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Abstract Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase’s role in normal and diseased human placenta.

Abstract Background Midwifery Units (MUs) are associated with optimal perinatal outcomes, improved service users’ and professionals’ satisfaction as well as being the most cost-effective option. However, they still do not represent the mainstream option of maternity care in many countries. Understanding effective strategies to integrate this model of care into maternity services could support and inform the MU implementation process that many countries and regions still need to approach. Methods A systematic search and screening of qualitative and quantitative research about implementation of new MUs was conducted (Prospero protocol reference: CRD42019141443) using PRISMA guidelines. Included articles were appraised using the CASP checklist. A meta-synthesis approach to analysis was used. No exclusion criteria for time or context were applied to ensure inclusion of different implementation attempts even under different historical and social circumstances. A sensitivity analysis was conducted to reflect the major contribution of higher quality studies. Results From 1037 initial citations, twelve studies were identified for inclusion in this review after a screening process. The synthesis highlighted two broad categories: implementation readiness and strategies used. The first included aspects related to cultural, organisational and professional levels of the local context whilst the latter synthesised the main actions and key points identified in the included studies when implementing MUs. A logic model was created to synthesise and visually present the findings. Conclusions The studies selected were from a range of settings and time periods and used varying strategies. Nonetheless, consistencies were found across different implementation processes. These findings can be used in the systematic scaling up of MUs and can help in addressing barriers at system, service and individual levels. All three levels need to be addressed when implementing this model of care.

College science instructors need continuous professional development (PD) to meet the call to evidence-based practice. New PD efforts need to focus on the nuanced blend of factors that influence instructors' teaching practices. We used persona methodology to describe the diversity among instructors who were participating in a long-term PD initiative. Persona methodology originates from ethnography. It takes data from product users and compiles those data in the form of fictional characters. Personas facilitate user-centered design. We identified four personas among our participants: Emma the Expert views herself as the subject-matter expert in the classroom and values her hard-earned excellence in lecturing. Ray the Relater relates to students and focuses on their points of view about innovative pedagogies. Carmen the Coach coaches her students by setting goals for them and helping them develop skill in scientific practices. Beth the Burdened owns the responsibility for her students' learning and feels overwhelmed that students still struggle despite her use of evidence-based practice. Each persona needs unique PD. We suggest ways that PD facilitators can use our personas as a reflection tool to determine how to approach the learners in their PD. We also suggest further avenues of research on learner-centered PD.

The authors would like to publish this erratum to correct estimates generated from regression analyses due to errors discovered in the coding of some state laws.

Laws related to the sale, use, and carrying of firearms have been associated with differences in firearm homicide rates at the state level. Right-to-carry (RTC) and stand your ground (SYG) laws are associated with increases in firearm homicide; permit-to-purchase (PTP) laws and those prohibiting individuals convicted of violent misdemeanors (VM) have been associated with decreases in firearm homicide. Evidence for the effect of comprehensive background checks (CBC) not tied to PTP is inconclusive. Because firearm homicide tends to concentrate in urban areas, this study was designed to test the effects of firearm laws on homicide in large, urban U.S. counties. We conducted a longitudinal study using an interrupted time series design to evaluate the effect of firearm laws on homicide in large, urban U.S. counties from 1984 to 2015 (N = 136). We used mixed effects Poisson regression models with random intercepts for counties and year fixed effects to account for national trends. Models also included county and state characteristics associated with violence. Homicide was stratified by firearm versus all other methods to test for specificity of the laws' effects. PTP laws were associated with a 14% reduction in firearm homicide in large, urban counties (IRR = 0.86, 95% CI 0.82-0.90). CBC-only, SYG, RTC, and VM laws were all associated with increases in firearm homicide. None of the laws were associated with differences in non-firearm homicide rates. These findings are consistent with prior research at the state level showing PTP laws are associated with decreased firearm homicide. Testing the effects of PTP laws specifically in large, urban counties strengthens available evidence by isolating the effects in the geographic locations in which firearm homicides concentrate.

Introduction: The peripheral internal jugular (IJ), also called the “easy IJ,” is an alternative to peripheral venous access reserved for patients with difficult intravenous (IV) access. The procedure involves placing a single-lumen catheter in the IJ vein under ultrasound (US) guidance. As this technique is relatively new, the details regarding the ease of the procedure, how exactly it should be performed, and the safety of the procedure are uncertain. Our primary objective was to determine the success rate for peripheral IJ placement. Secondarily, we evaluated the time needed to complete the procedure and assessed for complications.Methods: This was a prospective, single-center study of US-guided peripheral IJ placement using a 2.5-inch, 18-gauge catheter on a convenience sample of patients with at least two unsuccessful attempts at peripheral IV placement by nursing staff. Peripheral IJ lines were placed by emergency medicine (EM) attending physicians and EM residents who had completed at least five IJ central lines. All physicians who placed lines for the study watched a 15-minute lecture about peripheral IJ technique. A research assistant monitored each line to assess for complications until the patient was discharged. Results: We successfully placed a peripheral IJ in 34 of 35 enrolled patients (97.1%). The median number of attempts required for successful cannulation was one (interquartile range (IQR): 1 to 2). The median time to successful line placement was 3 minutes and 6 seconds (IQR: 59 seconds to 4 minutes and 14 seconds). Two lines failed after placement, and one of the 34 successfully placed peripheral IJ lines (2.9%) had a complication – a local hematoma. There were, however, no arterial punctures or pneumothoraces. Although only eight of 34 lines were placed using sterile attire, there were no line infections.  Conclusion: Our research adds to the growing body of evidence supporting US-guided peripheral internal jugular access as a safe and convenient procedure alternative for patients who have difficult IV access.

Induction of labour (IOL), the process of starting labour artificially, is one of the most commonly performed procedures in maternity care in the United Kingdom (UK), yet there is debate whether inducing labour at ‘term’, in the absence of specific medical indication, is beneficial and reduces risk of stillbirth. Moreover, rates of routine IOL are rapidly rising in the UK, despite uncertainty about the evidence base and parents reporting receiving a lack of balanced information about the process. As a contested area of maternity care, the language used to debate, describe and discuss IOL takes on added significance and requires in-depth examination and analysis. To address this, we conducted a feminist critical discourse analysis on policy and professional writing about IOL in the UK, focusing on how these both reflect and construct social practices of pregnancy and birth. Our analysis identified a double discourse about IOL, which we term ‘explicit-implicit discourse of care’, revealing the differences between what is expected to be said and what is really said. Though most texts displayed an explicit discourse of care, which espoused women-centred care and informed choice, they also conveyed an implicit discourse of care, primarily composed of three key dimensions: women as absent actors, disembodiment, and evidence as a primary actor. We argue that this explicit-implicit discourse functions to preserve healthcare professionals' control over maternity care and further alienate women from their own bodies while maintaining a discursive position of women-centred care and informed choice.

Objective: Given the importance of understanding neighborhood context and geographic access to care on individual health outcomes, we sought to investigate the association of community primary care (PC) access on postoperative outcomes and survival in ovarian cancer patients. Methods: This was a retrospective cohort study of Stage III-IV ovarian cancer patients who underwent surgery at a single academic, tertiary care hospital between 2012 and 2015. PC access was determined using a Health Resources and Services Administration designation. Outcomes included 30-day surgical and medical complications, extended hospital stay, ICU admission, hospital readmission, progression-free and overall survival. Descriptive statistics and chi-squared analyses were used to analyze differences between patients from PC-shortage vs not PC-shortage areas. Results: Among 217 ovarian cancer patients, 54.4 % lived in PC-shortage areas. They were more likely to have Medicaid or no insurance and live in rural areas with higher poverty rates, significantly further from the treating cancer center and its affiliated hospital. Nevertheless, 49.2 % of patients from PC-shortage areas lived in urban communities. Residing in a PC-shortage area was not associated with increased surgical or medical complications, ICU admission, or hospital readmission, but was linked to more frequent prolonged hospitalization (26.3 % vs 14.1 %, p = 0.04). PC-shortage did not impact progression-free or overall survival. Conclusions: Patients from PC-shortage areas may require longer inpatient perioperative care in order to achieve the same 30-day postoperative outcomes as patients who live in non-PC shortage areas. Community access to PC is a critical factor to better understanding and reducing disparities among ovarian cancer patients.

Objectives: Assess and improve advance care planning (ACP) awareness and uptake among gynecologic oncology patients. Methods: Using a quality improvement Plan-Do-Check-Act framework, we completed a single institution needs assessment and intervention. The needs assessment was a 26-question survey assessing baseline ACP knowledge and preferences of gynecologic oncology patients. We used this survey to implement an outpatient intervention in which patients were offered ACP resources (pamphlet, discussion with their gynecologic oncologist, and/or social work referral). We conducted a post-intervention survey among patients who had and had not received ACP resource(s) to assess whether our intervention increased ACP knowledge, discussions, or uptake. Results: Among 106 patients surveyed in the needs assessment, 33 % had ACP documents, 26 % had discussed ACP with a physician, and 82 % thought discussing ACP was important. The majority preferred these conversations in the outpatient setting (52 %) with their gynecologic oncologist (80 %) instead of nurses or trainees. In the intervention, 526 patients were offered ACP resources. Compared to women who did not receive resources (n = 324), patients who received ACP resource(s) (n = 202) were more likely to have ACP discussions with their gynecologic oncologist (38 % vs 68 %, P = 0.001) and had greater proficiency regarding how to create ACP documents (median score 5/10 vs 8/10, P = 0.048), although they were no more likely to have ACP documented in their electronic medical record (27 % vs 9 %, p = 0.08). Conclusions: ACP uptake among gynecologic oncology patients is low, but ACP discussions with an oncologist during outpatient visits are important to patients and improve their knowledge regarding completing ACP documents.

Background: Evaluating and managing exposures to chemical, physical and biological stressors, which frequently interplay with psychological stressors as well as social and behavioural aspects, is crucial for protecting human and environmental health and transitioning towards a sustainable future. Advances in our understanding of exposure rely on input from well-trained exposure scientists. However, no education programmes in Europe are currently explicitly dedicated to cover the broader range of exposure science approaches, applications, stressors and receptors. Objective: To address this challenge, a curriculum is needed that yields credible, well-defined career pathways in exposure science. Methods: Needs and conditions for advancing exposure science education in Europe were identified. As a starting point for a way forward, harmonised learning outcomes for exposure science were defined at each level of the European Qualifications Framework. The course programme coordinators were recruited for three varying courses, with respect to the course level and the proportion of the curriculum dedicated to exposure science. These courses were assessed via our systematic course review procedure. Finally, strategic objectives and actions are proposed to build exposure science education programmes. Results: The ISES Europe ‘Education, Training and Communication’ expert working group developed a framework for creating a viable exposure science curriculum. Harmonised learning outcomes were structured under eight learning levels, categorised by knowledge, skills and competence. Illustrative case studies demonstrated how education providers integrated these learning outcomes for their educational context and aligned the overall exposure science curriculum. Conclusions: The international recognition and adoption of exposure science education will enable advances in addressing global exposure science challenges for various stressors, from behavioural aspects from individual to population scale, and effective communication between exposure scientists and relevant stakeholders and policy makers, as part of the European Exposure Science Strategy 2020–2030.

BackgroundThe incidence of endometrial cancer increases with age and is associated with medical comorbidities such as obesity and diabetes. Although a few cohort studies of

Summary: Background: Exercise is advised for young adults with elevated blood pressure, but no trials have investigated efficacy at this age. We aimed to determine whether aerobic exercise, self-monitoring and motivational coaching lowers blood pressure in this group. Methods: The study was a single-centre, open, two-arm, parallel superiority randomized clinical trial with open community-based recruitment of physically-inactive 18–35 year old adults with awake 24 h blood pressure 115/75mmHg-159/99 mmHg and BMI37 weeks) to the intervention group, who received 16-weeks aerobic exercise training (three aerobic training sessions per week of 60 min per session at 60–80% peak heart rate, physical activity self-monitoring with encouragement to do 10,000 steps per day and motivational coaching to maintain physical activity upon completion of the intervention. The control group were sign-posted to educational materials on hypertension and recommended lifestyle behaviours. Investigators performing statistical analyses were blinded to group allocation. The primary outcome was 24 h awake ambulatory blood pressure (systolic and diastolic) change from baseline to 16-weeks on an intention-to-treat basis. Clinicaltrials.gov registered on March 30, 2016 (NCT02723552). Findings: Enrolment occurred between 30/06/2016-26/10/2018. Amongst the 203 randomized young adults (n = 102 in the intervention group; n = 101 in the control group), 178 (88%; n = 76 intervention group, n = 84 control group) completed 16-week follow-up and 160 (79%; n = 68 intervention group, n = 69 control group) completed 52-weeks follow-up. There were no group differences in awake systolic (0·0 mmHg [95%CI, -2·9 to 2·8]; P = 0·98) or awake diastolic ambulatory blood pressure (0·6 mmHg [95%CI, -1·4. to 2·6]; P = 0·58). Aerobic training increased peak oxygen uptake (2·8 ml/kg/min [95%CI, 1·6 to 4·0]) and peak wattage (14·2watts [95%CI, 7·6 to 20·9]) at 16-weeks. There were no intervention effects at 52-weeks follow-up. Intepretation: These results do not support the exclusive use of moderate to high intensity aerobic exercise training for blood pressure control in young adults. Funding: Wellcome Trust, British Heart Foundation, National Institute for Health Research, Oxford Biomedical Research Centre.

The 5 A’s of Firearm Safety Counseling is a novel framework by which clinicians can approach firearm injury prevention counseling. To evaluate this methodology as a tool for clinicians, a single-center, simulation-based randomized controlled trial was performed with clinical trainees in psychiatry, medicine, and pediatrics in an urban quaternary care center. Participants received didactic education on firearm injury epidemiology and evidence-based policies and training on a specific counseling framework, the 5 A’s of Firearm Safety Counseling which they then implemented in a simulation setting with standardized patients. Of the 29 participants who were randomized, 28 completed the trial. Most participants were psychiatry trainees (residents or subspecialty fellows). While over 60% of participants were uncomfortable or extremely uncomfortable counseling on firearm injury prior to the interventions, only 4% reported being uncomfortable after receiving education and participating in simulated encounters. There was no significant difference between the quality and content of the counseling provided before and after the didactic-only session. There was a significant difference between the quality and content of the counseling provided before and after the specific training on the 5 A’s for Firearm Safety Counseling strategy. The 5 A’s for Firearm Safety Counseling is a promising educational tool to improve quality, content, and comfort delivering patient-centered counseling on firearm injury prevention in a simulation-based setting. These findings suggest that further validation in a clinical setting is warranted given there is an urgent need for feasible and effective firearm injury prevention strategies among clinicians.

Tinguely et al. develop a photonic chip-based correlative light-electron microscopy system to generate co-registered multi-modal total internal reflection fluorescence microscopy (TIRF) and electron microscopy (EM) images of biological samples at nanometer scale.

Introduction and objective Research activity was impacted by the novel COVID-19 pandemic, the PERCEPT myeloma trial was no exception. This pilot randomised trial delivered a face-to-face exercise intervention prior to and during autologous stem cell transplantation (ASCT) in myeloma patients, as a consequence of COVID-19 it required significant adaptions to continue. This brief communication describes how the previously published study protocol was adapted for virtual delivery. In addition, we highlight the challenge of continuing the study which was embedded within a clinical pathway also impacted by the pandemic.Summary The original trial protocol was amended and continued to recruit and deliver an exercise prehabilitation intervention virtually. Continued delivery of the intervention was deemed important to participants already enrolled within the trial and the adapted virtual version of the trial was acceptable to the research ethics committee as well as participants. Development of effective, remotely delivered rehabilitation and physical activity programmes are likely to benefit people living with myeloma. The COVID-19 pandemic provided an opportunity to explore the feasibility of a virtual programme for ASCT recipients, however, continued changes to the clinical pathway within which the study was embedded posed the greatest challenge and ultimately led to early termination of recruitment.Trial registration number ISRCTN15875290; pre-results

Introduction Globally, tuberculosis (TB) is a leading cause of death in women of reproductive age and there is high risk of reactivation of latent tuberculosis infection (LTBI) in pregnancy. The uptake of routine screening of migrants for LTBI in the UK in primary care is low. Antenatal care is a novel setting which could improve uptake and can lend insight into the feasibility and acceptability of offering opt-out screening for LTBI.Methods and analysis This is an observational feasibility study with a nested qualitative component. The setting will be the antenatal clinics in three hospitals in East London, UK . Inclusion criteria are pregnant migrant women aged 16–35 years attending antenatal clinics who are from countries with a TB incidence of greater than 150/100 000 including sub-Saharan Africa, and who have been in the UK for less than 5 years. Participants will be offered LTBI screening with an opt-out interferon gamma release assay blood test, and be invited to complete a questionnaire. Both participants and healthcare providers will be invited to participate in semistructured interviews or focus groups to evaluate understanding, feasibility and acceptability of routine opt-out LTBI screening. The primary analysis will focus on estimating the uptake of the screening programme along with the corresponding 95% CI. Secondary analysis will focus on estimating the test positivity. Qualitative analysis will evaluate the acceptability of offering routine opt-out LTBI screening to participants and healthcare providers.Ethics and dissemination The study has received the following approvals: Health Research Authority (IRAS 247388) and National Health Service Ethics Committee (19/LO/0557). The results will be made available locally to antenatal clinics and primary care physicians, nationally to NHS England and Public Health England and internationally through conferences and journals.Trial registration number NCT04098341.

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

922 I. 922 II. 922 III. 925 IV. 925 V. 926 VI. 927 VII. 928 VIII. 929 IX. 930 X. 931 XI. 932 XII. 933 XIII. Natural variation and genome-wide association studies 934 XIV. 934 XV. 935 XVI. 936 XVII. 937 937 References 937 SUMMARY: The year 2014 marked the 25(th) International Conference on Arabidopsis Research. In the 50 yr since the first International Conference on Arabidopsis Research, held in 1965 in Göttingen, Germany, > 54 000 papers that mention Arabidopsis thaliana in the title, abstract or keywords have been published. We present herein a citational network analysis of these papers, and touch on some of the important discoveries in plant biology that have been made in this powerful model system, and highlight how these discoveries have then had an impact in crop species. We also look to the future, highlighting some outstanding questions that can be readily addressed in Arabidopsis. Topics that are discussed include Arabidopsis reverse genetic resources, stock centers, databases and online tools, cell biology, development, hormones, plant immunity, signaling in response to abiotic stress, transporters, biosynthesis of cells walls and macromolecules such as starch and lipids, epigenetics and epigenomics, genome-wide association studies and natural variation, gene regulatory networks, modeling and systems biology, and synthetic biology.