Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

A case series of live attenuated vaccine administration in dupilumab-treated children with atopic dermatitis.

BACKGROUND AND OBJECTIVE: Current regulatory labeling recommends avoiding live vaccine use in dupilumab-treated patients. Clinical data are not available to support more specific guidance for live or live attenuated vaccines administration in dupilumab-treated patients. METHODS: Children (6 months-5 years old) with moderate-to-severe atopic dermatitis (AD) enrolled in a phase 2/3 clinical trial of dupilumab (LIBERTY AD PRESCHOOL Part A/B; NCT03346434) and subsequently participated in the LIBERTY AD PED-OLE (NCT02612454). During these studies, protocol deviations occurred in nine children who received measles, mumps, rubella (MMR) vaccine with or without varicella vaccine; five with a ≤12-week gap between dupilumab administration and vaccination and four with a >12-week gap after discontinuing dupilumab. RESULTS: Nine children (1 female; 8 male) had severe AD at baseline (8-56 months old). Of the nine children, five had a ≤12-week gap ranged 1-7 weeks between dupilumab administration and vaccination who received MMR vaccine (n = 2) or MMR and varicella vaccines (n = 3); among these, one resumed dupilumab treatment as early as 2 days and four resumed treatment 18-43 days after vaccination. No treatment-emergent adverse events, including serious adverse events and infections, were reported within the 4-week post-vaccination period in any children. CONCLUSIONS: In this case series of dupilumab-treated children with severe AD who received MMR vaccine with or without varicella vaccine, no adverse effects (including vaccine-related infection) were reported within 4 weeks after vaccination. Further studies are warranted to evaluate the safety, tolerability, and immune response to live attenuated vaccines in dupilumab-treated patients.

Utility of the capabilities, opportunities, motivations model for understanding changes in behavior.

BACKGROUND: Wearing face coverings to prevent airborne viral transmission has at times been legally mandated, followed by periods when rules were relaxed. The present study tracks changes in face covering and the impacts on people's perceptions of their capabilities, opportunities and motivations. METHODS: Three-wave survey. At wave 1 (25 January-6 February 2022), 10 622 UK adults reported: (a) sociodemographic characteristics; (b) face covering in work, public transport and indoor leisure settings and (c) capabilities, opportunities and motivations. Measures were repeated 1-18 March 2022 and 20 May-6 June 2022. Data were analyzed descriptively, within-participants analysis of covariance (ANCOVA) and multiple linear regression. RESULTS: Face covering decreased over time as rules around the wearing of face coverings relaxed. Perceptions of capabilities, opportunities and motivations to wear face coverings were consistently associated with the actual wearing of face coverings, with marked decreases in motivations over time. CONCLUSIONS: Decreases in motivations seem to explain best the reasons for declining levels of face covering. Further work is required to develop interventions to change people's motivations and promote the wearing of face coverings, should they be required in the future.

how these findings canPublic transport: lessons learned by the sector through the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic had a significant impact on the operations and functionality of the public transport sector in the UK. This paper reflects on the experience of this sector through the pandemic period, and considers recommendations for any future mitigations required for either new COVID-19 waves or a different public health emergency. METHODS: Semi-structured interviews were carried out with public transport experts, organisational leaders, workers and passengers in two phases: Phase 1 from January to May 2021, and Phase 2 from December 2021 to February 2022. Interviews were analysed thematically. RESULTS: Using the 'What? So What? Now What?' reflective model, ideas are drawn out to describe (a) what changes occurred, (b) what effects these changes had on service provision as well as perceptions of risk and mitigation and (c) what lessons have been learned and how these findings can feed into pandemic preparedness for the future. Respondent reflections focussed on the importance of communication, leadership, and maintaining compliance. CONCLUSIONS: The wealth of experience gained through the COVID-19 pandemic in the public transport sector is extremely valuable. Through reflection on this experience, specific recommendations are made relating to these factors, covering: maintaining links across industry, access to information and data, understanding of mitigation effectiveness, improving messaging, challenges of behavioural mitigations, and clear lines of accountability. The recommendations made on the basis of this reflective process will help to improve public health strategy within the public transport sector.

A deep dive into selected work sectors during the COVID-19 pandemic and the "living with COVID" phase: understanding similarities and differences in practice, perceptions, and preparedness.

OBJECTIVES: When it comes to controlling workplace transmission of SARS-CoV-2, the virus that causes COVID-19, different workplaces and industrial sectors face different challenges, both in terms of likely transmission routes and which control measures can be practically, economically, and effectively implemented. This article considers a large body of research in the United Kingdom across different work sectors and time points during the COVID-19 pandemic to better understand mitigation measures, challenges to mitigating the risk of SARS-COV-2 transmission, knowledge gaps, and barriers and enablers to control viral transmission. METHODS: Data is drawn from 2 phases of research. Phase 1 gathered data from an interactive workshop (April 2022) where PROTECT researchers working across 8 work sectors shared knowledge and expertise from research conducted between 2020 and 2022. Phase 2 revisited 6 of these sectors to explore participants' views on the "living with COVID" phase of the pandemic (February-October 2022) through qualitative interviews. RESULTS: Our findings emphasise the importance of considering the characteristics of each work sector (and their sub-sectors), relative to the physical workplace and workforce, the ways organisations operate, and how they interact with the public. Study findings show that participant's views and organisational practices changed quickly and significantly over the course of the pandemic. Most participants initially perceived that the majority of risk mitigations would remain in place for the foreseeable future. However, following the change in Government Guidance towards "living with COVID", most mitigation measures were quickly removed and it had become necessary for sectors/organisations to restore normal operations, thereby treating the COVID-19 virus like any other illness, while remaining prepared for future health emergencies that may arise. CONCLUSION: We suggest that national policy makers and organisational leaders remain mindful of the lessons learned and knowledge gained at all levels (national, regional, local, organisational, and individual) during the COVID-19 pandemic. We make recommendations in support of recovery as sectors/organisations continue "living with COVID" and other respiratory diseases; balanced with longer term planning for the next public health crisis.

Theory-based Trial to Promote Uptake and Sustained Use of Face Coverings During the COVID-19 Pandemic.

BACKGROUND: Transmission of airborne viruses can be mitigated by wearing face coverings but evidence suggests that face covering declines with the removal of relevant legislation, partly due to low automatic motivation. PURPOSE: Test whether an intervention based on implementation intentions could support people's automatic motivation and promote face covering during the COVID-19 pandemic. METHODS: Randomized controlled design. At baseline (May 20 to June 6, 2022), 7,835 UK adults reported how much time they spent wearing face coverings in work, public transport, and indoor leisure settings as well as their capabilities, opportunities, and motivations. 3,871 participants were randomized to form implementation intentions; 3,964 control participants completed questionnaires only. Measures were repeated 6 months postbaseline (November 1 to November 14, 2022). Data were analyzed using mixed measures ANOVAs and Bayes Factors to examine whether the observed data supported the experimental hypothesis. RESULTS: The proportion of time spend wearing face coverings declined substantially across the 6-month study period, from 15.28% to 9.87% in work settings, 38.31% to 24.55% on public transport, and 9.58% to 7.85% in leisure settings. Bayes Factors indicated moderate relative evidence of no effect of implementation intentions on behavior in work and leisure settings, and inconclusive evidence of a positive effect on public transport. CONCLUSIONS: In the context of declining COVID-19 rates and removal of legal mandates, implementation intentions were not effective in sustaining face covering. Further research is required to ensure that evidence-based interventions are prepared and deployed in the event of future pandemics.

The spread of viruses through the air can be reduced by people wearing face coverings. The evidence suggests that face covering reduces with the removal of relevant legislation, partly due to habits not being formed. The aim of the present study was to test whether an intervention designed to help people to form new habits could support people's face covering during the COVID-19 pandemic. We asked 7,835 UK adults how much time they spent wearing face coverings in work, public transport, and indoor leisure settings. We chose 3,871 participants at random to form new habits; 3,964 participants completed questionnaires only. Measures were repeated 6 months later. The proportion of time spend wearing face coverings declined sharply across the 6-month study period, from 15.28% to 9.87% in work settings, 38.31% to 24.55% on public transport, and 9.58% to 7.85% in leisure settings. Our analyses showed a small positive effect of forming new habits on wearing face coverings in public transport settings. In the context of declining COVID-19 rates and the removal of legal mandates, our intervention was not effective in sustaining face covering. Further research is required to ensure that evidence-based interventions are prepared and deployed in the event of future pandemics.

Areas of enduring COVID-19 prevalence: drivers of prevalence and mitigating strategies.

BACKGROUND: UK local authorities that experienced sustained high levels of COVID-19 between 1st March 2020 and 28th February 2021 were described by the UK Scientific Advisory Group for Emergencies as areas of enduring prevalence. This research was carried out in order to examine the views of local authority Directors of Public Health, who played a crucial role in the local response to COVID-19, on reasons for sustained high levels of prevalence in some areas, alongside an investigation of the mitigation strategies that they implemented during the course of the pandemic. METHODS: Interviews were conducted with Directors of Public Health in 19 local authority areas across England, between July and November 2021. This included nine areas identified as areas of enduring prevalence and ten 'comparison' areas. RESULTS: The outcomes of this study suggests that the geographical differences in prevalence rates are strongly influenced by health inequalities. Structural factors including deprivation, employment, and housing, due to their disproportionate impact on specific groups, converged with demographic factors, including ethnicity and age, and vaccination rates, and were identified as the main drivers of enduring prevalence. There are key differences in these drivers both within and, to a lesser extent, between local authorities. Other than these structural barriers, no major differences in facilitators or barriers to COVID-19 mitigation were identified between areas of varying prevalence. The main features of successful mitigation strategies were a locally tailored approach and partnership working involving local authority departments working with local health, community, voluntary and business organisations. CONCLUSIONS: This study is the first to add the voices of Directors of Public Health, who played a crucial role in the local COVID-19 response. Areas of enduring prevalence existed during the pandemic which were caused by a complex mix of structural factors related to inequalities. Participants advised that more research is needed on the effectiveness of mitigation strategies and other measures to reduce the impact of structural inequalities, to better understand the factors that drive prevalence. This would include an assessment of how these factors combine to predict transmission and how this varies between different areas.

SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics.

Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326). Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.

Scale and spread of innovation in health and social care: Insights from the evaluation of the New Care Model/Vanguard programme in England.

OBJECTIVE: Little is known about how to achieve scale and spread beyond the early local adoption of an innovative health care programme. We use the New Care Model - or 'Vanguard' - programme in the English National Health Service to illuminate the process, assessing why only one of five Vanguard programmes was successfully scaled up. METHODS: We interviewed a wide range of stakeholders involved in the Vanguard programme, including programme leads, provider organisations, and policymakers. We also consulted relevant documentation. RESULTS: A lack of direction near the end of the Vanguard programme, a lack of ongoing resources, and limited success in providing real-time monitoring and evaluation may all have contributed to the failure to scale and spread most of the Vanguard models. CONCLUSIONS: This programme is an example of the 'scale and spread paradox', in which localism was a key factor influencing the successful implementation of the Vanguards but ultimately limited their scale and spread.

Experiences, Perceptions of Risk, and Lasting Impacts of COVID-19 for Employees in the Public Transport Sector.

BACKGROUND: Age-standardized mortality rates for taxi drivers, chauffeurs, bus and coach drivers show that public transport workers were at high risk at the beginning of the COVID-19 pandemic. Nevertheless, the public transport sector was required to continue services throughout the pandemic. OBJECTIVES: This paper aims to develop a better understanding of the experiences of organizational leaders and workers within the UK public transport sector (bus, rail, and tram). Specifically, it aims to explore the perceived balance of risk and mitigation of SARS-CoV-2 transmission, report on their perceptions of safety in public transport during the pandemic and in the future, and consider how these perceptions and changes impact on long-term worker health and wellbeing. METHODS: This study formed part of a larger stakeholder engagement with the public transport sector. Organizational leaders and workers were recruited (n = 18) and semi-structured interviews carried out between January and May 2021. Data were analysed thematically. RESULTS: Overarching and subthemes were identified. Themes relating to perceptions and impacts of risk of COVID-19 for employees included: acceptability of risk for workers, perceptions of risk mitigation effectiveness, changes to working practices and their impact on morale and wellbeing, issues with compliance to mitigations such as social distancing and face coverings in passenger and co-worker groups alongside a lack of power to challenge behaviour effectively, and the roles of leadership and messaging. Themes related to long-lasting impacts of COVID-19 on working practices and effects on health and wellbeing included: continuing mitigations, impact of increasing passenger numbers, impact of vaccination programme, and impact of changes to business structure. CONCLUSIONS: Most public transport employees reported feeling safe, related to the extent to which their role was public-facing. However, data were collected during a time of very low passenger numbers. Current mitigation measures were thought effective in reducing the risk of viral transmission, although measures may have a detrimental effect on worker morale and wellbeing. Issues relating to non-compliance with guidance and 'in-group' behaviour were identified. Impacts on wider business sustainability and individual wellbeing of staff should be considered when developing responses to any future pandemics. Recommendations are made for prioritizing employee engagement with colleagues, and the importance of strong leadership and clear messaging in promoting adherence to behavioural mitigations.

Identifying targets for interventions to support public use of face coverings.

OBJECTIVES: Interventions to promote the wearing of face coverings if required in the future can only be developed if we know why people do or do not wear them. Study aims were, therefore, to assess public adherence to wearing face coverings to reduce transmission of SARS-CoV-2 and to gauge why people were or were not wearing face coverings in work, public transport, and indoor leisure settings. DESIGN: Cross-sectional survey. METHODS: 10,622 adults (25 January-6 February 2022) who were representative of the UK population were asked about their (a) wearing of face coverings in work, public transport, and leisure settings; (b) sociodemographic characteristics; and (c) perceptions of capabilities, opportunities, and motivations ("COM-B"). Data were analysed descriptively, using within-participants ANOVA and multiple linear regression. RESULTS: Participants reported mostly wearing face coverings in public transport settings (>80%), but substantially less in work (<50%) and leisure (<30%) contexts. Perceptions of capabilities, opportunities, and motivations to wear face coverings were consistently associated with the actual wearing of face coverings across the three settings, but there were marked deficits in automatic motivation and social opportunity. People living in England, describing themselves as White, and men were least likely to wear face coverings. CONCLUSIONS: Interventions targeted at men, people living in England, and those describing themselves as White that focus on increasing capabilities, providing greater opportunities and boosting motivations are suggested to promote the wearing of face coverings, with particular focus on addressing automatic motivation and social opportunity.

What makes a socially skilled leader? Findings from the implementation and operation of New Care Models (Vanguards) in England.

PURPOSE: The article aims to argue that the concept of "distributed leadership" lacks the specificity required to allow a full understanding of how change happens. The authors therefore utilise the "Strategic Action Field Framework" (SAF) (Moulton and Sandfort, 2017) as a more sensitive framework for understanding leadership in complex systems. The authors use the New Care Models (Vanguard) Programme as an exemplar. DESIGN/METHODOLOGY/APPROACH: Using the SAF framework, the authors explored factors affecting whether and how local Vanguard initiatives were implemented in response to national policy, using a qualitative case study approach. The authors apply this to data from the focus groups and interviews with a variety of respondents in six case study sites, covering different Vanguard types between October 2018 and July 2019. FINDINGS: While literature already acknowledges that leadership is not simply about individual leaders, but about leading together, this paper emphasises that a further interdependence exists between leaders and their organisational/system context. This requires actors to use their skills and knowledge within the fixed and changing attributes of their local context, to perform the roles (boundary spanning, interpretation and mobilisation) necessary to allow the practical implementation of complex change across a healthcare setting. ORIGINALITY/VALUE: The SAF framework was a useful framework within which to interrogate the data, but the authors found that the category of "social skills" required further elucidation. By recognising the importance of an intersection between position, personal characteristics/behaviours, fixed personal attributes and local context, the work is novel.

COL18A1 genotypic associations with endostatin levels and clinical features in pulmonary arterial hypertension: a quantitative trait association study.

Variation around the COL18A1 gene, which encodes the angiostatic peptide endostatin, may influence disease heterogeneity in pulmonary arterial hypertension https://bit.ly/3shXrNR.

Hepatoma-derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival.

Hepatoma-derived growth factor (HDGF) was previously shown to be associated with increased mortality in a small study of idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH). In this study, we measured serum HDGF levels in a large multicenter cohort (total 2017 adult PAH-Biobank enrollees), we analyzed the associations between HDGF levels and various clinical measures using linear or logistic regression models. Higher HDGF levels were found to be significantly associated with worse pulmonary hemodynamics, prostacyclin treatment; among PAH subtypes, higher HDGF levels were most associated with portopulmonary hypertension (beta = 0.469, p < 0.0001). Both Kaplan-Meier curve and Cox proportional hazard regression demonstrated that higher HDGF levels are associated with a higher risk of mortality (COX hazard ratio 1.31, p < 0.0001). Further, in the Sugen hypoxia (SuHx) rat model, the highest HDGF levels were post-pulmonary circulation, and HDGF levels significantly increased with the development of PAH. In pulmonary arteries, immunohistochemistry staining showed that HDGF was highly expressed in pulmonary smooth muscle cells in both PAH patients and SuHx rats. In conclusion, we found that higher serum HDGF was linked with increased mortality, and associated with disease severity in a large multi-center adult PAH cohort (n = 2017). In the SuHX PAH models, circulating HDGF levels are pulmonary in origin and increase with PAH progression. HDGF may be actively involved in vascular remodeling in PAH.

Transmission and control of SARS-CoV-2 on ground public transport: A rapid review of the literature up to May 2021.

Background: During a pandemic, public transport is strategically important for keeping the country going and getting people where they need to be. The essential nature of public transport puts into focus the risk of transmission of SARS-CoV-2 in this sector; rapid and diverse work has been done to attempt to understand how transmission happens in this context and what factors influence risk. Objectives: This review aimed to provide a narrative overview of the literature assessing transmission, or potential for transmission, of SARS-CoV-2 on ground-based public transport, as well as studies assessing the effectiveness of control measures on public transport during the early part of the pandemic (up to May 2021). Methods: An electronic search was conducted using Web of Science, Ovid, the Cochrane Library, ProQuest, Pubmed, and the WHO global COVID database. Searches were run between December 2020 and May 2021. Results: The search strategy identified 734 papers, of which 28 papers met the inclusion criteria for the review; 10 papers assessed transmission of SARS-CoV-2, 11 assessed control measures, and seven assessed levels of contamination. Eleven papers were based on modelling approaches; 17 studies were original studies reporting empirical COVID-19 data. Conclusions: The literature is heterogeneous, and there are challenges for measurement of transmission in this setting. There is evidence for transmission in certain cases, and mixed evidence for the presence of viral RNA in transport settings; there is also evidence for some reduction of risk through mitigation. However, the routes of transmission and key factors contributing to transmission of SARS-CoV-2 on public transport were not clear during the early stage of the pandemic. Gaps in understanding are discussed and six key questions for future research have been posed. Further exploration of transmission factors and effectiveness of mitigation strategies is required in order to support decision making.

The angiostatic peptide endostatin enhances mortality risk prediction in pulmonary arterial hypertension.

Currently available noninvasive markers for assessing disease severity and mortality risk in pulmonary arterial hypertension (PAH) are unrelated to fundamental disease biology. Endostatin, an angiostatic peptide known to inhibit pulmonary artery endothelial cell migration, proliferation and survival in vitro, has been linked to adverse haemodynamics and shortened survival in small PAH cohorts. This observational cohort study sought to assess: 1) the prognostic performance of circulating endostatin levels in a large, multicentre PAH cohort; and 2) the added value gained by incorporating endostatin into existing PAH risk prediction models. Endostatin ELISAs were performed on enrolment samples collected from 2017 PAH subjects with detailed clinical data, including survival times. Endostatin associations with clinical variables, including survival, were examined using multivariable regression and Cox proportional hazards models. Extended survival models including endostatin were compared to null models based on the REVEAL risk prediction tool and European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria using likelihood ratio tests, Akaike and Bayesian information criteria and C-statistics. Higher endostatin was associated with higher right atrial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, and with shorter 6-min walk distance (p<0.01). Mortality risk doubled for each log higher endostatin (hazard ratio 2.3, 95% CI 1.6-3.4, p<0.001). Endostatin remained an independent predictor of survival when incorporated into existing risk prediction models. Adding endostatin to REVEAL-based and ESC/ERS criteria-based risk assessment strategies improved mortality risk prediction. Endostatin is a robust, independent predictor of mortality in PAH. Adding endostatin to existing PAH risk prediction strategies improves PAH risk assessment.

Assembling the Healthopolis: Competitive city-regionalism and policy boosterism pushing Greater Manchester further, faster.

Health and care policy is increasingly promoted within visions of the competitive city-region. This paper examines the importance of policy boosterism within the political construction of city-regions in the context of English devolution. Based on a two-year case study of health and social care devolution in Greater Manchester, England, we trace the relational and territorial geographies of policy across and through new "devolved" city-regional arrangements. Contributing to geographical debates on policy assemblages and city-regionalism, we advance a conceptual framework linking crisis and opportunity, emulation and exceptionalism, and evidence and experimentation. The paper makes two key contributions. First, we argue health and care policy is increasingly drawn towards the logic of global competitiveness without being wholly defined by neoliberal political agendas. Fostering transnational policy networks helped embed global "best practice" policies while simultaneously hailing Greater Manchester as a place beyond compare. Second, we caution against positioning the city-region solely at the receiving end of devolutionary austerity. Rather, we illustrate how the urgency of devolution was conditioned by crisis, yet concomitantly framed as a unique opportunity by the local state harnessing policy to negotiate a more fluid politics of scale. In doing so, the paper demonstrates how attempts to resolve the "local problem" of governing health and care under austerity were rearticulated as a "global opportunity" to forge new connections between place, health, and economy. Consequently, we foreground the multiple tensions and contradictions accumulating through turning to health and care to push Greater Manchester further, faster. The paper concludes by asking what the present crisis might mean for city-regions in good health and turbulent times.

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. METHODS: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource - Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. RESULTS: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e-5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. CONCLUSIONS: Rare variant analysis of a large international consortium identified two new candidate genes-FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.