL-1beta were blocked (p < 0.03, 24 h). Conditioned media from ATII cells stimulated more leukocyte migration in vitro than conditioned media from macrophages (p < 0.0002). These results show differential activation of cytokine and chemokine release by ATII cells and macrophages following LPS exposure. Activated alveolar epithelium is an important source of chemokines that orchestrate leukocyte migration to the peripheral lung; early release of TNF-alpha and IL-1beta by stimulated macrophages may contribute to alveolar epithelial cell activation and chemokine production.