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•In patients with IEI, improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUC of 80 mg × h/L.•The data stress the importance of uniformly using a validated population pharmacokinetic model to estimate the busulfan cumulative exposure.

The purpose of this article is to describe how to teach students to use smartpens to record notes in their classes. Notetaking is a complex cognitive process that requires students to listen, process, organize, and record notes, while dealing with the temporal demands of trying to record notes fast enough to keep up with the teacher. Fortunately for students with disabilities, smartpens can help them compensate for slow writing and processing speed by allowing them to record partial notes and then easily amend them after the lecture.

Otolaryngologic manifestations of infection with Blastomycesspecies are extremely rare and restricted geographically to recognized endemic regions. Here, we describe a case of laryngeal blastomycosis that presented as slowly progressive dysphonia. While a preliminary diagnosis was made using routine histopathology, a species identification of Blastomyces dermatitidiswas made using polymerase chain reaction amplification and rapid genotyping without the need for fungal culture. All symptoms resolved following 1 month of antifungal therapy. Rapid molecular differentiation of B dermatitidisfrom Blastomyces gilchristiiprovides important insights into pathogenesis given recent recognition of differences in clinical spectra.

Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.

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Depletion of hematopoietic stem cells (HSCs) is used therapeutically in many malignant and nonmalignant blood disorders in the setting of a hematopoietic cell transplantation (HCT) to eradicate diseased HSCs, thus allowing donor HSCs to engraft. Current treatments to eliminate HSCs rely on modalities that cause DNA strand breakage (ie, alkylators, radiation) resulting in multiple short-term and long-term toxicities and sometimes even death. These risks have severely limited the use of HCT to patients with few to no comorbidities and excluded many others with diseases that could be cured with an HCT. 5-Azacytidine (AZA) is a widely used hypomethylating agent that is thought to preferentially target leukemic cells in myeloid malignancies. Here, we reveal a previously unknown effect of AZA on HSCs. We show that AZA induces early HSC proliferation in vivo and exerts a direct cytotoxic effect on proliferating HSCs in vitro. When used to pretreat recipient mice for transplantation, AZA permitted low-level donor HSC engraftment. Moreover, by combining AZA with a monoclonal antibody (mAb) targeting CD117 (c-Kit) (a molecule expressed on HSCs), more robust HSC depletion and substantially higher levels of multilineage donor cell engraftment were achieved in immunocompetent mice. The enhanced effectiveness of this combined regimen correlated with increased apoptotic cell death in hematopoietic stem and progenitor cells. Together, these findings highlight a previously unknown therapeutic mechanism for AZA which may broaden its use in clinical practice. Moreover, the synergy we show between AZA and anti-CD117 mAb is a novel strategy to eradicate abnormal HSCs that can be rapidly tested in the clinical setting.

Large, symptomatic and ruptured abdominal aortic aneurysms are usually treated surgically if patients are deemed fit enough. This may be achieved through endovascular or open surgical repair. The type of treatment that a patient receives is dependant on many factors, such as the rupture status of the aneurysm. Each approach is also associated with different risks and postoperative complications. Multiple guidelines exist to inform the surgical management of abdominal aortic aneurysms. This literature review combines these recommendations and explores the evidence upon which they are based. In addition, it highlights the key perioperative considerations that need to be considered in cases of unruptured and ruptured abdominal aortic aneurysms.

An abdominal aortic aneurysm is an irreversible dilatation of the abdominal aorta. The majority of abdominal aortic aneurysms are asymptomatic and identified incidentally while investigating a separate pathology. Others are detected by national screening programmes and some present due to a growth or rupture. Symptomatic or ruptured aneurysms require urgent or emergency repair in patients fit for surgery. Perioperative practitioners should therefore be aware of how patients with abdominal aortic aneurysms present and are investigated, so that they can implement timely management. Guidelines have been recently updated to reflect this. This literature review discusses these recommendations and explores the evidence upon which they are based. The aim of this article is to highlight the important preoperative principles that need to be considered in cases of abdominal aortic aneurysm.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome that complicates hematopoietic stem cell transplant (HSCT). Morbidity and mortality from TA-TMA remain high, making prevention critical. We describe our retrospective single-center experience of TA-TMA after pediatric allogeneic HSCT and present a novel pre-HSCT risk-stratification system and prophylaxis regimen. From January 2012 through October 2019, 257 patients underwent 292 allogeneic HSCTs. Prospective risk stratification was introduced in December 2016. High-risk (HR) patients were treated with combination prophylaxis with eicosapentaenoic acid and N-acetylcysteine. The 1-year cumulative incidence of TA-TMA was 6.3% (95% confidence interval [CI], 3.2-9.4). Age ≥10 years, myeloablative conditioning with total body irradiation, HLA mismatch, diagnosis of severe aplastic anemia or malignancy, prior calcineurin inhibitor exposure, and recipient cytomegalovirus seropositivity were found to be pre-HSCT risk factors for development of TA-TMA. Before routine prophylaxis, TA-TMA rates were significantly different between the HR and standard-risk groups, at 28.2% (95% CI, 0-12.7) vs 3.2% (0.1-6.3), respectively (P < .001). After introduction of prophylaxis, the 1-year cumulative incidence of TA-TMA in the HR group decreased to 4.5% (95% CI, 0-13.1; P = .062, compared with the incidence before prophylaxis). Multicenter pediatric studies are needed to validate these risk criteria and to confirm the efficacy of the prophylactic regimen.

Students with disabilities (SWD; e.g., learning disabilities) often struggle with slower processing speed and poor working memory skills, which reduce the quality of their notes. This study evaluated the effects of a note-taking intervention using the researcher-created smartpen strategy in conjunction with the assistive technology of the Livescribe™ Smartpen to assess the effects of students’ overall notes and lecture comprehension. Both SWD and without disabilities in ninth-grade English Language Arts classes participated in this study. The note-taking intervention was designed to assist SWD to take notes using the smartpen assistive technology, aid students in identifying key vocabulary content, amend their notes for errors or missed information, and establish a summary of the lecture. Results from the data analysis found that SWD in the experimental group recorded more words in their notes, as well as an increase in word count on the immediate free recall assessment.

Purpose:To investigate the long-term outcomes of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) from a single center over an 11-year period. Materials and Methods:A retrospective analysis was conducted of 121 patients (median age 78 years; 100 men) with rAAA who underwent emergency EVAR at a single tertiary vascular center from January 2006 to December 2016. The study included only ruptures confirmed by evidence of hematoma on preoperative computed tomography; both iliac and aortic aneurysm ruptures were eligible. The primary outcome measures included mortality and reintervention rates. Kaplan-Meier estimates of survival and freedom from reintervention are reported with the 95% confidence interval (CI). Results:In-hospital and 30-day mortality rates for emergency EVAR were 16.5%; 90-day mortality was 24.0%. The mortality estimates were 27.3% (95% CI 20% to 36%) at 1 year and 61.7% (95% CI 51% to 72%) at 5 years. In the observation period to 2017, 63 reinterventions were performed on 37 patients (30.6%). Median time to the first reintervention was 3.2 years. Freedom from reintervention in surviving patients at 1 year was 86% (95% CI 72% to 94%) and 51% (95% CI 26% to 71%) at 5 years. Four patients (3.3%) had a secondary sac rupture over the study period. Conclusion:Emergency EVAR for ruptured AAA can be performed with acceptable short-term outcomes; however, long-term surveillance is necessary, and reintervention is common.

ObjectiveTo monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects.MethodsRetrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018–2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends.ResultsAcross nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%–58.6%) and 52.9% (52.2%–53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1–2 weeks before lockdown and fell by 31%–88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93–0.95; total hospital admissions RR 0.96, 0.95–0.97) and after lockdown (attendances RR 0.63, 0.62–0.64; admissions RR 0.59, 0.57–0.60). There was limited recovery towards usual levels of some activities from mid-April 2020.ConclusionsSubstantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently.

•Nonoptimal rATG exposure increases nonrelapse mortality, relapse, and chronic graft-versus-host disease and worsens DFS in pediatric AB-TCD haploidentical HCT.•Targeting rATG dosing to a predicted exposure may improve immune reconstitution and preserve graft-versus-leukemia.

•A two-compartmental model with combined elimination well characterized the pharmacokinetics of briquilimab after a single intravenous infusion.•Body weight is a significant covariate on elimination and volume of distribution of briquilimab.•The median time required to fall below the target concentrations of 500, 1000, and 2000 ng/mL after a 0.6 mg/kg infusion is 12.3, 10.4, and 7.7 days, respectively.

•Cyclophosphamide and thiotepa increase the risk of TA-TMA.•The effect is greater in those of non-White race undergoing allogeneic HCT.•CMV seropositive status and CY ± TT increase the risk of developing TA-TMA.•Viral and fungal infections are risk factors for subsequent development of TA-TMA.

Introduction: Fanconi anemia (FA) is a rare, genetic disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF), and a predisposition to malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for BMF. In patients with FA who do not have a matched sibling donor, HSCT conditioning regimens typically use reduced doses of cyclophosphamide, fludarabine and anti-thymocyte globulin (ATG) with total body irradiation (TBI) or busulfan. However, treatment is complicated by conditioning related toxicities, graft vs host disease (GvHD) and increased predisposition to malignancies later in life. Prior attempts to remove TBI from FA conditioning regimens have been unsuccessful due to increased risk of graft rejection - and alternative approaches have replaced TBI with busulfan which is still genotoxic.

Children with Down syndrome acute lymphoblastic leukemia (DS-ALL) have worse prognosis compared to those with non-DS-ALL, largely due to higher treatment related mortality. Pegaspargase (PEG) is integral in protocols for the treatment of pediatric ALL and lymphoblastic lymphoma (LBL), and full exposure to all doses of PEG can be limited by toxicities, including hypersensitivity reactions (HSR) due to the production of anti-asparaginase antibodies rendering PEG therapy ineffective. To date, minimal data has been reported on the use of PEG in children with DS-ALL/LBL. We conducted a prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent ALL/LBL patients receiving PEG with antihistamines-H1 and -H2 blockers with subsequent therapeutic drug monitoring (TDM) to better identify patients with true HSR versus those with non-antibody mediated infusion reactions. Here, we report on the incidence of HSRs and PEG-associated toxicities in the cohort of children with DS-ALL/LBL.

Iron overload is a major cause of organ dysfunction and death in transfusion-dependent thalassemia (TDT) and advances in iron chelation are urgently needed. The iron chelator, deferasirox, is widely used in TDT, however, many patients accumulate iron despite taking maximum recommended doses and many experience dose-limiting toxicity, including renal and liver failure. There is high inter-individual variability in the plasma concentrations of patients taking comparable deferasirox doses and low exposure correlates with inadequate chelation response. The cause of variable drug levels remains unknown, in part because prior deferasirox PK studies primarily include limited sample sizes and/or homogenous patients. There is an urgent unmet need to determine (1) what patient characteristics contribute to the observed variability in deferasirox-plasma concentrations, and (2) how dosing strategies can be tailored to achieve optimal therapeutic plasma-drug concentrations in all patients.

Background:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAFV600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children's Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients.

The PTCTC ONC1401 trial reported a 75% 2-year disease-free survival (DFS) for pediatric patients with acute leukemia or MDS undergoing AB-TCR/CD19 depleted (AB-TCD) haploidentical HCT. Patients ≥10 years had significantly worse DFS. Conditioning for AB-TCD HCT typically includes rATG (Thymoglobulin®) 3 mg/kg/day on days -12 to -10. Models of rATG pharmacokinetics (PK) show slower clearance in older children. We hypothesized worse DFS seen in older patients may be due to excessive in vivoT-cell depletion by residual rATG post HCT.

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The use of fenestrated endovascular devices for repair of complex aortic aneurysms has increased to nearly 5,000 implantations annually among Medicare patients in the United States in recent years. Given that nearly all aspects of treatment for minimally invasive aortic intervention rely on medical devices to better care for patients with vascular disease, clearly understanding how new and innovative technology evolves over the life cycle of a medical device is an essential skill set for cardiovascular physicians. Despite the need for this understanding, there is no standard framework upon which cardiovascular physicians, regulators, and patients can rely on to better understand the evolution of evidence from product inception through adoption and long-term effectiveness evaluation. As the aforementioned devices are increasingly and broadly used, the need for a formal framework for regulation and device approval has emerged. The goal of this review is to describe the Idea, Development, Exploration, Assessment, Long-term Study Framework for Devices (IDEAL-D). This framework is a model developed recently by an international panel of experts dedicated to better understanding the data steps necessary to bring a device from idea to routine practice and further to marketing, approval, and monitoring. In this review, we use the example of fenestrated endovascular aortic devices to illustrate the IDEAL-D framework, how it can help cardiovascular physicians improve their understanding of new technology, and the evidence which surrounds it from inception to long-term use.

Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.

AbstractAll disasters are local but implementing a hyperlocal response in the midst of a public health emergency is challenging. The availability of neighborhood-level qualitative data that are both timely and relevant to evolving objectives and operations is a limiting factor. In 2020, the New York City Department of Health and Mental Hygiene (NYC DOHMH) responded to the COVID-19 emergency using a novel, hyperlocal approach. Key to the implementation of this approach was the creation of the Community Assessment to Inform Rapid Response (CAIRR), a process for rapid collection and analysis of neighborhood-specific, objective-focused, qualitative data to inform tailored response operations. This paper describes the process of developing the CAIRR and its contribution to the NYC DOHMH’s hyperlocal response in order to guide other jurisdictions seeking to employ a hyperlocal approach in future disaster responses.

Creativity, the ability to produce innovative ideas, is a key higher-order cognitive function that is poorly understood. At the level of macroscopic cortical network dynamics, recent electroencephalography (EEG) data suggests that cortical oscillations in the alpha frequency band (8–12 Hz) are correlated with creative thinking. However, whether alpha oscillations play a functional role in creativity has remained unknown. Here we show that creativity is increased by enhancing alpha power using 10 Hz transcranial alternating current stimulation (10 Hz-tACS) of the frontal cortex. In a study of 20 healthy participants with a randomized, balanced cross-over design, we found a significant improvement of 7.4% in the Creativity Index measured by the Torrance Test of Creative Thinking (TTCT), a comprehensive and most frequently used assay of creative potential and strengths. In a second similar study with 20 subjects, 40 Hz-tACS was used instead of 10 Hz-tACS to rule out a general “electrical stimulation” effect. No significant change in the Creativity Index was found for such frontal 40 Hz stimulation. Our results suggest that alpha activity in frontal brain areas is selectively involved in creativity; this enhancement represents the first demonstration of specific neuronal dynamics that drive creativity and can be modulated by non-invasive brain stimulation. Our findings agree with the model that alpha recruitment increases with internal processing demands and is involved in inhibitory top-down control, which is an important requirement for creative ideation.

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation.

To review the trends in patient selection and early death rate for patients undergoing elective endovascular repair of infrarenal abdominal aortic aneurysms (EVAR) in 3 countries. For this study, audit data from 4,163 patients who had undergone elective infrarenal EVAR were amalgamated. The data originated from Australia, Canada (Ontario), and England (London, Cambridge, and Leicester).

To identify risk factors associated with spontaneous recurrent epistaxis.

Busulfan is an anti-leukemic, DNA alkylating agent that is used in conditioning regimens for patients undergoing hematopoietic stem cell transplantation. Because of the large intraindividual and interindividual variations seen in busulfan pharmacokinetics, therapeutic drug monitoring is necessary. Currently at the authors' institution, plasma busulfan in adults is measured by gas chromatography–mass spectrometry (GC-MS) at a reference laboratory, whereas pediatric specimens are sent to a different reference laboratory also for GC-MS analysis. As the result turnaround time is not optimal and this practice is of significant cost, a liquid chromatography–tandem mass spectrometry assay to quantify plasma busulfan was developed.

Pang: Jasper Therapeutics, Inc: Current Employment, Current equity holder in private company. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

Very high temperature reactors (VHTRs) and high temperature gas-cooled reactors (HTGRs) can develop extreme temperatures in excess of 900°C that make them theoretically very efficient, potentially in the range of 45% to 50%. The high temperatures, however, can also lead to a corresponding increase in fission product transport out of the fuel, which is potentially a source term-related safety issue. The aim of this work was to develop a repeatable, accurate, and cost-effective process to measure the diffusion coefficients of fission products in graphitic VHTR materials, particularly those materials used in the fabrication of TRISO [tristructural isotropic] fuel pellets. Specifically, this work has focused on the diffusion of silver in graphite. We constructed graphite cells that could be filled with a silver diffusant in the form of silver flakes, silver powder, or a preloaded, silver-laden graphite powder. The cells were hermetically sealed and heated to temperatures comparable to those that will be found in VHTRs. After being kept at various amounts of time and temperature, these cells were imaged using microtomography and electron microscopy. Concentration profiles were measured by sectioning the heat-treated cells and analyzing them using neutron activation analysis. Estimated diffusion coefficients for silver in a commercial grade of graphite are reported, but the method is easily adapted to any grade of graphite material including nuclear grades and to a variety of other fission product species.

Purpose: To present an economic evaluation of endovascular versus open surgical repair of ruptured abdominal aortic aneurysms (AAA).Methods: Endovascular aneurysm repair (EVAR) is currently being appraised by the National Institute for Clinical Excellence. To aid in this appraisal, a health economic model developed to demonstrate the cost-effectiveness of EVAR for elective treatment of nonruptured AAAs versus OSR was used for an analysis in the emergency setting. The base case data on 730 patients undergoing EVAR was extracted from our recently published 22- study meta-analysis of 7040 patients presenting with acute AAA(ruptured or symptomatic) treated with either emergency EVAR or OSR. These data reflected a patient population with an average age of 70 years. The base case model, which assumed a time horizon of 30 years and applied all-cause mortality rates, was subjected to a number of 1-way sensitivity analyses. A multivariate analysis was undertaken using 10,000 Monte-Carlo simulations.Results: EVAR dominated OSR in the base case analysis, with a mean cumulative cost/patient of £17,422 ($26,133) for EVAR and £18,930 ($28,395) for OSR [-£1508 ($2262) difference]. The mean quality-adjusted life years (QALYs)/patient was 3.09 for EVAR versus 2.49 for OSR (0.64 difference). EVAR was cost-effective compared with OSR at a threshold value of £20,000 to £30,000 ($30,000-$45,000)/QALY. In no single combination tested did open surgical repair provide the patient with more QALYs than EVAR. Sensitivity analyses demonstrated that the results were most sensitive to length of hospital and intensive care stays, use of blood products, and the cost of the EVAR device, which were the main cost drivers.Conclusion: While the UK's National Institute for Clinical Excellence does not set an absolute limit at which treatments would not be funded, £30,000 ($45,000) is generally regarded as the upper limit of acceptability. At this level, there is almost a 100% probability that EVAR is a cost-effective treatment for ruptured AAA.

Purpose: To report a randomized clinical trial designed to determine if remote ischemic preconditioning (IP) has the ability to reduce renal and cardiac damage following endovascular aneurysm repair (EVAR).Methods: Forty patients (all men; mean age 76±7 years) with abdominal aortic aneurysms averaging 6.3±0.8 cm in diameter were enrolled in the trial from November 2006 to January 2008. Eighteen patients (mean age 74 years, range 72–81) were randomized to preconditioning and completed the full remote IP protocol; there were no withdrawals. Twenty-two patients (mean age 76 years, range 66–80) were assigned to the control group. Remote IP was induced using sequential lower limb ischemia. Serum and urinary markers of renal and cardiac injury were compared between the groups.Results: Urinary retinol binding protein (RBP) levels increased 10-fold from a median of 235 µmol/L to 2356 µmol/L at 24 hours (p=0.0001). There was a lower increase in the preconditioned group, from 167 µmol/L to 413 µmol/L at 24 hours (p=0.04). The median urinary albumin:creatinine ratio was significantly lower in the preconditioned group at 24 hours (5 versus 8.8, p=0.06). There were no differences in the rates of renal impairment or major adverse cardiac events.Conclusion: Remote preconditioning reduces urinary biomarkers of renal injury in patients undergoing elective EVAR. This small pilot trial was unable to detect an effect on clinical endpoints; further trials are warranted.

Purpose: To compare the perioperative morbidity and mortality following endovascular aneurysm repair (EVAR) with a bifurcated stent-graft versus an aortomonoiliac stent-graft combined with a femorofemoral crossover graft.Methods: A prospectively maintained database of patients undergoing EVAR over a 7-year period (January 2001 to June 2008) was interrogated retrospectively to identify all patients receiving either a bifurcated or an aortomonoiliac stent-graft. Patients undergoing emergency treatment or renal/mesenteric fenestrated or iliac branched EVAR were excluded. Data retrieval found 210 patients (194 men; mean age 75 years) who had been treated with 41 aortomonoiliac stent-grafts and 169 bifurcated devices. The impact of preoperative and intraoperative variables on postoperative morbidity was assessed by means of univariate and multivariate logistic regression analysis.Results: Significant postoperative complications occurred in 41% (17/41) of aortomonoiliac stent-graft patients compared to 14% (23/169) of bifurcated stent-graft patients (p=0.0001). Univariate logistic regression analyses identified patient age, operating time, and implantation of an aortomonoiliac stent-graft as significant predictors of postoperative complications. In a multivariate logistic regression model, only implantation of an aortomonoiliac stent-graft was independently associated with postoperative complications (p=0.003).Conclusion: Compared to EVAR with a bifurcated device, the implantation of an aortomonoiliac stent-graft and crossover bypass is associated with higher patient morbidity similar to rates reported after open repair. These patients comprise a high-risk endovascular group and require careful postoperative management in order to minimize complications.

Channel catfish Ictalurus punctatuswere intraperitoneally challenged with the bacterium Edwardsiella ictaluri(the causative agent of enteric septicemia of catfish), and the expression of genes presumed to function in the inducible innate defense was evaluated. End-binding protein 1 (EB1), ß1-integrin, natural-resistance-associated macrophage protein (Nramp), heat shock protein 70 (Hsp70), serum amyloid P (SAP), and transferrin gene expression profiles were determined using quantitative reverse-transcriptase–polymerase chain reaction on liver, anterior kidney, spleen, and gut. Fish were subsampled at 0, 24, 48, 72, and 96 h after bacterial or phosphate-buffered-saline injection. Posterior kidney sampling demonstrated increasing bacterial counts at 24–48 h postinjection (hpi), followed by a plateau to 96 hpi. The transferrin and SAP transcripts were liver specific. The other genes were expressed in all four tissues. In bacterially infected fish, expression of EB1 (anterior kidney, spleen, and liver), Hsp70 (anterior kidney and spleen), and Nramp (spleen and gut) significantly increased by 48 hpi. Transferrin was strongly up-regulated and SAP was down-regulated by 72 hpi, indicating positive and negative acute-phase reactants, respectively. The data indicate a substantial response of innate immunity effector cells by 48 hpi, followed by suppression of bacterial growth and induction of the acute-phase response. This suggests that the 48–72-hpi time frame is critical in our model for evaluating the effectiveness of innate defenses.

Marfan syndrome (MFS) is an inherited disorder of connective tissue that is historically associated with high mortality due to disorders of the cardiovascular system. Over the past 40 years, surgery to the aortic root and thoracoabdominal aorta has resulted in a significantly prolonged life expectancy. More recently, techniques for endovascular repair of the aortic complications of MFS have been described. In this article we review the relative merits of open and endovascular approaches to thoracic aortic complications in MFS, comparing outcomes from contemporary literature.A reasonably large body of evidence has developed concerning the surgical treatment of the aortic root, ascending thoracic aorta, and arch in MFS. It is clear from large series that pathology, such as acute type A dissections and aneurysmal dilatation, can be successfully repaired with low mortality. Recently published series, although reporting smaller numbers, have demonstrated that the same is true for open surgical replacement of descending thoracic and thoracoabdominal aortic aneurysms. The evidence for thoracic endovascular aortic repair in MFS is much more limited. Small series and registry or case reports describe a heterogeneous group of patients with only short-term follow-up. Outcomes of endovascular repair are mixed, with questionable longevity. Reoperation is, however, common in MFS, and minimally invasive techniques may provide a bridging role or alternative solution when revisiting the hostile surgical field.

Endovascular repair of ruptured abdominal aortic aneurysms is an evolving technique. Data from nonrandomized series suggest that it may be beneficial in selected patients. In the next few years, a number of large randomized clinical trials will clarify its role. Issues regarding anatomical suitability, techniques, perioperative care, and service provision need to be addressed in order to optimize outcomes.

For students with disabilities (SWD), note taking during content area classes can be a puzzling process. Students often aren’t certain about what specific content to record, how many details to record, and how to write fast enough to keep up with the teacher. Smartpens are an underutilized type of technology that can help students to become better note takers by storing verbal information during lectures and syncing it up later when students amend their notes. This article provides an overview of different types of smartpens and information for teachers about how to use smartpens in the classroom.

Ionizing radiation exposure is an inherent component of endovascular surgery. As procedures become more complex, greater radiation exposure is incurred by both staff and patient. Radiation doses during endovascular aneurysm repair are similar to those recorded during percutaneous coronary interventions. Ionizing radiation may cause skin injury, as well as increase the long-term risk of malignancy. Endovascular surgeons need to be aware of radiation hazards and take all reasonable steps to minimize the risks to both patients and staff.

Introduction:Total Body Irradiation (TBI) conditioning regimens are considered standard of care for pediatric hematopoietic cell transplant (HCT) recipients. However, TBI has many long-term effects, so avoiding it in young HCT recipients is critical. Fludarabine is frequently used in combination with other chemotherapeutic agents like busulfan and/or thiotepa in non-TBI based conditioning regimens. While multi-drug conditioning aims to avoid TBI-related late-effects, little is known about the effect of variations in genes that metabolize these drugs (pharmacogenomics/PGx) on clinical outcomes including engraftment, relapse, and acute drug-related toxicities. In this study, we investigated the pharmacogenomic effects on HCT outcomes such as event-free outcomes and re-transplantation outcomes, as well as fludarabine's pharmacokinetics (PK).

Successful hematopoietic cell transplantation (HCT) relies on conditioning of recipients to deplete hematopoietic stem cells (HSC) from marrow niches to allow healthy HSC to engraft. Currently, only genotoxic chemotherapy and/or radiation are used to achieve such niche clearance. We have developed a targeted non-genotoxic approach to deplete HSC using a monoclonal antibody, JSP191, that binds human CD117 (c-Kit), a receptor tyrosine kinase expressed on HSC and progenitor cells (HSPC). We have opened a phase 1 dose escalation trial using JSP191 as the sole conditioning agent in patients with SCID (ClinicalTrials.gov: NCT02963064). HCT is the only definitive cure for SCID, a uniformly lethal genetic immune disorder. Because infants with SCID lack functional T cells which can mediate transplant rejection and because of toxicity concerns, SCID infants may receive HCT without conditioning. This approach is associated with presumed engraftment of donor lymphoid progenitors but not HSC, resulting in incomplete and poorly sustained immune reconstitution, evidenced by naïve T cell production that wane over time and absent functional B cells requiring life-long immunoglobulin (Ig) replacement. Second donor HSC transplants (“boosts”) without conditioning have not led to HSC engraftment and thus immune defects persist.

Precise and accurate estimation of C and N in forest soils is important for monitoring long‐term site productivity and C stock changes. Obtaining such estimates remains a major challenge, however, especially because of high natural variability in the forest floor. Although most researchers have used simple random sampling (SRS) for within‐plot soil sampling, double sampling for stratification (DSS) can be used to decrease costs, increase precision, and increase power. Estimates of C and N stocks based on DSS were compared with those estimated by SRS in the humus forms of Douglas‐fir [Pseudotsuga menziesii(Mirb.) Franco] stands in the Cascade Mountains of Oregon. Generally, DSS was 1.34 to 5.11 times more efficient than SRS for total C, and 1.07 to 2.00 for total N. Coefficients of variation estimated from DSS were about one‐half of those estimated by SRS and reported elsewhere in the literature. The cost for sampling using DSS was one‐third to one‐half of that for SRS, depending on the number of strata used. Costs were reduced because fewer samples were required using DSS to provide the same precision as SRS. The DSS design was more powerful than SRS and could detect smaller changes than SRS with the same number of samples. Results suggested that the most efficient design for total C would use two strata where samples were allocated proportional to variance rather than proportional to area. Overall, large gains in efficiency can be realized with a more complex within‐plot sampling design, i.e., DSS, compared with SRS.