Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER)α agonist and unaffected by an ERβ antagonist

Oestrogen protects the heart from ischaemic injury. The current study aims to characterise two novel oestrogen receptor (ER) ligands, an ERα agonist ERA-45 and an ERβ antagonist ERB-88, and then use them to investigate the roles of ERα and ERβ in mediating the cardioprotection by E from ischaemia–reperfusion injury in the rat. The ER ligands were characterised by gene transactivation assay using ER-transfected Chinese hamster ovary (CHO) cells and in bioavailability studies in vivo. Female rats (n=48) were ovariectomised and implanted with 17β-oestradiol (17βE2) releasing or placebo pellets. ERA-45, ERB-88 or vehicle was administered for 5 days prior to ischaemia–reperfusion studies. Necrosis, neutrophil infiltration (myeloperoxidase activity) and oxidant stress production (electron paramagnetic resonance) from the area-at-risk were measured to assess reperfusion injury. The ERα agonist ERA-45 showed more than 35-fold selectivity for ERα compared with ERβ gene transactivation. In vitro, the ERβ antagonist ERB-88 inhibited transactivation by 17βE2 via ERβ with 46-fold selectivity relative to inhibition via ERα. In vivo, 17βE2 significantly reduced neutrophil infiltration, oxidant stress and necrosis following ischaemia and reperfusion. Cardioprotection by 17βE2 was not inhibited by ERB-88 but was completely reproduced by ERA-45. In conclusion, protection of the rat heart after ischaemia–reperfusion by 17βE2 is achieved through the reduction of cardiomyocyte death, neutrophil infiltration and oxygen-free radical availability.The results of this study indicate that these effects are primarily mediated via activation of ERα

The OMERACT emerging leaders program: The good, the bad, and the future

The Journal of Rheumatology Copyright © 2019. All rights reserved. Objective. To describe the experience of the first OMERACT Emerging Leaders Program (ELP). Methods. A Delphi process identified positive aspects, areas for improvement, and future directions. Core items were defined as essential if they received ≥ 70% ratings. Results. Participants valued relatable/accessible mentors (100%), including an OMERACT Executive mentor (100%), and a support network of peers (90%). Key items for future development were funding support (100%) and developing knowledge about OMERACT processes (90%) and politics (80%). Conclusion. The ELP has the potential to provide targeted training for early career researchers to develop relevant skills for future leadership roles within OMERACT

Phenological tracking of a seasonal climate window in a recovering tropical island bird species

Constraints on evolutionary adaptation and range shifts mean that phenotypic plasticity, which includes physiological, developmental or behavioural responses to environmental conditions, could be an important mode of adaptation to a changing climate for many species with small insular populations. While there is evidence to suggest adaptive plasticity to climate in some island populations, little is known about this capacity in species that have experienced a severe population bottleneck. In a changing climate, plasticity in the timing of life-history events, such as in breeding phenology, is adaptive if timing is optimised in seasonal environments, although these processes are poorly understood for tropical species. Here, we quantify the effects of climate on the breeding phenology and success of the Mauritius kestrel (Falco punctatus), a tropical raptor whose extinction has been averted by conservation management. We show that the timing of egg-laying is advancing in response to warming, at rates similar to temperate bird populations. Individual females show plasticity to temperature, although there is limited variation among individual responses. We show that advances in breeding phenology are likely to be adaptive, as they track changes in a seasonal climate window of favourable conditions, defined by late winter-early spring temperatures and the onset of the summer rainy season. Our results provide a rare example of a small and bottlenecked insular population that has adjusted to recent climate change through phenotypic plasticity. Furthermore, seasonal climate windows and their dynamics may be widespread mechanisms through which tropical species are impacted by and respond to climate change

Characterization of CDK(5) Inhibitor, 20-223 (aka CP668863) for Colorectal Cancer Therapy

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 – now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ~3.5-fold and ~65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average \u3e2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy

The MidPIC study : midwives’ knowledge, perspectives and learning needs regarding preconception and interconception care

Preconception and interconception care improves health outcomes of women and communities. Little is known about how prepared and willing Australian midwives are to provide preconception and interconception care. The aim of this study was to explore midwives’ knowledge, perspectives and learning needs, and barriers and enablers to delivering preconception and interconception care. We conducted a cross-sectional exploratory study of midwives working in any Australian maternity setting. An online survey measured midwives’ self-rated knowledge; education needs and preferences; attitudes towards pre and interconception care; and views on barriers, enablers; and, future service and workforce planning. Quantitative data were analysed descriptively and demographic characteristics (e.g., years of experience, model of care) associated with knowledge and attitudes regarding pre- and interconception care were examined using univariate logistic regression analysis. Qualitative data were captured through open-ended questions and analysed using inductive content analysis. We collected responses from (n = 338) midwives working across all models of care (full survey completion rate 96%). Most participants (n = 290; 85%) rated their overall knowledge about pre and interconception health as excellent, above average or average. Participants with over 11 years of experience were more likely to report above average to excellent knowledge (OR 3.11; 95% CI 1.09, 8.85). Online e-learning was the most preferred format for education on this topic (n = 244; 72%). Most (n = 257; 76%) reported interest in providing pre and interconception care more regularly and that this is within the midwifery scope of practice (n = 292; 87%). Low prioritisation in service planning was the most frequently selected barrier to providing preconception and interconception care, whereas continuity models and hybrid child health settings were reported as enablers of pre and interconception care provision. Findings revealed that midwives are prepared and willing to provide preconception and interconception care. Pre and post registration professional development; service and funding reform; and policy development are critical to enable Australian midwives’ provision of pre and interconception care

The Agrodiversity Experiment: three years of data from a multisite study in intensively managed grasslands

Intensively managed grasslands are globally prominent ecosystems. We investigated whether experimental increases in plant diversity in intensively managed grassland communities can increase their resource use efficiency. This work consisted of a coordinated, continental-scale 33-site experiment. The core design was 30 plots, representing 15 grassland communities at two seeding densities. The 15 communities were comprised of four monocultures (two grasses and two legumes) and 11 four-species mixtures that varied in the relative abundance of the four species at sowing. There were 1028 plots in the core experiment, with another 572 plots sown for additional treatments. Sites agreed a protocol and employed the same experimental methods with certain plot management factors, such as seeding rates and number of cuts, determined by local practice. The four species used at a site depended on geographical location, but the species were chosen according to four functional traits: a fast-establishing grass, a slow-establishing persistent grass, a fast-establishing legume, and a slow-establishing persistent legume. As the objective was to maximize yield for intensive grassland production, the species chosen were all high-yielding agronomic species. The data set contains species-specific biomass measurements (yield per species and of weeds) for all harvests for up to four years at 33 sites. Samples of harvested vegetation were also analyzed for forage quality at 26 sites. Analyses showed that the yield of the mixtures exceeded that of the average monoculture in >97% of comparisons. Mixture biomass also exceeded that of the best monoculture (transgressive overyielding) at about 60% of sites. There was also a positive relationship between the diversity of the communities and aboveground biomass that was consistent across sites and persisted for three years. Weed invasion in mixtures was very much less than that in monocultures. These data should be of interest to ecologists studying relationships between diversity and ecosystem function and to agronomists interested in sustainable intensification. The large spatial scale of the sites provides opportunity for analyses across spatial (and temporal) scales. The database can also complement existing databases and meta-analyses on biodiversity–ecosystem function relationships in natural communities by focusing on those same relationships within intensively managed agricultural grasslands

Comorbidity in patients with diabetes mellitus: impact on medical health care utilization

BACKGROUND: Comorbidity has been shown to intensify health care utilization and to increase medical care costs for patients with diabetes. However, most studies have been focused on one health care service, mainly hospital care, or limited their analyses to one additional comorbid disease, or the data were based on self-reported questionnaires instead of health care registration data. The purpose of this study is to estimate the effects a broad spectrum of of comorbidities on the type and volume of medical health care utilization of patients with diabetes. METHODS: By linking general practice and hospital based registrations in the Netherlands, data on comorbidity and health care utilization of patients with diabetes (n = 7,499) were obtained. Comorbidity was defined as diabetes-related comorbiiabetes-related comorbidity. Multilevel regression analyses were applied to estimate the effects of comorbidity on health care utilization. RESULTS: Our results show that both diabetes-related and non diabetes-related comorbidity increase the use of medical care substantially in patients with diabetes. Having both diabeterelated and non diabetes-related comorbidity incrases the demand for health care even more. Differences in health care utilization patterns were observed between the comorbidities. CONCLUSION: Non diabetes-related comorbidity increases the health care demand as much as diabetes-related comorbidity. Current single-disease approach of integrated diabetes care should be extended with additional care modules, which must be generic and include multiple diseases in order to meet the complex health care demands of patients with diabetes in the future

Simulated effect of pneumococcal vaccination in the Netherlands on existing rules constructed in a non-vaccinated cohort predicting sequelae after bacterial meningitis

BACKGROUND: Previously two prediction rules identifying children at risk of hearing loss and academic or behavioral limitations after bacterial meningitis were developed. Streptococcus pneumoniae as causative pathogen was an important risk factor in both. Since 2006 Dutch children receive seven-valent conjugate vaccination against S. pneumoniae. The presumed effect of vaccination was simulated by excluding all children infected by S. pneumoniae with the serotypes included in the vaccine, from both previous collected cohorts (between 1990-1995). METHODS: Children infected by one of the vaccine serotypes were excluded from both original cohorts (hearing loss: 70 of 628 children; academic or behavioral limitations: 26 of 182 children). All identified risk factors were included in multivariate logistic regression models. The discriminative ability of both new models was calculated. RESULTS: The same risk factors as in the original models were significant. The discriminative ability of the original hearing loss model was 0.84 and of the new model 0.87. In the academic or behavioral limitations model it was 0.83 and 0.84 respectively. CONCLUSION: It can be assumed that the prediction rules will also be applicable on a vaccinated population. However, vaccination does not provide 100% coverage and evidence is available that serotype replacement will occur. The impact of vaccination on serotype replacement needs to be investigated, and the prediction rules must be validated externally

Provision of obstetrics and gynaecology services during the COVID-19 pandemic:a survey of junior doctors in the UK National Health Service

Objective: The COVID-19 pandemic is disrupting health services worldwide. We aimed to evaluate the provision of obstetrics and gynaecology services in the UK during the acute-phase of the COVID-19 pandemic. Design: Interview-based national survey. Setting: Women’s healthcare units in the National Health Service. Population: Junior doctors in obstetrics and gynaecology. Methods: Participants were interviewed by members of the UKARCOG trainees’ collaborative between 28th March and 7th of April 2020. We used a quantitative analysis for closed-ended questions and a thematic framework analysis for open comments. Results: We received responses from 148/155 units (95%), majority of the participants were in years 3-7 of training (121/148, 82%). Most completed specific training drills for managing obstetric and gynaecological emergencies in women with COVID-19 (89/148, 60.1%) and two-persons donning and doffing of Personal Protective Equipment (PPE) (96/148, 64.9%). The majority of surveyed units implemented COVID-19 specific protocols (130/148, 87.8%), offered adequate PPE (135/148, 91.2%) and operated dedicated COVID-19 emergency theatres (105/148, 70.8%). Most units reduced face-to-face antenatal clinics (117/148, 79.1%), and suspended elective gynaecology services (131/148, 88.5%). The two-week referral pathway for oncology gynaecology was not affected in half of the units (76/148, 51.4%), while half reported a planned reduction in oncology operating (82/148, 55.4%). Conclusion: The provision of obstetrics and gynaecology services in the UK during the acute phase of the COVID-19 pandemic seems to be in line with current guidelines, but strategic planning is needed to restore routine gynaecology services and ensure safe access to maternity care on the longterm