A Comparison of Physical Activity Between Home-Based and Centre-Based Pulmonary Rehabilitation:A Randomised Controlled Secondary Analysis

Background: Pulmonary rehabilitation (PR) is a highly effective intervention for individuals with chronic obstructive pulmonary disease (COPD). Physical activity (PA) has been shown to increase after a centre-based programme, yet it is not clear if a home-based programme can offer the same benefit. This study aimed to evaluate the effect of home-based PR compared with the centre-based PR on the PA levels post 7 weeks of PR and 6 months follow-up.Method: In this study, 51 participants with COPD, of them, 36 (71%) men completed physical activity monitoring with a SenseWear Armband, at three time points (baseline, 7 weeks, and 6 months). The participants were randomly assigned to either centre-based supervised PR (n = 25; 69 ± 6 years; FEV1 55 ± 20% predicted) or home-based PR (n = 26; 68 ± 7 years; FEV1 42 ± 19% predicted) programmes lasting 7 weeks. The home-based programme includes one hospital visit, a self-management manual, and two telephone calls. The PA was measured as step count, time in moderate PA (3–6 metabolic equivalent of tasks [METs]) in bouts of more than 10 min and sedentary time (<2 METs).Results: Home-based PR increased step count significantly more than the centre-based PR after 7 weeks (mean difference 1,463 steps: 95% CI 280–2,645, p = 0.02). There was no difference in time spent in moderate PA was observed (mean difference 62 min: 95% CI −56 to 248, p = 0.24). Sedentary behaviour was also significantly different between the centre and home-based groups. The home group spent 52 min less time sedentary compared with the centre-based (CI −106 to 2, p = 0.039). However, after 6 months, the step count and time spent in moderate PA returned to baseline in both the groups.Conclusion: This study provides an important insight into the role of home-based PR which has the potential to be offered as an alternative to the centre-based PR. Understanding who may best respond from the centre or home-based PR warrants further exploration and how to maintain these initial benefits for the long-term.Trial Registry: ISRCTN: No.: ISRCTN81189044; URL: isrctn.com

Enhancing the Functionality of a Microscale Bioreactor System as an Industrial Process Development Tool for Mammalian Perfusion Culture

Without a scale-down model for perfusion, high resource demand makes cell line screening or process development challenging; therefore potentially successful cell lines or perfusion processes are unrealised and their ability untapped. We present here the re-functioning of a high capacity microscale system that is typically employed in fed-batch process development to allow perfusion operation utilising in situ gravity settling and automated sampling. In this low resource setting, which involved routine perturbations in mixing, pH and dissolved oxygen concentrations, the specific productivity and the maximum cell concentration were higher than 3.0x106 mg/cell/day and 7x107 cells/ml, respectively, across replicate microscale perfusion runs conducted at one vessel volume exchange per day. A comparative analysis was conducted at bench scale with vessels operated in perfusion mode utilising a cell retention device. Neither specific productivity nor product quality indicated by product aggregation [6%] was significantly different across scales 19 days post inoculation, thus demonstrating this setup to be a suitable and reliable platform for evaluating the performance of cell lines and the effect of process parameters relevant to perfusion mode of culturing

Can we predict ectotherm responses to climate change using thermal performance curves and body temperatures?

Thermal performance curves (TPCs), which quantify how an ectotherm\u27s body temperature (Tb ) affects its performance or fitness, are often used in an attempt to predict organismal responses to climate change. Here, we examine the key - but often biologically unreasonable - assumptions underlying this approach; for example, that physiology and thermal regimes are invariant over ontogeny, space and time, and also that TPCs are independent of previously experienced Tb. We show how a critical consideration of these assumptions can lead to biologically useful hypotheses and experimental designs. For example, rather than assuming that TPCs are fixed during ontogeny, one can measure TPCs for each major life stage and incorporate these into stage-specific ecological models to reveal the life stage most likely to be vulnerable to climate change. Our overall goal is to explicitly examine the assumptions underlying the integration of TPCs with Tb , to develop a framework within which empiricists can place their work within these limitations, and to facilitate the application of thermal physiology to understanding the biological implications of climate change

In silico and structural analyses demonstrate that intrinsic protein motions guide T cell receptor complementarity determining region loop flexibility

T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 Å in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions

Modelling the ARMv8 architecture, operationally: Concurrency and ISA

Copyright is held by the owner/author(s). In this paper we develop semantics for key aspects of the ARMv8 multiprocessor architecture: the concurrency model and much of the 64-bit application-level instruction set (ISA). Our goal is to clarify what the range of architecturally allowable behaviour is, and thereby to support future work on formal verification, analysis, and testing of concurrent ARM software and hardware. Establishing such models with high confidence is intrinsically difficult: it involves capturing the vendor's architectural intent, aspects of which (especially for concurrency) have not previously been precisely defined. We therefore first develop a concurrency model with a microarchitectural flavour, abstracting from many hardware implementation concerns but still close to hardware-designer intuition. This means it can be discussed in detail with ARM architects. We then develop a more abstract model, better suited for use as an architectural specification, which we prove sound w.r.t. the first. The instruction semantics involves further difficulties, handling the mass of detail and the subtle intensional information required to interface to the concurrency model. We have a novel ISA description language, with a lightweight dependent type system, letting us do both with a rather direct representation of the ARM reference manual instruction descriptions. We build a tool from the combined semantics that lets one explore, either interactively or exhaustively, the full range of architecturally allowed behaviour, for litmus tests and (small) ELF executables. We prove correctness of some optimisations needed for tool performance. We validate the models by discussion with ARM staff, and by comparison against ARM hardware behaviour, for ISA single-instruction tests and concurrent litmus tests.This work was partly funded by the EPSRC Programme Grant REMS: Rigorous Engineering for Mainstream Systems, EP/K008528/1, the Scottish Funding Council (SICSA Early Career Industry Fellowship, Sarkar), an ARM iCASE award (Pulte), and ANR grant WMC (ANR-11-JS02-011, Maranget)

Shotgun cholanomics of ileal fluid

In this study we have developed a rapid method for the shotgun analysis of bile acids in intestinal fluid. The method is semi-quantitative, and requires little sample preparation. Bile salts might contribute to the pathogenesis of Crohn's disease. In a pilot study we demonstrate the method by analysing the bile acid content of ileal fluid from seven Crohn's disease patients and three healthy controls. The dominant bile acids observed were di and/or trihydroxycholanoates, di- and/or trihydroxycholanoylglycines, di- and/or tri-hydroxycholanoyltaurines, monosulphated dihydroxycholanoates and monosulphated dihydroxycholanoylglycine. The method can be similarly applied to samples derived from other parts of the intestine

Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted CTL epitope produce the SLFNTIAVL triple mutant ‘ultimate’ escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent exposed residues in the peptide destabilize the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate reevaluation of this exemplar model of HIV TCR escape