Molecular mechanisms of pluripotency and reprogramming

Pluripotent stem cells are able to form any terminally differentiated cell. They have opened new doors for experimental and therapeutic studies to understand early development and to cure degenerative diseases in a way not previously possible. Nevertheless, it remains important to resolve and define the mechanisms underlying pluripotent stem cells, as that understanding will impact strongly on future medical applications. The capture of pluripotent stem cells in a dish is bound to several landmark discoveries, from the initial culture and phenotyping of pluripotent embryonal carcinoma cells to the recent induction of pluripotency in somatic cells. On this developmental time line, key transcription factors, such as Oct4, Sox2 or Nanog, have been revealed not only to regulate but also to functionally induce pluripotency. These early master regulators of development control developmental signalling pathways that affect the cell cycle, regulate gene expression, modulate the epigenetic state and repair DNA damage. Besides transcription factors, microRNAs have recently been shown to play important roles in gene expression and are embedded into the regulatory network orchestrating cellular development. However, there are species-specific differences in pluripotent cells, such as surface marker expression and growth factor requirements. Such differences and their underlying developmental pathways require clear definition and have major impacts on the preclinical test bed of pluripotent cells

Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.

IntroductionWeight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).MethodsAdult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years.ResultsAmong 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI).ConclusionsPWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration

Design for Social Value: Using design to improve the impact of CSR

This paper discusses the meaning of social value from the design perspective, especially in Corporate Social Responsibility practices, and the contextual issues and values derived from design, considering how companies could better use design for social value creation. The research identified consumer attitudes to corporate social value and where companies are perceived to have generated social value, and explored where design has contributed to such social value. The research illustrates that design has great potential to add value to the triple bottom line, mostly related directly to organisations, but also to areas relating to society, including the ‘lower levels of environmental degradation’ and ‘more solutions for social issues’, indicating design plays an influential role in creating socially responsible products/services. However, this research suggests that a clear definition of ‘social value’ from various perspectives and its relationship with CSR is required due to the complex and subjective nature of ‘social value’.Arts and Humanities Research Council (AHRC

Recommendations for exercise adherence measures in musculoskeletal settings : a systematic review and consensus meeting (protocol)

Background: Exercise programmes are frequently advocated for the management of musculoskeletal disorders; however, adherence is an important pre-requisite for their success. The assessment of exercise adherence requires the use of relevant and appropriate measures, but guidance for appropriate assessment does not exist. This research will identify and evaluate the quality and acceptability of all measures used to assess exercise adherence within a musculoskeletal setting, seeking to reach consensus for the most relevant and appropriate measures for application in research and/or clinical practice settings. Methods/design: There are two key stages to the proposed research. First, a systematic review of the quality and acceptability of measures used to assess exercise adherence in musculoskeletal disorders; second, a consensus meeting. The systematic review will be conducted in two phases and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a robust methodology. Phase one will identify all measures that have been used to assess exercise adherence in a musculoskeletal setting. Phase two will seek to identify published and unpublished evidence of the measurement and practical properties of identified measures. Study quality will be assessed against the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines. A shortlist of best quality measures will be produced for consideration during stage two: a meeting of relevant stakeholders in the United Kingdom during which consensus on the most relevant and appropriate measures of exercise adherence for application in research and/or clinical practice settings will be sought. Discussion: This study will benefit clinicians who seek to evaluate patients’ levels of exercise adherence and those intending to undertake research, service evaluation, or audit relating to exercise adherence in the musculoskeletal field. The findings will impact upon new research studies which aim to understand the factors that predict adherence with exercise and which test different adherence-enhancing interventions. PROSPERO reference: CRD4201300621

THE TREND TOWARDS IMPLEMENTING THE PRECAUTIONARY PRINCIPLE IN US REGULATION OF NANOMATERIALS

The precautionary principle provides a framework for regulating emerging technologies in general and nanomaterials in particular. It counsels action in the presence of uncertainties about risk instead of assuming that nanomaterials are safe unless proven hazardous. Nanomaterials are regulated under different statutory programs depending on whether they are drugs, pesticides or other commercial chemicals. Recent developments in the regulation of nanomaterials that are not drugs or pesticides have demonstrated a trend towards application of the precautionary principle. This is a paradigm shift away from the requirement built into past interpretations of the Toxic Substances Control Act (“TSCA”) that manufacturing, processing and use of chemical substances cannot be restricted unless the regulatory authority proves an unreasonable risk. This same paradigm shift is incorporated into recent legislative proposals to amend TSCA

A preliminary study of the effect of closed incision management with negative pressure wound therapy over high-risk incisions

Background Certain postoperative wounds are recognised to be associated with more complications than others and may be termed high-risk. Wound healing can be particularly challenging following high-energy trauma where wound necrosis and infection rates are high. Surgical incision for joint arthrodesis can also be considered high-risk as it requires extensive and invasive surgery and postoperative distal limb swelling and wound dehiscence are common. Recent human literature has investigated the use of negative pressure wound therapy (NPWT) over high-risk closed surgical incisions and beneficial effects have been noted including decreased drainage, decreased dehiscence and decreased infection rates. In a randomised, controlled study twenty cases undergoing distal limb high-energy fracture stabilisation or arthrodesis were randomised to NPWT or control groups. All cases had a modified Robert-Jones dressing applied for 72 h postoperatively and NPWT was applied for 24 h in the NPWT group. Morphometric assessment of limb circumference was performed at six sites preoperatively, 24 and 72 h postoperatively. Wound discharge was assessed at 24 and 72 h. Postoperative analgesia protocol was standardised and a Glasgow Composite Measure Pain Score (GCPS) carried out at 24, 48 and 72 h. Complications were noted and differences between groups were assessed. Results Percentage change in limb circumference between preoperative and 24 and 72 h postoperative measurements was significantly less at all sites for the NPWT group with exception of the joint proximal to the surgical site and the centre of the operated bone at 72 h. Median discharge score was lower in the NPWT group than the control group at 24 h. No significant differences in GCPS or complication rates were noted. Conclusions Digital swelling and wound discharge were reduced when NPWT was employed for closed incision management. Larger studies are required to evaluate whether this will result in reduced discomfort and complication rates postoperatively