Response of UK interventional radiologists to the COVID-19 pandemic - survey findings.

BACKGROUND: The COVID-19 pandemic has had an unprecedented effect upon the National Health Service (NHS). Like other specialties, Interventional Radiology (IR) rapidly adapted to the evolving situation. Members of BSIR were surveyed to obtain a snapshot of the experiences of UK IRs in response to COVID-19. An electronic survey was compiled using Google Forms, approved by the BSIR Council Officers and distributed to BSIR members by email on 18 th April 2020. A total of 228 responses were received. The survey was open for a 14-day period and the data analysed in Microsoft Excel 365. The response rate was 29% (228/800). RESULTS: Two thirds of respondents work in a Tertiary unit and 33% deliver IR in a District Hospital. 84% have a day-case facility. After the COVID-19 crisis, 81% of respondents were able to maintain 24-7 On-call service. 59% of respondents had been required change their day to day practice to allow the on-call service to continue. 55% of respondents were involved in providing a central line service. Of those questioned, 91% continued to offer endovascular services, 98% genitourinary and 92% hepatobiliary services, although a degree of service reduction was described. 38% have provided IR trainees with additional training material during this pandemic. CONCLUSIONS: This survey has confirmed that the responses of UK IR departments to the COVID-19 crisis have ensured vital on-call and urgent services have continued, including ongoing availability of most IR sub-specialties. Availability of a day case facility has possibly influenced the positive response.

Management of blunt splenic injury in a UK major trauma centre and predicting the failure of non-operative management: a retrospective, cross-sectional study.

PURPOSE: To review the management of patients >16 years with blunt splenic injury in a single, UK, major trauma centre and identify whether the following are associated with success or failure of non-operative management with selective use of arterial embolization (NOM ± AE): age, Injury Severity Score (ISS), head injury, haemodynamic instability, massive transfusion, radiological hard signs [contrast extravasation or pseudoaneurysm on the initial computed tomography (CT) scan], grade, and presence of intraparenchymal haematoma or splenic laceration. METHODS: Retrospective, cross-sectional study undertaken between April 2012 and October 2015. Paediatric patients, penetrating splenic trauma, and iatrogenic injuries were excluded. Follow-up was for at least 30 days. RESULTS: 154 patients were included. Median age was 38 years, 77.3% were male, and median ISS was 22. 14/87 (16.1%) patients re-bled following NOM in a median of 2.3 days (IQR 0.8-3.6 days). 8/28 (28.6%) patients re-bled following AE in a median of 2.0 days (IQR 1.3-3.7 days). Grade III-V injuries are a significant predictor of the failure of NOM ± AE (OR 15.6, 95% CI 3.1-78.9, p = 0.001). No grade I injuries and only 3.3% grade II injuries re-bled following NOM ± AE. Age ≥55 years, ISS, radiological hard signs, and haemodynamic instability are not significant predictors of the failure of NOM ± AE, but an intraparenchymal or subcapsular haematoma increases the likelihood of failure 11-fold (OR 10.9, 95% CI 2.2-55.1, p = 0.004). CONCLUSIONS: Higher grade injuries (III-V) and intraparenchymal or subcapsular haematomas are associated with a higher failure rate of NOM ± AE and should be managed more aggressively. Grade I and II injuries can be discharged after 24 h with appropriate advice.

Hypoxic proliferation requires EGFR-mediated ERK activation in human pulmonary microvascular endothelial cells.

We have previously shown that hypoxic proliferation of human pulmonary microvascular endothelial cells (hPMVECs) depends on epidermal growth factor receptor (EGFR) activation. To determine downstream signaling leading to proliferation, we tested the hypothesis that hypoxia-induced proliferation in hPMVECs would require EGFR-mediated activation of extracellular signal-regulated kinase (ERK) leading to arginase II induction. To test this hypothesis, hPMVECs were incubated in either normoxia (21% O2, 5% CO2) or hypoxia (1% O2, 5% CO2) and Western blotting was performed for EGFR, arginase II, phosphorylated-ERK (pERK), and total ERK (ERK). Hypoxia led to greater EGFR, pERK, and arginase II protein levels than did normoxia in hPMVECs. To examine the role of EGFR in these hypoxia-induced changes, hPMVECs were transfected with siRNA against EGFR or a scrambled siRNA and placed in hypoxia. Inhibition of EGFR using siRNA attenuated hypoxia-induced pERK and arginase II expression as well as the hypoxia-induced increase in viable cell numbers. hPMVECs were then treated with vehicle, an EGFR inhibitor (AG1478), or an ERK pathway inhibitor (U0126) and placed in hypoxia. Pharmacologic inhibition of EGFR significantly attenuated the hypoxia-induced increase in pERK level. Both AG1478 and U0126 also significantly attenuated the hypoxia-induced increase in viable hPMVECs numbers. hPMVECs were transfected with an adenoviral vector containing arginase II (AdArg2) and overexpression of arginase II rescued the U0126-mediated decrease in viable cell numbers in hypoxic hPMVECs. Our findings suggest that hypoxic activation of EGFR results in phosphorylation of ERK, which is required for hypoxic induction of arginase II and cellular proliferation.

Non-invasive assessment of portal hypertension using quantitative magnetic resonance imaging.

BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) measurement is currently the only validated technique to accurately evaluate changes in portal pressure. In this study, we evaluate the use of non-contrast quantitative magnetic resonance imaging (MRI) as a surrogate measure of portal pressure. METHODS: Thirty patients undergoing HVPG measurement were prospectively recruited. MR parameters of longitudinal relaxation time (T1), perfusion of the liver and spleen (by arterial spin labelling), and blood flow in the portal, splanchnic and collateral circulation (by phase contrast MRI) were assessed. We estimated the liver stiffness measurement (LSM) and enhanced liver fibrosis (ELF) score. The correlation of all non-invasive parameters with HVPG was evaluated. RESULTS: The mean (range) HVPG of the patients was 9.8 (1-22) mmHg, and 14 patients (48%) had clinically significant portal hypertension (CSPH, HVPG ⩾10mmHg). Liver T1 relaxation time, splenic artery and superior mesenteric artery velocity correlated significantly with HVPG. Using multiple linear regression, liver T1 and splenic artery velocity remained as the two parameters in the multivariate model significantly associated with HVPG (R=0.90, p<0.001). This correlation was maintained in patients with CSPH (R=0.85, p<0.001). A validation cohort (n=10) showed this linear model provided a good prediction of HVPG. LSM and ELF score correlated significantly with HVPG in the whole population but the correlation was absent in CSPH. CONCLUSIONS: MR parameters related to both hepatic architecture and splanchnic haemodynamics correlate significantly with HVPG. This proposed model, confirmed in a validation cohort, could replace the invasive HVPG measurement. LAY SUMMARY: In patients with cirrhosis, the development and progression of portal hypertension is related to worse outcomes. However, the standard technique of assessing portal pressure is invasive and not widely used in clinical practice. Here, we have studied the use of non-invasive MRI in evaluating portal pressure. The MRI measures of liver architecture and blood flow in the splenic artery correlated well with portal pressure. Therefore, this non-invasive method can potentially be used to assess portal pressure in clinical trials and monitoring treatment in practice.

The Src family tyrosine kinases src and yes have differential effects on inflammation-induced apoptosis in human pulmonary microvascular endothelial cells.

Endothelial cells are essential for normal lung function: they sense and respond to circulating factors and hemodynamic alterations. In inflammatory lung diseases such as acute respiratory distress syndrome, endothelial cell apoptosis is an inciting event in pathogenesis and a prominent pathological feature. Endothelial cell apoptosis is mediated by circulating inflammatory factors, which bind to receptors on the cell surface, activating signal transduction pathways, leading to caspase-3-mediated apoptosis. We hypothesized that yes and src have differential effects on caspase-3 activation in human pulmonary microvascular endothelial cells (hPMVEC) due to differential downstream signaling effects. To test this hypothesis, hPMVEC were treated with siRNA against src (siRNAsrc), siRNA against yes (siRNAyes), or their respective scramble controls. After recovery, the hPMVEC were treated with cytomix (LPS, IL-1ß, TNF-α, and IFN-γ). Treatment with cytomix induced activation of the extracellular signal-regulated kinase (ERK) pathway and caspase-3-mediated apoptosis. Treatment with siRNAsrc blunted cytomix-induced ERK activation and enhanced cleaved caspase-3 levels, while treatment with siRNAyes enhanced cytomix-induced ERK activation and attenuated levels of cleaved caspase-3. Inhibition of the ERK pathway using U0126 enhanced cytomix-induced caspase-3 activity. Treatment of hPMVEC with cytomix induced Akt activation, which was inhibited by siRNAsrc. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway using LY294002 prevented cytomix-induced ERK activation and augmented cytomix-induced caspase-3 cleavage. Together, our data demonstrate that, in hPMVEC, yes activation blunts the ERK cascade in response to cytomix, resulting in greater apoptosis, while cytomix-induced src activation induces the phosphatidylinositol 3-kinase pathway, which leads to activation of Akt and ERK and attenuation of apoptosis.

Disparities by race, ethnicity, and sex in treating acute coronary syndromes.

BACKGROUND: Disparities in the management of coronary artery disease were consistently documented in blacks and women in the 1980s and 1990s. Our objective was to determine if racial/ethnic and sex differences in the use of coronary revascularization persist in a more recent cohort. METHODS: We examined all 20,604 Medicare beneficiaries admitted for acute coronary syndrome in 2001 from a random sample of 750,000 enrollees that was oversampled for black and Hispanic subjects to assess any cardiac revascularization. RESULTS: After controlling for demographics and comorbidities, black men and women (odds ratios [OR] 0.47, 0.40), Hispanic men and women (ORs 0.61, 0.52), and white women (OR 0.67) had lower rates of revascularization compared with white men. Lower revascularization rates persisted for white women (OR 0.67) and black men and women (OR 0.55 and 0.54), controlling for income status and geographic variation, but were no longer present in the Hispanic population. CONCLUSION: The mechanisms by which disparities operate may differ for Hispanic and black populations.

Tracking abnormal cervical cancer screening: evaluation of an EMR-based intervention.

INTRODUCTION: System level barriers have been associated with inadequate follow-up of abnormal cervical cytology. OBJECTIVE: The aim of this study was to develop and evaluate an electronic tracking system to improve follow-up of abnormal Pap tests. PROGRAM DESCRIPTION: We implemented an electronic medical record (EMR)-based Pap test tracking system at two clinical practices at an inner-city academic health center. The system generated a provider-specific monthly report of all abnormal Pap results, and provided a patient-specific Pap tracking table embedded in the EMR for each subject. EVALUATION: We compared abnormal Pap test follow-up rates for the 24 months pre-intervention with rates 12 months following its implementation (post-intervention). The evaluation followed all subjects for 12 months from the date of their abnormal Pap test, looking for diagnostic resolution. RESULTS: Subjects were young women (mean age = 30.5) of primarily white (42%) and African American (37%) descent, who spoke English (88%). Forty-eight percent were insured through publicly subsidized insurance. Controlling for type of abnormality and practice location, the adjusted mean time to resolution decreased significantly from 108 days (confidence interval, CI 105-112 days) in the pre-intervention period to 86 days (CI 81-91 days). CONCLUSION: Our study cannot demonstrate that with follow up, we directly avoided cases of invasive cervical cancer. However, we show that in an at-risk urban population, an automated, EMR-based tracking system reduced the time to resolution, and increased the number of women who achieved diagnostic resolution.

Progress and priorities in the health of women and girls: a decade of advances and challenges.

OBJECTIVE: Following the initial wave of federal support to address women's health, there is a need to assess successes and determine the next priorities to advance the health of women. The objective of this study was to systematically collect expert opinion on the major advances in women's health in the past decade and priorities for women's health research and service in the coming decade. METHODS: We utilized a Delphi method to query the leadership from academic and community Centers of Excellence in Women's Health, as designated by the Department of Health and Human Services. Leaders from 36 of the 48 centers responded to a series of questions about the major advances and critical indicators to evaluate future needs in women's health. We utilized a social ecology model framework to organize the responses to each question. RESULTS: The experts identified increased health education for women and increased empowerment of women across multiple spheres as the major advances positively impacting the health of women. The experts selected the following areas as the most important indicators to measure the status of the health of women in the future: health education and promotion, rates and impact of interpersonal violence against women, and access to healthcare. The major advances and measures of the health of women did not focus on specific changes to individual women in illness management, clinical care, or individual behavioral change. CONCLUSIONS: As we move to address health reform, we must be able to recognize and incorporate a broad perspective on public health and policy initiatives critical to the health and wellness of women and girls and, therefore, central to the well-being of the nation.

A randomised controlled trial of cognitive behavioural treatment for obsessive compulsive disorder in children and adolescents.

Cognitive behaviour therapy (CBT) for young people with obsessive compulsive disorder (OCD) has become the treatment of first choice. However, the literature is largely based on studies emphasising exposure and response prevention. In this study, we report on a randomised controlled trial of CBT for young people carried out in typical outpatient clinic conditions which focused on cognitions. A randomised controlled trial compares 10 sessions of manualised cognitive behavioural treatment with a 12-week waiting list for adolescents and children with OCD. Assessors were blind to treatment allocation. 21 consecutive patients with OCD aged between 9 and 18 years were recruited. The group who received treatment improved more than a comparison group who waited for 3 months. The second group was treated subsequently using the same protocol and made similar gains. In conclusion, CBT can be delivered effectively to young people with OCD in typical outpatient settings.

Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors.

OBJECTIVE: Endothelial progenitor cells (EPCs) are used for angiogenic therapies or as biomarkers to assess cardiovascular disease risk. However, there is no uniform definition of an EPC, which confounds EPC studies. EPCs are widely described as cells that coexpress the cell-surface antigens CD34, AC133, and vascular endothelial growth factor receptor-2 (VEGFR-2). These antigens are also expressed on primitive hematopoietic progenitor cells (HPCs). Remarkably, despite their original identification, CD34+AC133+VEGFR-2+ cells have never been isolated and simultaneously plated in hematopoietic and endothelial cell (EC) clonogenic assays to assess the identity of their clonal progeny, which are presumably the cellular participants in vascular regeneration. METHODS: CD34+AC133+VEGFR-2+ cells were isolated from human umbilical cord blood (CB) or granulocyte colony-stimulating factor-mobilized peripheral blood and assayed for either EPCs or HPCs. RESULTS: CD34+AC133+VEGFR-2+ cells did not form EPCs and were devoid of vessel forming activity. However, CD34+AC133+VEGFR-2+ cells formed HPCs and expressed the hematopoietic lineage-specific antigen, CD45. We next tested whether EPCs could be separated from HPCs by immunoselection for CD34 and CD45. CD34+CD45+ cells formed HPCs but not EPCs, while CD34+CD45- cells formed EPCs but not HPCs. CONCLUSIONS: Therefore, CD34+AC133+VEGFR-2+ cells are HPCs that do not yield EC progeny, and the biological mechanism for their correlation with cardiovascular disease needs to be reexamined.

K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells.

p21(ras) (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1(+/-) mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.

Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells.

Genetic inactivation of tumor suppressor genes initiates human cancers. However, interaction of accessory cells with the tumor-initiating cell within the microenvironment is often required for tumor progression. This paradigm is relevant to understanding neurofibroma development in neurofibromatosis type I patients. Somatic inactivation of the Nf1 tumor suppressor gene, which encodes neurofibromin, is necessary but not sufficient to initiate neurofibroma development. In contrast, neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Neurofibromas are highly vascularized, and recent studies suggest that Nf1+/- mice have increased angiogenesis in vivo. However, the function of neurofibromin in human endothelial cells (ECs) and the biochemical mechanism by which neurofibromin regulates neoangiogenesis are not known. Utilizing Nf1+/- mice, primary human ECs and endothelial progenitor cells harvested from NF1 patients, we identified a discrete Ras effector pathway, which alters the proliferation and migration of neurofibromin-deficient ECs in response to neurofibroma-derived growth factors both in vitro and in vivo. Thus, these studies identify a unique biochemical pathway in Nf1+/- ECs as a potential therapeutic target in the neurofibroma microenvironment.

Neurofibromin is a novel regulator of RAS-induced signals in primary vascular smooth muscle cells.

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the NF1 tumor suppressor gene. Neurofibromin is encoded by NF1 and functions as a negative regulator of Ras activity. NF1 patients develop renal artery stenosis and arterial occlusions resulting in cerebral and visceral infarcts. Further, NF1 patients develop vascular neurofibromas where tumor vessels are invested in a dense pericyte sheath. Although it is well established that aberrations in Ras signaling lead to human malignancies, emerging data generated in genetically engineered mouse models now implicate perturbations in the Ras signaling axis in vascular smooth muscular cells (VSMCs) as central to the initiation and progression of neointimal hyperplasia and arterial stenosis. Despite these observations, the function of neurofibromin in regulating VSMC function and how Ras signals are terminated in VSMCs is virtually unknown. Utilizing VSMCs harvested from Nf1+/- mice and primary human neurofibromin-deficient VSMCs, we identify a discrete Ras effector pathway, which is tightly regulated by neurofibromin to limit VSMC proliferation and migration. Thus, these studies identify neurofibromin as a novel regulator of Ras activity in VSMCs and provide a framework for understanding cardiovascular disease in NF1 patients and a mechanism by which Ras signals are attenuated for maintaining VSMC homeostasis in blood vessel walls.

Genetic reduction of class IA PI-3 kinase activity alters fetal hematopoiesis and competitive repopulating ability of hematopoietic stem cells in vivo.

Class I(A) phosphatidylinositol-3 kinase (PI-3K) is a lipid kinase, which is activated in blood cells by hematopoietic growth factors. In vitro experiments using chemical inhibitors of PI-3K suggest that this kinase is potentially important for hematopoietic stem and progenitor cell (HSC/P) function, and recent studies identify PI-3K as a therapeutic target in treating different leukemias and lymphomas. However, the role of PI-3K in regulating fetal liver or adult hematopoiesis in vivo is unknown. Therefore, we examined PI-3K-deficient embryos generated by a targeted deletion of the p85alpha and p85beta regulatory subunits of PI-3K (p85alpha-/-p85beta+/-). The absolute frequency and number of hematopoietic progenitor cells were reduced in p85alpha-/- p85beta+/- fetal livers compared with wild-type (WT) controls. Further, p85alpha-/-p85beta+/- fetal liver hematopoietic stem cells (HSCs) had decreased multilineage repopulating ability in vivo compared with WT controls in competitive repopulation assays. Finally, purified p85alpha-/-p85beta+/- c-kit+ cells had a decrease in proliferation in response to kit ligand (kitL), a growth factor important for controlling HSC function in vivo. Collectively, these data identify PI-3K as an important regulator of HSC function and potential therapeutic target in treating leukemic stem cells.

K-Ras is essential for normal fetal liver erythropoiesis.

In vitro studies suggest that Ras activation is necessary for erythroid cell development. However, genetic inactivation of the Ras isoforms H-Ras, N-Ras, and K-Ras in mice reportedly did not affect adult or fetal erythropoiesis, though K-Ras(-/-) embryos were anemic. Given these discrepancies, we performed a more detailed analysis of fetal erythropoiesis in K-Ras(-/-) embryos. Day-13.5 K-Ras(-/-) embryos were pale with a marked reduction of mature erythrocytes in their fetal livers. The frequency and number of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) were reduced in K-Ras(-/-) fetal livers compared with wild-type controls and displayed a delay in terminal erythroid cell maturation. Further, K-Ras(-/-) hematopoietic progenitors had reduced proliferation in response to erythropoietin and Kit ligand compared with control cells. Thus, these studies identify K-Ras as a unique Ras isoform that is essential for regulating fetal erythropoiesis in vivo.

Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.

The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.

Functional p85alpha gene is required for normal murine fetal erythropoiesis.

In vitro studies suggest that activation of class IA phosphatidylinositol 3 (PI-3) kinase is necessary for normal erythroid cell development. However, when class IA PI-3 kinase-deficient mice were generated by a targeted deletion of the p85alpha regulatory subunit, fetal erythropoiesis was reportedly unaffected. Given the discrepancies between these studies, we performed a more detailed in vivo analysis of class IA PI-3 kinase-deficient embryos. Day-14.5 p85alpha-/- embryos are pale with a marked reduction of mature erythrocytes in their peripheral blood. Further, the absolute number and frequency of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) are reduced in p85alpha-/- fetal livers compared with wild-type controls, which is associated with reduced proliferation. Taken together, these data establish an important role for p85alpha and class IA PI-3 kinase in regulating the development of both early and late erythroid progenitors in fetal liver.