Does induction of labour in nulliparous hypertensive women result in vaginal birth? – A descriptive study utilising birth registry data

© 2018 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy. This manuscript version is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/ This author accepted manuscript is made available following 12 month embargo from date of publication (January 2018) in accordance with the publisher’s archiving policyBackground Induction of labour (IOL) is a common procedure yet we have little information on the efficacy of the process for women with a hypertensive disorder of pregnancy (HDP). Objective To describe the birth type and associated factors in nulliparous HDP women undergoing an induction of labour. Study design Statutorily collected datasets on every birth and hospital admission which occurred in the state of NSW Australia between the years 2000–2011 were analysed. Hypertensive women were compared to normotensive women. Results Of the nulliparous women, 9.9% had a HDP. IOL for HDP women were 56.2% in a cohort of 447 558 women. The AOR for a woman with a HDP undergoing an IOL resulting in a vaginal delivery when compared to a normotensive woman is 0.86 (95% CI 0.83–0.88). Prior to 33 weeks, the lowest perinatal mortality rates (PMR) are seen in women who undergo elective caesarean section (C/S). For women with preeclampsia (PE), lower PMR are seen in women who undergo IOL. Conclusion For women with PE and SPE, IOL resulted in lower rates of vaginal delivery than spontaneous labour when compared to normotensive women who also underwent IOL. Women with PE at ≥33 weeks who underwent IOL had the lowest PMR

Limited evidence exists on the effectiveness of education and training interventions on trial recruitment; a systematic review

Objective: To examine the effectiveness of education and training interventions on recruitment to randomised and non-randomised trials. Study Design and Setting: A systematic review of the effectiveness of education and training interventions for recruiters to trials. The review included randomised and non-randomised controlled trials of any type of education and training intervention for recruiters to trials, within any healthcare field. The primary outcome was recruitment rates, and secondary outcomes were: quality of informed consent, recruiter self-confidence, understanding/knowledge of trial information, numbers of potential trial participants approached, satisfaction with training, retention rates. Results: Of the 19 records reviewed at full text level, six met the inclusion criteria for our review. Due to heterogeneity of outcomes and methods between the included studies, meta-analysis was not possible for the primary outcome. Of the three studies that reported recruitment rates, one favoured the education and training intervention for increased recruitment; the remaining two found no differences between the groups. Of the reported secondary outcomes, quality of informed consent was improved, but no differences between groups in understanding/knowledge of trial information were found. Conclusion: There is limited evidence of effectiveness on the impact of education and training interventions on trial recruitment. Further work on developing a substantial evidence base around the effectiveness of education and training interventions for recruiters to trials is required. Keywords: trial recruitment, educational intervention, training intervention, systematic revie

Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis

Background: Although low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed. Methods: We evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays. Results: Low-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested. Conclusions: KRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC

Refining dosing by oral gavage in the dog: A protocol to harmonise welfare

Introduction: The dog is a frequently-used, non-rodent species in the safety assessment of new chemical entities. We have a scientific and ethical obligation to ensure that the best quality of data is achieved from their use. Oral gavage is a technique frequently used to deliver a compound directly into the stomach. As with other animals, in the dog, gavage is aversive and the frequency of its use is a cause for welfare concern but little research has been published on the technique nor how to Refine it. A Welfare Assessment Framework (Hall, 2014) was previously developed for use with the laboratory-housed dog and a contrasting pattern of behaviour, cardiovascular and affective measures were found in dogs with positive and negative welfare. Methods: Using the framework, this study compared the effects of sham dosing (used to attempt to habituate dogs to dosing) and a Refined training protocol against a control, no-training group to determine the benefit to welfare and scientific output of each technique. Results: Our findings show that sham dosing is ineffective as a habituation technique and ‘primes' rather than desensitises dogs to dosing. Dogs in the control group showed few changes in parameters across the duration of the study, with some undesirable changes during dosing, while dogs in the Refined treatment group showed improvements in many parameters. Discussion: It is recommended that if there is no time allocated for pre-study training a no-sham dosing protocol is used. However, brief training periods show a considerable benefit for welfare and quality of data to be obtained from the dogs' use

Generations Active Together: an example of using physical activity promotion and digital technology to bring together adolescents and older people in Stirling, Scotland

The Generations Active Together (GAT) program, delivered by Active Stirling in central Scotland, is an intergenerational physical activity (PA) program for adolescents in high school and older adults in care homes and community groups. The Generating Older Active Lives Digitally (GOALD) Research Team sought to use GAT to examine how digital technology developed for the purpose of PA and sports-based reminiscence can be used to improve social connectedness for older adults. This paper details the challenges and successes of delivering the GAT program and describes the differences between in-person pre-pandemic delivery of GAT with the attempted digital delivery during the pandemic. The transferable lessons learned from GAT delivery to GOALD project planning and implementation included, but are not limited to, the importance of in-person activities for both generations and using digital technology as a complementary, rather than a replacement tool for PA delivery. CONTRIBUTION TO THE FIELD Intergenerational activities focusing on PA involving adolescents and older adults is possible with attention to reciprocal inputs and benefits for all generations and are potentially more effective and easier to deliver in person. Where in-person PA delivery is impossible, digital-only PA is arguably better than no interaction but requires support in setting up technology to deliver PA effectively. Digital technology is likely to be more effective in supporting intergenerational PA when complemented by in-person interactions. Adolescents and older adults in care homes can engage in beneficial interaction, but attention should be paid to school commitments at this age and stage, as well as the practical aspects of travel and scheduling of this kind of contact

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35). CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the ''sensor'' cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease. © 2012, Published by Cold Spring Harbor Laboratory Press.Link_to_subscribed_fulltex

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

The role of war in deep transitions: exploring mechanisms, imprints and rules in sociotechnical systems

This paper explores in what ways the two world wars influenced the development of sociotechnical systems underpinning the culmination of the first deep transition. The role of war is an underexplored aspect in both the Techno-Economic Paradigms (TEP) approach and the Multi-level perspective (MLP) which form the two key conceptual building blocks of the Deep Transitions (DT) framework. Thus, we develop a conceptual approach tailored to this particular topic which integrates accounts of total war and mechanisms of war from historical studies and imprinting from organisational studies with the DT framework’s attention towards rules and meta-rules. We explore in what ways the three sociotechnical systems of energy, food, and transport were affected by the emergence of new demand pressures and logistical challenges during conditions of total war; how war impacted the directionality of sociotechnical systems; the extent to which new national and international policy capacities emerged during wartime in the energy, food, and transport systems; and the extent to which these systems were influenced by cooperation and shared sacrifice under wartime conditions. We then explore what lasting changes were influenced by the two wars in the energy, food, and transport systems across the transatlantic zone. This paper seeks to open up a hitherto neglected area in analysis on sociotechnical transitions and we discuss the importance of further research that is attentive towards entanglements of warfare and the military particularly in the field of sustainability transitions