Validation of an AI-based algorithm for measurement of the thoracic aortic diameter in low-dose chest CT.

OBJECTIVES: To evaluate the performance of artificial intelligence (AI) software for automatic thoracic aortic diameter assessment in a heterogeneous cohort with low-dose, non-contrast chest computed tomography (CT). MATERIALS AND METHODS: Participants of the Imaging in Lifelines (ImaLife) study who underwent low-dose, non-contrast chest CT (August 2017-May 2022) were included using random samples of 80 participants <50y, ≥80y, and with thoracic aortic diameter ≥40 mm. AI-based aortic diameters at eight guideline compliant positions were compared with manual measurements. In 90 examinations (30 per group) diameters were reassessed for intra- and inter-reader variability, which was compared to discrepancy of the AI system using Bland-Altman analysis, paired samples t-testing and linear mixed models. RESULTS: We analyzed 240 participants (63 ± 16 years; 50 % men). AI evaluation failed in 11 cases due to incorrect segmentation (4.6 %), leaving 229 cases for analysis. No difference was found in aortic diameter between manual and automatic measurements (32.7 ± 6.4 mm vs 32.7 ± 6.0 mm, p = 0.70). Bland-Altman analysis yielded no systematic bias and a repeatability coefficient of 4.0 mm for AI. Mean discrepancy of AI (1.3 ± 1.6 mm) was comparable to inter-reader variability (1.4 ± 1.4 mm); only at the proximal aortic arch showed AI higher discrepancy (2.0 ± 1.8 mm vs 0.9 ± 0.9 mm, p < 0.001). No difference between AI discrepancy and inter-reader variability was found for any subgroup (all: p > 0.05). CONCLUSION: The AI software can accurately measure thoracic aortic diameters, with discrepancy to a human reader similar to inter-reader variability in a range from normal to dilated aortas.

Influenza season influence on outcome of new nodules in the NELSON study.

We evaluated the impact of the influenza season on outcome of new lung nodules in a LDCT lung cancer screening trial population. NELSON-trial participants with ≥ 1 new nodule detected in screening rounds two and three were included. Outcome (resolution or persistence) of new nodules detected per season was calculated and compared. Winter (influenza season) was defined as 1st October to 31st March, and compared to the summer (hay-fever season), 1st April to 30th September. Overall, 820 new nodules were reported in 529 participants. Of the total new nodules, 482 (59%) were reported during winter. When considering the outcome of all new nodules, there was no statistically significant association between summer and resolving nodules (OR 1.07 [CI 1.00-1.15], p = 0.066), also when looking at the largest nodule per participant (OR 1.37 [CI 0.95-1.98], p = 0.094). Similarly, there was no statistically significant association between season and screen detected cancers (OR 0.47 [CI 0.18-1.23], p = 0.123). To conclude, in this lung cancer screening population, there was no statistically significant association between influenza season and outcome of new lung nodules. Hence, we recommend new nodule management strategy is not influenced by the season in which the nodule is detected.

Addition of FFRct in the diagnostic pathway of patients with stable chest pain to reduce unnecessary invasive coronary angiography (FUSION) : Rationale and design for the multicentre, randomised, controlled FUSION trial.

BACKGROUND: Coronary computed tomography angiography (CCTA) is widely used in the diagnostic work-up of patients with stable chest pain. CCTA has an excellent negative predictive value, but a moderate positive predictive value for detecting coronary stenosis. Computed tomography-derived fractional flow reserve (FFRct) is a non-invasive, well-validated technique that provides functional assessment of coronary stenosis, improving the positive predictive value of CCTA. However, to determine the value of FFRct in routine clinical practice, a pragmatic randomised, controlled trial (RCT) is required. We will conduct an RCT to investigate the impact of adding FFRct analysis in the diagnostic pathway of patients with a coronary stenosis on CCTA on the rate of unnecessary invasive coronary angiography, cost-effectiveness, quality of life and clinical outcome. METHODS: The FUSION trial is a prospective, multicentre RCT that will randomise 528 patients with stable chest pain and anatomical stenosis of ≥ 50% but < 90% in at least one coronary artery of ≥ 2 mm on CCTA, to FFRct-guided care or usual care in a 1:1 ratio. Follow-up will be 1 year. The primary endpoint is the rate of unnecessary invasive coronary angiography within 90 days. CONCLUSION: The FUSION trial will evaluate the use of FFRct in stable chest pain patients from the Dutch perspective. The trial is funded by the Dutch National Health Care Institute as part of the research programme 'Potentially Promising Care' and the results will be used to assess if FFRct reimbursement should be included in the standard health care package.

Automatic Cardiac Structure Contouring for Small Datasets with Cascaded Deep Learning Models.

Cardiac structure contouring is a time consuming and tedious manual activity used for radiotherapeutic dose toxicity planning. We developed an automatic cardiac structure segmentation pipeline for use in low-dose non-contrast planning CT based on deep learning algorithms for small datasets. Fifty CT scans were retrospectively selected and the whole heart, ventricles and atria were contoured. A two stage deep learning pipeline was trained on 41 non contrast planning CTs, tuned with 3 CT scans and validated on 6 CT scans. In the first stage, An InceptionResNetV2 network was used to identify the slices that contained cardiac structures. The second stage consisted of three deep learning models trained on the images containing cardiac structures to segment the structures. The three deep learning models predicted the segmentations/contours on axial, coronal and sagittal images and are combined to create the final prediction. The final accuracy of the pipeline was quantified on 6 volumes by calculating the Dice similarity coefficient (DC), 95% Hausdorff distance (95% HD) and volume ratios between predicted and ground truth volumes. Median DC and 95% HD of 0.96, 0.88, 0.92, 0.80 and 0.82, and 1.86, 2.98, 2.02, 6.16 and 6.46 were achieved for the whole heart, right and left ventricle, and right and left atria respectively. The median differences in volume were -4, -1, + 5, -16 and -20% for the whole heart, right and left ventricle, and right and left atria respectively. The automatic contouring pipeline achieves good results for whole heart and ventricles. Robust automatic contouring with deep learning methods seems viable for local centers with small datasets.

The impact and challenges of implementing CTCA according to the 2019 ESC guidelines on chronic coronary syndromes: a survey and projection of CTCA services in the Netherlands.

BACKGROUND: The 2019 ESC-guidelines on chronic coronary syndromes (ESC-CCS) recommend computed tomographic coronary angiography (CTCA) or non-invasive functional imaging instead of exercise ECG as initial test to diagnose obstructive coronary artery disease. Since impact and challenges of these guidelines are unknown, we studied the current utilisation of CTCA-services, status of CTCA-protocols and modeled the expected impact of these guidelines in the Netherlands. METHODS AND RESULTS: A survey on current practice and CTCA utilisation was disseminated to every Dutch hospital organisation providing outpatient cardiology care and modeled the required CTCA capacity for implementation of the ESC guideline, based on these national figures and expert consensus. Survey response rate was 100% (68/68 hospital organisations). In 2019, 63 hospital organisations provided CTCA-services (93%), CTCA was performed on 99 CTCA-capable CT-scanners, and 37,283 CTCA-examinations were performed. Between the hospital organisations, we found substantial variation considering CTCA indications, CTCA equipment and acquisition and reporting standards. To fully implement the new ESC guideline, our model suggests that 70,000 additional CTCA-examinations would have to be performed in the Netherlands. CONCLUSIONS: Despite high national CTCA-services coverage in the Netherlands, a substantial increase in CTCA capacity is expected to be able to implement the 2019 ESC-CCS recommendations on the use of CTCA. Furthermore, the results of this survey highlight the importance to address variations in image acquisition and to standardise the interpretation and reporting of CTCA, as well as to establish interdisciplinary collaboration and organisational alignment.

Ultra-low-dose CT combined with noise reduction techniques for quantification of emphysema in COPD patients: An intra-individual comparison study with standard-dose CT.

PURPOSE: Phantom studies in CT emphysema quantification show that iterative reconstruction and deep learning-based noise reduction (DLNR) allow lower radiation dose. We compared emphysema quantification on ultra-low-dose CT (ULDCT) with and without noise reduction, to standard-dose CT (SDCT) in chronic obstructive pulmonary disease (COPD). METHOD: Forty-nine COPD patients underwent ULDCT (third generation dual-source CT; 70ref-mAs, Sn-filter 100kVp; median CTDIvol 0.38 mGy) and SDCT (64-multidetector CT; 40mAs, 120kVp; CTDIvol 3.04 mGy). Scans were reconstructed with filtered backprojection (FBP) and soft kernel. For ULDCT, we also applied advanced modelled iterative reconstruction (ADMIRE), levels 1/3/5, and DLNR, levels 1/3/5/9. Emphysema was quantified as Low Attenuation Value percentage (LAV%, ≤-950HU). ULDCT measures were compared to SDCT as reference standard. RESULTS: For ULDCT, the median radiation dose was 84 % lower than for SDCT. Median extent of emphysema was 18.6 % for ULD-FBP and 15.4 % for SDCT (inter-quartile range: 11.8-28.4 % and 9.2 %-28.7 %, p = 0.002). Compared to SDCT, the range in limits of agreement of emphysema quantification as measure of variability was 14.4 for ULD-FBP, 11.0-13.1 for ULD-ADMIRE levels and 10.1-13.9 for ULD-DLNR levels. Optimal settings were ADMIRE 3 and DLNR 3, reducing variability of emphysema quantification by 24 % and 27 %, at slight underestimation of emphysema extent (-1.5 % and -2.9 %, respectively). CONCLUSIONS: Ultra-low-dose CT in COPD patients allows dose reduction by 84 %. State-of-the-art noise reduction methods in ULDCT resulted in slight underestimation of emphysema compared to SDCT. Noise reduction methods (especially ADMIRE 3 and DLNR 3) reduced variability of emphysema quantification in ULDCT by up to 27 % compared to FBP.

Should germline genome editing be allowed? The effect of treatment characteristics on public acceptability.

STUDY QUESTION: To what extent do characteristics of germline genome editing (GGE) determine whether the general public supports permitting the clinical use of GGE? SUMMARY ANSWER: The risk that GGE would cause congenital abnormalities had the largest effect on support for allowing GGE, followed by effectiveness of GGE, while costs, the type of application (disease or enhancement) and the effect on child well-being had moderate effects. WHAT IS KNOWN ALREADY: Scientific progress on GGE has increased the urgency of resolving whether and when clinical application of GGE may be ethically acceptable. Various expert bodies have suggested that the treatment characteristics will be key in determining whether GGE is acceptable. For example, GGE with substantial risks (e.g. 15% chance of a major congenital abnormality) may be acceptable to prevent a severe disease but not to enhance non-medical characteristics or traits of an otherwise healthy embryo (e.g. eye colour or perhaps in the future more complex traits, such as intelligence). While experts have called for public engagement, it is unclear whether and how much the public acceptability of GGE is affected by the treatment characteristics proposed by experts. STUDY DESIGN, SIZE, DURATION: The vignette-based survey was disseminated in 2018 among 1857 members of the Dutch general public. An online research panel was used to recruit a sample representing the adult Dutch general public. PARTICIPANTS/MATERIALS, SETTING, METHODS: A literature review identified the key treatment characteristics of GGE: the effect on the well-being of the future child, use for disease or enhancement, risks for the future child, effectiveness (here defined as the chance of a live birth, assuming that if the GGE was not successful, the embryo would not be transferred), cost and availability of alternative treatments/procedures to prevent the genetic disease or provide enhancement (i.e. preimplantation genetic testing (PGT)), respectively. For each treatment characteristic, 2-3 levels were defined to realistically represent GGE and its current alternatives, donor gametes and ICSI with PGT. Twelve vignettes were created by fractional factorial design. A multinominal logit model assessed how much each treatment characteristic affected participants' choices. MAIN RESULTS AND THE ROLE OF CHANCE: The 1136 respondents (response rate 61%) were representative of the Dutch adult population in several demographics. Respondents were between 18 and 89 years of age. When no alternative treatment/procedure is available, the risk that GGE would cause (other) congenital abnormalities had the largest effect on whether the Dutch public supported allowing GGE (coefficient = -3.07), followed by effectiveness (coefficient = 2.03). Costs (covered by national insurance, coefficient = -1.14), the type of application (disease or enhancement; coefficient = -1.07), and the effect on child well-being (coefficient = 0.97) had similar effects on whether GGE should be allowed. If an alternative treatment/procedure (e.g. PGT) was available, participants were not categorically opposed to GGE, however, they were strongly opposed to using GGE for enhancement (coefficient = -3.37). The general acceptability of GGE was higher than participants' willingness to personally use it (P < 0.001). When participants considered whether they would personally use GGE, the type of application (disease or enhancement) was more important, whereas effectiveness and costs (covered by national insurance) were less important than when they considered whether GGE should be allowed. Participants who were male, younger and had lower incomes were more likely to allow GGE when no alternative treatment/procedure is available. LIMITATIONS, REASONS FOR CAUTION: Some (e.g. ethnic, religious) minorities were not well represented. To limit complexity, not all characteristics of GGE could be included (e.g. out-of-pocket costs), therefore, the views gathered from the vignettes reflect only the choices presented to the respondents. The non-included characteristics could be connected to and alter the importance of the studied characteristics. This would affect how closely the reported coefficients reflect 'real-life' importance. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to quantify the substantial impact of GGE's effectiveness, costs (covered by national insurance), and effect on child well-being on whether the public considered GGE acceptable. In general, the participants were strikingly risk-averse, in that they weighed the risks of GGE more heavily than its benefits. Furthermore, although only a single study in one country, the results suggests that-if sufficiently safe and effective-the public may approve of using GGE (presumably combined with PGT) instead of solely PGT to prevent passing on a disease. The reported public views can serve as input for future consideration of the ethics and governance of GGE. STUDY FUNDING/COMPETING INTEREST(S): Young Academy of the Royal Dutch Academy of Sciences (UPS/RB/745), Alliance Grant of the Amsterdam Reproduction and Development Research Institute (2017-170116) and National Institutes of Health Intramural Research Programme. No competing interests. TRIAL REGISTRATION NUMBER: N/A.

Computed tomography for myocardial characterization in ischemic heart disease: a state-of-the-art review.

This review provides an overview of the currently available computed tomography (CT) techniques for myocardial tissue characterization in ischemic heart disease, including CT perfusion and late iodine enhancement. CT myocardial perfusion imaging can be performed with static and dynamic protocols for the detection of ischemia and infarction using either single- or dual-energy CT modes. Late iodine enhancement may be used for the analysis of myocardial infarction. The accuracy of these CT techniques is highly dependent on the imaging protocol, including acquisition timing and contrast administration. Additionally, the options for qualitative and quantitative analysis and the accuracy of each technique are discussed.

Application of artificial intelligence in cardiac CT: From basics to clinical practice.

Research into the possibilities of AI in cardiac CT has been growing rapidly in the last decade. With the rise of publicly available databases and AI algorithms, many researchers and clinicians have started investigations into the use of AI in the clinical workflow. This review is a comprehensive overview on the types of tasks and applications in which AI can aid the clinician in cardiac CT, and can be used as a primer for medical researchers starting in the field of AI. The applications of AI algorithms are explained and recent examples in cardiac CT of these algorithms are further elaborated on. The critical factors for implementation in the future are discussed.

Computerized fetal heart rate analysis in early preterm fetal growth restriction.

OBJECTIVE: To assess the value of computerized cardiotocography (cCTG) with calculation of fetal heart rate (FHR) short-term variability (STV) in early preterm fetal growth restriction (FGR) for prevention of fetal death and neonatal asphyxia, neonatal morbidity, and 2-year neurodevelopmental impairment. METHODS: This was a retrospective cohort study of all women who were admitted to the Amsterdam University Medical Center-AMC between 2003 and 2015 due to FGR and/or pre-eclampsia, and who were delivered by prelabor Cesarean section, or had a fetal death, before 32 weeks' gestation. STV of all available cCTG registrations during the 5 days preceding fetal death or delivery was calculated retrospectively, and FHR decelerations were classified visually as absent, 1-2/h or recurrent (> 2/h). Adverse outcome endpoints were defined as fetal death, neonatal asphyxia at birth (including fetal death), neonatal death, major neonatal morbidity and 2-year neurodevelopmental outcome. A simulation analysis was performed to assess the incidence of adverse outcome using two thresholds for cCTG: (1) highly abnormal (STV < 2.6 ms before 29 weeks and < 3.0 ms thereafter, and/or recurrent FHR decelerations); and (2) moderately abnormal (STV < 3.5 ms before 29 weeks and < 4.0 ms thereafter, and/or recurrent FHR decelerations). Three management strategies were assessed using a strict schedule for the frequency of cCTG recordings: (1) cCTG without use of fetal arterial Doppler; (2) cCTG with additional fetal arterial Doppler after 29 weeks; and (3) cCTG with additional fetal arterial Doppler after 27 weeks. RESULTS: Included were 367 pregnancies (3295 cCTG recordings), of which 20 resulted in fetal death and 347 were delivered by Cesarean section before the onset of labor. Cesarean delivery was indicated by fetal condition in 94% of cases and by maternal condition in 6%. Median gestational age at delivery was 30 (interquartile range (IQR), 28-31) weeks and median birth weight was 900 (IQR, 740-1090) g. Six cases of fetal death were not anticipated by standard practice using visual assessment of CTG. A last highly abnormal cCTG was associated with fetal death and with neonatal asphyxia (including fetal death; n = 99), but not with major neonatal morbidity and 2-year neurodevelopmental outcome. Moderately abnormal cCTG had no significant association with any endpoint. Simulation analysis showed that a strategy that combined cCTG results with umbilicocerebral ratio or umbilical absent or reversed end-diastolic flow could detect all fetal deaths. CONCLUSIONS: Computerized CTG in combination with fetal arterial Doppler, with a strict protocol for the frequency of recordings, is likely to be more effective than visual CTG assessment for preventing fetal death in early preterm FGR. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Enhancing cardiovascular artificial intelligence (AI) research in the Netherlands: CVON-AI consortium.

BACKGROUND: Machine learning (ML) allows the exploration and progressive improvement of very complex high-dimensional data patterns that can be utilised to optimise specific classification and prediction tasks, outperforming traditional statistical approaches. An enormous acceleration of ready-to-use tools and artificial intelligence (AI) applications, shaped by the emergence, refinement, and application of powerful ML algorithms in several areas of knowledge, is ongoing. Although such progress has begun to permeate the medical sciences and clinical medicine, implementation in cardiovascular medicine and research is still in its infancy. OBJECTIVES: To lay out the theoretical framework, purpose, and structure of a novel AI consortium. METHODS: We have established a new Dutch research consortium, the CVON-AI, supported by the Netherlands Heart Foundation, to catalyse and facilitate the development and utilisation of AI solutions for existing and emerging cardiovascular research initiatives and to raise AI awareness in the cardiovascular research community. CVON-AI will connect to previously established CVON consortia and apply a cloud-based AI platform to supplement their planned traditional data-analysis approach. RESULTS: A pilot experiment on the CVON-AI cloud was conducted using cardiac magnetic resonance data. It demonstrated the feasibility of the platform and documented excellent correlation between AI-generated ventricular function estimates as compared to expert manual annotations. The resulting AI solution was then integrated in a web application. CONCLUSION: CVON-AI is a new consortium meant to facilitate the implementation and raise awareness of AI in cardiovascular research in the Netherlands. CVON-AI will create an accessible cloud-based platform for cardiovascular researchers, demonstrate the clinical applicability of AI, optimise the analytical methodology of other ongoing CVON consortia, and promote AI awareness through education and training.

Prognostic value of CT myocardial perfusion imaging and CT-derived fractional flow reserve for major adverse cardiac events in patients with coronary artery disease.

OBJECTIVES: The purpose of this study was to analyze the prognostic value of dynamic CT perfusion imaging (CTP) and CT derived fractional flow reserve (CT-FFR) for major adverse cardiac events (MACE). METHODS: 81 patients from 4 institutions underwent coronary computed tomography angiography (CCTA) with dynamic CTP imaging and CT-FFR analysis. Patients were followed-up at 6, 12, and 18 months after imaging. MACE were defined as cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, or revascularization. CT-FFR was computed for each major coronary artery using an artificial intelligence-based application. CTP studies were analyzed per vessel territory using an index myocardial blood flow, the ratio between territory and global MBF. The prognostic value of CCTA, CT-FFR, and CTP was investigated with a univariate and multivariate Cox proportional hazards regression model. RESULTS: 243 vessels in 81 patients were interrogated by CCTA with CT-FFR and 243 vessel territories (1296 segments) were evaluated with dynamic CTP imaging. Of the 81 patients, 25 (31%) experienced MACE during follow-up. In univariate analysis, a positive index-MBF resulted in the largest risk for MACE (HR 11.4) compared to CCTA (HR 2.6) and CT-FFR (HR 4.6). In multivariate analysis, including clinical factors, CCTA, CT-FFR, and index-MBF, only index-MBF significantly contributed to the risk of MACE (HR 10.1), unlike CCTA (HR 1.2) and CT-FFR (HR 2.2). CONCLUSION: Our study provides initial evidence that dynamic CTP alone has the highest prognostic value for MACE compared to CCTA and CT-FFR individually or a combination of the three, independent of clinical risk factors.

Respiratory level tracking with visual biofeedback for consistent breath-hold level with potential application in image-guided interventions.

BACKGROUND: To present and evaluate a new respiratory level biofeedback system that aids the patient to return to a consistent breath-hold level with potential application in image-guided interventions. METHODS: The study was approved by the local ethics committee and written informed consent was waived. Respiratory motion was recorded in eight healthy volunteers in the supine and prone positions, using a depth camera that measures the mean distance to thorax, abdomen and back. Volunteers were provided with real-time visual biofeedback on a screen, as a ball moving up and down with respiratory motion. For validation purposes, a conversion factor from mean distance (in mm) to relative lung volume (in mL) was determined using spirometry. Subsequently, without spirometry, volunteers were given breathing instructions and were asked to return to their initial breath-hold level at expiration ten times, in both positions, with and without visual biofeedback. For both positions, the median and interquartile range (IQR) of the absolute error in lung volume from initial breath-hold were determined with and without biofeedback and compared using Wilcoxon signed rank tests. RESULTS: Without visual biofeedback, the median difference from initial breath-hold was 124.6 mL (IQR 55.7-259.7 mL) for the supine position and 156.3 mL (IQR 90.9-334.7 mL) for the prone position. With the biofeedback, the difference was significantly decreased to 32.7 mL (IQR 12.8-59.6 mL) (p < 0.001) and 22.3 mL (IQR 7.7-47.0 mL) (p < 0.001), respectively. CONCLUSIONS: The use of a depth camera to provide visual biofeedback increased the reproducibility of breath-hold expiration level in healthy volunteers, with a potential to eliminate targeting errors caused by respiratory movement during lung image-guided procedures.

Non-invasive assessment of coronary artery geometry using coronary CTA.

AIM: To assess the association of coronary artery geometry with the severity of coronary artery disease (CAD). METHODS: 73 asymptomatic individuals at increased risk of CAD due to peripheral vascular disease (18 women, mean age 63.5 ±â€¯8.2 years) underwent coronary computed tomography angiography (coronary CTA) using first generation dual-source CT. Curvature and tortuosity of the coronary arteries were quantified using semi-automatically generated centerlines. Measurements were performed for individual segments and for the entire artery. Coronary segments were labeled according to the presence of significant stenosis, defined as >70% luminal narrowing, and the presence of plaque. Comparisons were made by segment and by artery, using linear mixed models. RESULTS: Overall, median curvature and tortuosity were, respectively, 0.094 [0.071; 0.120] and 1.080 [1.040; 1.120] on a per-segment level, and 0.096 [0.078; 0.118] and 1.175 [1.090; 1.420] on a per-artery level. Curvature was associated with significant stenosis at a per-segment (p < 0.001) and per-artery level (p = 0.002). Curvature was 16.7% higher for segments with stenosis, and 13.8% higher for arteries with stenosis. Tortuosity was associated with significant stenosis only at the per-segment level (p = 0.002). Curvature was related to the presence of plaque at the per-segment (p < 0.001) and per-artery level (p < 0.001), tortuosity was only related to plaque at the per-segment level (p < 0.001). CONCLUSION: Coronary artery geometry as derived from coronary CTA is related to the presence of plaque and significant stenosis.

Broad support for regulating the clinical implementation of future reproductive techniques.

STUDY QUESTION: Do gynaecologists, infertile patients and the general public, consider that regulation of the clinical implementation of stem cell-based fertility treatments is required? SUMMARY ANSWER: There is broad support from gynaecologists, patients and the general public for regulating the clinical implementation of future stem cell-based fertility treatments. WHAT IS KNOWN ALREADY: There is debate on the need to regulate the clinical implementation of novel techniques. Regulation may hinder their swift adoption and delay benefits for patients, but may prevent the implementation of ineffective or harmful techniques. Stem cell-based fertility treatments, which involve creating oocytes or spermatozoa by manipulating stem cells, are likely to be implemented in clinical practice in the near future and will probably impact future generations as well as the current one. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey was conducted among gynaecologists working in fertility clinics (n = 179), patients with severe infertility (n = 348) and a representative sample of the general public (n = 1250). The questionnaire was disseminated in the Netherlands in the winter of 2015-2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The newly developed questionnaire was reviewed by experts and tested among the general public. The questionnaire assessed whether participants wanted each of nine potential negative consequences of the clinical implementation of stem cell-based fertility treatments to be regulated. In addition, the importance of all negative and positive potential consequences, the appropriate regulatory body and its need to consult with advisors from various backgrounds was questioned. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 958 respondents completed the questionnaire (response rate: 54%). A large majority of each participant group (>85%) wanted regulation, for at least one potential negative consequence of the clinical implementation of stem cell-based fertility treatments. The majority of all participant groups wanted regulation for serious health risks for intended parents, serious health risks for children and the disposal of human embryos. Regulation for out-of-pocket costs and the burden of treatment received little support. The majority of gynaecologists and the general public, but not the patients, requested regulation for the risk of minor congenital abnormalities, the success rates and the naturalness of treatments. Nevertheless, the majority of patients did consider the former two potential negative consequences important. The majority of all groups preferred a national bioethics committee as the regulatory body. This committee should consult with advisors from various backgrounds and should consider the broader context of potential consequences of the stem cell-based fertility treatments. LIMITATIONS, REASONS FOR CAUTION: This empirical study focuses on only three stakeholder groups. This study reports on the perspective of the majority and this is not per definition the morally right perspective. The transferability of our findings to other cultures and other techniques remains unclear. WIDER IMPLICATIONS OF THE FINDINGS: A national bioethics committee, consulting with advisors from various backgrounds, should regulate the clinical implementation of future stem cell-based fertility treatments. Whether this broad support for regulation applies to novel techniques from other fields of medicine should be examined. STUDY FUNDING/COMPETING INTEREST(S): The Young Academy of the Royal Netherlands Academy of Arts and Sciences. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Influence of heart rate on coronary calcium scores: a multi-manufacturer phantom study.

To evaluate the influence of heart rate on coronary calcium scores (CCS) using a dynamic phantom on four high-end computed tomography (CT) systems from different manufacturers. Artificial coronary arteries were moved in an anthropomorphic chest phantom at linear velocities, corresponding to < 60, 60-75 and > 75 beats per minute (bpm). Data was acquired with routinely used clinical protocols for CCS on four high-end CT systems (CT1-CT4). CCS, quantified as Agatston and mass scores were compared to reference scores at < 60 bpm. Influence of heart rate was assessed for each system with the cardiac motion susceptibility (CMS) Index. At increased heart rates (> 75 bpm), Agatston scores of the low mass calcification were similar to the reference score, while Agatston scores of the medium and high mass calcification increased significantly up to 50% for all CT systems. Threefold CMS increases at > 75 bpm in comparison with < 60 bpm were shown. For medium and high mass calcifications, significant differences in CMS between CT systems were found. Heart rate substantially influences CCS for high-end CT systems of four major manufacturers, but CT systems differ in motion susceptibility. Follow-up CCS CT scans should be acquired on the same CT system and protocol, and preferably with comparable heart rates.

Diagnostic performance of semi-quantitative and quantitative stress CMR perfusion analysis: a meta-analysis.

BACKGROUND: Stress cardiovascular magnetic resonance (CMR) perfusion imaging is a promising modality for the evaluation of coronary artery disease (CAD) due to high spatial resolution and absence of radiation. Semi-quantitative and quantitative analysis of CMR perfusion are based on signal-intensity curves produced during the first-pass of gadolinium contrast. Multiple semi-quantitative and quantitative parameters have been introduced. Diagnostic performance of these parameters varies extensively among studies and standardized protocols are lacking. This study aims to determine the diagnostic accuracy of semi- quantitative and quantitative CMR perfusion parameters, compared to multiple reference standards. METHOD: Pubmed, WebOfScience, and Embase were systematically searched using predefined criteria (3272 articles). A check for duplicates was performed (1967 articles). Eligibility and relevance of the articles was determined by two reviewers using pre-defined criteria. The primary data extraction was performed independently by two researchers with the use of a predefined template. Differences in extracted data were resolved by discussion between the two researchers. The quality of the included studies was assessed using the 'Quality Assessment of Diagnostic Accuracy Studies Tool' (QUADAS-2). True positives, false positives, true negatives, and false negatives were subtracted/calculated from the articles. The principal summary measures used to assess diagnostic accuracy were sensitivity, specificity, andarea under the receiver operating curve (AUC). Data was pooled according to analysis territory, reference standard and perfusion parameter. RESULTS: Twenty-two articles were eligible based on the predefined study eligibility criteria. The pooled diagnostic accuracy for segment-, territory- and patient-based analyses showed good diagnostic performance with sensitivity of 0.88, 0.82, and 0.83, specificity of 0.72, 0.83, and 0.76 and AUC of 0.90, 0.84, and 0.87, respectively. In per territory analysis our results show similar diagnostic accuracy comparing anatomical (AUC 0.86(0.83-0.89)) and functional reference standards (AUC 0.88(0.84-0.90)). Only the per territory analysis sensitivity did not show significant heterogeneity. None of the groups showed signs of publication bias. CONCLUSIONS: The clinical value of semi-quantitative and quantitative CMR perfusion analysis remains uncertain due to extensive inter-study heterogeneity and large differences in CMR perfusion acquisition protocols, reference standards, and methods of assessment of myocardial perfusion parameters. For wide spread implementation, standardization of CMR perfusion techniques is essential. TRIAL REGISTRATION: CRD42016040176 .

Effects of caffeine intake prior to stress cardiac magnetic resonance perfusion imaging on regadenoson- versus adenosine-induced hyperemia as measured by T1 mapping.

The antagonistic effects of caffeine on adenosine receptors are a possible cause of false-negative stress perfusion imaging. The purpose of this study was to determine the effects of coffee intake <4 h prior to stress perfusion cardiac magnetic resonance imaging (CMR) in regadenoson- versus adenosine-induced hyperemia as measured with T1-mapping. 98 consecutive patients with suspected coronary artery disease referred for either adenosine or regadenoson perfusion CMR were included in this analysis. Twenty-four patients reported coffee consumption <4 h before CMR (15 patients with adenosine, and 9 patients with regadenoson); 74 patients reported no coffee intake (50 patients with adenosine, and 24 patients with regadenoson). T1 mapping was performed using a modified look-locker inversion recovery sequence. T1 reactivity was determined by subtracting T1rest from T1stress. T1rest, T1stress, and T1 reactivity in patients referred for regadenoson perfusion CMR were not significantly different when comparing patients with <4 h coffee intake and patients who reported no coffee intake (976 ± 4 ms, 1019 ± 48 ms, and 4.4 ± 3.2% vs 971 ± 33 ms, 1023 ± 43 ms, and 5.4 ± 2.4%) (p = 0.70, 0.79, and 0.40), and similar to values in patients without coffee intake undergoing adenosine CMR. In patients with <4 h coffee intake, T1stress, and T1 reactivity were significantly lower for adenosine (898 ± 51 ms, and -7.8 ± 5.0%) compared to regadenoson perfusion CMR (p < 0.001). Coffee intake <4 h prior to regadenoson perfusion CMR has no effect on stress-induced hyperemia as measured with T1 mapping.

The acceptability of stem cell-based fertility treatments for different indications.

STUDY QUESTION: What is the acceptability of using stem cell-based fertility treatments (SCFT) for different indications according to gynaecologists and the general public? SUMMARY ANSWER: The majority of gynaecologists and the general public accept SCFT for the indications female or male infertility in young heterosexual couples, and female infertility in single women and same-sex couples. WHAT IS KNOWN ALREADY: SCFT could result in genetic parenthood for intended parents with indications that cannot be treated using currently available methods, such as being in a same-sex relationship or female post-menopausal age. It is unclear whether the acceptability of SCFT differs between indications for treatment and whether gynaecologists and the general public differ in their assessments. STUDY DESIGN SIZE, DURATION: In November 2015, a cross-sectional survey was disseminated among 179 gynaecologists and a panel of 1250 respondents comprising a representative sample of the Dutch general public. PARTICIPANTS/MATERIALS, SETTING, METHODS: The potential indications for future SCFT to achieve genetic parenthood were identified by literature review. A questionnaire was developed, reviewed by experts from different disciplines and tested among the general public. The questionnaire asked whether treating eight groups of intended parents with SCFT was acceptable or not. Regression analysis examined whether demographic characteristics influenced choices and whether the general public and gynaecologists differed in opinion. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 82 (46%) gynaecologists and 772 (62%) members of the general public completed the survey. The acceptability of using SCFT varied according to both gynaecologists and the general public between the eight groups of intended parents (P < 0.001). The majority of the Dutch general public accepts SCFT for six out of eight possible indications, namely female infertility in young heterosexual couples (94%), male infertility in young heterosexual couples (94%), unexplained infertility in young heterosexual couples (83%), female infertility in single women (69%), lesbian couples (68%) and gay couples (62%). The majority of gynaecologists also found treating these groups acceptable, except for the indication of unexplained infertility, which was only accepted by a minority of gynaecologists (43%). A minority of both the general public and gynaecologists accepted SCFT for fertile women who want a child that is genetically only her own (27 and 6%, respectively) and for female infertility in heterosexual couples in which the woman is over 50 years of age (17% and 26%, respectively). Attaching low importance to religion, having progressive political preferences, not having a university degree, having experienced infertility, being a woman, being older and not being of European ethnicity were positively associated with considering using SCFT acceptable for one or multiple indications. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The generalizability of our findings to future decades or other countries might be limited as opinions about novel technologies change over time and might vary across cultures. Support among gynaecologists and the general public is interesting but not proof of ethical acceptability. WIDER IMPLICATIONS OF THE FINDINGS: Once proven safe and effective, fear of limited acceptability by the general public is unwarranted, and thus should not stop gynaecologists from offering SCFT to single infertile women and same-sex couples in addition to young infertile heterosexual couples. STUDY FUNDING AND COMPETING INTEREST(S): Funded by the Young Academy of the Royal Netherlands Academy of Arts and Sciences and the Universities of Amsterdam and Leuven. No conflict of interest to declare.

Bone density loss on computed tomography at 3-year follow-up in current compared to former male smokers.

OBJECTIVES: Cigarette smoking negatively affects bone quality and increases fracture risk. Little is known on the effect of smoking cessation and computed tomography (CT)-derived bone mineral density (BMD) decline in the spine. We evaluated the association of current and former smoking with BMD decline after 3-year follow-up. METHODS: Male current and former smokers participating in a lung cancer screening trial who underwent baseline and 3-year follow-up CT were included. BMD was measured by manual placement of a region of interest in the first lumbar vertebra and expressed in Hounsfield Unit (HU). Multiple linear regression analysis was used to evaluate the association between pack years smoked and smoking status with BMD decline. RESULTS: 408 participants were included with median (25th-75th percentile) age of 59.4 (55.9-63.5) years. At the start of the study, 197 (48.3%) participants were current smokers and 211 (51.7%) were former smokers and had a similar amount of pack years. Current smokers had quit smoking for 6 (4-8) years prior to inclusion. There was no difference in BMD between current and former smokers at baseline (109±34 HU vs. 108±32 HU, p=0.96). At 3-year follow-up, current smokers had a mean BMD decline of -3±13 HU (p=0.001), while BMD in former smokers did not change as compared to baseline (1±13 HU, p=0.34). After adjustment for BMD at baseline and body mass index, current smoking was independently associated with BMD decline (-3.8 HU, p=0.003). Age, pack years, and the presence of a fracture at baseline did not associate with BMD decline. CONCLUSIONS: Current smokers showed a more rapid BMD decline over a 3-year period compared to former smokers. This information might be important to identify subjects at risk for osteoporosis and emphasizes the importance of smoking cessation in light of BMD decline.