Cyclooxygenase Polymorphisms and Risk of Cardiovascular Events: The Atherosclerosis Risk in Communities (ARIC) Study

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case–cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 −1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P = 0.027). In African Americans, the reduced function PTGS2 −765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P = 0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P = 0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations, and death in patients with acquired thrombotic thrombocytopenic purpura.

BACKGROUND Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations and death. In the Phase II TITAN study, treatment with caplacizumab, an anti-vWF Nanobody(®) , was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. OBJECTIVE The clinical benefit of caplacizumab was further investigated in a post-hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and TTP-related death during the study. METHODS The Standardized MedDRA Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients of whom 35 received caplacizumab and 37 received placebo. RESULTS Four events (1 pulmonary embolism and 3 aTTP exacerbations) were reported in 4 patients in the caplacizumab group, while 20 such events were reported in 14 patients in the placebo group (2 acute myocardial infarctions, 1 ischemic and 1 hemorrhagic stroke, 1 pulmonary embolism, 1 deep vein thrombosis, 1 venous thrombosis and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. CONCLUSION In total, 11.4% of caplacizumab-treated patients versus 43.2% of placebo-treated patients experienced one or more major thromboembolic event, an exacerbation or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP. This article is protected by copyright. All rights reserved

NAG-1/GDF15 Transgenic Mouse Has Less White Adipose Tissue and a Reduced Inflammatory Response

NAG-1/GDF15 is a TGF-β superfamily member with poorly characterized biological activity proposed to inhibit inflammatory cytokine production. Transgenic mice expressing human NAG-1/GDF15 (NAG-1(Tg/Lox)) are leaner with lower body weight and are resistant to chemically or genetically induced intestinal tumors. Because of the link between obesity, inflammation, and cancer, we examined whether these mice exhibit a reduced response to inflammatory stimuli. The NAG-1(Tg/Lox) mice had a reduced inflammatory response to LPS based on the serum levels of cytokines KC, IL-6, MCP-1, and TNFα. In contrast to literature reports and our in vivo results, NAG-1 did not inhibit LPS-induced cytokine expression in vitro in RAW264.7 cells, mouse peritoneal macrophages, or mouse liver Kupffer cells, suggesting that NAG-1/GDF15 does not directly inhibit LPS-induced inflammatory cytokine production. However, NAG-1(Tg/Lox) mice have less white adipose tissue, the major source of inflammatory adipokines including leptin. Basal and LPS-treated serum leptin and mRNA levels in the adipose tissue of NAG-1(Tg/Lox) mice were lower than those in WT mice. We propose that the reduced white adipose tissue and reduced leptin expression may be responsible, in part, for the reduced inflammatory response to LPS and the decrease in intestinal tumors observed in NAG-1(Tg/Lox) mice

Using social cognitive career theory to understand why students choose to study computer science

The aim of this research is to use Social Cognitive Career Theory (SCCT) to identify and understand reasons why students choose to study Computer Science (CS) at university. SCCT focuses on students’ prior experience, social support, self-efficacy and outcome expectation. The research is part motivated by the desire to increase female participation rates in CS, particularly in the UK. Policymakers can use the factors that both females and males identify as influencing their choice of studying CS to enhance the experiences of all students prior to coming to university, but female students in particular. The study uses a semi-structured interview with 17 mixed gender subjects currently studying CS at three Scottish universities. The findings are that social support from family, teachers, friends and mentors is a particularly important factor in choosing to study CS, especially for female subjects. The career paths offered by a CS degree is another major factor, not just the potential jobs, but also the general value of a CS education and the potential to make useful contributions to society. School education appeared to have limited influence, though exposure to problem solving, programming, online self-learning and internships are positive influences. The stereotypical view of CS students as ‘geeks’ is outdated and unhelpful – it is more appropriate to see them as ‘analytical’ or ‘over-achievers’. Subjects make many suggestions for improving the CS education provided at school, especially to make it more attractive to females, including: make it compulsory, teach it earlier, include more programming and problem solving, and increase the visibility of female exemplars and role models

Postresectional lung injury in thoracic surgery pre and intraoperative risk factors: a retrospective clinical study of a hundred forty-three cases

<p>Abstract</p> <p>Introduction</p> <p>Acute respiratory dysfunction syndrome (ARDS), defined as acute hypoxemia accompanied by radiographic pulmonary infiltrates without a clearly identifiable cause, is a major cause of morbidity and mortality after pulmonary resection. The aim of the study was to determine the pre and intraoperative factors associated with ARDS after pulmonary resection retrospectively.</p> <p>Methods</p> <p>Patients undergoing elective pulmonary resection at Adnan Menderes University Medical Faculty Thoracic Surgery Department from January 2005 to February 2010 were included in this retrospective study. The authors collected data on demographics, relevant co-morbidities, the American Society of Anesthesiologists (ASA) Physical Status classification score, pulmonary function tests, type of operation, duration of surgery and intraoperative fluid administration (fluid therapy and blood products). The primary outcome measure was postoperative ARDS, defined as the need for continuation of mechanical ventilation for greater than 48-hours postoperatively or the need for reinstitution of mechanical ventilation after extubation. Statistical analysis was performed with Fisher exact test for categorical variables and logistic regression analysis for continuous variables.</p> <p>Results</p> <p>Of one hundred forty-three pulmonary resection patients, 11 (7.5%) developed postoperative ARDS. Alcohol abuse (p = 0.01, OR = 39.6), ASA score (p = 0.001, OR: 1257.3), resection type (p = 0.032, OR = 28.6) and fresh frozen plasma (FFP)(p = 0.027, OR = 1.4) were the factors found to be statistically significant.</p> <p>Conclusion</p> <p>In the light of the current study, lung injury after lung resection has a high mortality. Preoperative and postoperative risk factor were significant predictors of postoperative lung injury.</p

Female senior secondary physics students’ engagement in science: a qualitative study of constructive influences

Background: Prompted by fewer females compared to males enrolling in physics and advanced mathematics at both secondary and university levels, our research investigated the views and experiences of female students currently studying upper secondary school physics. We interviewed 18 female students about influences they considered important to their own science education, interest in science, and future science-related aspirations. Our purpose was to identify the experiences that these students most strongly associated with the generation and maintenance of their engagement in science, particularly represented in this research by their enrolment in upper secondary physics. Results: The research team used a systematic, iterative process to identify the main themes in the transcribed interview data. We identified the influence each girl reported as the strongest (ranked first). We also combined all influences that the participants had nominated, regardless of their ranking, to further examine all factors participants suggested as influential in their sustained engagement in school science (represented by their decision to study upper secondary physics). Systematic analysis of the interview data confirms that the influences on these females’ choices to study physics at upper secondary originate from a combination of their teachers, their school’s science culture, members of their family, the participants themselves and their peers. Conclusions: The interviews highlighted the idiographic complexities in understanding the wide range of important influences on these students studying physics at upper secondary school and their engagement in science. The unique contribution of this work is giving voice to the participants and reflecting on what these high achieving females have to say about the influential factors in their decisions to pursue science. Supportive teachers and the school science culture play essential roles, and other cultural and/or social factors such as family members and peers are identified as important. References to the culture and expectations of the school, family holidays, and conversations with siblings are support factors that seem to interact and overlap. At the same time, the importance of policy-amenable factors such as competent and caring science teachers, and science-supportive school cultures should be emphasised and encouraged

Multi-tissue profiling of oxylipins reveal a conserved up-regulation of epoxide:diol ratio that associates with white adipose tissue inflammation and liver steatosis in obesity

Data sharing statement: The individual-level data used in this study cannot be publicly shared due to ethical approval. Data set will be made available upon request through contact with the corresponding author. For sharing of data within a scientific collaboration any proposal should be directed to the corresponding author. Data will only be shared in accordance with legal frameworks, and when the integrity of the individual study participant can be guaranteed. This will be decided by the corresponding author on a case-by-case basis.Background: Obesity drives maladaptive changes in the white adipose tissue (WAT) which can progressively cause insulin resistance, type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated liver disease (MASLD). Obesity-mediated loss of WAT homeostasis can trigger liver steatosis through dysregulated lipid pathways such as those related to polyunsaturated fatty acid (PUFA)-derived oxylipins. However, the exact relationship between oxylipins and metabolic syndrome remains elusive and cross-tissue dynamics of oxylipins are ill-defined. Methods: We quantified PUFA-related oxylipin species in the omental WAT, liver biopsies and plasma of 88 patients undergoing bariatric surgery (female N = 79) and 9 patients (female N = 4) undergoing upper gastrointestinal surgery, using UPLC-MS/MS. We integrated oxylipin abundance with WAT phenotypes (adipogenesis, adipocyte hypertrophy, macrophage infiltration, type I and VI collagen remodelling) and the severity of MASLD (steatosis, inflammation, fibrosis) quantified in each biopsy. The integrative analysis was subjected to (i) adjustment for known risk factors and, (ii) control for potential drug-effects through UPLC-MS/MS analysis of metformin-treated fat explants ex vivo. Findings: We reveal a generalized down-regulation of cytochrome P450 (CYP)-derived diols during obesity conserved between the WAT and plasma. Notably, epoxide:diol ratio, indicative of soluble epoxide hydrolyse (sEH) activity, increases with WAT inflammation/fibrosis, hepatic steatosis and T2DM. Increased 12,13-EpOME:DiHOME in WAT and liver is a marker of worsening metabolic syndrome in patients with obesity. Interpretation: These findings suggest a dampened sEH activity and a possible role of fatty acid diols during metabolic syndrome in major metabolic organs such as WAT and liver. They also have implications in view of the clinical trials based on sEH inhibition for metabolic syndrome.Wellcome Trust (PS3431_WMIH); Duke-NUS (Intramural Goh Cardiovascular Research Award (Duke-NUS-GCR/2022/0020); National Medical Research Council (OFLCG22may-0011); National Institute of Environmental Health Sciences (Z01 ES025034); NIHR Imperial Biomedical Research Centre

Institutional creativity and pathologies of potential space: The modern university

This paper proposes the applicability of object relations psychoanalytic conceptions of dialogue (Ogden, 1986, 1993) to thinking about relationships and relational structures and their governance in universities. It proposes that: the qualities of dialogic relations in creative institutions are the proper index of creative productivity; that is of, as examples, ’thinking’ (Evans, 2004), ’emotional learning’ (Salzberger-Wittenburg et al., 1983) or ’criticality’ (Barnett, 1997); contemporary institutions’ explicit preoccupation in assuring, monitoring and managing creative ’dialogue’ can, in practice, pervert creative processes and thoughtful symbolic productivity, thus inhibiting students’ development and the quality of ’thinking space’ for teaching and research. In this context the paper examines uncanny and perverse connections between Paulo Freire’s (1972) account of educational empowerment and dialogics (from his Pedagogy of the oppressed) to the consumerist (see, for example, Clarke & Vidler, 2005) rhetoric of student empowerment, as mediated by some strands of managerialism in contemporary higher education. The paper grounds its critique of current models of dialogue, feedback loops, audit and other mechanisms of accountability (Power, 1997; Strathern, 2000), in a close analysis of how creative thinking emerges. The paper discusses the failure to maintain a dialogic space in humanities and social science areas in particular, exploring psychoanalytic conceptions from Donald Winnicott (1971), Milner (1979), Thomas Ogden (1986) and Csikszentmihalyi (1997). Coleridge’s ideas about imagination as the movement of thought between subjective and objective modes are discussed in terms of both intra- and inter-subjective relational modes of ’dialogue’, which are seen as subject to pathology in the pathologically structured psychosocial environment. Current patterns of institutional governance, by micromanaging dialogic spaces, curtail the ’natural’ rhythms and temporalities of imagination by giving an over-emphasis to the moment of outcome, at the expense of holding the necessary vagaries of process in the institutional ’mind’. On the contrary, as this paper argues, creative thinking lies in sporadic emergences at the conjunction of object/(ive) outcome and through (thought) processes

Cytochrome P450-derived eicosanoids: the neglected pathway in cancer

Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed