"I didn’t take it too seriously because I’d just never heard of it” : experiential knowledge and genetic screening for thalassaemia in the UK

Members of the public face particular challenges when undergoing reproductive genetic screening. Lack of family history with genetic disease has been identified as a key barrier affecting screening uptake and responses to genetic risk. This study explores this obstacle using beta thalassaemia as a case study. Fifteen in-depth qualitative interviews were conducted exploring the reproductive views and decisions of people at risk of transmitting thalassaemia. Eleven participants had thalassaemia themselves and/or were members of an affected family. Four participants were identified as thalassaemia carriers through genetic screening programmes with no family history. Notable differences were observed between these two groups. For thalassaemic individuals and families, past experience clarified and facilitated their sense of reproductive responsibility, however carriers struggled to relate to, and incorporate the information into their lives. It was witnessing their child becoming symptomatic - rather than receiving a diagnosis or genetic risk information per se- that had the most substantial influence on carriers’ subsequent views and decisions. Educational resources used to support genetic screening programmes would benefit from an engagement with the experiential accounts of life with genetic disease in order to more effectively bridge the chasm in knowledge and understanding between affected families and the general public, towards whom expansive genetic screening is aimed

Vascular permeability, angiogenesis and the role of delta-like ligand 4

Cardiovascular disease, of which ischaemic diseases such as stroke and peripheral arterial disease make up a large proportion, are the leading cause of death worldwide. The endogenous response to ischaemia is to upregulate growth factors to stimulate the growth of new vessels and in some cases, form a collateral network. The concept of therapeutic stimulation has therefore become a priority area of cardiovascular research. The collateral network formed must consist of intact, stable, non-leaky vessels that can respond appropriately to stimuli. While the potent angiogenic driver, vascular endothelial growth factor (VEGF) appeared to be a promising target, trials in peripheral ischaemia patients have been disappointing. Upregulated by VEGF during angiogenesis, the Notch ligand Dll4 is a key regulator of vessel maturation and function. Widely known to regulate tip and stalk cell selection during sprouting angiogenesis, its role in the recruitment and growth of mural cells, regulation of permeability, compliance and signalling is poorly understood. Inhibition of Dll4 results in non-functional, poorly perfused vessels with reduced pericyte coverage suggesting a greater role for Dll4 in the formation of mature, intact, operative vessels. I therefore tested the hypothesis that the physiological characteristics of the neovasculature are regulated by Dll4 during physiological neovascularisation. A recombinant human sDll4 protein was used to induce Notch signalling in an endothelial cell monolayer and resulted in increased expression of VE-Cadherin and cell-cell contacts. Using the Landis-Michel microvascular permeability technique, Dll4 signalling was shown to decrease the permeability of rat mesenteric vessels and then subsequent experiments showed that this could be prevented by the proteins kinase A (PKA) inhibitor H89 dihydrochloride. In the rat mesenteric angiogenesis model, inducing Notch with an adenovirus (Ad.) encoding sDll4 (Ad.sDll4) resulted in a less angiogenic vasculature and when added into arteriolargenesis stimulating adenovirus combinations it led to a more endogenous-like vasculature and a switch from sprouting to branching. In a mouse hindlimb ischaemia model, Ad.sDll4 hindered blood flow recovery to the hind paw but led to increase capillary and arteriolar density. These results show that Dll4 plays a key role in regulating vascular permeability and that this is through a cAMP/PKA dependent pathway and involves VE-Cadherin expression. They also demonstrate a role for Dll4 in arteriolargenesis in both physiological and pathological settings and the possibility of using Dll4 as part of an ischaemic therapeutic strategy cannot yet be ruled out

Values-Led Design Cards: Building Ethically Engaged Archaeology and Heritage Experiences

The agenda for an engaged and impactful archaeology has been set out emphatically in a variety of recent reports, positioning archaeology and heritage as important sources of public value and social benefit. While many ascribe to these aims, how to put them into practice in concrete terms remains a real challenge. Tools, methods and methodologies developed for the wider research community as it engages with the “impact agenda” at large have been adapted and applied in archaeological and heritage practice with variable success. In this paper, we discuss the creation of a values-led, card-based design toolkit and the considerations involved in customising it for use by archaeology and heritage sector practitioners. We evaluate reflexive feedback from participants in a toolkit testing workshop, together with our own reflections on the workshop experience. Building on these, we assess the potential and limitations of the toolkit and its underpinning values-led design theory to generate critically engaged archaeological and heritage experiences

Activation of Notch signalling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway

© 2019 the American Physiological Society. The Notch ligand delta-like ligand 4 (Dll4), upregulated by VEGF, is a key regulator of vessel morphogenesis and function, controlling tip and stalk cell selection during sprouting angiogenesis. Inhibition of Dll4 results in hypersprouting, nonfunctional, poorly perfused vessels, suggesting a role for Dll4 in the formation of mature, reactive, functional vessels, with low permeability and able to restrict fluid and solute exchange. We tested the hypothesis that Dll4 controls transvascular fluid exchange. A recombinant protein expressing only the extracellular portion of Dll4 [soluble Dll4 (sDll4)] induced Notch signaling in endothelial cells (ECs), resulting in increased expression of vascular-endothelial cadherin, but not the tight junctional protein zonula occludens 1, at intercellular junctions. sDll4 decreased the permeability of FITC-labeled albumin across EC monolayers, and this effect was abrogated by coculture with the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester. One of the known molecular effectors responsible for strengthening EC-EC contacts is PKA, so we tested the effect of modulation of PKA on the sDll4-mediated reduction of permeability. Inhibition of PKA reversed the sDll4-mediated reduction in permeability and reduced expression of the Notch target gene Hey1. Knockdown of PKA reduced sDLL4-mediated vascular-endothelial cadherin junctional expression. sDll4 also caused a significant decrease in the hydraulic conductivity of rat mesenteric microvessels in vivo. This reduction was abolished upon coperfusion with the PKA inhibitor H89 dihydrochloride. These results indicate that Dll4 signaling through Notch activation acts through a cAMP/PKA pathway upon intercellular adherens junctions, but not tight junctions, to regulate endothelial barrier function. NEW & NOTEWORTHY Notch signaling reduces vascular permeability through stimulation of cAMP-dependent protein kinase A

Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia

IntroductionArteriolargenesis can be induced by concomitant stimulation of nitric Oxide (NO)‐Angiopoietin receptor (Tie)‐Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia.Results and MethodsNO‐Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO‐Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO‐Tie‐VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO‐Tie‐VEGF compared with NO‐Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO‐Tie‐sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.ConclusionThese results suggest that Dll4 activation early on in revascularization can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for ideal functional and anatomical revascularisation

The interactive effect of neighborhood peer cigarette use and 5HTTLPR genotype on individual cigarette use

Previous cross-sectional research has shown that adolescents’ cigarette use is interactively associated with that of their school peers and their 5HTTLPR genotype, such that the cigarette use of persons with more copies of the 5HTTLPR*S’ allele is more dependent on school peers’ cigarette use behaviors than their counterparts. This analysis seeks to extend this novel finding by examining whether the same conclusion can be reached when substituting neighborhood peers for school peers and examining the timing of the initiation of any and regular smoking in adolescence. A similar conclusion is reached using an independent sample with longitudinal measures of cigarette use among 6th through 8th graders clustered in 82 neighborhoods, of whom 1,098 contributed genetic data. The proportion of respondents who had ever smoked cigarettes by the first wave was calculated for each Census block group in the study. 5HTTLPR genotype was assayed using the method of Whisman and colleagues (2011). The timing of any or regular smoking initiation and over four years were modeled as dependent variables using Cox proportional hazards models. The interaction of neighborhood peer smoking behavior in the first wave and 5HTTLPR genotype statistically significantly predicted any smoking initiation (hazard ratio: 3.532; p-value=0.002) and regular smoking initiation (hazard ratio: 5.686; p-value=0.000), net of controls for sex, race/ethnicity, grade in the first wave of data, and parental educational attainment. These findings reach the same conclusions as previous cross-sectional research. The findings for any smoking initiation are consistent with the diathesis-stress model of gene-environment interaction; the findings for regular smoking initiation are consistent with the differential susceptibility model

Pressure injury and risk in the inpatient paediatric and neonatal populations: a single centre point-prevalence study

Introduction: Prevention and management of pressure injury is a key nurse-sensitive quality indicator. From clinical insights, pressure injury effects hospitalised neonates and children, however it is unclear how prevalent this is. The aim of this study was to quantify prevalence of pressure injury, assess skin integrity risk level, and quantify preventive interventions in both neonatal and child inpatient populations at a large children’s hospital in the UK. Methods: A cross-sectional study was undertaken, assessing the skin integrity of all children allocated to a paediatric or neonatal bed in June/July 2020. A data collection tool was adapted from two established pressure ulcer point prevalence surveys (EUPAP and Medstrom pre-prevalence survey). Risk assessment was performed using the Braden QD scale.Results: Eighty-eight participants were included, with median age of 0.85 years [range 0-17.5 years), with 32 (36%) of participants being preterm. Median length of hospital stay was 11 days [range 0 – 174 days]. Pressure ulcer prevalence was 3.4%. The majority of participants had at least two medical devices, with 16 (18.2%) having more than four. Having a medical device was associated with increased risk score of developing pressure injury (odds ratio [OR] 0.03, 95% Confidence Interval [CI] 0.01 – 0.05, p = 0.02). Most children (39 (44%)) were reported not having proposed preventive measures in place aligned to their risk assessment. However, for those that did , 2 to 4 hourly repositioning was associated with a risk reduction on pressure damage (OR 0.13, 95% CI 0.03 – 0.23, p = 0.01).Conclusion: Overall, we found a low prevalence of pressure injury across preterm infants, children and young people at a tertiary children’s hospital. Accurate risk assessment as well as availability and implementation of preventive interventions are a priority for healthcare institutes to avoid pressure injury

'If You Desire to Enjoy Life, Avoid Unpunctual People': Women, Timetabling and Domestic Advice, 1850–1910

In the second half of the nineteenth century domestic advice manuals applied the language of modern, public time management to the private sphere. This article uses domestic advice and cookery books, including Isabella Beeton's Book of Household Management, to argue that women in the home operated within multiple, overlapping temporalities that incorporated daily, annual, linear and cyclical scales. I examine how seasonal and annual timescales coexisted with the ticking clock of daily time as a framework within which women were instructed to organize their lives in order to conclude that the increasing concern of advice writers with matters of timekeeping and punctuality towards the end of the nineteenth century indicates not the triumph of 'clock time' but rather its failure to overturn other ways of thinking about and using time