498 research outputs found

    Developing a person-centred approach in dentistry beyond NHS recall intervals: a commentary

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    Person-centred care (PCC) is acknowledged as a fundamental dimension of quality within health care and provides significant benefits for patients and clinicians. Models of PCC have primarily been developed from the medical literature, with limited consideration of their application within dentistry. The Personalised Care Institute was established to deliver education and training on PCC and is working with the Office of the Chief Dental Officer for England to develop resources on shared decision-making (SDM) to promote tailored recall intervals.This paper seeks to promote the value of PCC and SDM in delivering high-quality care but cautions against the use of generic models or training in view of the potential differences which may exist within dentistry, particularly general dental practice. The authors highlight the need to develop materials and training which are appropriate, contextualised and relevant to dentistry. The capacity and desire to deliver PCC is strongly influenced by the healthcare system which is in operation. The current units of dental activity (UDA) system operating in England would appear to act as a barrier to the delivery of PCC. Unless significant and rapid changes are introduced to the NHS Contract, UDA targets will continue to take precedence over PCC, SDM and tailored recall intervals

    Genetic inactivation of Semaphorin 3C protects mice from acute kidney injury

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    To guide the development of therapeutic interventions for acute kidney injury, elucidating the deleterious pathways of this global health problem is highly warranted. Emerging evidence has indicated a pivotal role of endothelial dysfunction in the etiology of this disease. We found that the class III semaphorin SEMA3C was ectopically upregulated with full length protein excreted into the blood and truncated protein secreted into the urine upon kidney injury and hypothesized a role for SEAM3C in acute kidney injury. Sema3c was genetically abrogated during acute kidney injury and subsequent kidney morphological and functional defects in two well-characterized models of acute kidney injury; warm ischemia/reperfusion and folic acid injection were analyzed. Employing a beta actin-dependent, inducible knockout of Sema3c, we demonstrate that in acute kidney injury SEMA3C promotes interstitial edema, leucocyte infiltration and tubular injury. Additionally, intravital microscopy combined with Evans Blue dye extravasation and primary culture of magnetically sorted peritubular endothelial cells identified a novel role for SEMA3C in promoting vascular permeability. Thus, our study points to microvascular permeability as an important driver of injury in acute kidney injury, and to SEMA3C as a novel permeability factor and potential target for therapeutic intervention

    Bcar1/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract.

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    AIMS: The adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions. METHODS AND RESULTS: We crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterized these conditional knock outs using a combination of histological and molecular biology techniques. Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5-15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and postnatally. CONCLUSION: Our work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialization and EMT/cell cycle regulation and differentiation to myogenic lineages

    Setd5 is required in cardiopharyngeal mesoderm for heart development and its haploinsufficiency is associated with outflow tract defects in mouse.

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    Congenital heart defects are a feature of several genetic haploinsufficiency syndromes, often involving transcriptional regulators. One property of haploinsufficient genes is their propensity for network interactions at the gene or protein level. In this article we took advantage of an online dataset of high throughput screening of mutations that are embryonic lethal in mice. Our aim was to identify new genes where the loss of function caused cardiovascular phenotypes resembling the 22q11.2 deletion syndrome models, that is, heterozygous and homozygous loss of Tbx1. One gene with a potentially haploinsufficient phenotype was identified, Setd5, thought to be involved in chromatin modification. We found murine Setd5 haploinsufficiency to be associated with double outlet right ventricle and perimembranous ventricular septal defect, although no genetic interaction with Tbx1 was detected. Conditional mutagenesis revealed that Setd5 was required in cardiopharyngeal mesoderm for progression of the heart tube through the ballooning stage to create a four-chambered heart

    Bcar1/p130Cas is essential for ventricular development and neural crest cell remodelling of the cardiac outflow tract.

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    AIM: The adapter protein p130Cas, encoded by the Bcar1 gene, is a key regulator of cell movement, adhesion, and cell cycle control in diverse cell types. Bcar1 constitutive knockout mice are embryonic lethal by embryonic days (E) 11.5-12.5, but the role of Bcar1 in embryonic development remains unclear. Here, we investigated the role of Bcar1 specifically in cardiovascular development and defined the cellular and molecular mechanisms disrupted following targeted Bcar1 deletions. METHODS AND RESULTS: We crossed Bcar1 floxed mice with Cre transgenic lines allowing for cell-specific knockout either in smooth muscle and early cardiac tissues (SM22-Cre), mature smooth muscle cells (smMHC-Cre), endothelial cells (Tie2-Cre), second heart field cells (Mef2c-Cre), or neural crest cells (NCC) (Pax3-Cre) and characterised these conditional knock outs using a combination of histological and molecular biology techniques.Conditional knockout of Bcar1 in SM22-expressing smooth muscle cells and cardiac tissues (Bcar1SM22KO) was embryonically lethal from E14.5-15.5 due to severe cardiovascular defects, including abnormal ventricular development and failure of outflow tract (OFT) septation leading to a single outflow vessel reminiscent of persistent truncus arteriosus. SM22-restricted loss of Bcar1 was associated with failure of OFT cushion cells to undergo differentiation to septal mesenchymal cells positive for SMC-specific α-actin, and disrupted expression of proteins and transcription factors involved in epithelial-to-mesenchymal transformation (EMT). Furthermore, knockout of Bcar1 specifically in NCC (Bcar1PAX3KO) recapitulated part of the OFT septation and aortic sac defects seen in the Bcar1SM22KO mutants, indicating a cell-specific requirement for Bcar1 in NCC essential for OFT septation. In contrast, conditional knockouts of Bcar1 in differentiated smooth muscle, endothelial cells, and second heart field cells survived to term and were phenotypically normal at birth and post-natally. CONCLUSIONS: Our work reveals a cell-specific requirement for Bcar1 in NCC, early myogenic and cardiac cells, essential for OFT septation, myocardialisation and EMT/cell cycle regulation and differentiation to myogenic lineages. TRANSLATIONAL PERSPECTIVE: The molecular pathways coordinating cardiogenesis and the remodelling of the OFT are complex, and dysregulation of these pathways causes human heart defects. Our findings highlight a specific requirement for Bcar1 essential for cardiogenesis. Furthermore, the failure of OFT septation in Bcar1SM22KO mice resembles persistent truncus arteriosus (PTA), a feature of several human congenital heart diseases, including DiGeorge Syndrome. Our findings have implications for the mechanisms underlying the pathogenesis of congenital heart disease, and suggest that mice with conditional Bcar1 deletions may be useful models for dissecting mechanisms involved in the pathogenesis of human heart defects

    'In the hospital all is taken care of' : A practice-theoretical approach to understand patients' medication use

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    Drawing from case examples of medication review implementation in three hospital settings in Sweden, this article examines patients’ medication use. Based on a practice theory approach and utilising data from interviews with patients and participant observation, we reconstruct three practices of everyday medication use centring on accepting, challenging or appropriating medication orders. This article argues that patients’ medication practices are embedded in wider practice arrangements that afford different modes of agency. Reconceptualising patients’ medication use from a practice‐based perspective revealed the meaning‐making, order‐producing and identity‐forming features of these practices. Also, we illustrated how different modes of agency were achieved in patients’ medication practices, suggesting a fluidity of both the meanings attached to and the identities related to medication use. Our findings have practical implications as these practices of medication use can be transformed when altering the arrangements they are embedded in, thus going beyond the clinical encounter.Funding agencies: Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilSwedish Research Council for Health Working Life &amp; Welfare (Forte) [2014-4657]; Medical Research Council of Southeast Sweden [568651, 476971]; County Council of Ostergotl</p

    From shame to blame: institutionalising oppression through the moralisation of mental distress in austerity England

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    This paper interrogates qualitative data regarding the changing experiences of men- tal health service and welfare state interventions for those who self-identify as experiencing long-term mental distress. We focus on austerity-related reforms in the English welfare and mental health policy architecture to explore the socio-cultural and material bases of benefit claims-making in relation to long-term illness and incapac- ity. Recent neoliberal social policy reforms contest the ontological status of mental distress, in effect recasting distress as a ‘moral’ status. This tendency is reinforced via three primary dynamics in contemporary mental health and welfare policy: the delegitimisation of sick role status in relation to mental distress; the foregrounding of individual responsibility and concomitant re-orientation of services towards self-help; and an increasing punitive conditionality. These intersecting processes represent an institutionalisation of ‘blame’ in various policy contexts (Scambler in Sociol Health Illn 31(3): 441–455, 2009; Sociol Rev Monogr 66(4):766–782, 2018), the moral stigmatisation of mental distress and escalating experiences of oppression for mental health service users and welfare recipients. Shifting conceptions of distress are thereby entwined with transformations in social policy regimes and political economies. Presenting distress as a personal failure legitimates austerity-related restrictions on benefit and service entitlements as part of a wider project of neoliberal welfare state transformation

    Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

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    Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development
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