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What would it mean to put environmental sustainability at the heart of education? This article describes a process of inclusive, participatory manifesto-making to identify young people’s (aged 16-18 years) and teachers’ priorities for education for environmental sustainability across the UK. Drawing on analysis of qualitative data from over 200 teachers and young people who participated in futures and visualisation workshops, we identify key educational priorities at the levels of classroom, school, community and policy, based on consensus between teacher and youth perspectives. Whilst consensus-seeking comes with a risk of favouring ‘soft’ actions which reinforce unsustainable practices and systems, the process of identifying more desirable futures and immediate barriers, which must be negotiated to reach them, has the potential to create spaces for more critical pedagogies and practices. There is a need for policy makers and school leaders to recognise the interests of teachers and young people to enable greater participation in decision making at different scales, and to ensure that those with the greatest capacity bear their burden of responsibility for education for environmental sustainability.

Obstetric anal sphincter injury (OASI) during childbirth is associated with urino-genital pain and dysfunction. Waterbirth is a popular birth choice for women, but controversy remains around the risk of OASI during waterbirth. This study reports on the incidence of OASI, and factors associated with OASI, for a cohort of women who gave birth in water. This secondary analysis used prospectively collected data from 2,908 women who gave birth in water in a hospital setting. The incidence of OASI was calculated. Univariable and multivariable logistic regression analysis evaluated factors associated with OASI. The incidence of OASI was 1.9% (95% confidence interval (CI) 1.4, 2.4) for all women. In nulliparae it was higher (3.2%, 95% CI 2.3, 4.3) than in multiparae (0.9%, 95% CI 0.5, 1.4). In the multivariable analysis, two variables were associated with OASI; multiparity was negatively associated with OASI (adjusted odds ratio [aOR] 0.24, 95% CI 0.12, 0.50, p

Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of all pediatric brain tumors. The current standard of care includes both craniospinal and focal radiation therapy which leads to long term consequences in the pediatric population such as bone and tissue hypoplasia, decreased neurocognitive functioning, as well as an increased risk for secondary radiation induced cancers. Thus, there is a need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing radiation toxicity in healthy tissue in the pediatric patient population. The dysregulation and constitutive activation of the Sonic Hedgehog (SHH) signaling pathway accounts for ~30% of all medulloblastomas. In addition to playing a role in tumorigenesis, the SHH pathway is known to play a role in the radiation sensitivity and risk of tumor recurrence. We hypothesize that inhibiting the SHH pathway at Smoothened (Smo) or Gli1 will increase DNA damage, resulting in increased cell killing following radiation therapy. We found that treatment of medulloblastoma cells with the drug Sonidegib or GANT61 decreased the expression of the respective targets Smo and Gli1. Both drugs also significantly decreased expression of FANCD2, a DNA damage repair gene essential for homologous recombination. Pretreatment with Sonidegib or GANT61 resulted functionally with decreased tumor cell viability and self-renewal following radiation. These data suggest that Smo and Gli1 inhibition are promising targets for increasing the radiation sensitivity of pediatric SHH medulloblastoma.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure. 1745 patients with idiopathic or connective tissue disease-associated PAH who had completed emPHasis-10 questionnaires between 2014-17 at 6 UK referral centres were identified. Correlations with exercise capacity and WHO functional class (FC) were assessed, and exploratory risk stratification thresholds were tested. Moderate correlations were seen between emPHasis-10 scores and 6-minute walk distance (r=-0.546), incremental shuttle walking distance (r=-0.504) and WHO FC (r=0.497; p all

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Sexual and gender minorities (SGMs) are at a heightened vulnerability for a range of adverse outcomes as a function of the bias and discrimination they face in their social environment. Many of these adverse outcomes, in turn, become added stressors for these individuals. The stressor-mediator-outcome model creates a visual representation of how many SGM persons find themselves embedded in a cycle of adversity. Religious experiences interweave into this cycle, often mediating the relationships between stressors and negative outcomes. The violence of discrimination and internalized stigma is mediated by the influences of religion/spirituality, which alleviate or exacerbate negative outcomes for SGM persons. A secondary cycle, employing the perspective of a parent, addresses the identification of an SGM child as a stressor. Religiosity carries the potential to mediate the resulting parental responses from rejection to acceptance. In the extreme case of child ejection, a sub-cycle of homelessness develops. Homelessness, in turn, becomes a stressor that often results in street violence and victimization for sexual and/or gender minorities. Implications for treatment and recommendations for future research are reviewed in each section of the chapter.

Introduction: Congenital thoracic malformations (CTM) are increasingly detected through antenatal screening but there is no universal guidance on the management of small asymptomatic lesions. All infants with antenatally detected CTM will have a chest computed tomography (CT) by 3m of age at the Children9s Hospital for Wales. Aim: To evaluate the management and outcome of CTM detected antenatally and postnatally in the last 10 years. Methods: All infants with chest CT performed under one year of age from 2010-2019 were identified through specific search criteria related to CTM. CT findings and clinical management and outcomes were obtained from clinical record. Results: 79 infants (41females, 38males) were identified with CTM. 6 were diagnosed postnatally due to respiratory symptoms of which 5 required surgery (1 was a bronchopulmonary sequestration (BPS), 3 were congenital lobar overinflation (CLO) and 1 was a benign tumour). Of the 73 antenatal cases, 33(45%) were congenital pulmonary airway malformations (CPAM), 23(32%) BPS, 9(12%) CLO, 4(5%) "others" and 4(5%) normal CT. 37(54%) were resected due to size of lesions, feeder vessels or parental choice. Ten (7 CPAM, 2 BPS and 1 CLO) required early surgery for respiratory distress or recurrent chest infections. One neonate died after surgery due to prematurity. 32(46%) were managed conservatively and monitored over median duration of 12m (range: 1-72m). None of these children had lower respiratory tract infections or malignancy. Conclusions: This study revealed that 19% of CTM in Wales required surgery. Low complication rate exists for small CTM managed conservatively in the medium term and its results could be utilised for parental counselling with regards to treatment.

Introduction: Congenital thoracic malformations (CTM) can be detected antenatally. There is no universal guidance for asymptomatic lesions although surgical resection has been advocated due to potential complications. Current Welsh guideline for neonates with antenatally detected CTM include CXR after birth with hospital observation for 24 hours. Chest computed tomography(CT) is performed at the Children9s Hospital for Wales within the first 3m of age. Aim: To investigate whether initial CXR can predict CTM and subsequent need for surgery. Methods: All infants with chest CT performed under a year of age were identified from 2010-2019 through search criteria for congenital lung lesions. Initial CXR of those with antenatal diagnosis were reviewed together with their clinical records. Results: 67 antenatally detected infants had initial CXR; 23(34%) were normal, 44(66%) were abnormal irrespective of size of lung lesions. 20(87%) with normal CXR had CT confirmed lung lesions of which 9 had elective resection (39% of those with normal CXR). All with abnormal CXR had abnormal CT and 25 required surgery (57% with abnormal CXR) but 10 required emergency resection. Sensitivity, specificity, positive and negative predictive values of CXR confirming CT lung lesions are 69%,100%,100% and 13% respectively whilst CXR as a screening test for surgical resection is poor (74%,42%,56%,61%). Conclusions: Initial CXR is not useful in confirming antenatally detected CTM or surgery. However in the absence of CXR abnormalities, no infants required emergency surgery. This may reassure neonatologists in the safe discharge of neonates until definitive evaluation.

Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.

Background Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. Methods Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. Results A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. Conclusions These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

Purpose Peer support (PS) has, over recent years, been implemented across a variety of NHS adult mental health settings. In November 2015, peer support workers (PSW) were introduced to an Early Intervention in Psychosis Service (EIS) in the Midlands. The purpose of this paper is to focus on organisational factors, asking how do PS impact on an early intervention in psychosis multi-disciplinary team (MDT). Design/methodology/approach Six EIS MDT members participated in an hour-long focus group. The data were analysed using thematic analysis, in line with a qualitative methodology (Braun and Clarke, 2006). Findings Two themes were generated, including “The values of PS” (consisting of three sub-themes: improving service engagement; personal qualities; and the peer relationship); and “The peer support role” (consisting of three sub-themes: living experience; boundaries; and alternative perspectives). Findings imply that PS in the current EIS related to: improved service engagement and greater understanding between service providers and users; which could be linked to better outcomes for service users (such as reduced duration of untreated psychosis (DUP)). Originality/value It has been suggested that PSWs facilitate an improved understanding between service providers and service users (Repper and Watson, 2012). However, research into organisational and team benefits of PS is lacking, with a need for more exploration (Repper, 2013). The current study begins to address the lack of literature regarding the organisational impact of PS, and even further regarding early intervention.

Objective Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified. Methods We reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology. Results Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. Interpretation APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758–774

In this paper, I introduce knitting as a popular and underexplored creative practice. Geographers have begun to take interest in craft, skill, and ‘the power of making’ to transform social and material relations and offer new possibilities for urban life. In this paper, I sketch ways that geographers may begin to engage with collective and interventionist knitting in urban environments - in terms of socialities, interventions, and materialities. From knitting circles, yarnbombing to community projects, knitters have begun to stitch new enthusiasms, temporalities, sensorial possibilities, and enchantments into the urban fabric. I conclude the paper - with future directions for geographical engagement with a variety of craft practices that encourage reflection on the people, places, and economies, of ‘making things’ through the example of knitting.

In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort.Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (3.4 m/s), intermediate (2.9-3.4 m/s) and low (2.8 m/s) probabilities of PH were evaluated against RHC testing.RHC testing confirmed PH in 86% of subjects with a peak TR velocity3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH.In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC.

Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca

After the Second World War, the wool textile industry faced a significant labour shortage as its traditional workers escaped the poor wages and conditions of wool mills for better-paying, cleaner jobs. Three broad solutions to this crisis were adopted: the employment of immigrants, mainly from the Indian Subcontinent and Eastern Europe, the re-formatting and promotion of apprenticeships and the recruitment work undertaken by the Wool Industry Training Board. Of these solutions, employing immigrants was by far the most successful in bringing workers into the industry, while the latter two were resounding failures. In prioritising the recruitment of young, white, British men, the industry, trade unions and government missed a key opportunity to train immigrants and women to take the places of the skilled workers they so desperately sought.

ADP receptors, P2Y1 and P2Y12 have been recognized as potential targets for antithrombotic drugs. A series of P2Y1 antagonists that contain 2-aminothiazoles as urea surrogates were discovered. Extensive SAR of the thiazole ring is described. The most potent compound 7j showed good P2Y1 binding (Ki = 12 nM), moderate antagonism of platelet aggregation (PA IC50 = 5.2 μM) and acceptable PK in rats.

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.

Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.