Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease.

AIMS: Quiescent, differentiated adult vascular smooth muscle cells (VSMCs) can be induced to proliferate and switch phenotype. Such plasticity underlies blood vessel homeostasis and contributes to vascular disease development. Oligoclonal VSMC contribution is a hallmark of end-stage vascular disease. Here, we aim to understand cellular mechanisms underpinning generation of this VSMC oligoclonality. METHODS AND RESULTS: We investigate the dynamics of VSMC clone formation using confocal microscopy and single-cell transcriptomics in VSMC-lineage-traced animal models. We find that activation of medial VSMC proliferation occurs at low frequency after vascular injury and that only a subset of expanding clones migrate, which together drives formation of oligoclonal neointimal lesions. VSMC contribution in small atherosclerotic lesions is typically from one or two clones, similar to observations in mature lesions. Low frequency (<0.1%) of clonal VSMC proliferation is also observed in vitro. Single-cell RNA-sequencing revealed progressive cell state changes across a contiguous VSMC population at onset of injury-induced proliferation. Proliferating VSMCs mapped selectively to one of two distinct trajectories and were associated with cells showing extensive phenotypic switching. A proliferation-associated transitory state shared pronounced similarities with atypical SCA1+ VSMCs from uninjured mouse arteries and VSMCs in healthy human aorta. We show functionally that clonal expansion of SCA1+ VSMCs from healthy arteries occurs at higher rate and frequency compared with SCA1- cells. CONCLUSION: Our data suggest that activation of proliferation at low frequency is a general, cell-intrinsic feature of VSMCs. We show that rare VSMCs in healthy arteries display VSMC phenotypic switching akin to that observed in pathological vessel remodelling and that this is a conserved feature of mouse and human healthy arteries. The increased proliferation of modulated VSMCs from healthy arteries suggests that these cells respond more readily to disease-inducing cues and could drive oligoclonal VSMC expansion.

Gambling-Related Intimate Partner Violence Against Women: A Grounded Theory Model of Individual and Relationship Determinants.

This study aimed to examine how problem gambling interacts with gendered drivers of intimate partner violence (IPV) against women to exacerbate this violence. Interviews were conducted with 48 female victims of IPV linked to a male partner's gambling; 24 female victims of IPV linked to their own gambling; and 39 service practitioners from 25 services. Given limited research into gambling-related IPV, but a stronger theoretical base relating to IPV against women, this study used an adaptive grounded theory approach. It engaged with existing theories on gendered drivers of violence against women, while also developing a grounded theory model of individual and relationship determinants based on emergent findings from the data. Gambling-related IPV against women was found to occur in the context of expressions of gender inequality, including men's attitudes and behaviors that support violence and rigid gender expectations, controlling behaviors, and relationships condoning disrespect of women. Within this context, the characteristics of problem gambling and the financial, emotional and relationship stressors gambling causes intensified the IPV. Alcohol and other drug use, and co-morbid mental health issues, also interacted with gambling to intensify the IPV. Major implications. Reducing gambling-related IPV against women requires integrated, multi-level interventions that reduce both problem gambling and gendered drivers of violence. Gambling operators can act to reduce problem gambling and train staff in responding to IPV. Financial institutions can assist people to limit their gambling expenditure and families to protect their assets. Service providers can be alert to the co-occurrence of gambling problems and IPV and screen, treat, and refer clients appropriately. Public education can raise awareness that problem gambling increases the risk of IPV. Reducing gender inequality is also critical.

An efficient system for bioconjugation based on a widely applicable engineered O-glycosylation tag.

Bioconjugates are an important class of therapeutic molecules. To date, O-glycan-based metabolic glycoengineering has had limited use in this field, due to the complexities of the endogenous O-glycosylation pathway and the lack of an O-glycosylation consensus sequence. Here, we describe the development of a versatile on-demand O-glycosylation system that uses a novel, widely applicable 5 amino acid O-glycosylation tag, and a metabolically engineered UDP-galactose-4-eperimase (GALE) knock-out cell line. Optimization of the primary sequence of the tag enables the production of Fc-based proteins with either single or multiple O-glycans with complexity fully controlled by media supplementation. We demonstrate how the uniformly labeled proteins containing exclusively N-azido-acetylgalactosamine are used for CLICK chemistry-based bioconjugation to generate site-specifically fluorochrome-labeled antibodies, dual-payload molecules, and bioactive Fc-peptides for applications in basic research and drug discovery. To our knowledge, this is the first description of generating a site-specific O-glycosylation system by combining an O-glycosylation tag and a metabolically engineered cell line.

Impacts of Male Intimate Partner Violence on Women: A Life Course Perspective.

The nature and extent of the impacts of intimate partner violence (IPV) on victims are well documented, particularly male partner violence against women. However, less is known about how these impacts might change over time, including their legacy after women leave an abusive relationship and the lasting effects in their later lives. The purpose of this study was to examine women's experiences of IPV at different stages over their life courses. Interviews with a cohort of 18 older women who had left an abusive relationship were analysed using thematic narrative analysis and the findings were presented according to trajectories, transitions, and turning points over their life courses. When in the relationship, the women experienced direct impacts on their physical, mental, social, and financial wellbeing. During separation, many experienced continued abuse and housing, legal, and financial stress. Life after separation was marked by loneliness, trauma, financial insecurity, and damaged relationships. Some women reached a turning point in their recovery through helping others. Understanding these impacts can inform interventions during each stage. Crisis support is critical when women are in an abusive relationship and during the dangerous phase of separation. Interventions can also assist women's longer-term wellbeing and help them recover through post-traumatic growth.

Silencing by design: Lessons learned about child sexual abuse from a university sexual assault survey.

BACKGROUND: University students have been recognized as particularly being vulnerable to sexual victimization. PURPOSE: With little research to date, and acknowledgement for the need of a better understanding of sexual violence, our study analysed the CQUniversity Sexual Assault Survey's qualitative responses. An open-ended qualitative question allowed students to provide information anonymously. METHODS: A total of 109 participants contributed responses with 17 respondents commenting on the fact that the survey omitted to ask about child sexual abuse prior to the cut-off age of 12 years. RESULTS: University students revealed unexpected disclosures of prepubescent child sexual abuse victimization and ongoing sexual victimization into adulthood. Furthermore, students' comments indicated negative impacts including distress, mental health and substance use problems, distrust, and interpersonal difficulties. Strong feelings about 'silencing' prepubescent child sexual abuse in university surveys were expressed with a request that questions about child sexual abuse prior to the age of 12 years be included. CONCLUSION: Our study found that child sexual abuse victimization is important to students. Recommendations indicate the need for future research about sexual violence among university students without age restrictions to gain a better understanding about the impact of trauma including revictimization experiences.

Conducting integrative reviews: a guide for novice nursing researchers.

BACKGROUND: Integrative reviews within healthcare promote a holistic understanding of the research topic. Structure and a comprehensive approach within reviews are important to ensure the reliability in their findings. AIM: This paper aims to provide a framework for novice nursing researchers undertaking integrative reviews. DISCUSSION: Established methods to form a research question, search literature, extract data, critically appraise extracted data and analyse review findings are discussed and exemplified using the authors' own review as a comprehensive and reliable approach for the novice nursing researcher undertaking an integrative literature review. CONCLUSION: Providing a comprehensive audit trail that details how an integrative literature review has been conducted increases and ensures the results are reproducible. The use of established tools to structure the various components of an integrative review increases robustness and readers' confidence in the review findings. IMPLICATIONS FOR PRACTICE: Novice nursing researchers may increase the reliability of their results by employing a framework to guide them through the process of conducting an integrative review.

The provision of emergency healthcare for women who experience intimate partner violence: part 2. Strategies to address knowledge deficits and negative attitudes.

The first article in this two-part series evaluated healthcare professionals' approaches to the care of women who present to the emergency department (ED) with injuries related to intimate partner violence (IPV). It identified barriers to appropriate care provision, which included a lack of knowledge on the part of healthcare professionals and negative professional attitudes. This second article details the findings of a literature review of three databases that aimed to evaluate strategies to address the lack of knowledge of healthcare professionals and negative attitudes concerning IPV. A total of 11 articles were included in the review. Two main strategies to address ED healthcare professionals' knowledge deficits and negative attitudes about IPV were identified. These were developed into the themes of IPV/domestic violence specialists, and education and training.

The role of nurses and midwives in the provision of abortion care: A scoping review.

AIMS AND OBJECTIVES: To define the role and scope of the nurse and midwife within the global context of abortion. BACKGROUND: An estimated 56 million women seek abortions each year; nurses and midwives are commonly involved in their care (Singh et al., 2018, https://www.guttmacher.org/sites/default/files/report_pdf/abortion-worldwide-2017.pdf). As new models of abortion care emerge, there is a pressing need to develop a baseline understanding of the role and scope of nurses and midwives who care for women seeking abortions. DESIGN: The review design was Arksey and O'Malley's five-stage methodological framework. The review follows the PRISMA-ScR checklist. METHODS: MEDLINE, CINAHL, Scopus and ScienceDirect were used to identify original research, commentaries and reports, published between 2008-2019, from which we selected 74 publications reporting on the nursing or midwifery role in abortion care. RESULTS: Nurses and midwives provide abortion care in a variety of practice. Three themes emerged from the literature: the regulated role; providing psychosocial care; and the expanding scope of practice. CONCLUSIONS: The literature on nursing and midwifery practice in abortion care is broad. Abortion-related practices are potentially over-regulated. Appropriately trained nurses and midwives can provide abortions as safely as physicians. The preparation of nurses and midwives to provide abortion care requires further research. Also, healthcare organisations should explore person-centred models of abortion care. RELEVANCE TO CLINICAL PRACTICE: Abortion care is a common procedure performed across many healthcare settings. Nurses and midwives provide technical and psychosocial care to women who seek abortions. Governments and regulatory bodies could safely extend their scope of practice to increase women's access to safe abortions. Introduction of education programmes, as well as embedding practice in person-centred models of care, may improve outcomes for women seeking abortions.

The provision of emergency healthcare for women who experience intimate partner violence: part 1. An integrative review.

This integrative review is the first of a two-part series about intimate partner violence (IPV). Part 2 will explore strategies to address barriers to the care of women who experience IPV in the emergency department (ED). IPV has become a major concern globally and specifically in Australia. Healthcare professionals in the ED are often the first point of contact for women experiencing IPV and therefore the provision of a comprehensive healthcare response to these vulnerable patients remains a priority. The review evaluated healthcare professionals' approaches to the care of women who present to the ED with injuries related to IPV. A systematic search of studies was undertaken using four databases. After the selection process, a total of 24 articles was identified. Six themes emerged: IPV care protocols, physical care provision, psychosocial care provision, provision of safety, role of referrals and barriers to appropriate care provision. There is a lack of evidence supporting healthcare approaches in the ED to address IPV. ED healthcare professionals experience numerous barriers that hinder their ability to provide patient-centred care, which suggests that patients presenting with IPV-related concerns may not be receiving adequate or appropriate healthcare in ED settings.

Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling.

OBJECTIVE: Vascular inflammation underlies cardiovascular disease. Vascular smooth muscle cells (VSMCs) upregulate selective genes, including MMPs (matrix metalloproteinases) and proinflammatory cytokines upon local inflammation, which directly contribute to vascular disease and adverse clinical outcome. Identification of factors controlling VSMC responses to inflammation is therefore of considerable therapeutic importance. Here, we determine the role of Histone H3 lysine 9 di-methylation (H3K9me2), a repressive epigenetic mark that is reduced in atherosclerotic lesions, in regulating the VSMC inflammatory response. Approach and Results: We used VSMC-lineage tracing to reveal reduced H3K9me2 levels in VSMCs of arteries after injury and in atherosclerotic lesions compared with control vessels. Intriguingly, chromatin immunoprecipitation showed H3K9me2 enrichment at a subset of inflammation-responsive gene promoters, including MMP3, MMP9, MMP12, and IL6, in mouse and human VSMCs. Inhibition of G9A/GLP (G9A-like protein), the primary enzymes responsible for H3K9me2, significantly potentiated inflammation-induced gene induction in vitro and in vivo without altering NFκB (nuclear factor kappa-light-chain-enhancer of activated B cell) and MAPK (mitogen-activated protein kinase) signaling. Rather, reduced G9A/GLP activity enhanced inflammation-induced binding of transcription factors NFκB-p65 and cJUN to H3K9me2 target gene promoters MMP3 and IL6. Taken together, these results suggest that promoter-associated H3K9me2 directly attenuates the induction of target genes in response to inflammation in human VSMCs. CONCLUSIONS: This study implicates H3K9me2 in regulating the proinflammatory VSMC phenotype. Our findings suggest that reduced H3K9me2 in disease enhance binding of NFκB and AP-1 (activator protein-1) transcription factors at specific inflammation-responsive genes to augment proinflammatory stimuli in VSMC. Therefore, H3K9me2-regulation could be targeted clinically to limit expression of MMPs and IL6, which are induced in vascular disease.

Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms.

Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair.

The provision of emergency healthcare for women who experience intimate partner violence: part 1. An integrative review.

This integrative review is the first of a two-part series about intimate partner violence (IPV). Part 2 will explore strategies to address barriers to the care of women who experience IPV in the emergency department (ED). IPV has become a major concern globally and specifically in Australia. Healthcare professionals in the ED are often the first point of contact for women experiencing IPV and therefore the provision of a comprehensive healthcare response to these vulnerable patients remains a priority. The review evaluated healthcare professionals' approaches to the care of women who present to the ED with injuries related to IPV. A systematic search of studies was undertaken using four databases. After the selection process, a total of 24 articles was identified. Six themes emerged: IPV care protocols, physical care provision, psychosocial care provision, provision of safety, role of referrals and barriers to appropriate care provision. There is a lack of evidence supporting healthcare approaches in the ED to address IPV. ED healthcare professionals experience numerous barriers that hinder their ability to provide patient-centred care, which suggests that patients presenting with IPV-related concerns may not be receiving adequate or appropriate healthcare in ED settings.

Publisher Correction: Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

The original version of this Article contained errors in the author affiliations.Martin R. Bennett was incorrectly associated with Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, Phoebe Oldach was incorrectly associated with Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.This has now been corrected in the HTML version of the Article. The PDF version of the Article was correct at the time of publication.

Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific developmental history and show heterogeneous expression of vascular disease-associated genes involved in inflammation, adhesion and migration. We detect a rare population of VSMC-lineage cells that express the multipotent progenitor marker Sca1, progressively downregulate contractile VSMC genes and upregulate genes associated with VSMC response to inflammation and growth factors. We find that Sca1 upregulation is a hallmark of VSMCs undergoing phenotypic switching in vitro and in vivo, and reveal an equivalent population of Sca1-positive VSMC-lineage cells in atherosclerotic plaques. Together, our analyses identify disease-relevant transcriptional signatures in VSMC-lineage cells in healthy blood vessels, with implications for disease susceptibility, diagnosis and prevention.

Disclosure of domestic violence and sexual assault within the context of abortion: meta-ethnographic synthesis of qualitative studies protocol.

BACKGROUND: One third of women will have an abortion in their lifetime (Kerr, QUT Law Rev 14:15, 2014; Aston and Bewley, Obstetrician & Gynaecologist 11:163-8, 2009). These women are more likely to have experienced domestic violence or sexual assault than women who continue with their pregnancies. Frontline health personnel involved in the care of women seeking abortions are uniquely positioned to support patients who choose to disclose their violence. Yet, the disclosure of domestic violence or sexual assault within the context of abortion is not well understood. To enhance service provision, it is important to understand the disclosure experience, that is, how frontline health personnel manage such disclosures and how victims/survivors perceive this experience. This review aims to provide a systematic synthesis of qualitative literature to increase understanding of the phenomena and identify research gaps. METHODS: A meta-ethnography of qualitative evidence following PRISMA-P recommendations for reporting systematic reviews will be performed to better understand the experiences of domestic violence and sexual assault disclosure from the perspective of frontline health personnel providing support and women seeking an abortion. A three-stage search strategy including database searching, citation searching and Traditional Pearl Growing will be applied starting with the terms "domestic violence", "sexual assault", "disclosure" and "abortion", their common synonyms and MeSH terms. The database search will include CINAHL, MEDLINE, Embase and PsycINFO. Published studies from 1970, written in English and from all countries will be included. Two reviewers will screen titles and abstracts and if suitable will then perform a full-text review. To attribute weight to each study, two reviewers will perform the critical appraisal using a modified version of the "Guidelines for Extracting Data and Quality Assessing Primary Studies in Educational Research". Data extraction and coding will occur using EPPI-Reviewer 4 and will be carried out by two reviewers. DISCUSSION: The reviewers will illuminate what transpires at the interface when women seeking an abortion in the context of domestic violence and sexual assault meet frontline health personnel. Increased knowledge in this area will improve the frontline health personnel's practices and responsiveness to women who seek out healthcare in the context of violence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016051136.

Adult functioning of mothers with traumatic brain injury at high risk of child abuse: a pilot study.

BACKGROUND: There is little information regarding the impact that traumatic brain injury (TBI) has on the functioning of mothers at risk of child abuse. OBJECTIVE: This study evaluated adult functioning (e.g. child abuse, substance use, criminal convictions, and mental health problems) of mothers, at high risk for child abuse, who also had a history of TBI compared with those without TBI. It was hypothesised that mothers with a history of TBI would engage in higher rates of dysfunctional behaviour compared to those with no history of TBI. METHOD: Participants were 206 women engaged in a child abuse prevention programme for mothers who are highly socially disadvantaged, and at high risk for child abuse. Using historical data collected as part of the referral, and self report intake process, this study compared child abuse, mental health problems (depression, anxiety, substance use) and rates of criminal offending for mothers with a history of TBI versus those with no history of TBI. RESULTS: Mothers with TBI were no more likely than those without TBI to have engaged in child abuse. However, mothers with a history of TBI were significantly more likely to have one or more mental health problems, engage in substance use and have a history of criminal offending. CONCLUSIONS: Parents with TBI who have been identified as high risk for engaging in child abuse have increased risk for mental health problems and criminal offending. These issues need to be considered when designing parenting programmes in order for intervention strategies to be effective.