Cholinergic system adaptations are associated with cognitive function in people recently abstinent from smoking: a (-)-[18F]flubatine PET study.

The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the ß2-subunit containing nicotinic acetylcholine receptor (ß2*-nAChR) partial agonist radioligand (-)-[18F]flubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-[18F]Flubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (VT) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-[18F]flubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-[18F]flubatine VT, consistent with increased cortical acetylcholine levels reducing the number of ß2*-nAChR sites available for (-)-[18F]flubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-[18F]flubatine VT was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.

Capillary electrophoresis Western blot using inkjet transfer to membrane.

Traditional Western blots are commonly used to separate and assay proteins; however, they have limitations including a long, cumbersome process and large sample requirements. Here, we describe a system for Western blotting where capillary gel electrophoresis is used to separate sodium dodecyl sulfate-protein complexes. The capillary outlet is threaded into a piezoelectric inkjetting head that deposits the separated proteins in a quasi-continuous stream of <100 pL droplets onto a moving membrane. Through separations at 400 V/cm and protein capture on a membrane moving at 2 mm/min, we are able to detect actin with a limit of detection at 8 pM, or an estimated 5 fg injected. Separation and membrane capture of sample containing 10 proteins ranging in molecular weights from 11 - 250 kDa was achieved in 15 min. The system was demonstrated with Western blots for actin, ß-tubulin, ERK1/2, and STAT3 in human A431 epidermoid carcinoma cell lysate.

Surgical aortic valve replacement in the era of transcatheter aortic valve implantation: a review of the UK national database.

OBJECTIVES: To date the reported outcomes of surgical aortic valve replacement (SAVR) are mainly in the settings of trials comparing it with evolving transcatheter aortic valve implantation. We set out to examine characteristics and outcomes in people who underwent SAVR reflecting a national cohort and therefore 'real-world' practice. DESIGN: Retrospective analysis of prospectively collected data of consecutive people who underwent SAVR with or without coronary artery bypass graft (CABG) surgery between April 2013 and March 2018 in the UK. This included elective, urgent and emergency operations. Participants' demographics, preoperative risk factors, operative data, in-hospital mortality, postoperative complications and effect of the addition of CABG to SAVR were analysed. SETTING: 27 (90%) tertiary cardiac surgical centres in the UK submitted their data for analysis. PARTICIPANTS: 31 277 people with AVR were identified. 19 670 (62.9%) had only SAVR and 11 607 (37.1%) had AVR+CABG. RESULTS: In-hospital mortality for isolated SAVR was 1.9% (95% CI 1.6% to 2.1%) and was 2.4% for AVR+CABG. Mortality by age category for SAVR only were: <60 years=2.0%, 60-75 years=1.5%, >75 years=2.2%. For SAVR+CABG these were; 2.2%, 1.8% and 3.1%. For different categories of EuroSCORE, mortality for SAVR in low risk people was 1.3%, in intermediate risk 1% and for high risk 3.9%. 74.3% of the operations were elective, 24% urgent and 1.7% emergency/salvage. The incidences of resternotomy for bleeding and stroke were 3.9% and 1.1%, respectively. Multivariable analyses provided no evidence that concomitant CABG influenced outcome. However, urgency of the operation, poor ventricular function, higher EuroSCORE and longer cross clamp and cardiopulmonary bypass times adversely affected outcomes. CONCLUSIONS: Surgical SAVR±CABG has low mortality risk and a low level of complications in the UK in people of all ages and risk factors. These results should inform consideration of treatment options in people with aortic valve disease.

A Novel Immunoassay for Malondialdehyde-Conjugated Low-Density Lipoprotein Measures Dynamic Changes in the Blood of Patients Undergoing Coronary Artery Bypass Graft Surgery.

Oxidized low-density lipoproteins play an important role in tissue pathology. In this study, we report a sensitive novel enzyme-linked immunosorbent assay for the detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a key component of oxidized LDL. The assay is capable of measuring a variable presence of MDA-LDL within human plasma and serum. We demonstrate the robust nature of the assay on samples stored for over 20 months, as well as high inter-operator reproducibility (r = 0.74, p < 0.0001). The assay was capable of detecting dynamic changes in patient blood samples after coronary artery bypass graft surgery, indicating synthesis or release of MDA-LDL with the oxidative stress of surgery, followed by homeostatic clearance. This robust, sensitive and specific assay for circulating MDA-LDL will serve as a valuable translational tool for the improved detection of oxidative forms of LDL in response to a range of physiological or pathological stimuli, with potential clinical applicability.

Assessment of transient dopamine responses to smoked cannabis.

BACKGROUND: Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D2/3 receptor antagonist [11C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. METHODS: PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [11C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (Kbol = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ9-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [11C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). RESULTS: Cannabis smoking increased plasma Δ9-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [11C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. CONCLUSIONS: These preliminary data support the sensitivity of [11C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.

Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence.

Chronic alcohol use has important effects on the glutamate system. The metabotropic glutamate 5 (mGlu5) receptor has shown promise in preclinical models as a target to reduce drinking-related behaviors and cue-induced reinstatement, motivating human studies of mGlu5 receptor negative allosteric modulators. The goal of this work was to measure levels of mGlu5 receptor availability with positron emission tomography (PET) imaging using the mGlu5 receptor-specific radiotracer [18F]FPEB during early and extended alcohol abstinence. Subjects who met DSM-5 criteria for alcohol use disorder (AUD; n = 17) were admitted inpatient for the study duration. [18F]FPEB PET scans were acquired first during early abstinence (6 ± 4 days after last drink) and a second time during extended abstinence (n = 13; 27 ± 6 days after last drink). A single scan was acquired in healthy controls matched for sex and smoking status (n = 20). [18F]FPEB total volumes of distribution (VT) corrected for partial volume effects were measured using equilibrium analysis throughout the brain. A linear mixed model controlling for smoking status and sex identified significantly higher [18F]FPEB VT in AUD subjects at early abstinence compared to controls (F(1,32) = 7.23, p = 0.011). Post-hoc analyses revealed this effect to occur in cortical brain regions. No evidence for significant changes in [18F]FPEB VT over time were established. These findings provide human evidence consistent with a robust preclinical literature supporting mGlu5 receptor drugs as pharmacotherapies for AUD.

The Pre-Registry Commercial Driver Medical Examination: Screening Sensitivity and Certification Lengths for Two Safety-Related Medical Conditions.

OBJECTIVE: Use independent diagnostic data to analyze the screening effectiveness of the pre-Registry commercial driver medical examination (CDME) for obstructive sleep apnea (OSA), and its sensitivity for hypertension; analyze certification lengths where relevant. METHODS: CDME screening results for 1668 drivers were compared to polysomnogram diagnostic test results, and CDME screening results were evaluated for 1155 drivers with at least one insurance claim with a hypertension diagnostic code. Any CDME documentation of the medical condition was considered as detection by screening. RESULTS: CDME sensitivity was 20.7% for moderate OSA (AHI ≥ 15). While sensitivity was 77.5% for hypertension, 93.3% of drivers with Stage 3 hypertension were certified, contrary to Federal Motor Carrier Safety Administration standards. CONCLUSIONS: The pre-Registry CDME was ineffective in screening commercial drivers for OSA. Screening was better for hypertension; incorrect certifications were given to many hypertensive drivers.

Patient and operating room staff radiation dose during fenestrated/branched endovascular aneurysm repair using premanufactured devices.

INTRODUCTION: Fenestrated endovascular aneurysm repair (FEVAR) is the highest radiation dose procedure performed by vascular surgeons. We sought to characterize the radiation dose to patients and staff during FEVAR procedures with different premanufactured devices. METHODS: A single-center prospective study of FEVARs was performed over 24 months. Three FEVAR devices were included: off-the-shelf (OTS; t-Branch, p-Branch), Zenith Fenestrated (ZFen), and investigational custom-made devices (CMDs). Radiation doses to the surgeon, trainee, anesthesiologist, and scrub/circulating nurses were measured using a personal dosimetry system (DoseAware, Philips Healthcare, Amsterdam, The Netherlands). Procedure type, patient body mass index (BMI), reference air kerma (RAK), and kerma area product (KAP) were recorded. RAK and KAP were corrected for BMI based on an exponential fit of fluoroscopy dose rate and the dose per radiographic frame. Operator dose was corrected for BMI by the ratio of corrected to actual KAP. A one-sided Wilcox rank-sum test was used to compare personnel radiation doses, RAKs, and KAPs between procedure types. Statistical significance was set at P ≤ .05. RESULTS: There were 80 FEVARs performed by a single surgeon on a Philips Allura XperFD20 fluoroscopy system equipped with Clarity technology. Average BMI was 27 kg/m2. Sixty CMDs (36 four-, 21 three-, and 3 two-vessel fenestrations), 11 ZFens (8 three- and 3 two-vessel fenestrations), and 9 OTS devices (4 p-Branch, 5 t-Branch) were included. ZFens had significantly lower patient (1800 mGy vs 2950 mGy; P = .004), operator (120 µSv vs 370 µSv; P = .004), assistant (60 µSv vs 210 µSv; P = .003), circulator (10 µSv vs 30 µSv; P = .049), and scrub nurse dose (10 µSv vs 40 µSv; P = .02) compared with CMDs. OTS devices had significantly lower operator (220 µSv vs 370 µSv; P = .04), assistant (110 µSv vs 210 µSv; P = .02), and circulator doses (4 µSv vs 30 µSv; P = .001) compared with CMDs. Four-vessel fenestrated devices had significantly higher patient dose (3020 mGy) compared with three-vessel FEVARs (2670 mGy; P = .03) and two-vessel FEVARs (1600 mGy; P = .0007), and significantly higher operator dose (440 µSv) compared with three-vessel FEVARs (170 µSv; P = .0005). Patient dose was lowest with ZFens. Operating room personnel dose was lower with ZFens and OTS devices compared with CMDs. Four-vessel fenestrations required significantly more radiation compared with those involving three-vessel fenestrations; however, the dose increase was only 12% and should not preclude operators from extending coverage, if anatomically required. CONCLUSIONS: Overall, patient and personnel radiation doses during FEVAR with all devices were within acceptable limits and lower in our series than previously reported.

Radiation brain dose to vascular surgeons during fluoroscopically guided interventions is not effectively reduced by wearing lead equivalent surgical caps.

OBJECTIVE: Radiation to the interventionalist's brain during fluoroscopically guided interventions (FGIs) may increase the incidence of cerebral neoplasms. Lead equivalent surgical caps claim to reduce radiation brain doses by 50% to 95%. We sought to determine the efficacy of the RADPAD (Worldwide Innovations & Technologies, Lenexa, Kan) No Brainer surgical cap (0.06 mm lead equivalent at 90 kVp) in reducing radiation dose to the surgeon's and trainee's head during FGIs and to a phantom to determine relative brain dose reductions. METHODS: Optically stimulated, luminescent nanoDot detectors (Landauer, Glenwood, Ill) inside and outside of the cap at the left temporal position were used to measure cap attenuation during FGIs. To check relative brain doses, nanoDot detectors were placed in 15 positions within an anthropomorphic head phantom (ATOM model 701; CIRS, Norfolk, Va). The phantom was positioned to represent a primary operator performing femoral access. Fluorography was performed on a plastic scatter phantom at 80 kVp for an exposure of 5 Gy reference air kerma with or without the hat. For each brain location, the percentage dose reduction with the hat was calculated. Means and standard errors were calculated using a pooled linear mixed model with repeated measurements. Anatomically similar locations were combined into five groups: upper brain, upper skull, midbrain, eyes, and left temporal position. RESULTS: This was a prospective, single-center study that included 29 endovascular aortic aneurysm procedures. The average procedure reference air kerma was 2.6 Gy. The hat attenuation at the temporal position for the attending physician and fellow was 60% ± 20% and 33% ± 36%, respectively. The equivalent phantom measurements demonstrated an attenuation of 71% ± 2.0% (P < .0001). In the interior phantom locations, attenuation was statistically significant for the skull (6% ± 1.4%) and upper brain (7.2% ± 1.0%; P < .0001) but not for the middle brain (1.4% ± 1.0%; P = .15) or the eyes (-1.5% ± 1.4%; P = .28). CONCLUSIONS: The No Brainer surgical cap attenuates direct X rays at the superficial temporal location; however, the majority of radiation to an interventionalist's brain originates from scatter radiation from angles not shadowed by the cap as demonstrated by the trivial percentage brain dose reductions measured in the phantom. Radiation protective caps have minimal clinical relevance.

Use of Electronic Cigarettes Leads to Significant Beta2-Nicotinic Acetylcholine Receptor Occupancy: Evidence From a PET Imaging Study.

Background: Electronic cigarettes (ECs) can influence nicotine addiction by delivering aerosolized nicotine. We investigated if nicotine from ECs is delivered to the brain ß2*-nicotinic acetylcholine receptors (ß2*-nAChR) and how this relates to the behavioral effects and nicotine delivery from cigarettes. Methods: Seven nicotine users participated in positron emission tomography (PET) studies with (-)-[18F]Flubatine before and after nicotine challenge with 0, 8, and 36 mg/ml nicotine in a 3.3 Volt, 1.5 Ohm EC or a standard tobacco cigarette. Craving was evaluated before and after product use. Results: Average ß2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared to 8 mg/ml EC at trend level. Average ß2*-nAChR occupancy after tobacco cigarette smoking was 68 ± 18% and was not different compared with 8 mg/ml (64 ± 17%,) or 36 mg/ml (84 ± 3%) nicotine in EC users. Area under the curve (AUC) of blood nicotine level was higher in the cigarette smoking group compared with the 8mg/ml group (p = 0.03), but similar compared with the 36 mg/ml EC (p = 0.29). Drug craving was reduced after use of the tobacco cigarette, 8 mg/ml EC, and 36 mg/ml EC. Conclusions: In this novel investigation of EC effects at ß2*-nAChRs, we show that average ß2*-nAChR occupancy was higher after 36 mg/ml EC challenge compared with 8 mg/ml EC. Receptor occupancy and arterial blood nicotine levels after cigarette smoking were similar to 36 mg/ml EC use under controlled conditions. These findings suggest that the ECs studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers. Implications: This is the first study to directly determine the neurologic effects of electronic cigarettes on human brain beta-2 nicotinic acetylcholine receptors using PET neuroimaging with (-)-[18F]Flubatine, a novel radiotracer. Our findings suggest that the e-cigarettes studied here have abuse liability and may provide an adequate alternative nicotine delivery system for cigarette smokers.

New image-processing and noise-reduction software reduces radiation dose during complex endovascular procedures.

BACKGROUND: A new proprietary image-processing system known as AlluraClarity, developed by Philips Healthcare (Best, The Netherlands) for radiation-based interventional procedures, claims to lower radiation dose while preserving image quality using noise-reduction algorithms. This study determined whether the surgeon and patient radiation dose during complex endovascular procedures (CEPs) is decreased after the implementation of this new operating system. METHODS: Radiation dose to operators, procedure type, reference air kerma, kerma area product, and patient body mass index were recorded during CEPs on two Philips Allura FD 20 fluoroscopy systems with and without Clarity. Operator dose during CEPs was measured using optically stimulable, luminescent nanoDot (Landauer Inc, Glenwood, Ill) detectors placed outside the lead apron at the left upper chest position. nanoDots were read using a microStar ii (Landauer Inc) medical dosimetry system. For the CEPs in the Clarity group, the radiation dose to surgeons was also measured by the DoseAware (Philips Healthcare) personal dosimetry system. Side-by-side measurements of DoseAware and nanoDots allowed for cross-calibration between systems. Operator effective dose was determined using a modified Niklason algorithm. To control for patient size and case complexity, the average fluoroscopy dose rate and the dose per radiographic frame were adjusted for body mass index differences and then compared between the groups with and without Clarity by procedure. Additional factors, for example, physician practice patterns, that may have affected operator dose were inferred by comparing the ratio of the operator dose to procedural kerma area product with and without Clarity. A one-sided Wilcoxon rank sum test was used to compare groups for radiation doses, reference air kermas, and operating practices for each procedure type. RESULTS: The analysis included 234 CEPs; 95 performed without Clarity and 139 with Clarity. Practice patterns of operators during procedures with and without Clarity were not significantly different. For all cases, procedure radiation dose to the patient and the primary and assistant operators were significantly decreased in the Clarity group by 60% compared with the non-Clarity group. By procedure type, fluorography dose rates decreased from 44% for fenestrated endovascular repair and up to 70% with lower extremity interventions. Fluoroscopy dose rates also significantly decreased, from about 37% to 47%, depending on procedure type. CONCLUSIONS: The AlluraClarity system reduces the patient and primary operator's radiation dose by more than half during CEPs. This feature appears to be an effective tool in lowering the radiation dose while maintaining image quality.

Nonadherence with Employer-Mandated Sleep Apnea Treatment and Increased Risk of Serious Truck Crashes.

STUDY OBJECTIVES: To evaluate the effect of an employer-mandated obstructive sleep apnea (OSA) program on the risk of serious preventable truck crashes. METHODS: Data are from the first large-scale, employer-mandated program to screen, diagnose, and monitor OSA treatment adherence in the US trucking industry. A retrospective analysis of cohorts was constructed: polysomnogram-diagnosed drivers (OSA positive n = 1,613, OSA negative n = 403) were matched to control drivers unlikely to have OSA (n = 2,016) on two factors affecting crash risk, experience-at-hire and length of job tenure; tenure was matched on the date of each diagnosed driver's polysomnogram. Auto-adjusting positive airway pressure (APAP) treatment was provided to all cases (i.e. OSA positive drivers); treatment adherence was objectively monitored. Cases were grouped by treatment adherence: "Full Adherence" (n = 682), "Partial Adherence" (n = 571), or "No Adherence" (n = 360). Preventable Department-of-Transportation-reportable crashes/100,000 miles were compared across study subgroups. Robustness was assessed. RESULTS: After the matching date, "No Adherence" cases had a preventable Department of Transportation-reportable crash rate that was fivefold greater (incidence rate ratio = 4.97, 95% confidence interval: 2.09, 10.63) than that of matched controls (0.070 versus 0.014 per 100,000 miles). The crash rate of "Full Adherence" cases was statistically similar to controls (incidence rate ratio = 1.02, 95% confidence interval: 0.48, 2.04; 0.014 per 100,000 miles). CONCLUSIONS: Nontreatment-adherent OSA-positive drivers had a fivefold greater risk of serious preventable crashes, but were discharged or quit rapidly, being retained only one-third as long as other subjects. Thus, the mandated program removed risky nontreatment-adherent drivers and retained adherent drivers at the study firm. Current regulations allow nonadherent OSA cases to drive at another firm by keeping their diagnosis private. COMMENTARY: A commentary on this article appears in this issue on page 961.

Nicotine and Nicotine Abstinence Do Not Interfere with GABAA Receptor Neuroadaptations During Alcohol Abstinence.

BACKGROUND: Alcohol dependence and tobacco smoking are highly comorbid, and treating both conditions simultaneously is controversial. Previously, we showed that tobacco smoking interferes with GABAA receptor neuroadaptations during alcohol withdrawal in humans, while this effect did not occur with continued nicotine use during alcohol abstinence in nonhuman primates. Here, we extend our previous work by measuring GABAA receptor availability with positron emission tomography (PET) during drug abstinence in nonhuman primates exposed to alcohol alone, nicotine and alcohol together, and alcohol abstinence with continued nicotine exposure. METHODS: Twenty-four adolescent male rhesus macaques orally self-administered alcohol and nicotine, available separately in water and saccharin, over 20 weeks. The groups included alcohol alone (n = 8); nicotine and alcohol with simultaneous abstinence (n = 8); nicotine and alcohol with alcohol abstinence while nicotine was still available (n = 8); and a pilot group of animals consuming nicotine alone (n = 6). Animals were imaged with [(11)C]flumazenil PET to measure binding potential (BPND), an index of GABAA receptor availability. Imaging occurred at baseline (drug-naíve), and following alcohol and/or nicotine cessation at 1 day, 8 days, and 12 weeks of abstinence. Generalized linear mixed models were used to examine the time course of [(11)C]flumazenil BPND during alcohol abstinence across groups. RESULTS: Animals consumed 3.95 ± 1.22 g/kg/d alcohol and 55.4 ± 35.1 mg/kg/d nicotine. No significant group effects were observed in [(11)C]flumazenil BPND during alcohol abstinence; however, a main effect of time was detected. Post hoc analyses indicated that all groups abstaining from alcohol exhibited significantly increased GABAA receptor availability at 1 day and 8 days (but not 12 weeks) of abstinence relative to baseline, while no changes in [(11)C]flumazenil BPND during nicotine abstinence alone were observed. CONCLUSIONS: These data indicate that neither nicotine nor nicotine abstinence interferes with GABAA receptor neuroadaptations during alcohol withdrawal. This conclusion is consistent with our previous study and does not contradict the use of nicotine replacement therapies or non-nicotinic-acting pharmaceuticals to quit smoking during alcohol withdrawal from a GABAergic perspective.

Mini Bypass and Proinflammatory Leukocyte Activation: A Randomized Controlled Trial.

BACKGROUND: Coronary artery bypass grafting (CABG) with conventional cardiopulmonary bypass (CPB) induces systemic inflammation. Miniaturized CPB may attenuate systemic inflammatory activation. The intracellular signaling pathways promoting inflammation in cardiac operations and the relative effects of CPB on these processes are uncertain. In this study, induction of reactive oxygen species (ROS) and activation of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK) within leukocytes, and leukocyte accumulation in cantharidin-induced blisters was compared in patients exposed to miniaturized CPB (mCPB) and those who underwent conventional CPB (cCPB). METHODS: Patients undergoing CABG were randomized to receive either cCPB (n = 13) or mCPB (n = 13). Blood samples were collected preoperatively and 5 times after initiating CPB (up to 5 hours) and analyzed by flow cytometry for intracellular markers of activation (ROS, p38-MAPK, and NF-κB phosphorylation). RESULTS: ROS in lymphocytes were elevated in cCPB compared with mCPB (p < 0.01), whereas ROS in granulocytes and monocytes were similar between groups. After initiation of CPB, p38-MAPK was higher in patients receiving cCPB compared with those receiving mCPB (p < 0.05). NF-κB phosphorylation in leukocyte subsets was similar in patients exposed to cCPB and those exposed to mCPB. Leukocyte accumulation in cantharidin-induced blisters, white cell counts, and serum C-reactive protein (CRP) was enhanced in response to cardiac operations, but no differences were observed between mCPB and cCPB groups. Postoperative serum creatinine levels were reduced in the mCPB group compared with the cCPB group (p < 0.05). CONCLUSIONS: Both p38-MAPK activation and ROS were attenuated with the use of mCPB compared with cCPB, providing a potential mechanism for reduced inflammation in association with CPB miniaturization.

Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts.

Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when radiolabeled with (111)In through conjugation with a bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). In vitro binding of (111)In-DOTA-Bavituximab to PS was determined by enzyme-linked immunosorbent assay (ELISA). Biodistribution of (111)In-DOTA-Bavituximab was conducted in normal rats, which provided data for dosimetry calculation. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging was performed in athymic nude rats bearing A549 NSCLC xenografts. At the molar conjugation ratio of 0.54 DOTA per Bavituximab, the PS binding affinity of (111)In-DOTA-Bavituximab was comparable to that of unmodified Bavituximab. Based on the quantitative SPECT/CT imaging data analysis, (111)In-DOTA-Bavituximab demonstrated tumor-specific uptake as measured by the tumor-tomuscle ratio, which peaked at 5.2 at 72 hr post-injection. In contrast, the control antibody only presented a contrast of 1.2 at the same time point.These findings may underlie the diagnostic efficacy and relative low rates of systemic vascular and immune-related toxicities of this immunoconjugate. Future applications of (111)In-DOTA-bavituximab may include prediction of efficacy, indication of tumor immunologic status, or characterization of radiographic findings.

Surgeon radiation dose during complex endovascular procedures.

BACKGROUND: Surgeon radiation dose during complex fluoroscopically guided interventions (FGIs) has not been well studied. We sought to characterize radiation exposure to surgeons during FGIs based on procedure type, operator position, level of operator training, upper vs lower body exposure, and addition of protective shielding. METHODS: Optically stimulable, luminescent nanoDot (Landauer, Inc, Glenwood, Ill) detectors were used to measure radiation dose prospectively to surgeons during FGIs. The nanoDot dosimeters were placed outside the lead apron of the primary and assistant operators at the left upper chest and left lower pelvis positions. For each case, the procedure type, the reference air kerma, the kerma-area product, the relative position of the operator, the level of training of the fellow, and the presence or absence of external additional shielding devices were recorded. Three positions were assigned on the right-hand side of the patient in decreasing relative proximity to the flat panel detector (A, B, and C, respectively). Position A (main operator) was closest to the flat panel detector. Position D was on the left side of the patient at the brachial access site. The nanoDots were read using a microSTARii medical dosimetry system (Landauer, Inc) after every procedure. The nanoDot dosimetry system was calibrated for scattered radiation in an endovascular suite with a National Institute of Standards and Technology traceable solid-state radiation detector (Piranha T20; RTI Electronics, Fairfield, NJ). Comparative statistical analysis of nanoDot dose levels between categories was performed by analysis of variance with Tukey pairwise comparisons. Bonferroni correction was used for multiple comparisons. RESULTS: There were 415 nanoDot measurements with the following case distribution: 16 thoracic endovascular aortic repairs/endovascular aneurysm repairs, 18 fenestrated endovascular aneurysm repairs (FEVARs), 13 embolizations, 41 lower extremity interventions, 10 fistulograms, 13 visceral interventions, and 3 cerebrovascular procedures. The mean operator effective dose for FEVARs was higher than for other case types (P < .03), 20 µSv at position A and 9 µSv at position B. For all case types, position A (9.0 µSv) and position D (20 µSv) received statistically higher effective doses than position B (4 µSv) or position C (0.4 µSv) (P < .001). However, the mean operator effective dose for position D was not statistically different from that for position A. The addition of the lead skirt significantly decreased the lower body dose (33 ± 3.4 µSv to 6.3 ± 3.3 µSv) but not the upper body dose (6.5 ± 3.3 µSv to 5.7 ± 2.2 µSv). Neither ceiling-mounted shielding nor level of fellow training affected operator dose. CONCLUSIONS: Surgeon radiation dose during FGIs depends on case type, operator position, and table skirt use but not on the level of fellow training. On the basis of these data, the primary operator could perform approximately 12 FEVARs/wk and have an annual dose <10 mSv, which would not exceed lifetime occupational dose limits during a 35-year career. With practical case loads, operator doses are relatively low and unlikely to exceed occupational limits.

Investigating the effect of remote ischaemic preconditioning on biomarkers of stress and injury-related signalling in patients having isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass: study protocol for a randomized controlled trial.

BACKGROUND: Ischaemia-reperfusion injury occurs during heart surgery that uses cardiopulmonary bypass (CPB) and cardioplegic arrest. It is hypothesised that remote ischaemic preconditioning (RIPC) protects the heart against such injury. Despite the numerous studies investigating the protective effects of RIPC, there is still uncertainty about the interpretation of the findings as well as conflicting results between studies. The objective of this trial is to investigate the cardioprotective effect of RIPC in patients having coronary artery bypass grafting (CABG) or aortic valve replacement surgery. This will be achieved by estimating the effect of the intervention in the two groups of pathologies and by investigating the signalling mechanisms that may underpin the cardioprotective effect. METHODS/DESIGN: A two-centre randomised controlled trial will be used to investigate the effects of RIPC in two pathologies: patients having isolated CABG and those having aortic valve replacement surgery (AVR) with CPB. Participants will be randomised to RIPC or control (sham RIPC), stratified by surgical stratum. The intervention will be delivered by a research nurse. Data will be collected by a research nurse blinded to the intervention. The patient and the theatre staff are also blinded to the allocation. Markers of myocardial injury and inflammation will be measured in myocardial biopsies and in blood samples at different times. DISCUSSION: This trial is designed to investigate whether RIPC will reduce myocardial injury and inflammation following heart surgery and whether there is a difference in effect between participants having CABG or AVR. This trial is a unique opportunity to study the mechanisms associated with RIPC using human myocardial tissue and blood, and to relate these to the extent of myocardial injury/protection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33084113 (25 March 2013).

Leiomyosarcoma of the thoracic aorta in a patient with hypertrophic cardiomyopathy.

We report a case of leiomyosarcoma of the thoracic aorta in a 49-year-old male patient with history of hypertrophic cardiomyopathy. The only presenting symptom was back pain localized under the left scapula with the frequency and severity of the pain increasing with time. Imaging studies detected the presence of an aortic tumor. The tumor was excised en bloc, and an interposition graft was implanted. The histology showed a fully excised grade 3 leiomyosarcoma. This article discusses features of this rare condition.

Deterministic effects after fenestrated endovascular aortic aneurysm repair.

BACKGROUND: Endovascular aortic aneurysm repairs (EVARs) with fenestrated (FEVAR) stent grafts are high radiation dose cases, yet no skin injuries were found retrospectively in our 61 cases with a mean peak skin dose (PSD) of 6.8 Gy. We hypothesize that skin injury is under-reported. This study examined deterministic effects in FEVARs after procedural changes implemented to detect skin injury. METHODS: All FEVARs during a 6-month period with a radiation dose of 5 Gy reference air kerma (RAK; National Council on Radiation Protection and Measurements threshold for substantial radiation dose level [SRDL]) were included. Patients were questioned about skin erythema, epilation, and necrosis, with a physical examination of the back completed daily until discharge and then at 2 and 4 weeks and at 3 and 6 months. PSD distributions were calculated with custom software using input data from fluoroscopic machine logs. These calculations have been validated against Gafchromic (Ashland Inc, Covington, Ky) film measurements. Dose was summed for the subset of patients with multiple procedures ≤6 months of the SRDL event, consistent with the joint commission recommendations. RESULTS: Twenty-two patients, 21 FEVARs and one embolization, reached an RAK of 5 Gy. The embolization procedure was excluded from review. The average RAK was 7.6 ± 2.0 Gy (range, 5.1-11.4 Gy), with a mean PSD of 4.8 ± 2.0 Gy (range, 2.3-10.4 Gy). Fifty-two percent of patients had multiple endovascular procedures ≤6 months of the SRDL event. The mean RAK for this subset was 10.0 ± 2.9 Gy (range, 5.5-15.1 Gy), with a mean PSD of 6.6 ± 1.9 Gy (range, 3.4-9.4 Gy). One patient died before the first postoperative visit. No radiation skin injuries were found. Putative risk factors for skin injury were evaluated and included smoking (32%), diabetes (14%), cytotoxic drugs (9%), and fair skin type (91%). No other risk factors were present (hyperthyroidism, collagen vascular disorders). CONCLUSIONS: Deterministic skin injuries are uncommon after FEVAR, even at high RAK levels, regardless of cumulative dose effects. This study addresses the concern of missed injuries based on the retrospective clinical examination findings that were published in our previous work. Even with more comprehensive postoperative skin examinations and patient questioning, the fact that no skin injuries were found suggests that radiation-induced skin injuries are multifactorial and not solely dose dependent.

Understanding and using fluoroscopic dose display information.

Fluoroscopically guided procedures are an area of radiology in which radiation exposure to the patient is highly operator dependent. Modern fluoroscopy machines display a variety of information, including technique factors, field of view, operating geometry, exposure mode, fluoroscopic time, air kerma at the reference point (RAK), and air kerma area-product. However, the presentation of this information is highly vendor specific, and many users are unaware of how to interpret this information and use it to perform a study with the minimum necessary dose. A conceptual framework for understanding the radiation dose readout during a procedure is to compare it to the dashboard of an automobile, where the rate at which radiation is being applied (the RAK rate [mGy/min]) is the dose "speed" and the cumulative amount of radiation applied (cumulative RAK [mGy]) is the dose "odometer." This analogy can be used as a starting point to improve knowledge of these parameters, including how RAK is measured, how RAK correlates with skin dose, and how parameters are displayed differently during fluoroscopy and fluorography. Awareness of these factors is critical to understanding how dose parameters translate to patient risk and the consequences of high-dose studies. With this increased awareness, physicians performing fluoroscopically guided procedures can understand how to use built-in features of the fluoroscopic equipment (pulse rate, beam filtration, and automatic exposure control) and fluoroscopic techniques (procedure planning, patient positioning, proper collimation, and magnification) to reduce patient radiation dose, thereby improving patient safety.