The feasibility of a flexible exercise participation programme (FEPP) for individuals with multiple sclerosis

Background and purpose Individuals with multiple sclerosis (MS) want health advice regarding participation in their choice of exercise. To address this need, a flexible exercise participation programme (FEPP) was developed, underpinned by the MS aerobic exercise guidelines and supported by a physiotherapist using behaviour change techniques. The aim of this study was to investigate the feasibility of the FEPP for individuals with minimal disability from MS. Methods A feasibility study utilising a single group pre/post-intervention design was conducted. The 12-week FEPP was completed by 10 individuals with MS (EDSS 0–3.5). Exercise progression in duration, intensity or frequency of exercise (in line with MS exercise guidelines) was guided by a self-perceived weekly energy level score, and weekly telephone coaching sessions using behavioural change techniques. Trial feasibility was assessed via measures of process (recruitment and retention), resources/management (communication time; data entry) and scientific feasibility (safety; compliance). Secondary FEPP feasibility outcomes included the Goal Attainment Scale (GAS) T-score, exercise participation (weekly exercise diary), high-level mobility (HiMAT), vitality (Subjective Vitality Scale), biomarkers for inflammation (cytokines levels [IL2, IL4, IL6, IL10, TNF and IFNγ]), and acceptability (participant survey). Results Process: In total, 11 (85%) of 13 eligible participants enroled at baseline with 10 (91%) completing the study. Resources/management: Coaching sessions included a baseline interview—mean 39 min (SD: 6.6) and telephone coaching—mean 10 min (SD: 3.8) per week. Outcome measure data collection time—mean 44 min (SD: 2.1). Scientific feasibility: Two participants experienced a fall during their exercise participation. Self-reported compliance was high (99%). GAS T-scores increased significantly, indicating achievement of exercise participation goals. Secondary outcomes showed trends towards improvement. Discussion The FEPP was feasible, safe and highly acceptable for use with individuals with MS and warrants a larger trial to explore effectiveness

Pseudomonas expression of an oxygen sensing prolyl hydroxylase homologue regulates neutrophil host responses in vitro and in vivo

Background: Pseudomonas species are adapted to evade innate immune responses and can persist at sites of relative tissue hypoxia, including the mucus-plugged airways of patients with cystic fibrosis and bronchiectasis. The ability of these bacteria to directly sense and respond to changes in local oxygen availability is in part consequent upon expression of the 2-oxoglutarate oxygenase, Pseudomonas prolyl hydroxylase (PPHD), which acts on elongation factor Tu (EF-Tu), and is homologous with the human hypoxia inducible factor (HIF) prolyl hydroxylases. We report that PPHD expression regulates the neutrophil response to acute pseudomonal infection. Methods: In vitro co-culture experiments were performed with human neutrophils and PPHD-deficient and wild-type bacteria and supernatants, with viable neutrophil counts determined by flow cytometry. In vivo consequences of infection with PPHD deficient P. aeruginosa were determined in an acute pneumonia mouse model following intra-tracheal challenge. Results: Supernatants of PPHD-deficient bacterial cultures contained higher concentrations of the phenazine exotoxin pyocyanin and induced greater acceleration of neutrophil apoptosis than wild-type PAO1 supernatants in vitro. In vivo infection with PPHD mutants compared to wild-type PAO1 controls resulted in increased levels of neutrophil apoptosis and impaired control of infection, with higher numbers of P. aeruginosa recovered from the lungs of mice infected with the PPHD-deficient strain. This resulted in an overall increase in mortality in mice infected with the PPHD-deficient strain. Conclusions: Our data show that Pseudomonas expression of its prolyl hydroxylase influences the outcome of host-pathogen interactions in vitro and in vivo, demonstrating the importance of considering how both host and pathogen adaptations to hypoxia together define outcomes of infection. Given that inhibitors for the HIF prolyl hydroxylases are in late stage trials for the treatment of anaemia and that the active sites of PPHD and human HIF prolyl hydroxylases are closely related, the results are of current clinical interest

Less is more: Low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells

Background: Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) is a multifunctional protease implicated in metastatic progression ostensibly due to its ability to degrade extracellular matrix (ECM) components and allow migration of cells through the basement membrane. Despite in vitro studies demonstrating this principle, this knowledge has not translated into the use of MMP inhibitors (MMPi) as effective cancer therapeutics, or been corroborated by evidence of in vivo ECM degradation mediated by MT1-MMP, suggesting that our understanding of the role of MT1-MMP in cancer progression is incomplete. Methods: MCF-7 and MDA-MB 231 breast cancer cell lines were created that stably overexpress different levels of MT1-MMP. Using 2D culture, we analyzed proMMP-2 activation (gelatin zymography), ECM degradation (fluorescent gelatin), ERK signaling (immunoblot), cell migration (transwell/scratch closure/time-lapse imaging), and viability (colorimetric substrate) to assess how different MT1-MMP levels affect these cellular parameters. We also utilized Matrigel 3D cell culture and avian embryos to examine how different levels of MT1-MMP expression affect morphological changes in 3D culture, and tumourigenecity and extravasation efficiency in vivo. Results: In 2D culture, breast cancer cells expressing high levels of MT1-MMP were capable of widespread ECM degradation and TIMP-2-mediated proMMP-2 activation, but were not the most migratory. Instead, cells expressing low levels of MT1-MMP were the most migratory, and demonstrated increased viability and ERK activation. In 3D culture, MCF-7 breast cancer cells expressing low levels of MT1-MMP demonstrated an invasive protrusive phenotype, whereas cells expressing high levels of MT1-MMP demonstrated loss of colony structure and cell fragment release. Similarly, in vivo analysis demonstrated increased tumourigenecity and metastatic capability for cells expressing low levels of MT1-MMP, whereas cells expressing high levels were devoid of these qualities despite the production of functional MT1-MMP protein. Conclusions: This study demonstrates that excessive ECM degradation mediated by high levels of MT1-MMP is not associated with cell migration and tumourigenesis, while low levels of MT1-MMP promote invasion and vascularization in vivo

Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4TopBP1

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint

Initial-Final Mass Relationship for Stars of Different Metallicities

Following Paczy\'{n}ski & Zi\'{o}lkowski (1968) and Han et al. (1994), we assume that the envelope of an asymptotic giant branch (AGB) or a first giant branch (FGB) star is lost when the binding energy of the envelope is equal to zero ($\Delta W=0$) and the core mass of the AGB star or the FGB star at the point ($\Delta W=0$) is taken as the final mass. Using this assumption, we calculate the IFMRs for stars of different metallicities.We find that the IFMRs depends strongly on the metallicity, i.e. $Z=0.0001, 0.0003, 0.001, 0.004, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.08$ and 0.1. From $Z=0.04$, the final mass of the stars with a given initial mass increases with increasing or decreasing metallicity. The difference of the final mass due to the metallicity may be up to 0.4 $M_{\odot}$. A linear fit of the initial-final mass relationship in NGC 2099 (M37) shows a potential evidence of the effect of metallicity on the IFMR. The IFMR for stars of $Z=0.02$ obtained in the paper matches well with those inferred observationally in the Galaxy. For $Z\geq 0.02$, helium WDs are obtained from the stars of $M_{\rm i}\leq 1.0 M_{\odot}$ and this result is upheld by the discovery of numerous low-mass WDs in NGC 6791 which is a metal-rich old open cluster. Using the IFMR for stars of $Z=0.02$ obtained in the paper, we have reproduced the mass distribution of DA WDs in Sloan DR4 except for some ultra-massive white dwarfs. The trend that the mean mass of WDs decreases with effective temperature may originate from the increase of the initial metallicities of stars. We predict that metal-rich low-mass stars may become under-massive white dwarfs.Comment: 14 pages, 8 figures, accepted for publication in A&

Latest update of the clinical trials landscape in Australia (2006 – 2020)

The latest update of the clinical trials landscape in Australia (2006 – 2020) uses trial registration data to gain an understanding of the clinical trials occurring in Australia. This report is an update of the original report covering 2006-2015 and includes new data from 2016 to 2020. These data are sourced from the Australian New Zealand Clinical Trials Registry (ANZCTR) and US-based ClinicalTrials.gov registry. The purpose of this report is to provide a comprehensive outline of the key characteristics of clinical trials over time. Reporting on clinical trial activity is a crucial step in understanding where improvements may be needed in the clinical trials sector. This report can be used as a reference point when promoting Australian clinical trial activity at national or international forums. It is intended to be used by all those working in or with clinical trials including clinical trial investigators, researchers, funders, industry, policymakers, trial participants and the public. Previous reports analysing trial activity in Australia have helped to identify research gaps and prioritise funding schemes and to inform the design of new national infrastructure that facilitates clinical trial data sharing. We hope this updated report will be of similar use and help to inform the health research agenda in government and industry

Latest update of the clinical trials landscape in Australia (2006 – 2020)

The latest update of the clinical trials landscape in Australia (2006 – 2020) uses trial registration data to gain an understanding of the clinical trials occurring in Australia. This report is an update of the original report covering 2006-2015 and includes new data from 2016 to 2020. These data are sourced from the Australian New Zealand Clinical Trials Registry (ANZCTR) and US-based ClinicalTrials.gov registry. The purpose of this report is to provide a comprehensive outline of the key characteristics of clinical trials over time. Reporting on clinical trial activity is a crucial step in understanding where improvements may be needed in the clinical trials sector. This report can be used as a reference point when promoting Australian clinical trial activity at national or international forums. It is intended to be used by all those working in or with clinical trials including clinical trial investigators, researchers, funders, industry, policymakers, trial participants and the public. Previous reports analysing trial activity in Australia have helped to identify research gaps and prioritise funding schemes and to inform the design of new national infrastructure that facilitates clinical trial data sharing. We hope this updated report will be of similar use and help to inform the health research agenda in government and industry

Short-term behavioural responses to thermal stress by hawksbill turtles in the Arabian region

We present a previously unrecorded short-term behavioural response by hawksbill sea turtles to elevated sea surface temperatures in the Persian/Arabian Gulf. Surface waters typically exceed 30°C for sustained periods during the summer, and can be likened to a natural living laboratory for understanding thermoregulatory behaviour by marine species in the face of climate change and elevated global temperatures. We satellite-tracked 90 post-nesting hawksbill turtles between 2010 and 2013 as part of a larger programme to elucidate turtle foraging habitats and post-nesting behaviour. We used 66 of these datasets, where turtles clearly departed and returned to foraging grounds, for these analyses. Sea surface temperatures during the summer averaged 33.5°C and peaked at 34.9°C. During these elongated periods of elevated temperatures (June–August) the turtles temporarily migrated an average of 70km to deeper and cooler waters at northern latitudes, returning after 2–3months (September–October) back to original feeding grounds. Temperature differential T∆ between foraging and summer loop habitats was significantly different and approximated −2°C. Turtles undertaking summer migration loops generally moved in a north-easterly direction toward deeper water, returning in a south-westerly direction to the shallower foraging grounds. Swim speeds were significantly higher and orientation was less omnidirectional during the migrations than when foraging. The outbound migrations were significantly inversely correlated with temperature, but were not linked to chlorophyll-a, geostrophic currents or sea surface height. The turtles' preference for returning to the same foraging grounds suggests a lack of other substantial influences which might have precipitated the temporary summer migration loops. Our results indicate that Gulf hawksbills employ thermoregulatory responses which take them out of high temperature and potentially physiology-threatening conditions. These findings improve our overall understanding of hawksbill habitat use and behaviour in a climate-challenged environment, and support sea turtle conservation-related policy decision-making at national and regional levels.Emirates Wildlife Society—World Wild Fund for Nature Office. 7Days, Abu Dhabi Urban Planning Council, Bridgestone, CASP, College of the North Atlantic, Qatar, Deutsche Bank, Dubai Electricity & Water Authority, Dubai Festival City, Emirates Palace, Environment & Protected Areas Authority, Sharjah, Environment Agency—Abu Dhabi, Fairmont, Géant, Gulftainer, HSBC, Intercontinental, Dubai Festival City, Jebel Ali Golf Resort & Spa, Jumeirah Etihad Towers, Linklaters, Momentum Logistics, Mubadala, Murjan Marinas, Nokia, Sheikha Salama bint Hamdan Al Nahyan Foundation, The Club, TimeOut Dubai, and the Young Presidents Organisation

Identification of Important Sea Turtle Areas (ITAs) for hawksbill turtles in the Arabian Region

We present the first data on hawksbill turtle post-nesting migrations and behaviour in the Arabian region. Tracks from 90 post-nesting turtles (65 in the Gulf and 25 from Oman) revealed that hawksbills in the Arabian region may nest up to 6 times in a season with an average of 3 nests per turtle. Turtles from Qatar, Iran and the UAE generally migrated south and southwest to waters shared by the UAE and Qatar. A smaller number of turtles migrated northward towards Bahrain, Saudi Arabia and one reached Kuwait. Omani turtles migrated south towards Masirah island and to Quwayrah, staying close to the mainland and over the continental shelf. The widespread dispersal of hawksbill foraging grounds across the SW Gulf may limit habitat protection options available to managers, and we suggest these be linked to preservation of shallow water habitats and fishery management. In contrast, the two main foraging areas in Oman were small and could be candidates for protected area consideration. Critical migration bottlenecks were identified at the easternmost point of the Arabian Peninsula as turtles from Daymaniyat Islands migrate southward, and between Qatar and Bahrain. Overall, Gulf turtles spent 68% of the time in foraging ground with home ranges of 40–60km2 and small core areas of 6km2. Adult female turtles from Oman were significantly larger than Gulf turtles by ~11cm x¯=81.4CCL and spent 83% of their time foraging in smaller home ranges with even smaller core areas (~3km2), likely due to better habitat quality and food availability. Gulf turtles were among the smallest in the world x¯=70.3CCL and spent an average of 20% of time undertaking summer migration loops, a thermoregulatory response to avoid elevated sea surface temperatures, as the Gulf regularly experiences sustained sea surface temperatures >30°C. Fishery bycatch was determined for two of the 90 turtles. These spatio-temporal findings on habitat use will enable risk assessments for turtles in the face of multiple threats including oil and gas industries, urban and industrial development, fishery pressure, and shipping. They also improve our overall understanding of hawksbill habitat use and behaviour in the Arabian region, and will support sea turtle conservation-related policy decision-making at national and regional levels.Emirates Wildlife Society–World Wild Fund for Nature. 7Days, Abu Dhabi Urban Planning Council, Bridgestone, CASP, College of the North Atlantic-Qatar, Deutsche Bank, Dubai Electricity & Water Authority, Dubai Festival City, Emirates Palace, Environment & Protected Areas Authority, Sharjah, Environment Agency–Abu Dhabi, Fairmont, Géant, Gulftainer, HSBC, Intercontinental, Dubai Festival City, Jebel Ali Golf Resort & Spa, Jumeirah Etihad Towers, Linklaters, Momentum Logistics, Mubadala, Murjan Marinas, Nokia, Sheikha Salama bint Hamdan Al Nahyan Foundation, The Club, TimeOut Dubai, and the Young Presidents Organisation