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Advanced measurement and data storage technologies have enabled high-dimensional profiling of complex biological systems. For this, modern multiomics studies regularly produce datasets with hundreds of thousands of measurements per sample, enabling a new era of precision medicine. Correlation analysis is an important first step to gain deeper insights into the coordination and underlying processes of such complex systems. However, the construction of large correlation networks in modern high-dimensional datasets remains a major computational challenge owing to rapidly growing runtime and memory requirements. Here we address this challenge by introducing CorALS (Correlation Analysis of Large-scale (biological) Systems), an open-source framework for the construction and analysis of large-scale parametric as well as non-parametric correlation networks for high-dimensional biological data. It features off-the-shelf algorithms suitable for both personal and high-performance computers, enabling workflows and downstream analysis approaches. We illustrate the broad scope and potential of CorALS by exploring perspectives on complex biological processes in large-scale multiomics and single-cell studies.

Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, affects 5-6% of ever-pregnant individuals. Approximately half of these cases have no identifiable explanation. To generate hypotheses about RPL etiologies, we implemented a case-control study comparing the history of over 1,600 diagnoses between RPL and live-birth patients, leveraging the University of California San Francisco (UCSF) and Stanford University electronic health record databases. In total, our study included 8,496 RPL (UCSF: 3,840, Stanford: 4,656) and 53,278 Control (UCSF: 17,259, Stanford: 36,019) patients. Menstrual abnormalities and infertility-associated diagnoses were significantly positively associated with RPL in both medical centers. Age-stratified analysis revealed that the majority of RPL-associated diagnoses had higher odds ratios for patients

Introduction: Suicide rates have risen in England over the last decade and hanging, a highly lethal method of suicide, has been the most common method. Previous work in this area identified a lack of literature discussing emergency medical services (EMS) attendance at hangings. This article aims to describe hangings attended by EMS in the North East of England in order to inform future work in this area.Methods: A retrospective service evaluation was conducted using existing data from a comprehensive pre-hospital trauma audit database to describe patients with hanging documented in their records who were attended by ambulance clinicians between 1 December 2018 and 31 November 2020.Results: Hanging was recorded in 604 incidents. Most cases (n = 579/604) involved adults (aged 18 years or older) with a median age of 35 years (IQR 27‐45 years), who were male (n = 410/579, 71%). Just over half (n = 341/579, 59%) of adult hangings resulted in cardiac arrest and of these, 10% (n = 33/341) were resuscitated and survived to hospital admission. Threatened and non-fatal hangings appear to have increased dramatically in the latter half of 2020. Previous suicide attempts and mental health issues were frequently reported across this population.Conclusion: Hangings are a method of suicide which frequently result in a cardiac arrest. In the North East of England the ambulance service attends approximately one hanging per day and one fatal hanging every two days. When fatal hangings were resuscitated, pre-hospital outcomes were similar to other causes of cardiac arrest, highlighting that despite the traumatic nature of these cases resuscitation is not futile. In order to better understand this patient group and improve care, pre-hospital data need to be linked to data from other services such as mental health services and acute hospitals.

Purpose Despite increasing interest and scholarship on authentic leadership, definitions of the construct remain contested. In addition, limited research exists on its enactment in practice and its sustainability in a global context. The purpose of this study was to explore the practice of authentic leadership and understand more about how it is cultivated and sustained. Design/methodology/approach To address these issues, an international sample of leaders nominated by peers as exemplifying authenticity in their leadership was interviewed. This study used consensual qualitative research (CQR; Hill, 2012; Hill et al., 1997), a team-based, exploratory methodology, to conduct data analysis. Findings This study describes the results of the analysis, highlighting leaders’ beliefs, values and behaviors; their leadership development and the barriers and supportive factors they experienced as leaders. The findings from this exploratory analysis across all cases, including subgroups, may help contextualize the complexity of authentic and sustainable leadership and provide better understanding of authentic leadership development. Research limitations/implications Additional research on social identities and training in leadership are critical. The results of this study suggest new directions in studying the development of authentic leaders as well as in researching the experiences of organizations and team members. Practical implications This study provides insight and direction for individuals and organizations seeking to better understand the practice of authentic leadership, its development and how it can be sustained over time and across contexts and social identities. Originality/value This exploratory approach involving interviews with leaders around the globe provides information about the direct lived experiences of leaders identified as authentic by their peers. This study further highlights the leaders’ critical leadership beliefs and practices, as well as ways in which they cultivated and learned to sustain their leadership practices. This study also sheds light on ways in which experiences might differ across gendered and cultural contexts.

Background: In the United Kingdom (UK) there were 6507 deaths by suicide in 2018, with hanging being the most common method. Hanging will normally result in emergency medical services (EMS) being called and may result in resuscitation being attempted. Trauma audits conducted by North East Ambulance Service NHS Foundation Trust have identified an increased trend in hanging cases, which were also reported in national data. The aim of this scoping review was to explore the literature around EMS attendance at hangings to inform further research and clinical practice. Methods: A five-stage scoping review method was used. Relevant studies were identified by searching MEDLINE, CINAHL, EMBASE and EMCARE with the help of the Library and Knowledge Service for NHS Ambulance Services in England. Grey literature and reference lists were also searched. Studies were included based on relevance to hangings attended by EMS. Data were tabulated and narratively synthesised. Results: Sixteen papers were included in the review. Australia was the most frequent source of studies (n = 5, 31%). Most studies (n = 11, 69%) were published in the past 10 years. The median sample size was 53 (IQR 41‐988, range 10‐3981). All papers included varying levels of patient characteristics, EMS input and patient outcomes. Conclusion: Hanging is a highly lethal method of suicide that is increasingly used in the UK. This scoping review found that there is scarce literature focused on hangings attended by EMS. Treatment of the hanging patient in cardiac arrest is described in many of the papers included. Hanging patients may benefit from the presence of specialist resources who can deliver interventions such as sedation and advanced airway management. The psychological impact of attending, or witnessing, hanging patients is an area that needs further consideration. Further research is needed to describe and improve EMS treatment of hangings.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZ

MicroRNAs play an important role in the regulation of mRNA translation and have therapeutic potential in cancer and other diseases. To profile the landscape of microRNAs with significant cytotoxicity in the context of glioblastoma (GBM), we performed a high-throughput screen in adult and pediatric GBM cells using a synthetic oligonucleotide library representing all known human microRNAs. Bioinformatics analysis was used to refine this list and the top seven microRNAs were validated in a larger panel of GBM cells using state-of-the-art in vitro assays. The cytotoxic effect of our most relevant candidate was assessed in a preclinical model. Our screen identified ~100 significantly cytotoxic microRNAs with 70% concordance between cell lines. MicroRNA-1300 (miR-1300) was the most potent and robust candidate. We observed a striking binucleated phenotype in miR-1300 transfected cells due to cytokinesis failure followed by apoptosis. This was also observed in two stem-like patient-derived cultures. We identified the physiological role of miR-1300 as a regulator of endomitosis in megakaryocyte differentiation where blockade of cytokinesis is an essential step. In GBM cells, where miR-1300 is normally not expressed, the oncogene Epithelial Cell Transforming 2 (ECT2) was validated as a direct key target. ECT2 siRNA phenocopied the effects of miR-1300, and ECT2 overexpression led to rescue of miR-1300 induced binucleation. We showed that ectopic expression of miR-1300 led to decreased tumor growth in an orthotopic GBM model. Our screen provides a resource for the neuro-oncology community and identified miR-1300 as a novel regulator of endomitosis with translatable potential for therapeutic application.

Background. Prior studies have found that residential proximity to upstream oil and gas production is associated with increased risk of adverse health outcomes. Emissions of ambient air pollutants from oil and gas wells in the preproduction and production stages have been proposed as conferring risk of adverse health effects, but the extent of air pollutant emissions and resulting nearby pollution concentrations from wells is not clear.Objectives. We examined the effects of upstream oil and gas preproduction (count of drilling sites) and production (total volume of oil and gas) activities on concentrations of five ambient air pollutants in California.Methods. We obtained data on approximately 1 million daily observations from 314 monitors in the EPA Air Quality System, 2006-2019, including daily concentrations of five routinely monitored ambient air pollutants: PM2.5, CO, NO2, O3, and VOCs. We obtained data on preproduction and production operations from Enverus and the California Geographic Energy Management Division (CalGEM) for all wells in the state. For each monitor and each day, we assessed exposure to upwind preproduction wells and total oil and gas production volume within 10 km. We used a panel regression approach in the analysis and fit adjusted fixed effects linear regression models for each pollutant, controlling for geographic, seasonal, temporal, and meteorological factors.Results. We observed higher concentrations of PM2.5 and CO at monitors within 3 km of preproduction wells, NO2 at monitors at 1-2 km, and O3 at 2-4 km from the wells. Monitors with proximity to increased production volume observed higher concentrations of PM2.5, NO2, and VOCs within 1 km and higher O3 concentrations at 1-2 km. Results were robust to sensitivity analyses.Conclusion. Adjusting for geographic, meteorological, seasonal, and time-trending factors, we observed higher concentrations of ambient air pollutants at air quality monitors in proximity to preproduction wells within 4 km and producing wells within 2 km.

IntroductionRetrospective trauma scores are often used to categorise trauma, however, they have little utility in the prehospital or hyper-acute setting and do not define major trauma to non-specialists. This study employed a Delphi process in order to gauge degrees of consensus/disagreement amongst expert panel members to define major trauma.MethodA two round modified Delphi technique was used to explore subject-expert consensus and identify variables to define major trauma through systematically collating questionnaire responses.After initial descriptive analysis of variables, Kruskal-Wallis tests were used to determine statistically significant differences (p < 0.05) in response to the Delphi statements between professional groups. A hierarchical cluster analysis was undertaken to identify patterns of similarity/difference of response.A grounded theory approach to qualitative analysis of data allowed for potentially multiple iterations of the Delphi process to be influenced by identified themes.ResultsOf 55 expert panel members invited to participate, round 1 had 43 participants (Doctorn = 20, Paramedicn = 20, Nursen = 5, othern = 2). No consistent patterns of opinion emerged with regards to professional group. Cluster analysis identified three patterns of similar responses and coded as trauma minimisers, the middle ground and the risk averse. Round 2 had 35 respondents with minimum change in opinion between rounds.Consensus of> 70% was achieved on many variables which included the identification of life/limb threatening injuries, deranged physiology, need for intensive care interventions and that extremes of age need special consideration. It was also acknowledged that retrospective injury severity scoring has a role to play but is not the only method of defining major trauma. Various factors had a majority of agreement/disagreement but did not meet the pre-set criteria of 70% agreement. These included the topics of burns, spinal immobilisation and whether a major trauma centre is the only place where major trauma can be managed.ConclusionBased upon the output of this Delphi study, major trauma may be defined as: “Significant injury or injuries that have potential to be life-threatening or life-changing sustained from either high energy mechanisms or low energy mechanisms in those rendered vulnerable by extremes of age”.

Neural Tube Defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to cerebral folate deficiency by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased risk for NTDs by depressing embryonic folate concentrations. In this study, we examined CIC variants from whole genome sequencing (WGS) data of 140 isolated spina bifida cases and identified 8 missense variants of CIC gene. We tested the pathogenicity of the observed variants through multiple in vitro experiments. We determined that CIC variants decreased FOLR1 protein level and planar cell polarity (PCP) pathway signaling in a human cell line (HeLa). In a murine cell line (NIH3T3), CIC loss of function variants down regulated PCP signaling. Taken together, this study provides evidence supporting CIC as a risk gene for human NTD.

Background: Spinal cord injury (SCI) is a rare event, with high numbers of patients unnecessarily immobilised with no potential benefit based on limited evidence from the 1950s and 1960s. Contemporary opinion now challenges the notion that traditional immobilisation prevents movement and protects the spine. Current literature suggests that these methods which include semi-rigid collars can potentially cause more movement of the spine and harm the patient. The purpose of this study was to explore the views and perspectives of pre-hospital care providers on immobilising patients without the use of a semi-rigid collar.Methods: Focus groups were used to allow individuals to discuss and comment on a new method of immobilisation which omits the semi-rigid collar and to capture the thoughts, feelings and experiences of participants. Thematic analysis of the coded transcriptions was used to identify emerging themes.Results: Three focus groups were conducted with 15 participants in each. Participants were all exposed to patients sustaining trauma within their professional roles. Six intertwined themes emerged from the analysis: communication, conflict, education/training, empowerment, risk and the patient. Woven between these themes are the complex interactions that bring together the inter-professional relationships with other emergency services and hospital staff, the patient, the public and pre-hospital care providers.Discussion: Existing immobilisation practices are being challenged, with clinicians empowered to tailor practice to meet specific patient needs. There is limited empirical evidence to support current immobilisation practices. Contemporary literature suggests current practices may potentially cause harm. New pragmatic immobilisation practices are gradually being adopted by some pre-hospital care providers.Conclusion: This study explored the perspectives of pre-hospital care providers on immobilising patients without the use of a semi-rigid collar for potential SCI. The consensus of the participants supports a pragmatic approach to managing potential SCI that provides safe, high-quality patient-centred care.

INTRODUCTION: Major trauma in the elderly population has been increasingly reported over the past decade. Compared to younger populations, elderly patients may experience major trauma as a result of low mechanisms of injury (MOIs) and as a result, existing definitions for ‘major trauma’ should be challenged. This literature review provides an overview of previous conceptualisations of defining ‘major trauma’ and considers their utility in relation to the pre-hospital phase of care. METHODS: A systematic search strategy was performed using CINAHL, Cochrane Library and Web of Science (MEDLINE). Grey literature and key documents from cited references were also examined. RESULTS: A total of 121 articles were included in the final analysis. Predominantly, retrospective scoring systems, such as the Injury Severity Score (ISS), were used to define major trauma. Pre-hospital variables considered indicative of major trauma included: fatal outcomes, injury type/pattern, deranged physiology and perceived need for treatment sequelae such as intensive care unit (ICU) admission, surgical intervention or the administration of blood products. Within the pre-hospital environment, retrospective scoring systems as a means of identifying major trauma are of limited utility and should not detract from the broader clinical picture. Similarly, although MOI is often a useful consideration, it should be used in conjunction with other factors in identifying major trauma patients. CONCLUSIONS: In the pre-hospital environment, retrospective scoring systems are not available and other variables must be considered. Based upon this review, a working definition of major trauma is suggested as: ‘A traumatic event resulting in fatal injury or significant injury with accompanying deranged physiology, regardless of MOI, and/or is predicted to require significant treatment sequelae such as ICU admission, surgical intervention, or the administration of blood products’.

Objective: Advancing understanding of how early adversity arises, manifests, and contributes to health difficulties depends on accurate measurement of children’s experiences. In early life, exposure to adversity is often intertwined with that of one’s caregivers. We present preliminary psychometric properties of a novel measure of adversity, the Assessment of Parent and Child Adversity (APCA), which simultaneously characterizes parents’ and children’s adversity.Methods: During pregnancy, women reported their past adverse experiences. When their children were ages 3–5 years (47% female), 97 mothers (71% White, 17% Hispanic/Latinx) completed the APCA, the Childhood Trauma Questionnaire, and the Benevolent Childhood Experiences scale. They reported their current symptoms of depression and anxiety and their child’s emotional and behavioral problems. Using the APCA, we distinguished between maternal adversity during different life periods and obtained metrics of child witnessing of and direct exposure to adversity. Results: The APCA demonstrated validity with other measures of maternal adverse experiences, maternal positive childhood experiences, and maternal symptoms of psychopathology. Children whose mothers experienced greater adversity, particularly in the prenatal period, had more emotional and behavioral problems, as did children who were directly exposed to greater adversity.Conclusions: The APCA has good usability and validity. Leveraging the ability of the APCA to distinguish between adversity during different life stages and originating from different sources, our findings highlight potentially distinct effects of different aspects of maternal and child adversity on difficulties in maternal and child mental health.

Objective: To determine the association between treatment of persistent BV in pregnancy and risk for spontaneous preterm birth (sPTB). Design: The retrospective data from IBM® MarketScan® Commercial Database was analyzed. Setting: United States outpatient data. Population or Sample: Women aged 12–55 years with a singleton gestation. Methods: Women were linked to an outpatient medications database and medications taken during the pregnancy were analyzed. Treatment of BV in pregnancy was defined as a diagnosis of BV and treatment with Metronidazole and/or Clindamycin, and persistent treatment of BV was defined as BV in more than 1 trimester or BV requiring more than 1 antibiotic prescription. Odds ratios were calculated comparing sPTB in those with BV and persistent BV to women without BV in pregnancy. Survival analysis using Kaplan-Meier curves for the gestational age at delivery was also performed. Main outcome measures: sPTB Results: Among a cohort of 2,538,606 women, 216,611 had an associated ICD-9 or ICD-10 code for diagnosis of BV alone, and 63,817 had BV and were treated with either metronidazole and/or clindamycin. The sPTB rate among women treated with BV was 7.5% compared with 5.7% for women without BV who did not receive antibiotics. Relative to those without BV in pregnancy, odds ratios for sPTB were highest in those treated for BV in both the first and second trimester (1.66 [95% CI 1.52, 1.81]) or those with 3 or more prescriptions in pregnancy (1.48 [95% CI 1.35, 1.63]. Conclusions: Treatment of persistent BV is associated with increased sPTB risk.

Objective To evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation. Design Retrospective multi-omics discovery and longitudinal validation. Setting Maternity units in two US hospitals. Methods A multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays. Main outcome measures Interval from positive prediction to confirmative diagnosis. Results Genomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation. Conclusions Non-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test. Tweetable abstract Non-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.

The overall survival for patients with primary glioblastoma is very poor. Glioblastoma contains a subpopulation of glioma stem cells (GSC) that are responsible for tumour initiation, treatment resistance and recurrence. PPARα is a transcription factor involved in the control of lipid, carbohydrate and amino acid metabolism. We have recently shown that PPARα gene and protein expression is increased in glioblastoma and has independent clinical prognostic significance in multivariate analyses. In this work, we report that PPARα is overexpressed in GSC compared to foetal neural stem cells. To investigate the role of PPARα in GSC, we knocked down its expression using lentiviral transduction with short hairpin RNA (shRNA). Transduced GSC were tagged with luciferase and stereotactically xenografted into the striatum of NOD‐SCID mice. Bioluminescent and magnetic resonance imaging showed that knockdown (KD) of PPARα reduced the tumourigenicity of GSC in vivo. PPARα‐expressing control GSC xenografts formed invasive histological phenocopies of human glioblastoma, whereas PPARα KD GSC xenografts failed to establish viable intracranial tumours. PPARα KD GSC showed significantly reduced proliferative capacity and clonogenic potential in vitro with an increase in cellular senescence. In addition, PPARα KD resulted in significant downregulation of the stem cell factors c‐Myc, nestin and SOX2. This was accompanied by downregulation of the PPARα‐target genes and key regulators of fatty acid oxygenation ACOX1 and CPT1A, with no compensatory increase in glycolytic flux. These data establish the aberrant overexpression of PPARα in GSC and demonstrate that this expression functions as an important regulator of tumourigenesis, linking self‐renewal and the malignant phenotype in this aggressive cancer stem cell subpopulation. We conclude that targeting GSC PPARα expression may be a therapeutically beneficial strategy with translational potential as an adjuvant treatment. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Intercultural education (ICE) is a priority for schools and schooling systems worldwide. While extensive policy and academic literature exists that describes how ICE should be done in schools, relatively little has been published about the pragmatics of implementing and enacting ICE, despite evidence that principals, teachers and schools feel ill equipped to teach and engage in ICE. This article investigates how schools implementing ICE are confronted with distinctive challenges. Engaging methodological tools of social constructivism (Denzin and Lincoln, 2005) and an analytical lens supported by social cultural theories of identity and representation (Hall, 1997; Gee, 2004), we argue that the everyday experiences and practices of teachers need be explored, but also interrogated and understood otherwise (Lather, 1991). We draw on qualitative data from a large-scale study conducted in schools in Victoria, Australia. We present three vignettes that elucidate how ICE was enacted at the principal, curriculum and teacher levels. Each vignette is based upon a key challenge confronted by schools and illustrates the processes different schools used to tackle these issues and to embed ICE into the daily schooling practice.

Simple Summary High-grade gliomas remain difficult-to-treat cancers. Novel treatment options include targeting glycogen synthase kinase 3 (GSK-3) to induce cell death but the mode of drug activity remains unknown and combination with conventional treatment including radiotherapy has not been explored. Here, we describe the effect of targeting GSK-3 with the inhibitor AZD2858 in in vitro and in vivo models of glioma. We established that AZD2858 exposure induces mitotic defects leading to cell death in patient-derived glioma cell lines and tumor growth delay in glioma xenografts. Co-administration also enhanced the effect of radiotherapy. We therefore propose AZD2858 as an adjuvant to radiotherapy in high-grade glioma. Abstract Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.

BackgroundIn the United Kingdom (UK) there were 6,507 deaths by suicide in 2018 with hanging being the most common method. Hanging will normally result in emergency medical services (EMS) being called and may result in resuscitation being attempted.The lead author identified an increasing trend in hanging cases in the NHS Ambulance service trauma audit, which were also reported in national data. The aim of this scoping review was to explore the literature around EMS attendance at hangings to inform further research and clinical practice.MethodsA five-stage scoping review method was used. Relevant studies were identified by searching MEDLINE, CINAHL, EMBASE and EMCARE with the help of the Library and Knowledge Service for NHS Ambulance Services in England (LKS). Grey literature and reference lists were also searched. Studies were included based on relevance to hangings attended by EMS. Data were tabulated and narratively synthesised.ResultsSixteen papers were included in the review. Australia was the most frequent source of studies (n=5, 31%). Most studies (n=11, 69%) were published in the past ten years. The median sample size was 53 (IQR 41-988, range 10-3981). All papers included varying levels of patient characteristics, EMS input and patient outcomes.ConclusionHanging is a highly lethal method of suicide that is increasingly used in the UK. This scoping review found that there is scarce literature focussed on hangings attended by EMS. Treatment of the hanging patient in cardiac arrest is described in many of the papers included. Hanging patients may benefit from the presence of specialist resources who can deliver interventions such as sedation and advanced airway management. The psychological impact of attending, or witnessing, hanging patients is an area that needs further consideration. Further research is needed to describe and improve EMS treatment of hangings.

Perdue Farms, the highly successful marketer of brand-name chicken, is considering the introduction of a chicken hot dog to the market. The decision is complicated by a variety of factors, including top management's concerns and conditions, potential ramifications of the hot dog for the company's high-quality image, the uncertainty of market response, uncertainties about how to position the new product, potential consumer objections to use of mechanically deboned meat, and the uncertainty of profitability at recommended levels of marketing costs.

Late medieval legislation to try to control what clothes were purchased and worn according to social group is at the tantalising heart of a puzzling web of self, society, and stuff: things, inflect...

Background: Pre-hospital trauma is complex and challenging, with limited clinical exposure for clinicians. In addition, there is no standardised definition for major trauma, and retrospective scores commonly quantify injury severity, such as the injury severity score. This qualitative study aimed to explore the pre-hospital perspectives of major trauma and how pre-hospital trauma care providers define major trauma.Method: Three focus groups of 40‐60 minutes’ duration were conducted with paramedics, ambulance technicians, police, firefighters and emergency dispatchers. Digital recordings were transcribed verbatim, coded and reviewed to identify emerging themes. Constant comparison was undertaken throughout and codes were identified for qualitative thematic analysis.Results: Three overarching themes emerged: clinician factors, patient factors and situational factors. Clinician factors highlighted issues of experience and exposure (or lack of) to major trauma and its relationship to clinical concern, communication issues and the complex nature of pre-hospital trauma. Patient factors identified deranged physiology, actual injuries, life changing trauma, potential need for surgical intervention and rehabilitation as defining major trauma. These variables are often complicated by the extremities of age as well as previous medical history and medications. The situational factors identified that every traumatic encounter is unique, requiring bespoke management where high and low energy mechanisms of injury should be considered.Conclusion: Based on the analysis of the focus groups, a working pre-hospital definition is: Any injury (or injuries) that have the potential to be life-threatening or life-changing, including those sustained from low energy mechanisms in people rendered vulnerable by extremes of age, comorbidities or frailty, resulting in significant physiological compromise (haemodynamic instability, reduced consciousness, respiratory compromise) and/or significant anatomical abnormality that may require immediate intervention.

Summary Glycogen synthase kinase-3 (GSK-3) is a positive regulator of PD-1 expression in CD8+ T cells and GSK-3 inhibition enhances T cell function and is effective in the control of tumor growth. GSK-3 has two co-expressed isoforms, GSK-3α and GSK-3β. Using conditional gene targeting, we demonstrate that both isoforms contribute to T cell function to different degrees. Gsk3b−/− mice suppressed tumor growth to the same degree as Gsk3a/b−/− mice, whereas Gsk3a−/− mice behaved similarly to wild-type, revealing an important role for GSK-3β in regulating T cell-mediated anti-tumor immunity. The individual GSK-3α and β isoforms have differential effects on PD-1, IFNγ, and granzyme B expression and operate in synergy to control PD-1 expression and the infiltration of tumors with CD4 and CD8 T cells. Our data reveal a complex interplay of the GSK-3 isoforms in the control of tumor immunity and highlight non-redundant activity of GSK-3 isoforms in T cells, with implications for immunotherapy., Graphical abstract, Highlights • Conditional knockouts reveal a non-redundant role for GSK-3α and GSK-3β in T cells. • GSK-3α and GSK-3β act together to enhance PD-1 expression. • GSK-3β depletion alone enhances T cell mediated tumor rejection. • GSK-3β plays an important role in regulating T cell-mediated anti-tumor immunity., Cancer; Cell biology; Functional aspects of cell biology; Immunology

Patients with glioblastoma (GBM) have a poor prognosis, and inefficient delivery of drugs to tumors represents a major therapeutic hurdle. Hematopoietic stem cell (HSC)-derived myeloid cells efficiently home to GBM and constitute up to 50% of intratumoral cells, making them highly appropriate therapeutic delivery vehicles. Because myeloid cells are ubiquitously present in the body, we recently established a lentiviral vector containing matrix metalloproteinase 14 (MMP14) promoter, which is active specifically in tumor-infiltrating myeloid cells as opposed to myeloid cells in other tissues, and resulted in a specific delivery of transgenes to brain metastases in HSC gene therapy. Here, we used this novel approach to target transforming growth factor beta (TGFβ) as a key tumor-promoting factor in GBM. Transplantation of HSCs transduced with lentiviral vector expressing green fluorescent protein (GFP) into lethally irradiated recipient mice was followed by intracranial implantation of GBM cells. Tumor-infiltrating HSC progeny was characterized by flow cytometry. In therapy studies, mice were transplanted with HSCs transduced with lentiviral vector expressing soluble TGFβ receptor II–Fc fusion protein under MMP14 promoter. This TGFβ-blocking therapy was compared with the targeted tumor irradiation, the combination of the two therapies, and control. Tumor growth and survival were quantified (statistical significance determined by t-test and log-rank test). T cell memory response was probed through a repeated tumor challenge. Myeloid cells were the most abundant HSC-derived population infiltrating GBM. TGFβ-blocking HSC gene therapy in combination with irradiation significantly reduced tumor burden as compared with monotherapies and the control, and significantly prolonged survival as compared with the control and TGFβ-blocking monotherapy. Long-term protection from GBM was achieved only with the combination treatment (25% of the mice) and was accompanied by a significant increase in CD8+ T cells at the tumor implantation site following tumor rechallenge. We demonstrated a preclinical proof-of-principle for tumor myeloid cell-specific HSC gene therapy in GBM. In the clinic, HSC gene therapy is being successfully used in non-cancerous brain disorders and the feasibility of HSC gene therapy in patients with glioma has been demonstrated in the context of bone marrow protection. This indicates an opportunity for clinical translation of our therapeutic approach.

BackgroundPre-hospital trauma is complex and challenging, with limited clinical exposure for clinicians. In addition, there is no standardised definition for major trauma, and retrospective scores commonly quantify injury severity, such as the injury severity score. This qualitative study aimed to explore the pre-hospital perspectives of major trauma and how pre-hospital trauma care providers define major trauma.MethodThree focus groups of 40–60 minutes duration were conducted with paramedics, ambulance technicians, police, firefighters and emergency dispatchers. Digital recordings were transcribed verbatim, coded and reviewed to identify emerging themes. Constant comparison was undertaken throughout and codes identified for qualitative thematic analysis.ResultsThree overarching themes emerged: clinician factors, patient factors and situational factors. Clinician factors highlighted issues of experience and exposure (or lack of) to major trauma and its relationship to clinical concern, communication issues and the complex nature of pre-hospital trauma. Patient factors identified deranged physiology, actual injuries, life changing trauma, potential need for surgical intervention and rehabilitation as defining major trauma. These variables are often complicated by the extremities of age as well as previous medical history and medications. The situational factors identified that every traumatic encounter is unique, requiring bespoke management where high and low energy mechanisms of injury should be considered.ConclusionBased on the analysis of the focus groups, a working pre-hospital definition is: Any injury (or injuries) that have the potential to be life-threatening or life-changing, including those sustained from low energy mechanisms in people rendered vulnerable by extremes of age, comorbidities or frailty, resulting in significant physiological compromise (haemodynamic instability, reduced consciousness, respiratory compromise) and/or significant anatomical abnormality that may require immediate intervention.