Efficacy of High Dose Vitamin D Supplements for Elite Athletes.

PURPOSE: Supplementation with dietary forms of vitamin D is commonplace in clinical medicine, elite athletic cohorts and the general population, yet the response of all major vitamin D metabolites to high doses of vitamin D is poorly characterized. We aimed to identify the responses of all major vitamin D metabolites to moderate and high dose supplemental vitamin D3. METHODS: A repeated measures design was implemented in which 46 elite professional European athletes were block randomized based on their basal 25[OH]D concentration into two treatment groups. Athletes received either 35,000 or 70,000 IU.week vitamin D3 for 12 weeks and 42 athletes completed the trial. Blood samples were collected over 18 weeks to monitor the response to supplementation and withdrawal from supplementation. RESULTS: Both doses led to significant increases in serum 25[OH]D and 1,25[OH]2D3. 70,000 IU.week also resulted in a significant increase of the metabolite 24,25[OH]2D at weeks 6 and 12 that persisted following supplementation withdrawal at week 18, despite a marked decrease in 1,25[OH]2D3. Intact PTH was decreased in both groups by week 6 and remained suppressed throughout the trial. CONCLUSIONS: High dose vitamin D3 supplementation (70,000 IU.week) may be detrimental for its intended purposes due to increased 24,25[OH]2D production. Rapid withdrawal from high dose supplementation may inhibit the bioactivity of 1,25[OH]2D3 as a consequence of sustained increases in 24,25[OH]2D that persist as 25[OH]D and 1,25[OH]2D concentrations decrease. These data imply that lower doses of vitamin D3 ingested frequently may be most appropriate and gradual withdrawal from supplementation as opposed to rapid withdrawal may be favorable

Site-specific associations of muscle thickness with bone mineral density in middle-aged and older men and women

It is unknown whether age-related site-specific muscle loss is associated with areal bone mineral density (aBMD) in older adults. To examine the relationships between aBMD and whole-body muscle thickness distribution, 97 healthy adults (46 women and 51 men) aged 50–78 years volunteered. Total and appendicular lean soft tissue mass, aBMD of the lumbar spine (LS-aBMD) and femoral neck (FN-aBMD) were determined using dual-energy X-ray absorptiometry. Muscle thickness (MT) was measured by ultrasound at nine sites of the body (forearm, upper arm, trunk, upper leg, and lower leg). Relationships of each co-variate with aBMD were tested partialling out the effect of age. aBMD was not correlated with either MT of the trunk or anterior lower leg in either sex. In men, significant and relatively strong correlations were observed between anterior and posterior upper arms, posterior lower leg, and anterior upper leg MT and LS-aBMD or FN-aBMD. In women, significant correlations were observed between anterior and posterior upper legs, posterior lower leg, and anterior upper arm MT and FN-aBMD. LS-aBMD was only correlated with forearm and posterior upper leg MT in women. In conclusion, the site-specific association of MT and aBMD differs between sexes and may be associated with the participants’ daily physical activity profile

"Fuel for the Damage Induced": Untargeted Metabolomics in Elite Rugby Union Match Play.

The metabolic perturbations caused by competitive rugby are not well characterized. Our aim is to utilize untargeted metabolomics to develop appropriate interventions, based on the metabolic fluctuations that occur in response to this collision-based team sport. Seven members of an English Premiership rugby squad consented to provide blood, urine, and saliva samples daily, over a competitive week including gameday (GD), with physical demands and dietary intake also recorded. Sample collection, processing and statistical analysis were performed in accordance with best practice set out by the metabolomics standards initiative employing 700 MHz NMR spectroscopy. Univariate and multivariate statistical analysis were employed to reveal the acute energy needs of this high intensity sport are met via glycolysis, the TCA cycle and gluconeogenesis. The recovery period after cessation of match play and prior to training recommencing sees a re-entry to gluconeogenesis, coupled with markers of oxidative stress, structural protein degradation, and reduced fatty acid metabolism. This novel insight leads us to propose that effective recovery from muscle damaging collisions is dependent upon the availability of glucose. An adjustment in the periodisation of carbohydrate to increase GD+1 provision may prevent the oxidation of amino acids which may also be crucial to allay markers of structural tissue degradation. Should we expand the 'Fuel for the work required' paradigm in collision-based team sports to include 'Fuel for the damage induced'

Three weeks of a home-based "sleep low-train low" intervention improves functional threshold power in trained cyclists: A feasibility study.

BACKGROUND: "Sleep Low-Train Low" is a training-nutrition strategy intended to purposefully reduce muscle glycogen availability around specific exercise sessions, potentially amplifying the training stimulus via augmented cell signalling. The aim of this study was to assess the feasibility of a 3-week home-based "sleep low-train low" programme and its effects on cycling performance in trained athletes. METHODS: Fifty-five trained athletes (Functional Threshold Power [FTP]: 258 ± 52W) completed a home-based cycling training program consisting of evening high-intensity training (6 × 5 min at 105% FTP), followed by low-intensity training (1 hr at 75% FTP) the next morning, three times weekly for three consecutive weeks. Participant's daily carbohydrate (CHO) intake (6 g·kg-1·d-1) was matched but timed differently to manipulate CHO availability around exercise: no CHO consumption post- HIT until post-LIT sessions [Sleep Low (SL), n = 28] or CHO consumption evenly distributed throughout the day [Control (CON), n = 27]. Sessions were monitored remotely via power data uploaded to an online training platform, with performance tests conducted pre-, post-intervention. RESULTS: LIT exercise intensity reduced by 3% across week 1, 3 and 2% in week 2 (P < 0.01) with elevated RPE in SL vs. CON (P < 0.01). SL enhanced FTP by +5.5% vs. +1.2% in CON (P < 0.01). Comparable increases in 5-min peak power output (PPO) were observed between groups (P < 0.01) with +2.3% and +2.7% in SL and CON, respectively (P = 0.77). SL 1-min PPO was unchanged (+0.8%) whilst CON improved by +3.9% (P = 0.0144). CONCLUSION: Despite reduced relative training intensity, our data demonstrate short-term "sleep low-train low" intervention improves FTP compared with typically "normal" CHO availability during exercise. Importantly, training was completed unsupervised at home (during the COVID-19 pandemic), thus demonstrating the feasibility of completing a "sleep low-train low" protocol under non-laboratory conditions

Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Multi-spacecraft study of the solar wind at solar minimum: Dependence on latitude and transient outflows

Context: The recent launches of Parker Solar Probe, Solar Orbiter (SO), and BepiColombo, along with several older spacecraft, have provided the opportunity to study the solar wind at multiple latitudes and distances from the Sun simultaneously. Aims: We take advantage of this unique spacecraft constellation, along with low solar activity across two solar rotations between May and July 2020, to investigate how the solar wind structure, including the heliospheric current sheet (HCS), varies with latitude. Methods: We visualise the sector structure of the inner heliosphere by ballistically mapping the polarity and solar wind speed from several spacecraft onto the Sun’s source surface. We then assess the HCS morphology and orientation with the in situ data and compare this with a predicted HCS shape. Results: We resolve ripples in the HCS on scales of a few degrees in longitude and latitude, finding that the local orientations of sector boundaries were broadly consistent with the shape of the HCS but were steepened with respect to a modelled HCS at the Sun. We investigate how several CIRs varied with latitude, finding evidence for the compression region affecting slow solar wind outside the latitude extent of the faster stream. We also identified several transient structures associated with HCS crossings and speculate that one such transient may have disrupted the local HCS orientation up to five days after its passage. Conclusions: We have shown that the solar wind structure varies significantly with latitude, with this constellation providing context for solar wind measurements that would not be possible with a single spacecraft. These measurements provide an accurate representation of the solar wind within ±10° latitude, which could be used as a more rigorous constraint on solar wind models and space weather predictions. In the future, this range of latitudes will increase as SO’s orbit becomes more inclined

Substitution of adeno-associated virus Rep protein binding and nicking sites with human Chromosome 19 sequences

<p>Abstract</p> <p>Background</p> <p>Adeno-associated virus type 2 (AAV2) preferentially integrates its DNA at a ~2 kb region of human chromosome 19, designated <it>AAVS1 </it>(also known as <it>MBS85</it>). Integration at <it>AAVS1 </it>requires the AAV2 replication (Rep) proteins and a DNA sequence within <it>AAVS1 </it>containing a 16 bp Rep recognition sequence (RRS) and closely spaced Rep nicking site (also referred to as a terminal resolution site, or <it>trs</it>). The AAV2 genome is flanked by inverted terminal repeats (ITRs). Each ITR contains an RRS and closely spaced <it>trs</it>, but the sequences differ from those in <it>AAVS1</it>. These ITR sequences are required for replication and packaging.</p> <p>Results</p> <p>In this study we demonstrate that the <it>AAVS1 </it>RRS and <it>trs </it>can function in AAV2 replication, packaging and integration by replacing a 61 bp region of the AAV2 ITR with a 49 bp segment of <it>AAVS1 </it>DNA. Modifying one or both ITRs did not have a large effect on the overall virus titers. These modifications did not detectably affect integration at <it>AAVS1</it>, as measured by semi-quantitative nested PCR assays. Sequencing of integration junctions shows the joining of the modified ITRs to <it>AAVS1 </it>sequences.</p> <p>Conclusions</p> <p>The ability of these <it>AAVS1 </it>sequences to substitute for the AAV2 RRS and <it>trs </it>provides indirect evidence that the stable secondary structure encompassing the <it>trs </it>is part of the AAV2 packaging signal.</p

Simulations of extensional flow in microrheometric devices

We present a detailed numerical study of the flow of a Newtonian fluid through microrheometric devices featuring a sudden contraction–expansion. This flow configuration is typically used to generate extensional deformations and high strain rates. The excess pressure drop resulting from the converging and diverging flow is an important dynamic measure to quantify if the device is intended to be used as a microfluidic extensional rheometer. To explore this idea, we examine the effect of the contraction length, aspect ratio and Reynolds number on the flow kinematics and resulting pressure field. Analysis of the computed velocity and pressure fields show that, for typical experimental conditions used in microfluidic devices, the steady flow is highly three-dimensional with open spiraling vortical structures in the stagnant corner regions. The numerical simulations of the local kinematics and global pressure drop are in good agreement with experimental results. The device aspect ratio is shown to have a strong impact on the flow and consequently on the excess pressure drop, which is quantified in terms of the dimensionless Couette and Bagley correction factors. We suggest an approach for calculating the Bagley correction which may be especially appropriate for planar microchannels

Individualized Cost-Effectiveness Analysis

John Ioannidis and Alan Garber discuss how to use incremental cost-effectiveness ratios (ICER) and related metrics so they can be useful for decision-making at the individual level, whether used by clinicians or individual patients