CTC-177, a novel drug-Fc conjugate, shows promise as an immunoprophylactic agent against multidrug-resistant Gram-negative bacterial infections.

Background: The widespread emergence of antibiotic resistance including MDR in Gram-negative bacterial pathogens poses a critical challenge to the current antimicrobial armamentarium. Objectives: To create a novel drug-Fc conjugate (DFC) that can be delivered at sustained and prolonged levels while simultaneously activating the host immune response to combat MDR Gram-negative infections. Methods: The Cloudbreak™ platform was used to develop DFCs consisting of a targeting moiety (TM) (a polymyxin-derived dimer) attached via a non-cleavable linker to an effector moiety (EM) (the Fc domain of human IgG1). In vitro activities of the DFCs were assessed by MIC testing. Neutropenic mouse models of thigh infection, septicaemia and pneumonia were used to evaluate in vivo efficacy. Pharmacokinetics were evaluated in mice and cynomolgus monkeys. Results: A single prophylactic dose of our lead DFC, CTC-177, resulted in significantly decreased bacterial burdens and reduced inflammation comparable to daily treatment with colistin in septicaemia and pneumonia mouse models. Furthermore, CTC-177 prophylaxis was able to restore colistin efficacy in colistin-resistant septicaemia, reducing bacterial burdens beyond the limit of detection. Finally, CTC-177 displayed a long terminal half-life of over 24 and 65 h in mice and cynomolgus monkeys, respectively. Conclusions: These data support the continued development of Cloudbreak™ DFCs as broad-spectrum prophylactic agents against Gram-negative infections.

How did we reform our out of control massive transfusion protocol program?

BACKGROUND: The massive transfusion protocol (MTP) is designed to quickly provide blood products at a fixed ratio for the exsanguinating patient. At our academic medical center, the frequency of MTP activation increased over 10-fold between 2008 and 2015, putting inordinate stress on our transfusion service. STUDY DESIGN AND METHODS: Gathering a large number of relevant stakeholders, we performed a multidisciplinary root cause analysis (RCA) in response to the acute clinical need to reform our MTP. RESULTS: Through the RCA, we identified four principal opportunities for improvement (OFI) associated with our MTP: education, stewardship, process improvement, and communication. Through the deployment of new approaches to each of these OFI, we reduced MTP activations, blood product waste, and transfusion service technologist stress. CONCLUSION: The MTP is amenable to improvement, and, although time intensive, the RCA process yields significant favorable effects: improving communication with colleagues, reducing stress within the transfusion service, and improving resource utilization. Activation of the MTP at our institution is now more aligned with its primary purpose: rapidly providing large quantities of blood products to exsanguinating patients.

Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections.

The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgG1 (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutropenic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-resistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.

Race Disparities in the Use of Prevention, Screening, and Monitoring Services in Michigan Medicare Beneficiaries With Type 2 Diabetes and Combinations of Multiple Chronic Conditions.

People with diabetes need routine health care to prevent potential exacerbations of diabetes and detect or prevent the development of additional chronic conditions that can worsen the course of diabetes. Using 2012 Medicare claims data from the State of Michigan for 443,932 beneficiaries with type 2 diabetes, we determined that there are differences between white and racial/ethnic minority people with diabetes in accessing any preventive care and in the amount of service used once they do access care, even after adjusting for the presence of multiple chronic conditions.

Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists.

In humans, bitter taste is mediated by 25 TAS2Rs. Many compounds, including certain active pharmaceutical ingredients, excipients, and nutraceuticals, impart their bitter taste (or in part) through TAS2R8 activation. However, effective TAS2R8 blockers that can either suppress or reduce the bitterness of these compounds have not been described. We are hereby reporting a series of novel 3-(pyrazol-4-yl) imidazolidine-2,4-diones as potent and selective TAS2R8 antagonists. In human sensory tests, S6821 and S7958, two of the most potent analogues from the series, demonstrated efficacy in blocking TAS2R8-mediated bitterness and were selected for development. Following data evaluation by expert panels of a number of national and multinational regulatory bodies, including the US, the EU, and Japan, S6821 and S7958 were approved as safe under conditions of intended use as bitter taste blockers.

Speech Map: A Statistical Multimodal Atlas of 4D Tongue Motion During Speech from Tagged and Cine MR Images.

Quantitative measurement of functional and anatomical traits of 4D tongue motion in the course of speech or other lingual behaviors remains a major challenge in scientific research and clinical applications. Here, we introduce a statistical multimodal atlas of 4D tongue motion using healthy subjects, which enables a combined quantitative characterization of tongue motion in a reference anatomical configuration. This atlas framework, termed Speech Map, combines cine- and tagged-MRI in order to provide both the anatomic reference and motion information during speech. Our approach involves a series of steps including (1) construction of a common reference anatomical configuration from cine-MRI, (2) motion estimation from tagged-MRI, (3) transformation of the motion estimations to the reference anatomical configuration, and (4) computation of motion quantities such as Lagrangian strain. Using this framework, the anatomic configuration of the tongue appears motionless, while the motion fields and associated strain measurements change over the time course of speech. In addition, to form a succinct representation of the high-dimensional and complex motion fields, principal component analysis is carried out to characterize the central tendencies and variations of motion fields of our speech tasks. Our proposed method provides a platform to quantitatively and objectively explain the differences and variability of tongue motion by illuminating internal motion and strain that have so far been intractable. The findings are used to understand how tongue function for speech is limited by abnormal internal motion and strain in glossectomy patients.

A Sparse Non-Negative Matrix Factorization Framework for Identifying Functional Units of Tongue Behavior From MRI.

Muscle coordination patterns of lingual behaviors are synergies generated by deforming local muscle groups in a variety of ways. Functional units are functional muscle groups of local structural elements within the tongue that compress, expand, and move in a cohesive and consistent manner. Identifying the functional units using tagged-magnetic resonance imaging (MRI) sheds light on the mechanisms of normal and pathological muscle coordination patterns, yielding improvement in surgical planning, treatment, or rehabilitation procedures. In this paper, to mine this information, we propose a matrix factorization and probabilistic graphical model framework to produce building blocks and their associated weighting map using motion quantities extracted from tagged-MRI. Our tagged-MRI imaging and accurate voxel-level tracking provide previously unavailable internal tongue motion patterns, thus revealing the inner workings of the tongue during speech or other lingual behaviors. We then employ spectral clustering on the weighting map to identify the cohesive regions defined by the tongue motion that may involve multiple or undocumented regions. To evaluate our method, we perform a series of experiments. We first use two-dimensional images and synthetic data to demonstrate the accuracy of our method. We then use three-dimensional synthetic and in vivo tongue motion data using protrusion and simple speech tasks to identify subject-specific and data-driven functional units of the tongue in localized regions.

General population estimates of the association between college experience and the odds of forced intercourse.

Sexual assault on college campuses is a pervasive problem, recently receiving increased scientific and policy attention. However, the high focus on college student experience ignores general population prevalence, trends, and differences between those with college experience and those without. We analyze measures from the National Survey of Family Growth (NSFG) to provide a general population view of experiences with forced intercourse. Forced intercourse is a common experience in the U.S. population, has remained stable in recent years, and varies greatly by gender, age and race. The odds of forced intercourse are also significantly higher among those with less than four years of college. This ubiquitous public health problem is not limited to college campuses. Measures from the NSFG are an important resource for understanding population rates of (and trends in) forced intercourse, providing information to guide interventions and better target scientific investigation.

Alternative Approaches to Assessing Nonresponse Bias in Longitudinal Survey Estimates: An Application to Substance-Use Outcomes Among Young Adults in the United States.

We evaluated alternative approaches to assessing and correcting for nonresponse bias in a longitudinal survey. We considered the changes in substance-use outcomes over a 3-year period among young adults aged 18-24 years (n = 5,199) in the United States, analyzing data from the National Epidemiologic Survey on Alcohol and Related Conditions. This survey collected a variety of substance-use information from a nationally representative sample of US adults in 2 waves: 2001-2002 and 2004-2005. We first considered nonresponse rates in the second wave as a function of key substance-use outcomes in wave 1. We then evaluated 5 alternative approaches designed to correct for nonresponse bias under different attrition mechanisms, including weighting adjustments, multiple imputation, selection models, and pattern-mixture models. Nonignorable attrition in a longitudinal survey can lead to bias in estimates of change in certain health behaviors over time, and only selected procedures enable analysts to assess the sensitivity of their inferences to different assumptions about the extent of nonignorability. We compared estimates based on these 5 approaches, and we suggest a road map for assessing the risk of nonresponse bias in longitudinal studies. We conclude with directions for future research in this area given the results of our evaluations.

Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals.

Background: The ability to noninvasively assess arterial CD206+ macrophages may lead to improved understanding of human immunodeficiency virus (HIV)-associated cardiovascular disease. Methods: We trialed a novel macrophage-specific arterial imaging technique. Results: We demonstrated colocalization between technetium Tc 99m tilmanocept (99mTc-tilmanocept) and CD206+ macrophages ex vivo. In vivo application of 99mTc-tilmanocept single-photon emission computed tomography/computed tomography revealed high-level 99mTc-tilmanocept uptake across 20.4% of the aortic surface volume among HIV-infected subjects, compared with 4.3% among non-HIV-infected subjects (P = .009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake was related to noncalcified aortic plaque volume (r = 0.87; P = .003) on computed tomographic angiography, and this relationship held when we controlled for HIV status. Conclusion: These first-in-human data introduce a novel macrophage-specific arterial imaging technique in HIV. Clinical Trials Registration: NCT02542371.

Adherence to the 2010 American College of Cardiology Foundation Appropriate Use Criteria for Cardiac Computed Tomography: Quality Analysis at a Tertiary Referral Center.

BACKGROUND: In November 2010, the American College of Cardiology Foundation published revised appropriateness criteria (AC) for cardiac computed tomography (CT). We evaluated adherence to these criteria by providers of different subspecialties at a tertiary referral center. METHODS: Reports of 383 consecutive patients who underwent clinically indicated cardiac CT from December 1, 2010, to July 31, 2011, were reviewed by physicians with appropriate training in cardiac CT. Scans were classified as appropriate, inappropriate, or uncertain based on the revised 2010 AC. Studies that did not fall under any of the specified indications were labeled as unclassified. Adherence to the AC was also analyzed as a function of provider type. Research scans were excluded from this analysis. RESULTS: Three hundred eight exams (80%) were classified as appropriate; 26 (7%), as inappropriate; 30 (8%), as uncertain; and 19 (5%), as unclassified. Of the 19 (5%) unclassified cardiac CT exams, the most common indication was for evaluation of suspected aortic dissection. Three hundred five exams (80%) were referred by cardiologists; 73 (19%), by internists; and 5 (1%), by neurologists. Of the 305 cardiology-referred studies, 221 (73%) were ordered by general cardiologists; 28 (9%), by interventional cardiologists; and 56 (19%), by electrophysiologists. There was no significant difference in adherence to the criteria between provider specialties or between cardiology subspecialties (P > 0.05). CONCLUSIONS: high across provider specialties.

"Clustering by interviewer": a source of variance that is unaccounted for in single-stage health surveys.

Although the impact of interviewers on survey measurement has been studied for more than 85 years, such impacts are rarely considered in the analysis of health surveys. This issue is particularly important with single-stage surveys such as that used in the Behavioral Risk Factor Surveillance System (BRFSS), where there are no sampling clusters in which interviewer effects could be captured. The BRFSS involves an ongoing telephone survey of the health behaviors of US adults and was established in 1984 by the Centers for Disease Control and Prevention. Public-use BRFSS data files are widely used by epidemiologists and public health researchers to describe the health behaviors of adults in the United States. Since its onset, the BRFSS has provided identification codes for telephone interviewers completing BRFSS interviews in its public-use data files; however, a review of BRFSS publications shows no evidence that these codes have been used in estimating standard errors. In this paper we analyze data from the 2012 BRFSS, illustrate both design-based and model-based approaches to incorporating interviewer effects in variance estimation, and find evidence of substantial interviewer effects for 5 key estimates across states. These results suggest that BRFSS analysts should consider accounting for interviewer effects, and we provide example code enabling analysts to do so. We conclude with suggestions regarding possible directions for future research.

First human use of a radiopharmaceutical prepared by continuous-flow microfluidic radiofluorination: proof of concept with the tau imaging agent [18F]T807.

Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET) radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [18F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module. For this proof of concept, the flow system was integrated to a GE Tracerlab FXFN unit for high-performance liquid chromatography purification and formulation. Three consecutive productions of [18F]T807 were conducted to validate this radiopharmaceutical. Uncorrected radiochemical yields of 17 ± 1% of crude [18F]T807 (≈ 500 mCi, radiochemical purity 95%) were obtained from the microfluidic device. The crude material was then purified, and > 100 mCi of the final product was obtained in an overall uncorrected radiochemical yield of 5 ± 1% (n  =  3), relative to starting [18F]fluoride (end of bombardment), with high radiochemical purity (≥ 99%) and high specific activities (6 Ci/µmol) in 100 minutes. A clinical research study was carried out with [18F]T807, representing the first reported human imaging study with a radiopharmaceutical prepared by this technology.

Coronary artery disease detected by coronary computed tomographic angiography is associated with intensification of preventive medical therapy and lower low-density lipoprotein cholesterol.

BACKGROUND: Coronary computed tomographic angiography (CCTA) is an accurate test for the identification of coronary artery disease (CAD), yet the impact of CCTA results on subsequent medical therapy and risk factors has not been widely reported. METHODS AND RESULTS: We identified consecutive patients aged >18 years without prior CAD who underwent CCTA from 2004 to 2011 and had complete data on medications before and after CCTA. CCTA results were categorized as no CAD, <50% stenosis, and ≥50% stenosis. Based on the number of involved segments, extent of disease was categorized as nonextensive (≤4 segments) or extensive CAD (>4 segments). Electronic medical records and patient interviews were reviewed blinded to CCTA findings to assess initiation of aspirin and intensification of lipid-lowering therapies. Survival analysis was performed to evaluate intensification of lipid therapy as a predictor of cardiovascular death or nonfatal myocardial infarction. Among 2839 patients with mean follow-up of 3.6 years, the odds of physician intensification of lipid-lowering therapy significantly increased for those with nonobstructive CAD (odds ratio, 3.6; 95% confidence interval, 2.9-4.9; P<0.001) and obstructive CAD (odds ratio, 5.6; 95% confidence interval, 4.3-7.3; P<0.001). Low-density lipoprotein cholesterol levels declined significantly in association with intensification of lipid-lowering therapy after CCTA in all patient subgroups. In a hypothesis-generating analysis, among patients with nonobstructive but extensive CAD, statin use after CCTA was associated with a reduction in cardiovascular death or myocardial infarction (hazards ratio, 0.18; 95% confidence interval, 0.05-0.66; P=0.01). CONCLUSIONS: Abnormal CCTA findings are associated with downstream intensification in statin and aspirin therapy. In particular, CCTA may lead to increased use of prognostically beneficial therapies in patients identified as having extensive, nonobstructive CAD.

Synthesis of [(11)C]Bexarotene by Cu-Mediated [(11)C]Carbon Dioxide Fixation and Preliminary PET Imaging.

Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([(11)C-carbonyl]4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid) was synthesized using a Cu-mediated cross-coupling reaction employing an arylboronate precursor 1 and [(11)C]carbon dioxide under atmospheric pressure in 15 ± 2% uncorrected radiochemical yield (n = 3), based on [(11)C]CO2. Judicious choice of solvents, catalysts, and additives, as well as precursor concentration and purity of [(11)C]CO2, enabled the preparation of this (11)C-labeled carboxylic acid. Formulated [(11)C]bexarotene was isolated (>37 mCi) with >99% radiochemical purity in 32 min. Preliminary positron emission tomography-magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/µmol at time of injection), followed by slow clearance (Δ = -43%) over 60 min. Modest uptake (SUVmax = 0.8) was observed in whole brain and regions with high RXR expression.

MR-based motion correction for PET imaging using wired active MR microcoils in simultaneous PET-MR: phantom study.

PURPOSE: Artifacts caused by head motion present a major challenge in brain positron emission tomography (PET) imaging. The authors investigated the feasibility of using wired active MR microcoils to track head motion and incorporate the measured rigid motion fields into iterative PET reconstruction. METHODS: Several wired active MR microcoils and a dedicated MR coil-tracking sequence were developed. The microcoils were attached to the outer surface of an anthropomorphic(18)F-filled Hoffman phantom to mimic a brain PET scan. Complex rotation/translation motion of the phantom was induced by a balloon, which was connected to a ventilator. PET list-mode and MR tracking data were acquired simultaneously on a PET-MR scanner. The acquired dynamic PET data were reconstructed iteratively with and without motion correction. Additionally, static phantom data were acquired and used as the gold standard. RESULTS: Motion artifacts in PET images were effectively removed by wired active MR microcoil based motion correction. Motion correction yielded an activity concentration bias ranging from -0.6% to 3.4% as compared to a bias ranging from -25.0% to 16.6% if no motion correction was applied. The contrast recovery values were improved by 37%-156% with motion correction as compared to no motion correction. The image correlation (mean ± standard deviation) between the motion corrected (uncorrected) images of 20 independent noise realizations and static reference was R(2) = 0.978 ± 0.007 (0.588 ± 0.010, respectively). CONCLUSIONS: Wired active MR microcoil based motion correction significantly improves brain PET quantitative accuracy and image contrast.

Prognostic value of nonobstructive and obstructive coronary artery disease detected by coronary computed tomography angiography to identify cardiovascular events.

BACKGROUND: The contribution of plaque extent to predict cardiovascular events among patients with nonobstructive and obstructive coronary artery disease (CAD) is not well defined. Our objective was to evaluate the prognostic value of plaque extent detected by coronary computed tomography angiography. METHODS AND RESULTS: All consecutive patients without prior CAD referred for coronary computed tomography angiography to evaluate for CAD were included. Examination findings were classified as normal, nonobstructive (<50% stenosis), or obstructive (≥50%). Based on the number of segments with disease, extent of CAD was classified as nonextensive (≤4 segments) or extensive (>4 segments). The cohort included 3242 patients followed for the primary outcome of cardiovascular death or myocardial infarction for a median of 3.6 (2.1-5.0) years. In a multivariable analysis, the presence of extensive nonobstructive CAD (hazard ratio, 3.1; 95% confidence interval, 1.5-6.4), nonextensive obstructive (hazard ratio, 3.0; 95% confidence interval, 1.3-6.9), and extensive obstructive CAD (hazard ratio, 3.9; 95% confidence interval, 2.2-7.2) were associated with an increased rate of events, whereas nonextensive, nonobstructive CAD was not. The addition of plaque extent to a model that included clinical probability as well as the presence and severity of CAD improved risk prediction. CONCLUSIONS: Among patients with nonobstructive CAD, those with extensive plaque experienced a higher rate of cardiovascular death or myocardial infarction, comparable with those who have nonextensive disease. Even among patients with obstructive CAD, greater extent of nonobstructive plaque was associated with higher event rate. Our findings suggest that regardless of whether obstructive or nonobstructive disease is present, the extent of plaque detected by coronary computed tomography angiography enhances risk assessment.

Incremental prognostic value of coronary artery calcium score versus CT angiography among symptomatic patients without known coronary artery disease.

OBJECTIVE: To evaluate the prognostic value and test characteristics of coronary artery calcium (CAC) score for the identification of obstructive coronary artery disease (CAD) in comparison with coronary computed tomography angiography (CCTA) among symptomatic patients. METHODS: Retrospective cohort study at two large hospitals, including all symptomatic patients without prior CAD who underwent both CCTA and CAC. Accuracy of CAC for the identification of ≥ 50% and ≥ 70% stenosis by CCTA was evaluated. Prognostic value of CAC and CCTA were compared for prediction of major adverse cardiovascular events (MACE, defined as non-fatal myocardial infarction, cardiovascular death, late coronary revascularization (>90 days), and unstable angina requiring hospitalization). RESULTS: Among 1145 included patients, the mean age was 55 ± 12 years and median follow up 2.4 (IQR: 1.5-3.5) years. Overall, 406 (35%) CCTA were normal, 454 (40%) had <50% stenosis, and 285 (25%) had ≥ 50% stenosis. The prevalence of ≥ 70% stenosis was 16%. Among 483 (42%) patients with CAC zero, 395 (82%) had normal CCTA, 81 (17%) <50% stenosis, and 7 (1.5%) ≥ 50% stenosis. 2 (0.4%) patients had ≥ 70% stenosis. For diagnosis of ≥ 50% stenosis, CAC had a sensitivity of 98% and specificity of 55%. The negative predictive value (NPV) for CAC was 99% for ≥ 50% stenosis and 99.6% for ≥ 70% stenosis by CCTA. There were no adverse events among the 7 patients with zero calcium and ≥ 50% CAD. For prediction of MACE, the c-statistic for clinical risk factors of 0.62 increased to 0.73 (p < 0.001) with CAC versus 0.77 (p = 0.02) with CCTA. CONCLUSION: Among symptomatic patients with CAC zero, a 1-2% prevalence of potentially obstructive CAD occurs, although this finding was not associated with future coronary revascularization or adverse prognosis within 2 years.

Motion compensation for brain PET imaging using wireless MR active markers in simultaneous PET-MR: phantom and non-human primate studies.

Brain PET scanning plays an important role in the diagnosis, prognostication and monitoring of many brain diseases. Motion artifacts from head motion are one of the major hurdles in brain PET. In this work, we propose to use wireless MR active markers to track head motion in real time during a simultaneous PET-MR brain scan and incorporate the motion measured by the markers in the listmode PET reconstruction. Several wireless MR active markers and a dedicated fast MR tracking pulse sequence module were built. Data were acquired on an ACR Flangeless PET phantom with multiple spheres and a non-human primate with and without motion. Motions of the phantom and monkey's head were measured with the wireless markers using a dedicated MR tracking sequence module. The motion PET data were reconstructed using list-mode reconstruction with and without motion correction. Static reference was used as gold standard for quantitative analysis. The motion artifacts, which were prominent on the images without motion correction, were eliminated by the wireless marker based motion correction in both the phantom and monkey experiments. Quantitative analysis was performed on the phantom motion data from 24 independent noise realizations. The reduction of bias of sphere-to-background PET contrast by active marker based motion correction ranges from 26% to 64% and 17% to 25% for hot (i.e., radioactive) and cold (i.e., non-radioactive) spheres, respectively. The motion correction improved the channelized Hotelling observer signal-to-noise ratio of the spheres by 1.2 to 6.9 depending on their locations and sizes. The proposed wireless MR active marker based motion correction technique removes the motion artifacts in the reconstructed PET images and yields accurate quantitative values.

Cost-effectiveness analysis of coronary artery disease screening in HIV-infected men.

BACKGROUND: HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screening for HIV-positive men at intermediate or greater CAD risk. DESIGN: We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men. METHODS: Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the stress testing + medication and CCTA + medication strategies, patients with 1-2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the stress testing + intervention and CCTA + intervention strategies, patients with these results underwent ICA and received percutaneous coronary intervention. RESULTS: Compared to no screening, the stress testing + medication, stress testing + intervention, CCTA + medication, and CCTA + intervention strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost-effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 Euros per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening, but only stress testing + medication every 5 years remained cost-effective. At a willingness-to-pay threshold of 83,000 €/QALY (∼ 100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%. CONCLUSIONS: Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care.