Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48

Training Load and Carbohydrate Periodization Practices of Elite Male Australian Football Players: Evidence of Fueling for the Work Required.

The authors aimed to quantify (a) the periodization of physical loading and daily carbohydrate (CHO) intake across an in-season weekly microcycle of Australian Football and (b) the quantity and source of CHO consumed during game play and training. Physical loading (via global positioning system technology) and daily CHO intake (via a combination of 24-hr recall, food diaries, and remote food photographic method) were assessed in 42 professional male players during two weekly microcycles comprising a home and away fixture. The players also reported the source and quantity of CHO consumed during all games (n = 22 games) and on the training session completed 4 days before each game (n = 22 sessions). The total distance was greater (p < .05) on game day (GD; 13 km) versus all training days. The total distance differed between training days, where GD-2 (8 km) was higher than GD-1, GD-3, and GD-4 (3.5, 0, and 7 km, respectively). The daily CHO intake was also different between training days, with reported intakes of 1.8, 1.4, 2.5, and 4.5 g/kg body mass on GD-4, GD-3, GD-2, and GD-1, respectively. The CHO intake was greater (p < .05) during games (59 ± 19 g) compared with training (1 ± 1 g), where in the former, 75% of the CHO consumed was from fluids as opposed to gels. Although the data suggest that Australian Football players practice elements of CHO periodization, the low absolute CHO intakes likely represent considerable underreporting in this population. Even when accounting for potential underreporting, the data also suggest Australian Football players underconsume CHO in relation to the physical demands of training and competition

Ultrasound Does Not Detect Acute Changes in Glycogen in Vastus Lateralis of Man.

PURPOSE: To examine the validity of ultrasound (via cloud based software that measures pixilation intensity according to a scale of 0-100) to non-invasively assess muscle glycogen in human skeletal muscle. METHODS: In Study 1, 14 professional male rugby league players competed in an 80-minute competitive rugby league game. In Study 2 (in a randomized repeated measures design), 16 recreationally active males completed an exhaustive cycling protocol to deplete muscle glycogen followed by 36 hours of HIGH or LOW carbohydrate intake (8 v 3 g.kg body mass). In both studies, muscle biopsies and ultrasound scans were obtained from the vastus lateralis (at 50% of the muscle length) before and after match play in Study 1 and at 36 h after glycogen depletion in Study 2. RESULTS: Despite match play reducing (P0.05) were present between changes in muscle glycogen concentration and changes in ultrasound scores. CONCLUSION: Data demonstrate that ultrasound (as based on measures of pixilation intensity) is not valid to measure muscle glycogen status within the physiological range (i.e. 200-500 mmol.kg dw) that is applicable to exercise-induced muscle glycogen utilization and post-exercise muscle glycogen re-synthesis

Muscle Glycogen Utilisation during an Australian Rules Football Game.

PURPOSE: To better understand the carbohydrate (CHO) requirement of Australian Football (AF) match play by quantifying muscle glycogen utilisation during an in-season AF match. METHODS: After a 24 h CHO loading protocol of 8 g/kg and 2 g/kg in the pre-match meal, two elite male forward players had biopsies sampled from m. vastus lateralis before and after participation in a South Australian Football League game. Player A (87.2kg) consumed water only during match play whereas player B (87.6kg) consumed 88 g CHO via CHO gels. External load was quantified using global positioning system technology. RESULTS: Player A completed more minutes on the ground (115 vs. 98 min) and covered greater total distance (12.2 vs. 11.2 km) than Player B, though with similar high-speed running (837 vs. 1070 m) and sprinting (135 vs. 138 m), respectively. Muscle glycogen decreased by 66% in Player A (Pre-: 656, Post-: 223 mmol∙kg-1 dw) and 24% in Player B (Pre-: 544, Post-: 416 mmol∙kg-1 dw), respectively. CONCLUSION: Pre-match CHO loading elevated muscle glycogen concentrations (i.e. >500 mmol.kg-1 dw), the magnitude of which appears sufficient to meet the metabolic demands of elite AF match play. The glycogen cost of AF match play may be greater than soccer and rugby and CHO feeding may also spare muscle glycogen use. Further studies using larger sample sizes are now required to quantify the inter-individual variability of glycogen cost of match play (including muscle and fibre-type specific responses) as well examine potential metabolic and ergogenic effects of CHO feeding

Development of anthropometric characteristics in professional Rugby League players: Is there too much emphasis on the pre-season period?

Rugby League is a team sport requiring players to experience large impact collisions, thus requiring high amounts of muscle mass. Many players (academy and senior) strive to increase muscle mass during the pre-season, however, quantification of changes during this period have not been thoroughly investigated. We therefore assessed changes in body-composition using Dual X-Ray Absorptiometry (DXA) in eleven academy players over three successive pre-seasons and ninety-three senior players from four different European Super League clubs prior to, and at the end of, a pre-season training period. There was no meaningful change in lean mass of the academy players during any of the pre-season periods (year 1 = 72.3 ± 7.1–73.2 ± 7.2kg; ES 0.05, year 2 = 74.4 ± 6.9–75.5 ± 6.9kg; ES 0.07, year 3 = 75.9 ± 6.7–76.8 ± 6.6kg; ES 0.06) with small changes only occurring over the three-year study period (72.3–75.9kg; ES = 0.22). Senior players showed trivial changes in all characteristics during the pre-season period (total mass = 95.1–95.0kg; ES −0.01, lean mass = 74.6–75.1kg; ES 0.07, fat mass = 13.6–12.9kg; ES −0.17, body fat percentage = 14.8–14.1%; ES −0.19). These data suggest that academy players need time to develop towards profiles congruent with senior players. Moreover, once players reach senior level, body-composition changes are trivial during the pre-season and therefore teams may need to individualise training for players striving to gain muscle mass by reducing other training loads

Three-Dimensional Magnetic Reconnection

The importance of magnetic reconnection as an energy release mechanism in many solar, stellar, magnetospheric and astrophysical phenomena has long been recognised. Reconnection is the only mechanism by which magnetic fields can globally restructure, enabling them to access a lower energy state. Over the past decade, there have been some major advances in our understanding of three-dimensional reconnection. In particular, the key characteristics of 3D magnetohydrodynamic (MHD) reconnection have been determined. For instance, 3D reconnection (i) occurs with or without nulls, (ii) occurs continuously and continually throughout a diffusion region and (iii) is driven by counter rotating flows. Furthermore, analysis of resistive 3D MHD magnetic experiments have revealed some intriguing effects relating to where and how reconnection occurs. To illustrate these new features, a series of constant-resistivity experiments, involving the interaction of two opposite-polarity magnetic sources in an overlying field, are considered. Such a simple interaction represents a typical building block of the Sun's magnetic atmosphere. By following the evolution of the magnetic topology, we are able to explain where, how and at what rate the reconnection occurs. Remarkably there can be up to five energy release sites at anyone time (compared to one in the potential case) and the duration of the interaction increases (more than doubles) as the resistivity decreases (by a factor of 16). The decreased resistivity also leads to a higher peak ohmic dissipation and more energy being released in total, as a result of a greater injection of Poynting flux.Comment: To appear in "Magnetic Coupling between the Interior and the Atmosphere of the Sun", eds. S.S. Hasan and R.J. Rutten, Astrophysics and Space Science Proceedings, Springer-Verlag, Heidelberg, Berlin, 200

Phase Mixing of Alfvén Waves Near a 2D Magnetic Null Point

The propagation of linear Alfvén wave pulses in an inhomogeneous plasma near a 2D coronal null point is investigated. When a uniform plasma density is considered, it is seen that an initially planar Alfvén wavefront remains planar, despite the varying equilibrium Alfvén speed, and that all the wave collects at the separatrices. Thus, in the non-ideal case, these Alfvénic disturbances preferentially dissipate their energy at these locations. For a non-uniform equilibrium density, it is found that the Alfvén wavefront is significantly distorted away from the initially planar geometry, inviting the possibility of dissipation due to phase mixing. Despite this however, we conclude that for the Alfvén wave, current density accumulation and preferential heating still primarily occur at the separatrices, even when an extremely non-uniform density profile is considered

Strategies and challenges associated with recruiting retirement village communities and residents into a group exercise intervention

Background: Randomized controlled trials (RCTs) provide the highest level of scientific evidence, but successful participant recruitment is critical to ensure the external and internal validity of results. This study describes the strategies associated with recruiting older adults at increased falls risk residing in retirement villages into an 18-month cluster RCT designed to evaluate the effects of a dual-task exercise program on falls and physical and cognitive function. Methods: Recruitment of adults aged ≥65 at increased falls risk residing within retirement villages (size 60–350 residents) was initially designed to occur over 12 months using two distinct cohorts (C). Recruitment occurred via a three-stage approach that included liaising with: 1) village operators, 2) independent village managers, and 3) residents. To recruit residents, a variety of different approaches were used, including distribution of information pack, on-site presentations, free muscle and functional testing, and posters displayed in common areas. Results: Due to challenges with recruitment, three cohorts were established between February 2014 and April 2015 (14 months). Sixty retirement villages were initially invited, of which 32 declined or did not respond, leaving 28 villages that expressed interest. A total of 3947 individual letters of invitation were subsequently distributed to residents of these villages, from which 517 (13.1%) expressions of interest (EOI) were received. Across three cohorts with different recruitment strategies adopted there were only modest differences in the number of EOI received (10.5 to 15.3%), which suggests that no particular recruitment approach was most effective. Following the initial screening of these residents, 398 (77.0%) participants were deemed eligible to participate, but a final sample of 300 (58.0% of the 517 EOI) consented and was randomized; 7.6% of the 3947 residents invited. Principal reasons for not participating, despite being eligible, were poor health, lack of time and no GP approval. Conclusion: This study highlights that there are significant challenges associated with recruiting sufficient numbers of older adults from independent living retirement villages into an exercise intervention designed to improve health and well-being. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12613001 161718. Date registered 23rd October 2013

[Cost]effectiveness of withdrawal of fall-risk increasing drugs versus conservative treatment in older fallers: design of a multicenter randomized controlled trial (IMPROveFALL-study)

Background: Fall incidents represent an increasing public health problem in aging societies worldwide. A major risk factor for falls is the use of fall-risk increasing drugs. The primary aim of the study is to compare the effect of a structured medication assessment including the withdrawal of fall-risk increasing drugs on the number of new falls versus 'care as usual' in older adults presenting at the Emergency Department after a fall. Methods/Design. A prospective, multi-center, randomized controlled trial will be conducted in hospitals in the Netherlands. Persons aged 65 years who visit the Emergency Department due to a fall are invited to participate in this trial. All patients receive a full geriatric assessment at the research outpatient clinic. Patients are randomized between a structured medication assessment including withdrawal of fall-risk increasing drugs and 'care as usual'. A 3-monthly falls calendar is used for assessing the number of falls, fallers and associated injuries over a one-year follow-up period. Measurements will be at three, six, nine, and twelve months and include functional outcome, healthcare consumption, socio-demographic characteristics, and clinical information. After twelve months a second visit to the research outpatient clinic will be performed, and adherence to the new medication regimen in the intervention group will be measured. The primary outcome will be the incidence of new falls. Secondary outcome measurements are possible health effects of medication withdrawal, health-related quality of life (Short Form-12 and EuroQol-5D), costs, and cost-effectiveness of the intervention. Data will be analyzed using an intention-to-treat analysis. Discussion. The successful completion of this trial will provide evidence on the effectiveness of withdrawal of fall-risk increasing drugs in older patients as a method for falls reduction. Trial Registration. The trial is registered in the Netherlands Trial Register (NTR1593)