ActEarly: a City Collaboratory approach to early promotion of good health and wellbeing.

Economic, physical, built, cultural, learning, social and service environments have a profound effect on lifelong health. However, policy thinking about health research is dominated by the 'biomedical model' which promotes medicalisation and an emphasis on diagnosis and treatment at the expense of prevention. Prevention research has tended to focus on 'downstream' interventions that rely on individual behaviour change, frequently increasing inequalities. Preventive strategies often focus on isolated leverage points and are scattered across different settings. This paper describes a major new prevention research programme that aims to create City Collaboratory testbeds to support the identification, implementation and evaluation of upstream interventions within a whole system city setting. Prevention of physical and mental ill-health will come from the cumulative effect of multiple system-wide interventions. Rather than scatter these interventions across many settings and evaluate single outcomes, we will test their collective impact across multiple outcomes with the goal of achieving a tipping point for better health. Our focus is on early life (ActEarly) in recognition of childhood and adolescence being such critical periods for influencing lifelong health and wellbeing

Human papillomavirus (HPV) related Oropharynx Cancer in the United Kingdom – An evolution in the understanding of disease aetiology

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3-54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99-1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9-2.2); 2011: 4.1 (95% CI, 4.0-4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV- cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented.</p

Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins

Abstract Background The mechanisms underpinning the regenerative capabilities of mesenchymal stem cells (MSC) were originally thought to reside in their ability to recognise damaged tissue and to differentiate into specific cell types that would replace defective cells. However, recent work has shown that molecules produced by MSCs (secretome), particularly those packaged in extracellular vesicles (EVs), rather than the cells themselves are responsible for tissue repair. Methods Here we have produced a secretome from adipose-derived mesenchymal stem cells (ADSC) that is free of exogenous molecules by incubation within a saline solution. Various in vitro models were used to evaluate the effects of the secretome on cellular processes that promote tissue regeneration. A cardiotoxin-induced skeletal muscle injury model was used to test the regenerative effects of the whole secretome or isolated extracellular vesicle fraction in vivo. This was followed by bioinformatic analysis of the components of the protein and miRNA content of the secretome and finally compared to a secretome generated from a secondary stem cell source. Results Here we have demonstrated that the secretome from adipose-derived mesenchymal stem cells shows robust effects on cellular processes that promote tissue regeneration. Furthermore, we show that the whole ADSC secretome is capable of enhancing the rate of skeletal muscle regeneration following acute damage. We assessed the efficacy of the total secretome compared with the extracellular vesicle fraction on a number of assays that inform on tissue regeneration and demonstrate that both fractions affect different aspects of the process in vitro and in vivo. Our in vitro, in vivo, and bioinformatic results show that factors that promote regeneration are distributed both within extracellular vesicles and the soluble fraction of the secretome. Conclusions Taken together, our study implies that extracellular vesicles and soluble molecules within ADSC secretome act in a synergistic manner to promote muscle generation

In-Orbit Performance of the GRACE Follow-on Laser Ranging Interferometer

The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/Hz at Fourier frequencies above 100 mHz. © 2019 authors. Published by the American Physical Society

The effects of problem-oriented policing on crime and disorder

Problem-oriented Policing (POP) was first introduced by Herman Goldstein in 1979. The approach was one of a series of responses to a crisis in effectiveness and legitimacy in policing that emerged in the 1970s and 1980s. Goldstein argued that police were not being effective in preventing and controlling crime because they had become too focused on the “means” of policing and had neglected the “goals” of preventing and controlling crime and other community problems. Goldstein argued that the unit of analysis in policing must become the “problem” rather than calls or crime incidents as was the case during that period. POP has had tremendous impact on American policing, and is now one of the most widely implemented policing strategies in the US. To synthesize the extant problem-oriented policing evaluation literature and assess the effects of problem-oriented policing on crime and disorder Eligible studies had to meet three criteria: (1) the SARA model was used for a problemoriented policing intervention; (2) a comparison group was included; (3) at least one crime or disorder outcome was reported with sufficient data to generate an effect size. The unit of analysis could be people or places. Several strategies were used to perform an exhaustive search for literature fitting the eligibility criteria. First, a keyword search was performed on an array of online abstract databases. Second, we reviewed the bibliographies of past reviews of problem-oriented policing. Third, we performed forward searches for works that have cited seminal problem-oriented policing studies. Fourth, we performed hand searches of leading journals in the field. Fifth, we searched the publications of several research and professional agencies. Sixth, after finishing the above searches we e-mailed the list of studies meeting our eligibility criteria to leading policing scholars knowledgeable in the area of problem-oriented policing to ensure we had not missed any relevant studies. For our ten eligible studies, we provide both a narrative review of effectiveness and a meta-analysis. For the meta-analysis, we coded all primary outcomes of the eligible studies and we report the mean effect size (for studies with more than one primary outcome, we averaged effects to create a mean), the largest effect, and the smallest effect. Because of the heterogeneity of our studies, we used a random effects model. Based on our meta-analysis, overall problem-oriented policing has a modest but statistically significant impact on reducing crime and disorder. Our results are consistent when examining both experimental and quasi-experimental studies. Conclusions: We conclude that problem-oriented policing is effective in reducing crime and disorder, although the effect is fairly modest. We urge caution in interpreting these results because of the small number of methodologically rigorous studies on POP and the diversity of problems and responses used in our eligible studies

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis:a randomised, double-blind, placebo-controlled, phase 2b trial

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50–90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene–liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (&lt;70 vs ≥70%), age (&lt;18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1–7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials

Pharmaceutical Pill Counting and Inspection Using a Capacitive Sensor

A capacitive sensor for high-speed counting and inspection of pharmaceutical products is proposed and evaluated. The sensor is based on a patented Electrostatic Field Sensor (EFS) device, previously developed by Sparc Systems Limited. However, the sensor head proposed in this work has a significantly different geometry and has been designed with a rectangular inspection aperture of 160mm × 21mm, which best meets applications where a larger count throughput is required with a single sensor. Finite element modelling has been used to simulate the electrostatic fields generated within the sensor, and as a design tool for optimising the sensor head configuration. The actual and simulated performance of the sensor is compared and analysed in terms of the sensor performance at discriminating between damaged products or detection of miscount errors

DoD Architecture Framework and Software Architecture Workshop Report

During the Software Engineering Institute's Workshop on the Department of Defense Architecture Framework and Software Architecture, participants from government, industry, and academia discussed the similarities and differences between system and software architecture representations, and how these representations relate with one another. This technical note summarizes the activities of that workshop

Three-dimensional mathematical modelling of magnetic bead interactions within a magnetic separation system

Magnetic separation relates to the ability to separate particles based on their magnetic mobilities. This is often limited by the formation of bead agglomerates. Bead agglomerates are formed as a result of attractive magnetic induced interactions among magnetic beads suspended in fluid. A three-dimensional model of the interactions among three equal sized super-paramagnetic beads suspended in a static fluid within a uniform magnetic field is presented here. The beads’ trajectories were recorded on video while the relative axial displacement of the bead was obtained using the recorded off-focus images. A good agreement was obtained by comparing the beads’ simulated trajectories with the video data. Therefore, the model is able to predict the behaviour of magnetic beads in immunoassays as well as magnetic separation system

Additional file 2: of Secretome of adipose-derived mesenchymal stem cells promotes skeletal muscle regeneration through synergistic action of extracellular vesicle cargo and soluble proteins

Figure S2. (A) The secretome generated from fibroblast cells under identical conditions to ADSC contains a significantly lower amount of total protein. (B-C) Characterising the fibroblast EVs using NTA found a significantly lower concentration per mL, with a similar size range to ADSC EVs