EXPERTS 1 - experiences of long-term life-limiting conditions among patients and carers: protocol for a qualitative meta-synthesis and conceptual modelling study

Introduction Increasing numbers of the population are living with long-term life-limiting conditions with a significant proportion characterised by multimorbidity. Patients with these conditions often experience high volumes of clinical interaction involving them, their caregivers and healthcare providers in complex patterns of organising, coordinating, negotiating and managing care. A better understanding of the sources of experienced complexity and multimorbidity, from the patient perspective is paramount to improve capacity and manage workload to promote improved experience of illness, more effective healthcare utilisation and improved healthcare outcomes. To better understand the sources of complexity we will undertake an evidence synthesis of qualitative studies of patient and informal carer experiences of three common long-term life-limiting conditions. We will investigate what is known about these diseases at different stages in disease progression, treatment regimens and places of care. Method and analysis We will include qualitative studies of patients’ and carers’ (aged &gt;18) accounts of their experiences of healthcare provision in a range of settings and healthcare systems. We will conduct an extensive electronic database search of publications in English between 2000 and 2014. Results and discussions sections of the papers will be regarded as formal data using the constant comparison method of qualitative analysis. From the meta-synthesis results, we will build a conceptual model of mechanisms and processes that shape patients’ journeys towards end of life to suggest where in the patient journey new interventions to improve patient and carer experience can be developed and delivered. The study is being conducted between 1 December 2014 and 31 December 2015. Ethics and dissemination No human subjects or personal data are involved and no ethical issues are anticipated. An important element of dissemination is informing user communities about the practical implications of the work through workshops, meetings and social media. Scientific results will be published in peer reviewed journals and disseminated through conferences. Trial registration number PROSPERO CRD42014014547. <br/

Exploring Homogeneity in Today\u27s Cultural Expression

This article examines the increasing cultural homogeneity driven by the internet\u27s global reach and accessibility. Roderick Hunt—an educator, brand expert, and fashion designer—integrates writing into his creative practice and brand ethos. Through his label, Uniform Journal, he merges ideas and products, emphasizing both form and function. In a Q&A discussion, Hunt explores how the internet has influenced contemporary cultural practices and challenges the notion of originality in an era of digital interconnectedness

High speed synchrotron X-ray imaging studies of the ultrasound shockwave and enhanced flow during metal solidification processes

The highly dynamic behaviour of ultrasonic bubble implosion in liquid metal, the multiphase liquid metal flow containing bubbles and particles, and the interaction between ultrasonic waves and semisolid phases during solidification of metal were studied in situ using the complementary ultrafast and high speed synchrotron X-ray imaging facilities housed respectively at the Advanced Photon Source, Argonne National Laboratory, US, and Diamond Light Source, UK. Real-time ultrafast X-ray imaging of 135,780 frames per second (fps) revealed that ultrasonic bubble implosion in a liquid Bi-8 wt. %Zn alloy can occur in a single wave period (30 kHz), and the effective region affected by the shockwave at implosion was 3.5 times the original bubble diameter. Furthermore, ultrasound bubbles in liquid metal move faster than the primary particles, and the velocity of bubbles is 70 ~ 100% higher than that of the primary particles present in the same locations close to the sonotrode. Ultrasound waves can very effectively create a strong swirling flow in a semisolid melt in less than one second. The energetic flow can detach solid particles from the liquid-solid interface and redistribute them back into the bulk liquid very effectively

ReseArch with Patient and Public invOlvement: a RealisT evaluation - the RAPPORT study

Background Patient and public involvement (PPI) is a prerequisite for many funding bodies and NHS research ethics approval. PPI in research is defined as research carried out with or by the public rather than to, about or for them. While the benefits of PPI have been widely discussed, there is a lack of evidence on the impact and outcomes of PPI in research. Objectives To determine the types of PPI in funded research, describe key processes, analyse the contextual and temporal dynamics of PPI and explore the experience of PPI in research for all those involved. Mechanisms contributing to the routine incorporation of PPI in the research process were assessed, the impact of PPI on research processes and outcomes evaluated, and barriers and enablers to effective PPI identified. Design A three-staged realist evaluation drawing on Normalisation Process Theory to understand how far PPI was embedded within health-care research in six areas: diabetes mellitus, arthritis, cystic fibrosis, dementia, public health and learning disabilities. The first two stages comprised a scoping exercise and online survey to chief investigators to assess current PPI activity. The third stage consisted of case studies tracked over 18 months through interviews and document analysis. The research was conducted in four regions of England. Participants Non-commercial studies currently running or completed within the previous 2 years eligible for adoption on the UK Clinical Research Network portfolio. A total of 129 case study participants included researchers and PPI representatives from 22 research studies, and representatives from funding bodies and PPI networks

Testing Food Waste Reduction Targets: Integrating Transition Scenarios with Macro-Valuation in an Urban Living Lab

Bristol, one of the United Kingdom&rsquo;s (UK) nine Core Cities, is seeking to achieve Zero Waste City status by 2049. This study combines macro-economic valuation with transition pathway mapping and adapted participatory scenario planning to stress test the city&rsquo;s ambitious food waste targets. The primary aim is to enable better understanding of who might be affected by achieving these targets, both locally and nationally, the potential scale of impacts, and therefore the potential barriers and policy opportunities. The valuation focuses on household and commercial food waste, combining available site and city data with national level proxies. Impact areas include changes in sectoral income, employee income, capital owner income, tax revenue, and carbon emissions. Four scenarios, based on two extreme cases, are modelled to consider food waste reduction and potential shifts in consumption patterns. Results indicate that current market and governance failures incentivise waste, and suggest potential routes to transition, including trade-offs and resource reallocation, alongside the need to acknowledge and respond to these profound structural barriers. With further development and testing, the approach may contribute to a better understanding of how to achieve city socioenvironmental targets

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome

Introduction: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely-related paralogue KCTD1 cause scalp-ear-nipple (SEN) syndrome. Methods: Exome sequencing was performed on a 2-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. Results: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p. (Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. Conclusion: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex

EXPERTS 1-experiences of long-term life-limiting conditions among patients and carers: protocol for a qualitative meta-synthesis and conceptual modelling study.

INTRODUCTION: Increasing numbers of the population are living with long-term life-limiting conditions with a significant proportion characterised by multimorbidity. Patients with these conditions often experience high volumes of clinical interaction involving them, their caregivers and healthcare providers in complex patterns of organising, coordinating, negotiating and managing care. A better understanding of the sources of experienced complexity and multimorbidity, from the patient perspective is paramount to improve capacity and manage workload to promote improved experience of illness, more effective healthcare utilisation and improved healthcare outcomes. To better understand the sources of complexity we will undertake an evidence synthesis of qualitative studies of patient and informal carer experiences of three common long-term life-limiting conditions. We will investigate what is known about these diseases at different stages in disease progression, treatment regimens and places of care. METHOD AND ANALYSIS: We will include qualitative studies of patients' and carers' (aged >18) accounts of their experiences of healthcare provision in a range of settings and healthcare systems. We will conduct an extensive electronic database search of publications in English between 2000 and 2014. Results and discussions sections of the papers will be regarded as formal data using the constant comparison method of qualitative analysis. From the meta-synthesis results, we will build a conceptual model of mechanisms and processes that shape patients' journeys towards end of life to suggest where in the patient journey new interventions to improve patient and carer experience can be developed and delivered. The study is being conducted between 1 December 2014 and 31 December 2015. ETHICS AND DISSEMINATION: No human subjects or personal data are involved and no ethical issues are anticipated. An important element of dissemination is informing user communities about the practical implications of the work through workshops, meetings and social media. Scientific results will be published in peer reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014014547