Diagnostic accuracy of on-site coronary computed tomography-derived fractional flow reserve in the diagnosis of stable coronary artery disease.

PURPOSE: Invasive fractional flow reserve (FFR), the reference standard for identifying significant coronary artery disease (CAD), can be estimated non-invasively by computed tomography-derived fractional flow reserve (CT-FFR). Commercially available off-site CT-FFR showed improved diagnostic accuracy compared to coronary computed tomography angiography (CCTA) alone. However, the diagnostic performance of this lumped-parameter on-site method is unknown. The aim of this cross-sectional study was to determine the diagnostic accuracy of on-site CT-FFR in patients with suspected CAD. METHODS: A total of 61 patients underwent CCTA and invasive coronary angiography with FFR measured in 88 vessels. Significant CAD was defined as FFR and CT-FFR below 0.80. CCTA with stenosis above 50% was regarded as significant CAD. The diagnostic performance of both CT-FFR and CCTA was assessed using invasive FFR as the reference standard. RESULTS: Of the 88 vessels included in the analysis, 34 had an FFR of ≤ 0.80. On a per-vessel basis, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 91.2%, 81.4%, 93.6%, 75.6% and 85.2% for CT-FFR and were 94.1%, 68.5%, 94.9%, 65.3% and 78.4% for CCTA. The area under the receiver operating characteristic curve was 0.91 and 0.85 for CT-FFR and CCTA, respectively, on a per-vessel basis. CONCLUSION: On-site non-invasive FFR derived from CCTA improves diagnostic accuracy compared to CCTA without additional testing and has the potential to be integrated in the current clinical work-up for diagnosing stable CAD.

Coronary CT angiography for suspected acute coronary syndrome: sex-associated differences.

AIM: The optimal diagnostic test in the work-up of suspected acute coronary syndrome (ACS) may differ between men and women. The aim of this study was to compare sex-associated differences between using a diagnostic strategy including early coronary computed tomography angiography (CCTA) and standard of care (SOC). METHODS: In total, 500 patients who presented with symptoms suggestive of ACS at the emergency department were randomised between a diagnostic strategy supplemented with early CCTA and SOC. RESULTS: Women were generally older than men (mean ± standard deviation 56 ± 10 vs 53 ± 10 years, p < 0.01) and were less often admitted to hospital (33% vs 44%, p = 0.02). Obstructive coronary artery disease on CCTA (> 50% luminal narrowing) was less frequently seen in women (14% vs 26%, p = 0.02), and ACS was diagnosed less often in women (5% vs 10%, p = 0.03). Women underwent less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS (p = 0.008). CONCLUSION: Women had a lower incidence of obstructive CAD on CCTA and were less often admitted to hospital than men. They were subjected to less outpatient testing when early CCTA was used in the emergency department evaluation of suspected ACS.

ONCOR: design of the Dutch cardio-oncology registry.

BACKGROUND: The relative new subspecialty 'cardio-oncology' was established to meet the growing demand for an interdisciplinary approach to the management of cancer therapy-related cardiovascular adverse events. In recent years, specialised cardio-oncology services have been implemented worldwide, which all strive to improve the cardiovascular health of cancer patients. However, limited data are currently available on the outcomes and experiences of these specialised services, and optimal strategies for cardio-oncological care have not been established. AIM: The ONCOR registry has been created for prospective data collection and evaluation of cardio-oncological care in daily practice. METHODS: Dutch hospitals using a standardised cardio-oncology care pathway are included in this national, multicentre, observational cohort study. All patients visiting these cardio-oncology services are eligible for study inclusion. Data collection at baseline consists of the (planned) cancer treatment and the cardiovascular risk profile, which are used to estimate the cardiotoxic risk. Information regarding invasive and noninvasive tests is collected during the time patients receive cardio-oncological care. Outcome data consist of the incidence of cardiovascular complications and major adverse cardiac events, and the impact of these events on the oncological treatment. DISCUSSION: Outcomes of the ONCOR registry may aid in gaining more insight into the incidence of cancer therapy-related cardiovascular complications. The registry facilitates research on mechanisms of cardiovascular complications and on diagnostic, prognostic and therapeutic strategies. In addition, it provides a platform for future (interventional) studies. Centres with cardio-oncology services that are interested in contributing to the ONCOR registry are hereby invited to participate.

Global longitudinal strain to predict left ventricular dysfunction in asymptomatic patients with severe mitral valve regurgitation: literature review.

The optimal treatment strategy for asymptomatic patients with severe mitral valve regurgitation (MR) and preserved left ventricular (LV) function is challenging. This manuscript reviews the available literature on the value of left ventricular global longitudinal strain (LV-GLS) in predicting LV dysfunction after mitral valve surgery in these patients and discusses its current place in the treatment strategy. Studies were identified from Cochrane Library, SCOPUS, PubMed and Web of Science up to February 2018. The domain used was MR. The determinant was LV-GLS; other methods of deformation imaging were excluded. The examined outcome was LV dysfunction after surgery. A total of 144 articles were retrieved, of which 11 publications met the inclusion criteria, including a total of 2415 patients. Ten studies showed a significant correlation between preoperative LV-GLS and LV dysfunction postoperatively; one study reported a negative correlation. These studies suggest that LV-GLS is a predictor of LV dysfunction after surgery in asymptomatic patients with chronic MR. Hence, incorporation of LV-GLS for clinical decision-making in these patients might be of additional value. Further research is needed to confirm the role of LV-GLS in postoperative patients, and additionally in asymptomatic MR patients during a 'watchful waiting' strategy.

Added value of computed tomography fractional flow reserve in the diagnosis of coronary artery disease.

Multiple non-invasive tests are performed to diagnose coronary artery disease (CAD), but all are limited to either anatomical or functional assessments. Computed tomography derived Fractional Flow Reserve (CT-FFR) based on patient-specific lumped parameter models is a new test combining both characteristics simulating invasive FFR. This study aims to evaluate the added value of CT-FFR over other non-invasive tests to diagnose CAD. Patients with clinical suspicion of angina pectoris between 2010 and 2011 were included in this cross-sectional study. All underwent stress electrocardiography (X-ECG), SPECT, CT coronary angiography (CCTA) and CT-FFR. Invasive coronary angiography (ICA) and FFR were used as reference standard. Five models mimicking the clinical workflow were fitted and the area under receiver operating characteristic (AUROC) curve was used for comparison. 44% of the patients included in the analysis had a FFR of ≤ 0.80. The basic model including pre-test-likelihood and X-ECG had an AUROC of 0.79. The SPECT-strategy had an AUROC of 0.90 (p = 0.008), CCTA-strategy of 0.88 (p < 0.001), 0.93 when adding CT-FFR (p = 0.40) compared to 0.94 when combining CCTA and SPECT. This study shows adding on-site CT-FFR based on patient-specific lumped parameter models leads to an increased AUROC compared to the basic model. It improves the diagnostic work-up beyond SPECT or CCTA and is non-inferior to the combined strategy of SPECT and CCTA in the diagnosis of hemodynamically relevant CAD.

Comparison of four culture systems for Mycobacterium tuberculosis in the Zambian National Reference Laboratory.

SETTING: National TB Reference Laboratory, Zambia. OBJECTIVE: To compare four TB culture systems when used in a resource-limited setting. DESIGN: Comparison of four culture systems: automated Mycobacterium Growth Indicator Tube (AMGIT) 960, manual MGIT (MMGIT) and two Löwenstein-Jensen (LJ) culture media-commercial (CLJ) and homemade (HLJ). RESULTS: A total of 1916 sputum specimens were received, of which 261 (13.6%) were positive on microscopy. Mycobacterium tuberculosis complex (MTC) was isolated on at least one of the media in 410 (21.4%) specimens: MMGIT recovered 336 (17.5%) MTC, AMGIT 329 (17.2%), CLJ 192 (10.0%) and HLJ 184 (9.6%). The median time to detection for smear-negative specimens was 14 days for AMGIT, 16 days for MMGIT and 34 days for both LJ. Isolation of non-tuberculous mycobacteria (NTM) was more frequent in both MGIT systems (3.5%) than in CLJ (0.9%) and HLJ (0.8%). Contamination rates were high: 29.6% on AMGIT, 23.8% on MMGIT, 14.9% on CLJ and 12.5% on HLJ. CONCLUSION: Despite high contamination rates, either MGIT system considerably improved both the yield and the time to detection of MTC compared to LJ media. Investments in infrastructure and training are needed if culture is to be scaled up in low-income settings such as this.

Pembrolizumab: Role of Modeling and Simulation in Bringing a Novel Immunotherapy to Patients With Melanoma.

Recently, immunotherapy has yielded promising results in several cancer types. Contrary to the established classical chemotherapy-dosing paradigm, a maximum tolerated dose approach does not always produce better clinical outcomes for novel targeted therapies, as their efficacy is frequently robust at pharmacologically active doses below the maximum tolerated dose. Integrated safety and efficacy assessments are needed to inform clinical dose and trial design, and to support an early identification of potentially safe and efficacious combination treatments.

Using Model-Based "Learn and Confirm" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady-state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.

Translational Pharmacokinetic/Pharmacodynamic Modeling of Tumor Growth Inhibition Supports Dose-Range Selection of the Anti-PD-1 Antibody Pembrolizumab.

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition. Human simulations were performed using clinical pharmacokinetic data, literature values, and in vitro parameters for drug distribution and binding. Biological and mathematical uncertainties were included in simulations to generate expectations for dose response. The results demonstrated a minimal increase in efficacy for doses higher than 2 mg/kg. The findings of the translational model were successfully applied to select 2 mg/kg as the lowest dose for dose-ranging evaluations.

Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.

Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

Multivariate pharmacokinetic/pharmacodynamic (PKPD) analysis with metabolomics shows multiple effects of remoxipride in rats.

The study of central nervous system (CNS) pharmacology is limited by a lack of drug effect biomarkers. Pharmacometabolomics is a promising new tool to identify multiple molecular responses upon drug treatment. However, the pharmacodynamics is typically not evaluated in metabolomics studies, although being important properties of biomarkers. In this study we integrated pharmacometabolomics with pharmacokinetic/pharmacodynamic (PKPD) modeling to identify and quantify the multiple endogenous metabolite dose-response relations for the dopamine D2 antagonist remoxipride. Remoxipride (vehicle, 0.7 or 3.5mg/kg) was administered to rats. Endogenous metabolites were analyzed in plasma using a biogenic amine platform and PKPD models were derived for each single metabolite. These models were clustered on basis of proximity between their PKPD parameter estimates, and PKPD models were subsequently fitted for the individual clusters. Finally, the metabolites were evaluated for being significantly affected by remoxipride. In total 44 metabolites were detected in plasma, many of them showing a dose dependent decrease from baseline. We identified 6 different clusters with different time and dose dependent responses and 18 metabolites were revealed as potential biomarker. The glycine, serine and threonine pathway was associated with remoxipride pharmacology, as well as the brain uptake of the dopamine and serotonin precursors. This is the first time that pharmacometabolomics and PKPD modeling were integrated. The resulting PKPD cluster model described diverse pharmacometabolomics responses and provided a further understanding of remoxipride pharmacodynamics. Future research should focus on the simultaneous pharmacometabolomics analysis in brain and plasma to increase the interpretability of these responses.

Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

Phase differences in electrical discharge rhythms between neuronal populations of the left and right suprachiasmatic nuclei.

The circadian pacemaker of the suprachiasmatic nuclei is a complex multioscillator system, which controls circadian and seasonal rhythmicity. A number of clock genes have been identified that play a key role in the generation of circadian rhythms. These clock genes are expressed in a circadian manner as has been shown in mice, rats and hamsters. The time at which their expression reaches peak values differs among the several genes. Expression profiles for a specific gene may also differ among subdivisions of the suprachiasmatic nuclei. It has been shown that mPer1 peaks slightly out of phase in the left and right suprachiasmatic nuclei and that the rhythm in c-fos expression is significantly different between the dorsomedial and ventrolateral regions. In the special case that the animal shows splitting of its locomotor activity pattern, mPer1 in the left and right suprachiasmatic nuclei appeared to oscillate in antiphase. Whether the molecular organization within the suprachiasmatic nuclei plays a role in seasonal rhythmicity, allowing animals to track daylength and become reproductive at the proper phase of the annual cycle, receives increasing interest (). The differences in peak expression times that exist between different genes, and the spatial differences in peak time for single genes, are suggestive of a genetic mechanism underlying the multioscillator structure. It is unknown, however, whether phase differences that are observed at the molecular level exist at the level of electrical activity rhythms in the suprachiasmatic nuclei in order to become potentially functional. In this study we investigated the presence of phase differences in neuronal discharge rhythms in the suprachiasmatic nuclei of the rat. To this purpose we combined simultaneous electrophysiological recordings of neuronal populations in the left and right suprachiasmatic nuclei with a detailed analysis of the phase relationship between them. The results demonstrate that neuronal subpopulations of the suprachiasmatic nuclei show phase differences both in their peak and half-maximum times of up to 4 h. We propose that these phase differences may play a role in the plasticity of the circadian timing system.

Multiunit activity recordings in the suprachiasmatic nuclei: in vivo versus in vitro models.

The suprachiasmatic nuclei (SCN) of the hypothalamus continue to oscillate when they are isolated in a brain slice preparation. We recorded multiunit activity in the SCN of the rat both in vivo and in vitro to determine the circadian discharge pattern. The variability of the discharge pattern is larger and the amplitude of the rhythm is smaller in vivo than in vitro. Moreover we found evidence for a direct effect of the animal's behavioural activity on electrical activity of the SCN in vivo. These findings may provide an electrophysiological basis for the known effects of behavioural stimuli on the circadian pacemaker. This study underscores the importance of recordings in intact preparations in addition to in vitro work when generalisations to physiological conditions are to be made.

Circadian rhythm in light response in suprachiasmatic nucleus neurons of freely moving rats.

Long-term recordings of single SCN units were performed in freely moving rats simultaneously with multiunit recordings and evidence is presented for a daily change in light-responsiveness. SCN light response is high during the night and low during the day. We conclude that this difference is caused by a change in sensitivity, with higher sensitivities at night. Moreover, we demonstrate that the circadian rhythm in SCN light response is the result of the integrated behaviour of similarly behaving single SCN units.

Functional absence of extraocular photoreception in hamster circadian rhythm entrainment.

The mammalian circadian pacemaker is entrainable by light via the retina. The putative role of extraocular light perception was investigated in blinded hamsters. These animals were shaved and exposed to a light-emitting pad for either 30 min or 3 h. The absence of any phase-shifting effects on wheel running activity rhythms indicates that extraocular light perception plays no functional role in photic entrainment of the circadian pacemaker in the hamster.

Neurons of the rat suprachiasmatic nucleus show a circadian rhythm in membrane properties that is lost during prolonged whole-cell recording.

The suprachiasmatic nucleus is commonly considered to contain the main pacemaker of behavioral and hormonal circadian rhythms. Using whole-cell patch-clamp recordings, the membrane properties of suprachiasmatic nucleus neurons were investigated in order to get more insight in membrane physiological mechanisms underlying the circadian rhythm in firing activity. Circadian rhythmicity could not be detected either in spontaneous firing rate or in other membrane properties when whole-cell measurements were made following an initial phase shortly after membrane rupture. However, this apparent lack of rhythmicity was not due to an unhealthy slice preparation or to seal formation, as a clear day/night difference in firing rate was found in cell-attached recordings. Furthermore, in a subsequent series of whole-cell recordings, membrane properties were assessed directly after membrane rupture, and in this series we did find a significant day/night difference in spontaneous firing rate, input resistance and frequency adaptation. As concerns the participation of different subpopulations of suprachiasmatic nucleus neurons expressing circadian rhythmicity, cluster I neurons exhibited strong rhythmicity, whereas no day/night differences were found in cluster II neurons. Vasopressin-containing cells form a subpopulation of cluster I neurons and showed a more pronounced circadian rhythmicity than the total population of cluster I neurons. In addition to their strong rhythm in spontaneous firing rate they also displayed a day/night difference in membrane potential.

Quantitative analysis of vascular images, in particular of abdominal aorta aneurysms from 3D CTA data sets.

This article presents a combination of well known image processing techniques to automatically segment CTA images of the Abdominal Aortic Aneurysm. Current results are that about 80% of the contours need no manual corrections. The remaining 20% fail due to calcified plaque close to the lumen border. After correction a 3D surface model is created from the 2D contours which is used as input for flow simulations and for parameter extraction of the AAA by clinicians for selecting the proper size and shape endograft, and to plan the placement procedure of this endograft in the patient.

Desmopressin as a pharmacological tool in vasopressinergic hypothalamus-pituitary-adrenal axis modulation: neuroendocrine, cardiovascular and coagulatory effects.

Arginine-vasopressin (AVP) is a physiological co-activator of the hypothalamus-pituitary-adrenal (HPA) axis, together with corticotrophin releasing hormone (CRH). A synthetic analogue of AVP, desmopressin (dDAVP), is often used as a pharmacological tool to assess co-activation in health and disease. The relation between dDAVP's neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic and non-specific stress effects has not been studied. A randomized, double-blind, placebo-controlled, three-way crossover study was performed in 12 healthy male and female volunteers (6 : 6). dDAVP was administered intravenously as a 10 µg bolus (over 1 min) or a 30 µg incremental infusion (over 60 min). Neuroendocrine, cardiovascular, pro-coagulatory, anti-diuretic effects and adverse events (AEs) were recorded, and autonomic nervous system (ANS) activation evaluated. The incremental infusion reached 1.8-fold higher dDAVP concentrations than the bolus. Neuroendocrine effects were similar for the 10 µg dDAVP bolus and the 30 µg incremental infusion, while cardiovascular and coagulatory effects were greater with the 30 µg dose. Osmolality and ANS activity remained uninfluenced. AEs corresponded to dDAVP's side-effect profile. In conclusion, the neuroendocrine effects of a 10 µg dDAVP bolus administered over 1 min are similar to those of a 30 µg incremental infusion administered over one hour, despite higher dDAVP concentrations after the infusion. Cardiovascular and coagulatory effects showed clear dose-related responses. A 10 µg dDAVP bolus is considered a safe vasopressinergic function test at which no confounding effects of systemic or autonomic stress were seen.