Mild Hypoxia of a Skydiver Making Repeated, Medium-Altitude Aircraft Exits.

INTRODUCTION: Dramatic increases in parachuting safety over the last three decades have been attributed to advances in technology and training for parachutists. However, very little is known about the physiological condition of skydivers making repeated, medium-altitude aircraft exits without using supplemental oxygen. As in aviation, human error is broadly responsible for the majority of skydiving mishaps, although it is unclear what role, if any, physiological factors contribute to these mishaps. Over the course of 2 d, a healthy, 50-yr-old male skydiver executed four normal exits (two jumps per day) from an aircraft between 13,500 and 14,000 ft (4115 and 4267 m) pressure altitude while wearing a helmet-mounted biomonitoring device (SPYDR, Spotlight Labs). On both days, after the subject's second jump, he reported feeling lightheaded and dizzy, symptoms he experiences approximately once every five jumps, and had previously attributed to the excitement of the jump. Inspection of Spo2 and pulse data revealed that the subject was mildly hypoxic at jump altitude (Spo2 < 90%). For all four jumps, Spo2 did not return to normal levels until under canopy. Previous studies have evaluated the cognitive impairment of general aviation pilots operating unpressurized aircraft above 12,500 ft (3810 m) without supplemental oxygen. Alarmingly, mildly hypoxic pilots exhibited twice the rate of procedural errors as compared to normally oxygenated subjects. This study found that the skydiver exited the aircraft with mild hypoxia, which has been associated with cognitive impairment in pilots and could possibly be linked to injuries and/or fatalities.Bradke BS, Everman BR. Mild hypoxia of a skydiver making repeated, medium-altitude aircraft exits. Aerosp Med Hum Perform. 2020; 91(2):110-115.

Wireless Resonant Circuits Printed Using Aerosol Jet Deposition for MRI Catheter Tracking.

Interventional magnetic resonance imaging (MRI) could allow for diagnosis and immediate treatment of ischemic stroke; however, such endovascular catheter-based procedures under MRI guidance are inherently difficult. One major challenge is tracking the tip of the catheter, as standard fabrication methods for building inductively coupled coil markers are rigid and bulky. Here, we report a new approach that uses aerosol jet deposition to three-dimensional (3-D) print an inductively coupled RF coil marker on a polymer catheter. Our approach enables lightweight conforming markers on polymer catheters and these low-profile markers allow the catheter to be more safely navigated in small caliber vessels. Prototype markers with an inductor with the geometry of a double helix are incorporated on catheters for in vitro studies, and we show that these markers exhibit good signal amplification. We report temperature measurements and, finally, demonstrate feasibility in a preliminary in vivo experiment. We provide material properties and electromagnetic simulation performance analysis. This paper presents fully aerosol jet-deposited and functional wireless resonant markers on polymer catheters for use in 3T clinical scanners.

Measurements of Nonsinglet Moments of the Nucleon Structure Functions and Comparison to Predictions from Lattice QCD for Q

We present extractions of the nucleon nonsinglet moments utilizing new precision data on the deuteron F_{2} structure function at large Bjorken-x determined via the Rosenbluth separation technique at Jefferson Lab Experimental Hall C. These new data are combined with a complementary set of data on the proton previously measured in Hall C at similar kinematics and world datasets on the proton and deuteron at lower x measured at SLAC and CERN. The new Jefferson Lab data provide coverage of the upper third of the x range, crucial for precision determination of the higher moments. In contrast to previous extractions, these moments have been corrected for nuclear effects in the deuteron using a new global fit to the deuteron and proton data. The obtained experimental moments represent an order of magnitude improvement in precision over previous extractions using high x data. Moreover, recent exciting developments in lattice QCD calculations provide a first ever comparison of these new experimental results with calculations of moments carried out at the physical pion mass, as well as a new approach that first calculates the quark distributions directly before determining moments.

Genetic relatedness reveals total population size of white sharks in eastern Australia and New Zealand.

Conservation concerns exist for many sharks but robust estimates of abundance are often lacking. Improving population status is a performance measure for species under conservation or recovery plans, yet the lack of data permitting estimation of population size means the efficacy of management actions can be difficult to assess, and achieving the goal of removing species from conservation listing challenging. For potentially dangerous species, like the white shark, balancing conservation and public safety demands is politically and socially complex, often leading to vigorous debate about their population status. This increases the need for robust information to inform policy decisions. We developed a novel method for estimating the total abundance of white sharks in eastern Australia and New Zealand using the genetic-relatedness of juveniles and applying a close-kin mark-recapture framework and demographic model. Estimated numbers of adults are small (ca. 280-650), as is total population size (ca. 2,500-6,750). However, estimates of survival probability are high for adults (over 90%), and fairly high for juveniles (around 73%). This represents the first direct estimate of total white shark abundance and survival calculated from data across both the spatial and temporal life-history of the animal and provides a pathway to estimate population trend.

Treatment dynamics of bone-targeting agents among men with bone metastases from prostate cancer in the United States.

PURPOSE: To examine the dynamics of treatment with 2 bone-targeting agents (BTAs)-denosumab and zoledronic acid-among men with bone metastases from prostate cancer. METHODS: Using electronic health record data from oncology practices across the US, we identified prostate cancer patients diagnosed with bone metastasis in 2012/2013 without evidence of BTA use within 6 months prior to diagnosis. We examined the risk and predictors of BTA initiation, interruption, and re-initiation. RESULTS: Among 897 men diagnosed with prostate cancer, the cumulative incidence of BTA initiation after bone metastasis diagnosis was 34% (95% confidence interval [CI], 31-37%) at 30 days, 64% (95% CI, 61-68%) at 180 days, and 88% (95% CI, 85-91%) at 2 years. Denosumab was initiated more frequently than zoledronic acid. Men with diabetes, more bone lesions, history of androgen deprivation therapy, or no hospice enrollment were more likely to initiate treatment. Following initiation, the cumulative incidence of treatment interruption was 17% (95% CI, 14-19%) at 60 days and 70% (95% CI, 66-74%) at 2 years, with interruption more likely among patients receiving emerging therapies for prostate cancer or enrolling in hospice. The cumulative incidence of re-initiation following interruption was 36.3% (95% CI, 32.7-40.2%) at 15 days, 49.8% (95% CI, 45.9-54.1%) at 30 days, and 81.0% (95% CI, 77.5-84.7%) at 1 year. CONCLUSIONS: Bone-targeting agent therapy is initiated by the majority of men living with bone metastases following a prostate cancer diagnosis; however, the timing of initiation is highly variable. Once on treatment, gaps or interruptions in therapy are common.

Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer.

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Total depression and subtypes in prostate cancer survivors 10 years after treatment.

To describe the prevalence, severity and nature of depression in a sample of prostate cancer (PCa) survivors 10 years after diagnosis and treatment, 146 Australian patients from the RADAR trial who received their diagnosis 10 years previously completed the Zung Self-rating Depression Scale and a background questionnaire. Prevalence rates for clinically significant depression and severe depression were higher than those reported for the non-PCa men of the same age in Australia. The most common subtype of depression was Anhedonia, followed by Cognitive depression. Change in eating habits was the most powerful depression symptom predicting Anhedonia. By providing the first detailed documentation of major depression prevalence in PCa survivors, plus describing the nature of that depression, these data suggest that there is an ongoing need to provide treatments for these men and that those treatments should be focussed upon loss of previously available sources of enjoyment.

Experience of the National Cancer Institute Community Cancer Centers Program on Community-Based Cancer Clinical Trials Activity.

PURPOSE: A goal of the National Cancer Institute Community Cancer Centers Program (NCCCP) was to improve cancer research capacity in community settings. We examined research capacity development during the pilot phase of the NCCCP within the context of national trends in clinical trial activity with respect to the number and phase of trials, total accrual, and accrual of underserved populations. MATERIALS AND METHODS: We examined self-reported data from NCCCP sites during 2007 to 2010, supplemented with data from the National Cancer Institute Cancer Therapy Evaluation Program. RESULTS: Trial availability and accrual improved more quickly at NCCCP sites compared with national trends. Phase III trial availability increased 8% nationally versus 16% across NCCCP sites, and accrual increased 30% nationally versus 133% across NCCCP sites. Accrual of racial and ethnic minorities rose 82%, from 83 to 151 patients, and accrual of patients age ≥ 65 years rose by 221%, from 200 to 641 patients. Change in trial portfolio and accrual differed by sophistication of the site and by prior experience in conducting clinical trials at the site. CONCLUSION: Despite the short duration, the NCCCP pilot resulted in an increase in the number of open trials as well as patient accrual at a faster rate than that observed nationally. These results, coupled with insights into the relative success of sites with varying sophistication at the outset, provide promise that lessons learned can be applied more broadly to increase research participation.

Endovascular MR-guided Renal Embolization by Using a Magnetically Assisted Remote-controlled Catheter System.

Purpose To assess the feasibility of a magnetically assisted remote-controlled (MARC) catheter system under magnetic resonance (MR) imaging guidance for performing a simple endovascular procedure (ie, renal artery embolization) in vivo and to compare with x-ray guidance to determine the value of MR imaging guidance and the specific areas where the MARC system can be improved. Materials and Methods In concordance with the Institutional Animal Care and Use Committee protocol, in vivo renal artery navigation and embolization were tested in three farm pigs (mean weight 43 kg ± 2 [standard deviation]) under real-time MR imaging at 1.5 T. The MARC catheter device was constructed by using an intramural copper-braided catheter connected to a laser-lithographed saddle coil at the distal tip. Interventionalists controlled an in-room cart that delivered electrical current to deflect the catheter in the MR imager. Contralateral kidneys were similarly embolized under x-ray guidance by using standard clinical catheters and guidewires. Changes in renal artery flow and perfusion were measured before and after embolization by using velocity-encoded and perfusion MR imaging. Catheter navigation times, renal parenchymal perfusion, and renal artery flow rates were measured for MR-guided and x-ray-guided embolization procedures and are presented as means ± standard deviation in this pilot study. Results Embolization was successful in all six kidneys under both x-ray and MR imaging guidance. Mean catheterization time with MR guidance was 93 seconds ± 56, compared with 60 seconds ± 22 for x-ray guidance. Mean changes in perfusion rates were 4.9 au/sec ± 0.8 versus 4.6 au/sec ± 0.6, and mean changes in renal flow rate were 2.1 mL/min/g ± 0.2 versus 1.9 mL/min/g ± 0.2 with MR imaging and x-ray guidance, respectively. Conclusion The MARC catheter system is feasible for renal artery catheterization and embolization under real-time MR imaging in vivo, and quantitative physiologic measures under MR imaging guidance were similar to those measured under x-ray guidance, suggesting that the MARC catheter system could be used for endovascular procedures with interventional MR imaging. (©) RSNA, 2016.

Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

IMPORTANCE: Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized. OBJECTIVE: To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies. DATA SOURCE: A database of all oncology clinical trials registered at clinicaltrials.gov between October 1, 2007, and September 30, 2010. STUDY SELECTION: Trials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST). DATA EXTRACTION AND SYNTHESIS: A systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly. MAIN OUTCOMES AND MEASURES: For each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type. RESULTS: From 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (τ = 0.27, P < .001; τ = 0.12, P = .01); this relationship was stronger for single-agent therapies (τ = 0.49; τ = 0.41) than for combination regimens (τ = 0.28; τ = 0.17). Evaluation of ORR thresholds between 20% and 60% as potential trial end points demonstrated that ORR statistically exceeding 30% with a single agent had 98% specificity and 89% positive predictive value for identifying regimens achieving regulatory approval. CONCLUSIONS AND RELEVANCE: For single-agent regimens, high ORR was associated with regulatory approval; this relationship was less strong for combination regimens. Our data suggest that high ORR (eg, statistically exceeding an ORR of 30%) is an appropriate end point for single-arm trials aiming to demonstrate breakthrough activity of a single-agent anticancer therapy.

Procoagulant microparticles promote coagulation in a factor XI-dependent manner in human endotoxemia.

UNLABELLED: Essentials The procoagulant effects of microparticles (MPs) on coagulation in endotoxemia are not known. MPs from endotoxemia volunteers were evaluated for procoagulant activity in a plasma milieu. MPs from endotoxemia volunteers shortened clotting times and enhanced thrombin generation. MP procoagulant effects were mediated in a factor XI-dependent manner. SUMMARY: Background Human endotoxemia is characterized by acute inflammation and activation of coagulation, as well as increased numbers of circulating microparticles (MPs). Whether these MPs directly promote coagulation and through which pathway their actions are mediated, however, has not been fully explored. Objectives In this study, we aimed to further characterize endotoxin-induced MPs and their procoagulant properties using several approaches. Methods Enumeration and characterization of MPs were performed using a new-generation flow cytometer. Relative contributions of the extrinsic and intrinsic pathways in MP-mediated procoagulant activity were assessed using plasmas deficient in factor (F) VII or FXI or with blocking antibodies to tissue factor (TF) or FXIa. Results Total MPs and platelet MPs were significantly elevated in plasma at 6 h after infusion of endotoxin in healthy human subjects. MPs isolated from plasma following endotoxin infusion also demonstrated increased TF activity in a reconstituted buffer system. When added to recalcified platelet-poor plasma, these MPs also promoted coagulation, as judged by a decreased clotting time with shortening of the lag time and time to peak thrombin using calibrated automated thrombography (CAT). However, the use of FVII-deficient plasma or blocking antibody to TF did not inhibit these procoagulant effects. In contrast, plasma clotting time was prolonged in FXI-deficient plasma and a blocking antibody to FXIa inhibited all MP-mediated parameters in the CAT assay. Conclusions The initiation of coagulation by cellular TF in endotoxemia is in contrast to (and presumably complemented by) the intrinsic pathway-mediated procoagulant effects of circulating MPs.

Sequential Therapy in Metastatic Renal Cell Carcinoma.

The treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network's Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future.

Segregation or aggregation? Sex-specific patterns in the seasonal occurrence of white sharks Carcharodon carcharias at the Neptune Islands, South Australia.

The seasonal patterns of occurrence of male and female white sharks Carcharodon carcharias at the Neptune Islands in South Australia were reviewed. Analyses of a 14 year data series indicate that females seasonally aggregate in late autumn and winter coinciding with the maximum in-water availability of lactating female long-nose fur seals and seal pups. During this period, observed male:female sex ratios were similar; whereas during late spring and summer, males continued to visit, but females were rarely recorded. There was no evidence for segregation by sex or size at the Neptunes, but the highly focused seasonal pattern of occurrence of females compared with the year-round records of males suggests that there are likely to be differences between the sexes in overall distribution and movement patterns across southern Australia. It is suggested that foraging strategies and prey selection differ between sexes in C. carcharias across the life-history stages represented and that sex-specific foraging strategies may play an important role in structuring movement patterns and the sex ratios observed at such aggregation sites. Differences between sexes in distribution, movement patterns and foraging strategies are likely to have implications for modelling the consequences of fisheries by-catch between regions or jurisdictions and other spatially or temporally discrete anthropogenic effects on C. carcharias populations. Such differences urge for caution when estimating the size of C. carcharias populations based on observations at pinniped colonies due to the likelihood of sex-specific differences in movements and patterns of residency. These differences also suggest a need to account for sex-specific movement patterns and distribution in population and movement models as well as under conservation actions.

Clinical Trial Participants With Metastatic Renal Cell Carcinoma Differ From Patients Treated in Real-World Practice.

PURPOSE: Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials. PATIENTS AND METHODS: In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices. RESULTS: A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received. CONCLUSION: Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Initial Trends in the Use of the 21-Gene Recurrence Score Assay for Patients With Breast Cancer in the Medicare Population, 2005-2009.

IMPORTANCE: In 2006, the Centers for Medicare & Medicaid Services approved coverage for the use of the 21-gene recurrence score (RS) assay in women with early-stage, estrogen receptor-positive, node-negative breast cancers to help guide recommendations for adjuvant chemotherapy. Use of the assay in community settings has not been previously examined in a nationally representative sample of patients. OBJECTIVE: To examine trends in the use of the RS assay in routine clinical practice in a nationally representative sample of women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of Medicare beneficiaries diagnosed with incident breast cancer between 2005 and 2009, as recorded in a Surveillance, Epidemiology, and End Results data set with linked Medicare claims through 2010. MAIN OUTCOMES AND MEASURES: Demographic and clinical variables associated with the use of the assay. RESULTS: A total of 70,802 patients met the study criteria. Use of the RS assay increased from 1.1% in 2005 to 10.1% in 2009 (P < .001). The majority of tests (60.9%) occurred in patients with National Comprehensive Cancer Network-defined intermediate-risk disease (ie, estrogen receptor-positive, node-negative tumors >1 cm). Most patients with other than intermediate-risk disease had borderline indications for testing, including T1b (47.5%) or N1 (26.8%) disease. Testing was associated with younger age, fewer comorbid conditions, higher-grade disease, and being married. Among patients younger than 70 years with intermediate-risk disease, testing rates increased from 7.7% in 2005 to 38.8% in 2009 (P < .001). In multivariable analysis, testing was modestly higher in Northeast than in Western registries (odds ratio, 1.83; 95% CI, 1.49-2.26) but was otherwise not associated with region, local census tract demographic characteristics, black race, location in an urban area, or tumor histologic characteristics. CONCLUSIONS AND RELEVANCE: The RS assay was adopted quickly in clinical practice after the Medicare coverage decision in 2006, and use appears to be consistent with guidelines and equitable across geographic and racial groups. Factors influencing adoption of the assay and its impact on adjuvant chemotherapy use in clinical practice remain important areas of study.

Relationship Between Cancer and Cardiovascular Outcomes Following Percutaneous Coronary Intervention.

BACKGROUND: Cardiovascular disease and cancer increasingly coexist, yet relationships between cancer and long-term cardiovascular outcomes post-percutaneous coronary intervention (PCI) are not well studied. METHODS AND RESULTS: We examined stented PCI patients at Duke (1996-2010) using linked data from the Duke Information Systems for Cardiovascular Care and the Duke Tumor Registry (a cancer treatment registry). Our primary outcome was cardiovascular mortality. Secondary outcomes included composite cardiovascular mortality, myocardial infarction, or repeat revascularization and all-cause mortality. We used adjusted cause-specific hazard models to examine outcomes among cancer patients (cancer treatment pre-PCI) versus controls (no cancer treatment pre-PCI). Cardiovascular mortality was explored in a cancer subgroup with recent (within 1 year pre-PCI) cancer and in post-PCI cancer patients using post-PCI cancer as a time-dependent variable. Among 15 008 patients, 3.3% (n=496) were cancer patients. Observed rates of 14-year cardiovascular mortality (31.4% versus 27.7%, P=0.31) and composite cardiovascular death, myocardial infarction, or revascularization (51.1% versus 55.8%, P=0.37) were similar for cancer versus control groups; all-cause mortality rates were higher (79.7% versus 49.3%, P<0.01). Adjusted risk of cardiovascular mortality was similar for cancer patients versus controls (hazard ratio 0.95; 95% CI 0.76 to 1.20) and for patients with versus without recent cancer (hazard ratio 1.46; 95% CI 0.92 to 2.33). Post-PCI cancer, present in 4.3% (n=647) of patients, was associated with cardiovascular mortality (adjusted hazard ratio 1.51; 95% CI 1.11 to 2.03). CONCLUSIONS: Cancer history was present in a minority of PCI patients but was not associated with worse long-term cardiovascular outcomes. Further investigation into PCI outcomes in this population is warranted.

New-Generation Laser-lithographed Dual-Axis Magnetically Assisted Remote-controlled Endovascular Catheter for Interventional MR Imaging: In Vitro Multiplanar Navigation at 1.5 T and 3 T versus X-ray Fluoroscopy.

PURPOSE: To assess the feasibility of multiplanar vascular navigation with a new magnetically assisted remote-controlled (MARC) catheter with real-time magnetic resonance (MR) imaging at 1.5 T and 3 T and to compare it with standard x-ray guidance in simulated endovascular catheterization procedures. MATERIALS AND METHODS: A 1.6-mm-diameter custom clinical-grade microcatheter prototype with lithographed double-saddle coils at the distal tip was deflected with real-time MR imaging. Two inexperienced operators and two experienced operators catheterized anteroposterior (celiac, superior mesenteric, and inferior mesenteric arteries) and mediolateral (renal arteries) branch vessels in a cryogel abdominal aortic phantom. This was repeated with conventional x-ray fluoroscopy by using clinical catheters and guidewires. Mean procedure times and percentage success data were analyzed with linear mixed-effects regression. RESULTS: The MARC catheter tip was visible at 1.5 T and 3 T. Among inexperienced operators, MARC MR imaging guidance was not statistically different from x-ray guidance at 1.5 T (67% successful vessel selection turns with MR imaging vs 76% with x-ray guidance, P = .157) and at 3 T (75% successful turns with MR imaging vs 76% with x-ray guidance, P = .869). Experienced operators were more successful in catheterizing vessels with x-ray guidance (98% success within 60 seconds) than with 1.5-T (65%, P < .001) or 3-T (75%) MR imaging. Among inexperienced operators, mean procedure time was nearly equivalent by using MR imaging (31 seconds) and x-ray guidance (34 seconds, P = .436). Among experienced operators, catheterization was faster with x-ray guidance (20 seconds) compared with 1.5-T MR imaging (42 seconds, P < .001), but MARC guidance improved at 3 T (31 seconds). MARC MR imaging guidance at 3 T was not significantly different from x-ray guidance for the celiac (P = .755), superior mesenteric (P = .358), and inferior mesenteric (P = .065) arteries. CONCLUSION: Multiplanar navigation with a new MARC catheter with real-time MR imaging at 1.5 T and 3 T is feasible and comparable to x-ray guidance for anteroposterior vessels at 3 T in a vascular phantom.

Surface hydrolysis of sphingomyelin by the outer membrane protein Rv0888 supports replication of Mycobacterium tuberculosis in macrophages.

Sphingomyelinases secreted by pathogenic bacteria play important roles in host-pathogen interactions ranging from interfering with phagocytosis and oxidative burst to iron acquisition. This study shows that the Mtb protein Rv0888 possesses potent sphingomyelinase activity cleaving sphingomyelin, a major lipid in eukaryotic cells, into ceramide and phosphocholine, which are then utilized by Mtb as carbon, nitrogen and phosphorus sources, respectively. An Mtb rv0888 deletion mutant did not grow on sphingomyelin as a sole carbon source anymore and replicated poorly in macrophages indicating that Mtb utilizes sphingomyelin during infection. Rv0888 is an unusual membrane protein with a surface-exposed C-terminal sphingomyelinase domain and a putative N-terminal channel domain that mediated glucose and phosphocholine uptake across the outer membrane in an M. smegmatis porin mutant. Hence, we propose to name Rv0888 as SpmT (sphingomyelinase of Mycobacterium tuberculosis). Erythrocyte membranes contain up to 27% sphingomyelin. The finding that Rv0888 accounts for half of Mtb's hemolytic activity is consistent with its sphingomyelinase activity and the observation that Rv0888 levels are increased in the presence of erythrocytes and sphingomyelin by 5- and 100-fold, respectively. Thus, Rv0888 is a novel outer membrane protein that enables Mtb to utilize sphingomyelin as a source of several essential nutrients during intracellular growth.

Imaging of small animal peripheral artery disease models: recent advancements and translational potential.

Peripheral artery disease (PAD) is a broad disorder encompassing multiple forms of arterial disease outside of the heart. As such, PAD development is a multifactorial process with a variety of manifestations. For example, aneurysms are pathological expansions of an artery that can lead to rupture, while ischemic atherosclerosis reduces blood flow, increasing the risk of claudication, poor wound healing, limb amputation, and stroke. Current PAD treatment is often ineffective or associated with serious risks, largely because these disorders are commonly undiagnosed or misdiagnosed. Active areas of research are focused on detecting and characterizing deleterious arterial changes at early stages using non-invasive imaging strategies, such as ultrasound, as well as emerging technologies like photoacoustic imaging. Earlier disease detection and characterization could improve interventional strategies, leading to better prognosis in PAD patients. While rodents are being used to investigate PAD pathophysiology, imaging of these animal models has been underutilized. This review focuses on structural and molecular information and disease progression revealed by recent imaging efforts of aortic, cerebral, and peripheral vascular disease models in mice, rats, and rabbits. Effective translation to humans involves better understanding of underlying PAD pathophysiology to develop novel therapeutics and apply non-invasive imaging techniques in the clinic.

Deferred systemic therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: With the advent of small-molecule "targeted" therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described. METHODS: We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review. RESULTS: A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of ≤ 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as "other." CONCLUSIONS: The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy.