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Background: In US hospitals, the liquid embolic systems (LESs) n-butyl cyanoacrylate (n-BCA) and ethylene vinyl alcohol copolymer (EVOH) are used for brain arteriovenous malformation (bAVM) embolization to achieve presurgical devascularization. The aim of this study was to perform an economic analysis comparing four techniques for bAVM embolization based on LES, ancillary device, and angiography suite time costs., Methods: An economic model was developed comparing the embolization costs for n-BCA, EVOH with the plug and push technique, EVOH with detachable-tip microcatheters, and EVOH with balloon microcatheters. Per procedure costs were calculated for bAVMs with one to four pedicles. Annual cohort analyses were performed to evaluate the potential impact for low and high-volume centers. Sensitivity analyses were performed to determine cost drivers., Results: The analyses showed that the n-BCA technique was the least costly of the four techniques. Total per procedure costs for one to four embolized pedicles ranged from $5941 to $10,074 for the n-BCA technique, $8428 to $30,345 for the EVOH balloon microcatheter technique, $12,711 to $47,477 for the EVOH plug and push technique, and $13,900 to $52,233 for the EVOH detachable-tip microcatheter technique. Cohort analyses costs for 52 annual cases ranged from $308,953 to $523,838 with the n-BCA technique and from $722,816 to $2,716,096 with the EVOH detachable-tip microcatheter technique., Conclusions: Procedure costs associated with n-BCA are lower than those with each of the three EVOH techniques examined. Future cost analyses should compare the costs of new LES products once available.

Background: First-pass effect (FPE), restoring complete or near complete reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) 2c-3) in a single pass, is an independent predictor for good functional outcomes in the endovascular treatment of acute ischemic stroke. The economic implications of achieving FPE have not been assessed., Objective: To assess the economic impact of achieving complete or near complete reperfusion after the first pass., Methods: Post hoc analyses were conducted using ARISE II study data. The target population consisted of patients in whom mTICI 2c-3 was achieved, stratified into two groups: (1) mTICI 2c-3 achieved after the first pass (FPE group) or (2) after multiple passes (non-FPE group). Baseline characteristics, clinical outcomes, and healthcare resource use were compared between groups. Costs from peer-reviewed literature were applied to assess cost consequences from the perspectives of the United States (USA), France, Germany, Italy, Spain, Sweden, and United Kingdom (UK)., Results: Among patients who achieved mTICI 2c-3 (n=172), FPE was achieved in 53% (n=91). A higher proportion of patients in the FPE group reached good functional outcomes (90-day modified Rankin Scale score 0-2 80.46% vs 61.04%, p<0.01). The patients in the FPE group had a shorter mean length of stay (6.10 vs 9.48 days, p<0.01) and required only a single stent retriever, whereas 35% of patients in the non-FPE group required at least one additional device. Driven by improvement in clinical outcomes, the FPE group had lower procedural/hospitalization-related (24-33% reduction) and annual care (11-27% reduction) costs across all countries., Conclusions: FPE resulted in improved clinical outcomes, translating into lower healthcare resource use and lower estimated costs., Competing Interests: Competing interests: OOZ serves as a consultant for Neuravi, Stryker, Penumbra, and Medtronic. MR is a shareholder in Anaconda Biomed; consultant for Neuravi/Cerenovus, Medtronic, Stryker, Apta Targets, and Vesalio. HPM reports personal fees from Covidien/Medtronic, Neuravi/Cerenovus, Servier, and Bayer outside the submitted work; served on the steering committees of the SWIFT PRIME and ARISE studies. JLS is an employee of the University of California, which holds a patent on retriever devices for stroke. The University of California, Regents receives funding for the services of JLS as a scientific consultant regarding trial design and conduct to Covidien/Medtronic and Stryker; serves as a consultant for Modest, Abbott, Medtronic, Stryker, and Neuravi/Cerenovus; has contracted stock options for Modest and Rapid Medical. HB serves as a modest consultant for Neuravi/Cerenovus, and Stryker. AJY is a consultant for Cerenovus, Penumbra, Genentech, and Zoll Circulation; receives research grant support from Cerenovus, Penumbra, Medtronic, Stryker, and Genentech; and has equity interest in Insera Therapeutics. AE is an employee of Johnson and Johnson. EK is an employee of Cerenovus, a subsidiary of Johnson and Johnson. HLC and RAQ are paid consultants for Cerenovus. TA is a consultant for Neuravi/Cerenovus, Anaconda, Amnis Therapeutics, and Rapid Medical; served on the steering committees of the ARISE studies., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Endovascular coiling is a common modality for treating intracranial aneurysms; however, recanalization occurs in approximately 1 in 5 cases, with downstream consequences of regrowth and rupture. Aneurysm packing density >24% reduces recanalization risk; packing density can be increased by inserting additional coils or by using coils with larger volumetric filling. Coil volume depends on length and primary wind diameter (PWD). This study evaluated the influence of PWD on packing density and total case costs., Materials and Methods: Two hypothetical scenarios and one case study were analyzed. In scenario one, the number of coils required to achieve packing density >24% in a hypothetical aneurysm was determined for 0.012″ vs. 0.010″ PWD coils. In scenario two, the total length of 0.010″ vs. 0.012″ PWD coils required to achieve a packing density >24% was analyzed relative to aneurysm volume. In the case study, packing densities with one 0.012″ PWD coil (actual scenario) and one 0.010″ PWD coil (theoretical scenario) were compared., Results: In scenario one, cost savings would be realized by using four 0.012″ PWD coils vs. seven 0.010″ PWD coils to achieve packing density >24%. In scenario two, greater volumetric filling of 0.012″ vs. 0.010″ PWD coils was correlated with lower total length of coil required. In the case study, a 0.012″ PWD coil achieved packing density >24%, whereas an equivalent length 0.010″ PWD coil would not., Limitations: Theoretical modeling was used to explore the impact of coil PWD on aneurysm packing density. In clinical practice, packing density depends not only on PWD but on its length, shape, distribution within an aneurysm, and other recanalization risk factors., Conclusions: Coil PWD influences packing density, the number of coils required to achieve a specific packing density, and total case costs. Using 0.012″ PWD coils may provide cost and procedural efficiencies.

Background: The purpose of this quality improvement project was to develop, implement, and assess the effects of an alarm management policy and educational program on nurses' perceptions and practices of alarm management in an acute care hospital., Method: Nurses from an acute care hospital in the southeastern United States attended a mandatory alarm management education program. The hospital implemented the evidence-based alarm management education to achieve the NPSG.06.01.01: Alarm Management. Pre- and posttests were administered to evaluate the education and the changes in nurses' perceptions and practices of clinical alarms., Results: A total of 417 nurses received the educational intervention. All participants completed the pretest, and 215 (51%) completed the voluntary posttest. Significant improvements were made in alarm perceptions and practices. Nurses suggested unit-specific alarm education, improved staffing, and updated equipment., Conclusion: Findings support the benefits of continued education in alarm management for nurses. Bedside nurses are a critical member of a multidisciplinary alarm management team because they are at the forefront of patient safety and most at risk for experiencing alarm fatigue. J Contin Educ Nurs. 2018;49(5):207-215., (Copyright 2018, SLACK Incorporated.)

Objective: In patients with significant mitral regurgitation (MR) at high risk of mortality and morbidity from mitral valve surgery, transcatheter mitral valve repair with the MitraClip System is associated with a reduction in MR and improved quality-of-life and functional status compared with baseline. The objective was to evaluate the cost-effectiveness of MitraClip therapy compared with standard of care in patients with significant MR at high risk for mitral valve surgery from a Canadian payer perspective., Methods: A decision analytic model was developed to estimate the lifetime costs, life years, quality-adjusted life years (QALYs), and incremental cost per life year and QALY gained for patients receiving MitraClip therapy compared with standard of care. Treatment-specific overall survival, risk of clinical events, quality-of-life, and resource utilization were obtained from the Endovascular Valve Edge-to-Edge REpair High Risk Study (EVEREST II HRS). Health utility and unit costs (CAD $2013) were taken from the published literature. Sensitivity analyses were conducted to explore the impact of alternative assumptions and parameter uncertainty on results., Results: The base case incremental cost per QALY gained was $23,433. RESULTS were most sensitive to alternative assumptions regarding overall survival, time horizon, and risk of hospitalization for congestive heart failure (CHF). Probabilistic sensitivity analysis showed MitraClip therapy to have a 92% chance of being cost-effective compared with standard of care at a willingness-to-pay threshold of $50,000 per QALY gained., Study Limitations: Key limitations include the small number of patients included in the EVEREST II HRS which informed the analysis, the limited data available to inform clinical events and disease progression in the concurrent comparator group, and the lack of a comparator group from a randomized control trial., Conclusion: MitraClip therapy is likely a cost-effective option for the treatment of patients at high risk for mitral valve surgery with significant MR.

Breast cancer is the most common cancer in Western women and while its precise etiology is unknown, environmental factors are thought to play a role. The organochlorine pesticide dieldrin is a persistent environmental toxicant thought to increase the risk of breast cancer and reduce survival in the human population. The objective of this study was to define the effect of developmental exposure to environmentally relevant concentrations of dieldrin, on mammary tumor development in the offspring. Sexually mature FVB-MMTV/neu female mice were treated with vehicle (corn oil), or dieldrin (0.45, 2.25, and 4.5 microg/g body weight) daily by gavage for 5 days prior to mating and then once weekly throughout gestation and lactation until weaning. Dieldrin concentrations were selected to produce serum levels representative of human background body burdens, occupational exposure, and overt toxicity. Treatment had no effect on litter size, birth weight or the number of pups surviving to weaning. The highest dose of dieldrin significantly increased the total tumor burden and the volume and number of tumors found in the thoracic mammary glands. Increased mRNA and protein expression of the neurotrophin BDNF and its receptor TrkB was increased in tumors from the offspring of dieldrin treated dams. This study indicates that developmental exposure to the environmental contaminant dieldrin causes increased tumor burden in genetically predisposed mice. Dieldrin exposure also altered the expression of BNDF and TrkB, novel modulators of cancer pathogenesis.

Epidemiological evidence suggests that exposure to the pesticide dieldrin, is associated with increased risk of breast cancer and mortality. We hypothesize that dieldrin promotes breast cancer by increasing survival of breast cancer cells. The aims of this study were to measure the effect of dieldrin on survival of breast cancer cells and the expression of tyrosine kinase B (TrkB), a suppressor of anoikis (apoptosis triggered by inappropriate anchorage). The human breast cancer cell line MDA-MB-231 was treated with dieldrin and proliferation, viability and resistance to anoikis were measured. TrkB expression was measured by Western blot in lysates and by immunohistochemistry in human tissue specimens. Dieldrin increased resistance to anoikis and TrkB expression. TrkB was expressed in a subset of high-grade breast carcinoma specimens. Our results demonstrate that dieldrin increases resistance to anoikis and expression of TrkB and show for the first time TrkB protein expression in human breast cancer.

The intestinal epithelium acts as a barrier restricting uptake of luminal macromolecules such as dietary antigens and microbes. Here, we examined the role of cholinergic signalling in the regulation of permeability to macromolecules. Mouse jejunum was mounted in Ussing chambers and permeability was determined by measuring the flux of the antigen-sized protein, horseradish peroxidase (HRP), across the tissue. Baseline HRP permeability was significantly reduced by neural blockade with tetrodotoxin or cholinergic muscarinic antagonism with atropine, suggesting that ongoing release of endogenous acetylcholine from enteric nerves regulates barrier function. Exogenous addition of the muscarinic agonist bethanechol caused significant increases in both HRP flux and the area of HRP-containing endosomes in enterocytes. Bethanechol-enhanced HRP flux was abrogated by the M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), the phospholipase A(2) inhibitor quinacrine, and the cyclooxygenase inhibitor indomethacin. Complementary in vitro studies showed direct effects of bethanechol on T84 epithelial cells, where increased HRP uptake was associated with increased F-actin, and increased cytosolic phospholipase A(2) (cPLA(2)) phosphorylation. Taken together, these results provide evidence for cholinergic regulation of transepithelial transport of macromolecules, mainly mediated by activation of M3 receptors with subsequent involvement of phospholipase A(2) and cyclooxygenase products.

Stress-induced intestinal barrier dysfunction may be involved in chronic intestinal disorders. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic growth hormone that can rapidly improve intestinal epithelial barrier function. Here, we investigated whether mouse intestine is responsive to chronic psychological stress and whether pretreatment with GLP-2 can ameliorate stress-induced changes. Mice were subjected to water avoidance stress (WAS; 1 h/day for 10 days) with GLP-2 or saline administered 4 h before each WAS session. After the final stress period, the intestine was removed for assessment of physiological/morphological changes. Compared with controls (sham-stressed mice), stressed mice demonstrated enhanced ion secretion and permeability in the jejunum, ileum, and colon. In addition, increased numbers of bacteria were observed adhering to and/or penetrating the epithelium, associated with infiltration of mononuclear cells into the mucosa. GLP-2 treatment improved intestinal barrier function in stressed mice and ameliorated other aspects of impaired host defense. Our study extends previous findings in rats of stress-induced intestinal dysfunction and provides insights into potential novel therapeutics.

Penetration of the gut epithelial barrier by intact luminal antigen is necessary for immunologically mediated pathophysiology in the context of food allergy. We investigated if glucagon-like peptide-2 (GLP-2) could affect immediate hypersensitivity and late-phase allergic inflammation in a murine model. Mice were sensitized to horseradish peroxidase (HRP); studies were conducted 14 days later. Mice were treated with 5 microg GLP-2 subcutaneously 4 h before antigen challenge. For immediate hypersensitivity, jejunal segments in Ussing chambers were challenged by luminal HRP antigen. GLP-2 treatment reduced the uptake of HRP and the antigen-induced secretory response after luminal challenge. GLP-2 appears to reduce macromolecular uptake independent of the CD23-mediated enhanced antigen uptake pathway. For the late phase, mice were gavaged with antigen, and 48 h later the function and histology of the jejunum were examined. GLP-2 prevented the usual prolonged permeability defect and reduced the number of inflammatory cells in the mucosa. Our studies demonstrate that a single treatment of sensitized mice with GLP diminishes both immediate and late-phase hypersensitivity reactions characteristic of food allergy by inhibiting transepithelial uptake of antigen.

The possibility that hypokalaemia might increase the mortality of treated hypertensives in the Glasgow Blood Pressure Clinic has been examined by comparison of serum potassium in decedents and survivors and by calculation of age-adjusted mortality rates for patients grouped in quartiles of serum potassium measured at the last clinic visit. In this study, 3783 patients with non-malignant hypertension were followed for an average of 6.5 years and of these 1907 had one or more measurements of serum potassium during their last year of attendance. Serum potassium fell in 414 patients given diuretics with or without other drugs except beta-blockers. This fall was similar in those who died of ischaemic heart disease (3.71 mmol/l) and in those who survived (3.72 mmol/l). Serum potassium rose in 167 patients who received beta-blockers with or without other drugs except diuretics and fell slightly among 1326 patients taking other combinations of drugs. There were no significant differences in serum potassium between decedents and survivors in either of these treatment groups. Age-adjusted mortality in deaths per 1000 patient-years in the lowest quartile of serum potassium (less than 3.7 mmol/l) was 28.1 for men and 15.0 for women. Higher serum potassium was associated with slightly, but not significantly, higher mortality in both sexes. There was no relation between serum potassium and mortality in patients with left ventricular hypertrophy, nor was there a relation when death due to ischaemic heart disease was considered separately. Failure of hypokalaemia to predict outcome was confirmed by univariate and multivariate analyses which included, in addition to potassium, assessment of cigarette smoking, initial blood urea and electrocardiographic findings.(ABSTRACT TRUNCATED AT 250 WORDS)

The mortality of 3783 non-malignant hypertensive patients attending the Glasgow Blood Pressure Clinic between 1968 and 1983 and followed for an average of 6.5 years was compared with that in three control groups: the general population of Strathclyde a group of 15 422 subjects aged 45-64 years and screened in Renfrew and Paisley between 1972 and 1976, and a group of hypertensives seen in a blood pressure clinic based on general practice in Renfrew. Average blood pressure for men at entry to the Glasgow Clinic was 181/111 mmHg falling to 158/96 mmHg during treatment. Corresponding values for women were 185/109 mmHg and 161/96 mmHg. Seven hundred and fifty clinic patients (451 males) died during follow-up, the commonest causes of death in both sexes being myocardial infarction and stroke. All-cause age-adjusted mortality (deaths per 1000 patient-years) was 41.4 for men and 22.1 for women. At all ages in both sexes and for all levels of initial blood pressure mortality was less in patients whose blood pressure was reduced most. Without a randomized control group it is not certain that lower mortality in those with well controlled blood pressure was due to treatment, although this is the most likely explanation. Cigarette smoking, a history of myocardial infarction, angina or stroke, retinal arterio-venous nipping, raised blood urea, an abnormal electrocardiogram (ECG) and secondary hypertension were associated with increased risk, but heavy alcohol intake, obesity, haematocrit greater than 45%, hypokalaemia and social class were not. Life table analysis showed that, despite some reduction of mortality by treatment, the relative risk to men and women in the clinic remained two- to five-times that of the general population. The benefits of treatment were not such as to restore normal expectation of life even when blood pressure was well controlled. Excess mortality in the clinic could not be explained by difference of smoking habit or social class. This suggests that there is in the hypertensive patients of the Glasgow Clinic an element of irreducible risk, that treatment may be beneficial in some respects but harmful in others, or that patients at particularly high risk are selectively referred to the clinic.

The electrocardiograms (ECGs) of a series of 34 patients with primary hyperaldosteronism (PHA), 17 treated surgically (group I) nine treated medically (group II) and eight treated with/by both surgery and drug therapy (group III) were analysed to determine whether the treatment of PHA resulted in an improvement in the ECG changes of left ventricular hypertrophy (LVH) and also whether there was a difference in this improvement between medically and surgically treated patients. There was a significant reduction of blood pressure in the group as a whole (186/111 to 141/95 mmHg, P less than 0.001) and within each of the treatment groups (group I 183/108 to 137/98 mmHg, group II 188/112 to 147/93 mmHg, group III 193/115 to 144/92 mmHg). This reduction within each group was of a similar magnitude. There were reductions in both precordial voltages (SV1 + RV5) from 3.68 mV to 2.79 mV (P less than 0.01) and in the number of patients with ECG LVH from 15 to 8 (P less than 0.05). Again the reductions were of similar magnitude in each of the groups: group I 3.78 to 2.77 mV, group II 3.78 to 2.84 mV, group III 3.39 to 2.77 mV. Thus the improvement in blood pressure achieved by the treatment of PHA is accompanied by a reduction in precordial voltages and the number of patients with ECG-LVH. This improvement is independent of the type of treatment used.