The role of genetics in pre-eclampsia and potential pharmacogenomic interventions

The pregnancy-specific condition pre-eclampsia not only affects the health of mother and baby during pregnancy but also has long-term consequences, increasing the chances of cardiovascular disease in later life. It is accepted that pre-eclampsia has a placental origin, but the pathogenic mechanisms leading to the systemic endothelial dysfunction characteristic of the disorder remain to be determined. In this review we discuss some key factors regarded as important in the development of pre-eclampsia, including immune maladaptation, inadequate placentation, oxidative stress, and thrombosis. Genetic factors influence all of these proposed pathophysiological mechanisms. The inherited nature of pre-eclampsia has been known for many years, and extensive genetic studies have been undertaken in this area. Genetic research offers an attractive strategy for studying the pathogenesis of pre-eclampsia as it avoids the ethical and practical difficulties of conducting basic science research during the preclinical phase of pre-eclampsia when the underlying pathological changes occur. Although pharmacogenomic studies have not yet been conducted in pre-eclampsia, a number of studies investigating treatment for essential hypertension are of relevance to therapies used in pre-eclampsia. The pharmacogenomics of antiplatelet agents, alpha and beta blockers, calcium channel blockers, and magnesium sulfate are discussed in relation to the treatment and prevention of pre-eclampsia. Pharmacogenomics offers the prospect of individualized patient treatment, ensuring swift introduction of optimal treatment whilst minimizing the use of inappropriate or ineffective drugs, thereby reducing the risk of harmful effects to both mother and baby

Elliptical Fourier Analysis of Crown Shape in Permanent Mandibular Molars From The Late Neolithic Cave Burials of Belgium

Prehistoric remains from caves and rockshelters are known from more than 250 sites situated along the Meuse River Basin of Belgium. Most of these osteological remnants date to the Late Neolithic period beginning after 4,500 years before present (BP), and five of these cave burials have been subject to intensive study, including Hastière Caverne M and Hastière Trou Garçon C from an earlier period of the Late Neolithic (4,345 ± 60 to 4,220 ± 45 years BP), Sclaigneaux and Bois Madame from the final/late Neolithic (4,155 ± 35 to 3,910 ± 40 years BP) and Maurenne Caverne de la Cave which dates to the final/late Neolithic period, 4,160 ± 45 to 3,830 ± 90 years BP and Middle Neolithic, 4,635 ± 45 years BP. Since the majority of the remains comprise gnathic fragments with in situ dental elements, comparisons between the caves are largely restricted to the teeth. Elliptical Fourier analysis of 40 permanent mandibular molar crown outlines from 27 individuals is utilized to address the degree to which chronology and ecogeography can explain the variation in crown shape across the caves. Although the sample sizes are limited, the cave burial of Hastière Caverne M appears to be distinctive. The variation within the cave burials of Sclaigneaux and Maurenne Caverne de la Cave is extensive, and a pronounced overlapping characterizes some of the sites. The results may provide evidence for increasingly broader contact between Late Neolithic farming communities of the Belgian Meuse basin prior to the Bronze Age

The IPCRG's teach the teacher programme: an educational initiative to promote improved management of difficult to manage asthma

The IPCRG is a network of organisations committed to improving primary care assessment and treatment of chronic respiratory disease. We developed an evidence-based resource, SIMPLES (Ryan D, et al. Prim Care Respir J 2013;22:365-73) to aid structured asthma review for difficult to manage asthma. An educational initiative was introduced to disseminate research findings from U-BIOPRED and promote improved primary care management. We aimed to support participants from seven European countries to design and plan local programmes of education:teaching clinical colleagues key messages about difficult to manage asthma, encouraging local adaptation of existing IPCRG resources. These took place in autumn 2015 involving over 230 health professionals - including early career and GPs with a special interest in asthma/COPD, specialist nurses and others. We proposed an evaluation framework(Guskey,T.Teachers&Teaching 2002;8:3, 381-391) which includes - i) participant reaction, ii) learning, iii) organisational changes, iv) use of new knowledge and v) impact on practice and service users. Programmes were well received by participants. There were many challenges encountered: in assessing local learning needs, setting up education programmes and supporting clinical practice change. The impact on participants' clinical practice and service users is more challenging to demonstrate and will require more time to evaluate. We reflect on the challenge of meaningful evaluation of practice change. These insights are important in thinking about the design, implementation and evaluation of clinical educational programmes globally.info:eu-repo/semantics/publishedVersio

ESG Investing, Fall 2020

ESG Investing Project for Sustainability Exchange, Washington University in St. Louis, Fall 202

Evidence from high resolution topography for multiple earthquakes on high slip-to-length fault scarps: the Bilila-Mtakataka fault, Malawi

Geomorphological features such as fault scarps and stream knickpoints are indicators of recent fault activity. Determining whether these features formed during a single earthquake or over multiple earthquakes cycles has important implications for the interpretation of the size and frequency of past events. Here, we focus on the Bilila‐Mtakataka fault, Malawi, where the 20 m high fault scarps exceed the height expected from a single earthquake rupture. We use a high resolution digital elevation model (< 1 m) to identify complexity in the fault scarp and knickpoints in river profiles. Of 39 selected scarp profiles, 20 showed evidence of either multi‐scarps or composite scarps and of the seven selected river and stream profiles, five showed evidence for multiple knickpoints. A near uniform distribution of vertical offsets on the sub‐scarps suggests they were formed by separate earthquakes. These independent methods agree that at least two earthquakes have occurred with an average vertical offset per event of 10 and 12 m. This contrasts earlier studies which proposed that this scarp formed during a single event, and demonstrates the importance of high‐resolution topographic data for understanding tectonic geomorphology. We use a one‐dimensional diffusion model of scarp degradation to demonstrate how fault splays form multi‐scarps and estimate the diffusion age κt of the Bilila‐Mtakataka fault scarp to be 48 ± m25 m2, corresponding to 6400 ± 4000 years since formation. We calculate that a continuous rupture would equate to a MW 7.8 ± 0.3 earthquake, greater than the largest seismic event previously recorded in East Africa

Altered placental expression of kisspeptin and its receptor in pre-eclampsia

Kisspeptin, originally identified as metastatin, important in preventing cancer metastasis, has more recently been shown to be important in pregnancy. Roles indicated for kisspeptin in pregnancy include regulating trophoblast invasion and migration during placentation. The pregnancy-specific disorder pre-eclampsia (PE) is now accepted to begin with inadequate trophoblast invasion and the current study therefore sets out to characterise placental expression of both kisspeptin (KISS1) and its receptor (KISS1R) throughout pregnancy and in PE. Placental tissue was obtained from women undergoing elective surgical termination of early pregnancy (n=10) and from women following Caesarean section at term in normal pregnancy (n=10) and with PE (n=10). Immunohistochemistry of paraffin embedded sections and western immunoblotting were performed to assess protein localisation and expression. Quantitative real-time PCR was carried out to evaluate mRNA expression of both KISS1 and KISS1R. Protein and mRNA expression was found to mirror each other with KISS1 expression found to be reduced in PE compared with that in normal term pregnancy. Interestingly, KISS1R expression at both the mRNA and protein levels was found to be increased in PE compared with that in normal term pregnancy. The current findings of increased KISS1R expression may represent a mechanism by which functional activity of KISS1 is higher in PE than in normal pregnancy. Higher levels of activity of KISS1R may be involved in inhibition of trophoblast invasion and angiogenesis, which are associated with PE

Risk prediction models for colorectal cancer in people with symptoms: a systematic review

Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related death in Europe and the United States. Detecting the disease at an early stage improves outcomes. Risk prediction models which combine multiple risk factors and symptoms have the potential to improve timely diagnosis. The aim of this review is to systematically identify and compare the performance of models that predict the risk of primary CRC among symptomatic individuals. Methods We searched Medline and EMBASE to identify primary research studies reporting, validating or assessing the impact of models. For inclusion, models needed to assess a combination of risk factors that included symptoms, present data on model performance, and be applicable to the general population. Screening of studies for inclusion and data extraction were completed independently by at least two researchers. Results Twelve thousand eight hundred eight papers were identified from the literature search and three through citation searching. 18 papers describing 15 risk models were included. Nine were developed in primary care populations and six in secondary care. Four had good discrimination (AUROC > 0.8) in external validation studies, and sensitivity and specificity ranged from 0.25 and 0.99 to 0.99 and 0.46 depending on the cut-off chosen. Conclusions Models with good discrimination have been developed in both primary and secondary care populations. Most contain variables that are easily obtainable in a single consultation, but further research is needed to assess clinical utility before they are incorporated into practice

Research Evaluating Staff Training Online for Resilience (RESTORE): Protocol for a single-arm feasibility study of an online acceptance and commitment therapy intervention to improve staff wellbeing in palliative care settings

Background Palliative care workers commonly experience workplace stress and distress. General stressors include unmanageable workloads and staff shortages. Stressors specific to palliative care include regular exposure to death, loss and grief. The COVID pandemic exacerbated exhaustion and burnout across the healthcare system, including for those providing palliative care. Evidence based psychological support interventions, tailored to the needs and context of palliative care workers, are needed. Acceptance and Commitment Therapy (ACT) is an established form of cognitive behavioural therapy which uses behavioural psychology, values, acceptance, and mindfulness techniques to improve mental health and wellbeing. ACT is effective in improving workplace wellbeing in many occupational settings. Our study examines the acceptability and feasibility of an online ACT-based intervention to improve mental health and wellbeing in staff caring for people with an advanced progressive illness. Methods A single-arm feasibility trial. We will seek to recruit 30 participants to take part in an 8- week online ACT-based intervention, consisting of three synchronous facilitated group sessions and five asynchronous self-directed learning modules. We will use convergent mixed methods to evaluate the feasibility of the intervention. Quantitative feasibility outcomes will include participant recruitment and retention rates, alongside completion rates of measures assessing stress, quality of life, wellbeing, and psychological flexibility. Focus groups and interviews will explore participant perspectives on the intervention. We will run a stakeholder workshop to further refine the intervention and identify outcomes for use in a future evaluation. We will describe participant perspectives on intervention acceptability, format, content, and perceived impact alongside rates of intervention recruitment, retention, and outcome measure completion. Conclusion We will show whether a brief, online ACT intervention is acceptable to, and feasible for palliative care workers. Findings will be used to further refine the intervention and provide essential information on outcome assessment prior to a full-scale evaluation

Risk prediction models for colorectal cancer in people with symptoms: a systematic review

Abstract Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related death in Europe and the United States. Detecting the disease at an early stage improves outcomes. Risk prediction models which combine multiple risk factors and symptoms have the potential to improve timely diagnosis. The aim of this review is to systematically identify and compare the performance of models that predict the risk of primary CRC among symptomatic individuals. Methods We searched Medline and EMBASE to identify primary research studies reporting, validating or assessing the impact of models. For inclusion, models needed to assess a combination of risk factors that included symptoms, present data on model performance, and be applicable to the general population. Screening of studies for inclusion and data extraction were completed independently by at least two researchers. Results Twelve thousand eight hundred eight papers were identified from the literature search and three through citation searching. 18 papers describing 15 risk models were included. Nine were developed in primary care populations and six in secondary care. Four had good discrimination (AUROC > 0.8) in external validation studies, and sensitivity and specificity ranged from 0.25 and 0.99 to 0.99 and 0.46 depending on the cut-off chosen. Conclusions Models with good discrimination have been developed in both primary and secondary care populations. Most contain variables that are easily obtainable in a single consultation, but further research is needed to assess clinical utility before they are incorporated into practice

Is the atherosclerotic phenotype of pre-eclamptic placentas due to altered lipoprotein concentrations and placental lipoprotein receptors?: role of a small-for-gestational-age phenotype

Artherosis of spiral arteries in uteroplacental beds from pre-eclamptic women resemble those of atherosclerosis, characterised by increased plasma lipids and lipoproteins. We hypothesised 1) lipoproteins receptors/transporter in placenta would be up-regulated in pre-eclampsia, associated with increased maternal and fetal lipoprotein concentrations; 2) expression of these would be reduced in pre-eclamptic placentae from women delivering small-for-gestational-age (SGA) infants. Placental biopsies, maternal and umbilical serum samples were taken from 27 normotensive and 24 pre-eclamptic women. Maternal/umbilical cord serum LDL; HDL; total cholesterol and triglycerides were measured. Placental mRNA expression of lipoprotein receptors/transporters were quantified using qRT-PCR. Protein localisation/expression of LRP-1 in the pre-eclamptic with/without SGA was measured by immunohistochemistry. Placental mRNA expression of all genes except PON-1, MTTP and PDIA2 were observed. No differences for any lipoprotein receptors/transporters were found between groups; however, in the pre-eclamptic group placental LRP-1 expression was lower in SGA delivering mothers (n = 7; P=0.036). LRP-1 protein was localised around fetal vessels and Hofbauer cells. This is the first detailed study of maternal/fetal lipoprotein concentrations and placental lipoprotein receptor mRNA expression in normotensive and pre-eclamptic pregnancies. These findings do not support a role of altered lipid metabolism in pre-eclampsia, but may be involved in fetal growth