A self-management programme to reduce falls and improve safe mobility in people with secondary progressive MS: the BRiMS feasibility RCT

This is the final version, also available from NIHR journals library via the DOI in this record.Abstract Background Balance, mobility impairments and falls are common problems for people with multiple sclerosis (MS). Our ongoing research has led to the development of Balance Right in MS (BRiMS), a 13-week home- and group-based exercise and education programme intended to improve balance and encourage safer mobility. Objective This feasibility trial aimed to obtain the necessary data and operational experience to finalise the planning of a future definitive multicentre randomised controlled trial. Design Randomised controlled feasibility trial. Participants were block randomised 1 : 1. Researcher-blinded assessments were scheduled at baseline and at 15 and 27 weeks post randomisation. As is appropriate in a feasibility trial, statistical analyses were descriptive rather than involving formal/inferential comparisons. The qualitative elements utilised template analysis as the chosen analytical framework. Setting Four sites across the UK. Participants Eligibility criteria included having a diagnosis of secondary progressive MS, an Expanded Disability Status Scale (EDSS) score of between ≥ 4.0 and ≤ 7.0 points and a self-report of two or more falls in the preceding 6 months. Interventions Intervention – manualised 13-week education and exercise programme (BRiMS) plus usual care. Comparator – usual care alone. Main outcome measures Trial feasibility, proposed outcomes for the definitive trial (including impact of MS, mobility, quality of life and falls), feasibility of the BRiMS programme (via process evaluation) and economic data. Results A total of 56 participants (mean age 59.7 years, standard deviation 9.7 years; 66% female; median EDSS score of 6.0 points, interquartile range 6.0–6.5 points) were recruited in 5 months; 30 were block randomised to the intervention group. The demographic and clinical data were broadly comparable at baseline; however, the intervention group scored worse on the majority of baseline outcome measures. Eleven participants (19.6%) withdrew or were lost to follow-up. Worsening of MS-related symptoms unrelated to the trial was the most common reason (n = 5) for withdrawal. Potential primary and secondary outcomes and economic data had completion rates of > 98% for all those assessed. However, the overall return rate for the patient-reported falls diary was 62%. After adjusting for baseline score, the differences between the groups (intervention compared with usual care) at week 27 for the potential primary outcomes were MS Walking Scale (12-item) version 2 –7.7 [95% confidence interval (CI) –17.2 to 1.8], MS Impact Scale (29-item) version 2 (MSIS-29vs2) physical 0.6 (95% CI –7.8 to 9) and MSIS-29vs2 psychological –0.4 (95% CI –9.9 to 9) (negative score indicates improvement). After the removal of one outlier, a total of 715 falls were self-reported over the 27-week trial period, with substantial variation between individuals (range 0–93 falls). Of these 715 falls, 101 (14%) were reported as injurious. Qualitative feedback indicated that trial processes and participant burden were acceptable, and participants highlighted physical and behavioural changes that they perceived to result from undertaking BRiMS. Engagement varied, influenced by a range of condition- and context-related factors. Suggestions to improve the utility and accessibility of BRiMS were highlighted. Conclusions The results suggest that the trial procedures are feasible and acceptable, and retention, programme engagement and outcome completion rates were sufficient to satisfy the a priori progression criteria. Challenges were experienced in some areas of data collection, such as completion of daily diaries.National Institute for Health Research (NIHR

Most soil trophic guilds increase plant growth: a meta-analytical review

Trophic cascades are important drivers of plant and animal abundances in aquatic and aboveground systems, but in soils trophic cascades have been thought to be of limited importance due to omnivory and other factors. Here we use a meta-analysis of 215 studies with 1526 experiments that measured plant growth responses to additions or removals of soil organisms to test how different soil trophic levels affect plant growth. Consistent with the trophic cascade hypothesis, we found that herbivores and plant pathogens (henceforth pests) decreased plant growth and that predators of pests increased plant growth. The magnitude of this trophic cascade was similar to that reported for aboveground systems. In contrast, we did not find evidence for trophic cascades in decomposer- and symbiont-based (henceforth mutualist) food chains. In these food chains, mutualists increased plant growth and predators of mutualists also increased plant growth, presumably by increasing nutrient cycling rates. Therefore, mutualists, predators of mutualists and predators of pests all increased plant growth. Further, experiments that added multiple organisms from different trophic levels also increased plant growth. As a result, across the dataset, soil organisms increased plant growth 29% and non-pest soil organisms increased plant growth 46%. Omnivory has traditionally been thought to confound soil trophic dynamics, but here we suggest that omnivory allows for a simplified perspective of soil food webs – one in which most soil organisms increase plant growth by preying on pests or increasing nutrient cycling rates. An implication of this perspective is that processes that decrease soil organism abundance (e.g. soil tillage) are likely to decrease aboveground productivity. Synthesis Soil foodwebs have resisted generalizations due to their diversity and interconnectedness. Here we use results from a meta-analysis to inform a simplified perspective of soil foodwebs: one in which most soil trophic guilds increase plant growth. Our review also includes the first widespread support for the presence of trophic cascades in soils

A new framework for global data regulation

Under the current regulatory framework for data protections, the protection of human rights writ large and the corresponding outcomes are regulated largely independently from the data and tools that both threaten those rights and are needed to protect them. This separation between tools and the outcomes they generate risks overregulation of the data and tools themselves when not linked to sensitive use cases. In parallel, separation risks under-regulation if the data can be collected and processed under a less-restrictive framework, but used to drive an outcome that requires additional sensitivity and restrictions. A new approach is needed to support differential protections based on the genuinely high-risk use cases within each sector. Here, we propose a regulatory framework designed to apply not to specific data or tools themselves, but to the outcomes and rights that are linked to the use of these data and tools in context. This framework is designed to recognize, address, and protect a broad range of human rights, including privacy, and suggests a more flexible approach to policy making that is aligned with current engineering tools and practices. We test this framework in the context of open banking and describe how current privacy-enhancing technologies and other engineering strategies can be applied in this context and that of contract tracing applications. This approach for data protection regulations more effectively builds on existing engineering tools and protects the wide range of human rights defined by legislation and constitutions around the globe.Comment: 15 pages, 2 figure

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Can Inflation be Falsified?

Despite its central role in modern cosmology, doubts are often expressed as to whether cosmological inflation is really a falsifiable theory. We distinguish two facets of inflation, one as a theory of initial conditions for the hot big bang and the other as a model for the origin of structure in the Universe. We argue that the latter can readily be excluded by observations, and that there are also a number of ways in which the former can find itself in conflict with observational data. Both aspects of the theory are indeed falsifiable.Comment: 7 pages LaTeX file with two figures incorporated by epsf. Fifth Prize in Gravity Research Foundation Essay Competition. To appear, General Relativity and Gravitatio

Exposure to the antimicrobial peptide LL-37 produces dendritic cells optimized for immunotherapy

Immunization of patients with autologous, ex vivo matured dendritic cell (DC) preparations, in order to prime antitumor T-cell responses, is the focus of intense research. Despite progress and approval of clinical approaches, significant enhancement of these personalized immunotherapies is urgently needed to improve efficacy. We show that immunotherapeutic murine and human DC, generated in the presence of the antimicrobial host defense peptide LL-37, have dramatically enhanced expansion and differentiation of cells with key features of the critical CD103 + /CD141 + DC subsets, including enhanced cross-presentation and co-stimulatory capacity, and upregulation of CCR7 with improved migratory capacity. These LL-37-DC enhanced proliferation, activation and cytokine production by CD8 + (but not CD4 + ) T cells in vitro and in vivo. Critically, tumor antigen-presenting LL-37-DC increased migration of primed, activated CD8 + T cells into established squamous cell carcinomas in mice, and resulted in tumor regression. This advance therefore has the potential to dramatically enhance DC immunotherapy protocols

Objectively measured physical activity and fat mass in a large cohort of children

Background Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. Methods and Findings We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend < 0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. Conclusions We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity