Search

Background and Aims: Whether index testing using coronary computed tomography angiography (CTA) improves outcomes in stable chest pain is debated. The risk factor weighted clinical likelihood (RF-CL) model provides likelihood estimation of obstructive coronary artery disease. This study investigated the prognostic effect of coronary CTA vs. usual care by RF-CL estimates., Methods: Large-scale studies randomized patients (N = 13 748) with stable chest pain to coronary CTA as part of the initial work-up in addition to or instead of usual care including functional testing. Patients were stratified according to RF-CL estimates [RF-CL: very-low (≤5%), low (>5%-15%), and moderate/high (>15%)]. The primary endpoint was myocardial infarction or death at 3 years., Results: The primary endpoint occurred in 313 (2.3%) patients. Event rates were similar in patients allocated to coronary CTA vs. usual care [risk difference (RD) 0.3%, hazard ratio (HR) 0.84 (95% CI 0.67-1.05)]. Overall, 33%, 44%, and 23% patients had very-low, low, and moderate/high RF-CL. Risk was similar in patients with very low and moderate/high RF-CL allocated to coronary CTA vs. usual care [very low: RD 0.3%, HR 1.27 (0.74-2.16); moderate/high: RD 0.5%, HR 0.88 (0.63-1.23)]. Conversely, patients with low RF-CL undergoing coronary CTA had lower event rates [RD 0.7%, HR 0.67 (95% CI 0.47-0.97)]. The number needed to test using coronary CTA to prevent one event within 3 years was 143., Conclusions: Despite an overall good prognosis, low RF-CL patients have reduced risk of myocardial infarction or death when allocated to coronary CTA vs. usual care. Risk is similar in patients with very-low and moderate/high likelihood., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: In patients with coronary artery disease, coronary plaques with high-risk features and low-attenuation plaque burden are independent measures associated with major adverse cardiovascular events (MACEs). Patients with chronic kidney failure may have different coronary artery disease characteristics. The aim was to assess the association of coronary plaque characteristics and coronary artery disease extent with MACE and all-cause mortality in patients with chronic kidney failure., Methods: Potential kidney transplant candidates who underwent coronary computed tomography angiography as part of the cardiac screening program before kidney transplantation were included. We evaluated high-risk plaques and diameter stenosis semiqualitatively and quantified coronary artery calcium score and plaque burden (percentage atheroma volume)., Results: In 484 patients with chronic kidney failure and few or no symptoms of coronary artery disease (mean age, 53±12 years; 62% men; 32% on dialysis), 56 (12%) patients suffered MACE and 69 (14%) patients died during a median follow-up of 4.9 years. High-risk plaques were present in 39 (70%) patients with MACE. Median calcified plaque burden was 3.7% in patients with MACE versus 0.2% in patients without MACE. The median low-attenuation plaque burden was 0.3% versus 0.03%, respectively. In semiqualitative analyses, the presence of high-risk plaque and a higher coronary artery calcium score were associated with increased risk of MACE (hazard ratio (HR), 2.0 [95% CI, 1.0-3.7]; P =0.040; HR, 1.2 [95% CI, 1.0-1.3]; P =0.014), respectively. Neither were associated with all-cause mortality. In quantified analysis, increasing levels of both calcified and low-attenuation plaque burdens were associated with risk of MACE (HR, 2.6 [95% CI, 1.8-3.7]; P <0.001; HR, 2.6 [95% CI, 1.5-4.5]; P =0.001 [per variable doubling, respectively]) and all-cause mortality (HR, 1.6 [95% CI, 1.2-2.1]; P =0.002; HR, 1.8 [95% CI, 1.1-3.0]; P =0.028, respectively)., Conclusions: In patients with chronic kidney failure, calcified and low-attenuation plaque burdens were independently associated with MACE and all-cause mortality, while high-risk plaques and coronary artery calcium score were only associated with MACE., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01344434., Competing Interests: Dr Winther had a nonfinancial collaboration agreement with Medis, the Netherlands, which sponsored the QAngio software. The provider had no role in the collection or the analysis of data nor in the interpretation of the results or writing of the article. Aside from this, the authors’ disclosures are unrelated to the present study. Dr Winther acknowledges support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). Dr Rasmussen acknowledges support in terms of a research grant (PD5Y-2023001-DCA) from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation (grant NNF20SA0067242) and the Danish Heart Foundation. Dr Ivarsen discloses consultancy/advisory board participation for CSL Vifor Pharma, Otsuka, and Novartis, speaker’s honorarium from Otsuka, and research grants from the Augustinus Foundation and CSL Vifor Pharma. Dr Svensson discloses funding from Novo Nordisk and the Augustinus Foundation. Dr Birn discloses consultancy and advisory board participation for NOVO Nordisk, AstraZeneca, Boehringer Ingelheim, Bayer, Alexion, Vifor Pharma, Otsuka, and Galapagos; speaker’s honorarium from AstraZeneca, Astellas, Novartis, and MSD; and research grants from Vifor Pharma, GSK, the NOVO Foundation, the Karen Elise Jensen Foundation, and the Augustinus Foundation. Dr Bøttcher discloses advisory board participation for NOVO Nordisk, AstraZeneca, Pfizer, Boehringer Ingelheim, Bayer, Sanofi, Novartis, Amgen, CSL Behring, and Acarix. The other authors report no conflicts.

Background: Selection for invasive angiography is recommended to be based on pretest probabilities (PTPs), and physiological measures of hemodynamical impairment by, for example, fractional flow reserve (FFR) should guide revascularization. The risk factor-weighted clinical likelihood (RF-CL) and coronary artery calcium score-weighted clinical likelihood (CACS-CL) models show superior discrimination of patients with suspected obstructive coronary artery disease (CAD), but validation against hemodynamic impairment is warranted., Objectives: The aim of this study was to validate the RF-CL and CACS-CL models against hemodynamically obstructive CAD., Methods: Stable de novo chest pain patients (N = 4,371) underwent coronary computed tomography angiography and subsequently invasive coronary angiography with FFR measurements. Hemodynamically obstructive CAD was defined as invasive FFR ≤0.80 or high-grade stenosis by visual assessment (>90% diameter stenosis). For comparison, a guideline-endorsed basic PTP model was calculated based on age, sex, and symptom typicality. The RF-CL model additionally included the number of risk factors, and the CACS-CL model incorporated the coronary artery calcium score into the RF-CL., Results: In total, 447 of 4,371 (10.9%) patients had hemodynamically obstructive CAD. Both the RF-CL and CACS-CL models classified more patients with a very low clinical likelihood (≤5%) of obstructive CAD compared to the basic PTP model (33.0% and 53.7% vs 12.0%; P < 0.001) with a preserved low prevalence of hemodynamically obstructive CAD (<5% for all models). Against hemodynamically obstructive CAD, calibration and discrimination of the RF-CL and CACS-CL models were superior to the basic PTP model., Conclusions: The RF-CL and CACS-CL models are well calibrated and superior to a currently recommended basic PTP model to predict hemodynamically obstructive CAD. (Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease [Dan-NICAD]; NCT02264717; Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 2 [Dan-NICAD 2]; NCT03481712, Danish Study of Non-Invasive Diagnostic Testing in Coronary Artery Disease 3 [Dan-NICAD 3]; NCT04707859)., Competing Interests: Funding Support and Author Disclosures Dr Rasmussen has received support in terms of a research grant (PD5Y-2023001-DCA) from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and The Danish Heart Foundation. Dr Knuuti has received consulting fees from GE Healthcare and Synektik; and has received speaker fees from Lundbeck, Bayer, Boehringer-Ingelheim, Pfizer, and Siemens Healthineers. Dr Schmidt has received a research grant from Acarix AB. Dr Holm has received institutional research grants from Abbott, Boston Scientific, and Medis Medical Imaging; and has received speaker fees from Abbott and Terumo. Dr Christiansen has received consulting fees from Abbott, Phillips, and Boston Scientific. Dr Bøttcher has served on the Advisory Boards for NOVO Nordisk, AstraZeneca, Pfizer, Boehringer Ingelheim, Bayer, Sanofi, Novartis, AMGEN, CLS-Behring, and Acarix. Dr Winther has received support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Osteoporosis is under-diagnosed while detectable by measuring bone mineral density (BMD) using quantitative computer tomography (QCT). Opportunistic screening for low BMD has previously been suggested using lumbar QCT. However, thoracic QCT also possesses this potential to develop upper and lower cut-off values for low thoracic BMD, corresponding to the current cut-offs for lumbar BMD. In participants referred with chest pain, lumbar and thoracic BMD were measured using non-contrast lumbar- and cardiac CT scans. Lumbar BMD cut-off values for very low (< 80 mg/cm 3 ), low (80-120 mg/cm 3 ), and normal BMD (> 120 mg/cm 3 ) were used to assess the corresponding thoracic values. A linear regression enabled identification of new diagnostic thoracic BMD cut-off values. The 177 participants (mean age 61 [range 31-74] years, 51% women) had a lumbar BMD of 121.6 mg/cm 3 (95% CI 115.9-127.3) and a thoracic BMD of 137.0 mg/cm 3 (95% CI: 131.5-142.5), p < 0.001. Categorization of lumbar BMD revealed 14%, 35%, and 45% in each BMD category. When applied for the thoracic BMD measurements, 25% of participants were reclassified into a lower group. Linear regression predicted a relationship of Thoracic BMD = 0.85 * Lumbar BMD + 33.5, yielding adjusted thoracic cut-off values of < 102 and > 136 mg/cm 3 . Significant differences in BMD between lumbar and thoracic regions were found, but a linear relationship enabled the development of thoracic upper and lower cut-off values for low BMD in the thoracic spine. As Thoracic CT scans are frequent, these findings will strengthen the utilization of CT images for opportunistic detection of osteoporosis., (© 2024. The Author(s).)

Background and Aims: The microvascular resistance reserve (MRR) is a novel invasive index of the microcirculation, which is independent of epicardial stenoses, and MRR has both diagnostic and prognostic implications. This study investigates whether MRR is associated with health status outcomes by revascularization in patients with moderate coronary stenoses., Methods: Consecutive patients with stable chest pain and moderate (30-90% diameter) stenoses on invasive coronary angiography (n=222) underwent invasive physiology assessment. Revascularization was performed by guideline recommendations. At baseline and follow-up, health status and myocardial perfusion were assessed by Seattle Angina Questionnaire (SAQ) and positron emission tomography. The primary endpoint was freedom from angina at follow-up with secondary endpoints including changes in health status by SAQ domains and myocardial perfusion by MRR and revascularization status. Low MRR was defined as ≤3.0., Results: Freedom from angina occurred in 38/173 patients. In multivariate analyses, MRR was associated with freedom from angina at follow-up (odds ratio 0.860, 95% confidence interval 0.740-0.987). By MRR and revascularization groups, patients with normal MRR who did not undergo revascularization, and patients with abnormal MRR who underwent revascularization, improved health status of angina frequency (mean difference SAQ angina frequency score 8.5 [3.07-13.11] and 13.5 [2.82-23.16], respectively). For both groups, health status of physical limitation (mean difference in SAQ physical limitation score 9.7 [4.79-11.93] and 8.7 [0.53-13.88], respectively) and general health status (mean difference in SAQ summary score 9.3 [5.18-12.50] and 10.8 [2.51-17.28], respectively) also improved. Only patients with abnormal MRR who underwent revascularization improved myocardial perfusion., Conclusions: In patients with moderate coronary stenoses, MRR seems to predict symptomatic and perfusion benefit of revascularization., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Patients with atherosclerotic plaques containing high-risk features have an increased likelihood of events and a worse prognosis. Whether increased levels of Troponin I (TnI) and C-reactive protein (CRP) are associated with the presence of high-risk coronary atherosclerotic plaques (HRP) is not well described. We assessed the association between 1) TnI and 2) CRP with quantified coronary plaque burden, luminal diameter stenosis, and HRP in patients with low/intermediate pre-test probability of obstructive coronary artery disease (CAD) referred for coronary computed tomography angiography (CCTA)., Methods: The CCTA from 1615 patients were analyzed using a semiautomatic software for coronary artery plaque characterization. Patients with high TnI (>6 ​ng/L) and high CRP (>2 ​mg/L) were identified. Associations of TnI and CRP with plaque burden, stenosis (≥50% luminal diameter stenosis on CCTA), and HRP were investigated., Results: TnI and CRP were both positively correlated with total plaque burden (TnI rs ​= ​0.14, p ​< ​0.001; CRP rs ​= ​0.08, p ​< ​0.001). In multivariate logistic regression analyses, high TnI was associated with stenosis (OR 1.43, 95% confidence interval (CI) 1.03-1.99, p ​= ​0.034), the presence of HRP (OR 1.79, 95% CI: 1.17-2.74, p ​= ​0.008), and the subtypes of HRP; low attenuation plaque (OR 1.93, 95% CI: 1.24-3.00, p ​= ​0.003), and positive remodeling (OR 1.51, 95% CI: 1.07-2.13, p ​= ​0.018). For CRP, only stenosis and napkin ring sign correlated significantly., Conclusion: In patients with suspected CAD, TnI and CRP are associated with HRP features. These findings may suggest that inflammatory and particularly ischemic biomarkers might improve early risk stratification and affect patient management., Gov Identifier: NCT02264717., Competing Interests: Declaration of competing interest Nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to compare antibody trajectories among individuals with SARS-CoV-2 hybrid and vaccine-induced immunity., Methods: Danish adults receiving three doses of BTN162b2 or mRNA-1237 were included prior to first vaccination (Day 0). SARS-CoV-2 anti-spike IgG levels were assessed before each vaccine dose, at Day 90, Day 180, 28 days after 3rd vaccination (Day 251), Day 365, and prior to 4th vaccination (Day 535). SARS-CoV-2 PCR results were extracted from the national microbiology database. Mixed-effect multivariable linear regression investigated the impact of hybrid-immunity (stratified into 4 groups: no hybrid immunity, PCR+ prior to 3rd dose, PCR+ after 3rd dose and before Day 365, PCR+ after Day 365) on anti-spike IgG trajectories., Results: A total of 4,936 individuals were included, 47% developed hybrid-immunity. Anti-spike IgG increases were observed in all groups at Day 251, with the highest levels in those PCR+ prior to 3rd dose (Geometric Mean; 535,647AU/mL vs. 374,665AU/mL with no hybrid-immunity, P<0.0001). Further increases were observed in participants who developed hybrid immunity after their 3rd dose. Anti-spike IgG levels declined from Day 251-535 in individuals without hybrid-immunity and in those who developed hybrid-immunity prior to their 3rd dose, with lower rate of decline in those with hybrid-immunity., Conclusion: Hybrid-immunity results in higher and more durable antibody trajectories in vaccinated individuals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In 2020, Denmark buried approximately four million culled, farmed mink in mass graves treated with slaked lime due to widespread SARS-CoV-2 infections. After six months, environmental concerns prompted the exhumation of these cadavers. Our analysis encompassed visual inspections, soil pH measurements, and gas emission assessments of the grave environment. Additionally, we evaluated carcasses for decay status, cadaverine content, and the presence of various pathogens, including SARS-CoV-2 and mink coronavirus. Our findings revealed minimal microbial activity and limited carcass decomposition. Although viral RNA from SARS-CoV-2 and mink coronavirus, along with DNA from Aleutian mink disease virus, were detected, the absence of infectious SARS-CoV-2 in cell culture assays suggests slow natural degradation processes. This study provides critical insights for future considerations in managing mass burial scenarios during outbreaks of livestock-associated zoonotic pathogens., (© 2024. The Author(s).)

Background: Despite recent guideline recommendations, quantitative perfusion (QP) estimates of myocardial blood flow from cardiac magnetic resonance (CMR) have only been sparsely validated. Furthermore, the additional diagnostic value of utilizing QP in addition to the traditional visual expert interpretation of stress-perfusion CMR remains unknown. The aim was to investigate the correlation between myocardial blood flow measurements estimated by CMR, positron emission tomography, and invasive coronary thermodilution. The second aim is to investigate the diagnostic performance of CMR-QP to identify obstructive coronary artery disease (CAD)., Methods: Prospectively enrolled symptomatic patients with >50% diameter stenosis on computed tomography angiography underwent dual-bolus CMR and positron emission tomography with rest and adenosine-stress myocardial blood flow measurements. Subsequently, an invasive coronary angiography (ICA) with fractional flow reserve and thermodilution-based coronary flow reserve was performed. Obstructive CAD was defined as both anatomically severe (>70% diameter stenosis on quantitative coronary angiography) or hemodynamically obstructive (ICA with fractional flow reserve ≤0.80)., Results: About 359 patients completed all investigations. Myocardial blood flow and reserve measurements correlated weakly between estimates from CMR-QP, positron emission tomography, and ICA-coronary flow reserve (r<0.40 for all comparisons). In the diagnosis of anatomically severe CAD, the interpretation of CMR-QP by an expert reader improved the sensitivity in comparison to visual analysis alone (82% versus 88% [ P =0.03]) without compromising specificity (77% versus 74% [ P =0.28]). In the diagnosis of hemodynamically obstructive CAD, the accuracy was only moderate for a visual expert read and remained unchanged when additional CMR-QP measurements were interpreted., Conclusions: CMR-QP correlates weakly to myocardial blood flow measurements by other modalities but improves diagnosis of anatomically severe CAD., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712., Competing Interests: Disclosures Dr Rasmussen acknowledges support in terms of a research grant (PD5Y-2023001-DCA) from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation, grant NNF20SA0067242, and The Danish Heart Foundation. Dr Winther acknowledges support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). Dr Bøttcher is a previous employee and a shareholder of Circle Cardiovascular Imaging, Inc. S.E. Petersen provides consultancy to and was a previous stockowner of Circle Cardiovascular Imaging, Inc. Dr Bøttcher discloses advisory board participation for NOVO Nordisk, AstraZeneca, Pfizer, Boehringer Ingelheim, Bayer, Sanofi, Novartis, AMGEN, CLS-Behring, and Acarix. The other authors report no conflicts.

Background: Although people with HIV might be at risk of severe outcomes from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus 2019 [COVID-19]), regional and temporal differences in SARS-CoV-2 testing in people with HIV across Europe have not been previously described., Methods: We described the proportions of testing, positive test results, and hospitalizations due to COVID-19 between 1 January 2020 and 31 December 2021 in the EuroSIDA cohort and the factors associated with being tested for SARS-CoV-2 and with ever testing positive., Results: Of 9012 participants, 2270 (25.2%, 95% confidence interval [CI] 24.3-26.1) had a SARS-CoV-2 polymerase chain reaction test during the study period (range: 38.3% in Northern to 14.6% in Central-Eastern Europe). People from Northern Europe, women, those aged <40 years, those with CD4 cell count <350 cells/mm 3 , and those with previous cardiovascular disease or malignancy were significantly more likely to have been tested, as were people with HIV in 2021 compared with those in 2020. Overall, 390 people with HIV (4.3%, 95% CI 3.9-4.8) tested positive (range: 2.6% in Northern to 7.1% in Southern Europe), and the odds of testing positive were higher in all regions than in Northern Europe and in 2021 than in 2020. In total, 64 people with HIV (0.7%, 95% CI 0.6-0.9) were hospitalized, of whom 12 died. Compared with 2020, the odds of positive testing decreased in all regions in 2021, and the associations with cardiovascular disease, malignancy, and use of tenofovir disoproxil fumarate disappeared in 2021. Among study participants, 58.9% received a COVID-19 vaccine (range: 72.0% in Southern to 14.8% in Eastern Europe)., Conclusions: We observed large heterogeneity in SARS-CoV-2 testing and positivity and a low proportion of hospital admissions and deaths across the regions of Europe., (© 2024 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: Coronary artery calcium scoring (CACS) improves management of chest pain patients. However, it is unknown whether the benefit of CACS is dependent on the clinical likelihood (CL)., Objectives: This study aims to investigate for which patients CACS has the greatest benefit when added to a CL model., Methods: Based on data from a clinical database, the CL of obstructive coronary artery disease (CAD) was calculated for 39,837 patients referred for cardiac imaging due to symptoms suggestive of obstructive CAD. Patients were categorized according to the risk factor-weighted (RF-CL) model (very low, ≤5%; low, >5 to ≤15%; moderate >15 to ≤50%; high, >50%). CL was then recalculated incorporating the CACS result (CACS-CL). Reclassification rates and the number needed to test with CACS to reclassify patients were calculated and validated in 3 independent cohorts (n = 9,635)., Results: In total, 15,358 (39%) patients were down- or upclassified after including CACS. Reclassification rates were 8%, 75%, 53%, and 30% in the very low, low, moderate, and high RF-CL categories, respectively. Reclassification to very low CACS-CL occurred in 48% of reclassified patients. The number needed to test to reclassify 1 patient from low RF-CL to very low CACS-CL was 2.1 with consistency across age, sex, and cohorts. CACS-CL correlated better to obstructive CAD prevalence than RF-CL., Conclusions: Added to an RF-CL model for obstructive CAD, CACS identifies more patients unlikely to benefit from further testing. The number needed to test with CACS to reclassify patients depends on the pretest RF-CL and is lowest in patients with low (>5% to ≤15%) likelihood of CAD., Competing Interests: Funding Support and Author Disclosures Drs Newby and Williams have received support from the British Heart Foundation (FS/ICRF/20/26002, CH/09/002, RG/16/10/32375, RE/18/5/34216). The PROMISE study was supported by grants from the National Heart, Lung, and Blood Institute (R01HL098237, R01HL098236, R01HL098305, and R01HL098235). Dr Winther has received support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). Dr Williams has been a speaker for Canon Medical Systems, Siemens Healthineers, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Wastewater sequencing has become a powerful supplement to clinical testing in monitoring SARS-CoV-2 infections in the post-COVID-19 pandemic era. While its applications in measuring the viral burden and main circulating lineages in the community have proved their efficacy, the variations in sequencing quality and coverage across the different regions of the SARS-CoV-2 genome are not well understood. Furthermore, it is unclear how different sample origins, viral extraction and concentration methods and environmental factors impact the reads sequenced from wastewater. Using high-coverage, amplicon-based, paired-end read sequencing of viral RNA extracted from wastewater collected directly from aircraft, pooled from different aircraft and airport buildings or from regular wastewater plants, we assessed the genome coverage across the sample groups with a focus on the 5'-end region covering the leader sequence and investigated whether it was possible to detect subgenomic RNA from viral material recovered from wastewater. We identified distinct patterns in the persistence of the different genomic regions across the different types of wastewaters and the existence of chimeric reads mapping to non-amplified regions. Our findings suggest that preservation of the 5'-end of the genome and the ability to detect subgenomic RNA reads, though highly susceptible to environment and sample processing conditions, may be indicative of the quality and amount of the viral RNA present in wastewater., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP. We aimed to (1) identify proteomic and genetic features associated with HRP presence and (2) investigate the effect of combining CRFs, proteomics, and genetics to predict HRP presence., Methods: Consecutive chest pain patients (n = 1462) undergoing CCTA to diagnose obstructive coronary artery disease (CAD) were included. Coronary plaques were assessed using a semi-automatic plaque analysis tool. Measurements of 368 circulating proteins were obtained with targeted Olink panels, and DNA genotyping was performed in all patients. Imputed genetic variants were used to compute a multi-trait multi-ancestry genome-wide polygenic score (GPS Mult ). HRP presence was defined as plaques with two or more high-risk characteristics (low attenuation, spotty calcification, positive remodeling, and napkin ring sign). Prediction of HRP presence was performed using the glmnet algorithm with repeated fivefold cross-validation, using CRFs, proteomics, and GPS Mult as input features., Results: HRPs were detected in 165 (11%) patients, and 15 input features were associated with HRP presence. Prediction of HRP presence based on CRFs yielded a mean area under the receiver operating curve (AUC) ± standard error of 73.2 ± 0.1, versus 69.0 ± 0.1 for proteomics and 60.1 ± 0.1 for GPS Mult . Combining CRFs with GPS Mult increased prediction accuracy (AUC 74.8 ± 0.1 (P = 0.004)), while the inclusion of proteomics provided no significant improvement to either the CRF (AUC 73.2 ± 0.1, P = 1.00) or the CRF + GPS Mult (AUC 74.6 ± 0.1, P = 1.00) models, respectively., Conclusions: In patients with suspected CAD, incorporating genetic data with either clinical or proteomic data improves the prediction of high-risk plaque presence., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02264717 (September 2014)., (© 2024. The Author(s).)

The microbiological analysis of wastewater samples is increasingly used for the surveillance of SARS-CoV-2 globally. We described the setup process of the national SARS-CoV-2 wastewater-based surveillance system in Denmark, presented its main results during the first year of activities, from July 2021 to June 2022, and discussed their operational significance. The Danish SARS-CoV-2 wastewater-based surveillance system was designed to cover 85 % of the population in Denmark and it entailed taking three weekly samples from 230 sites. Samples were RT-qPCR tested for SARS-CoV-2 RNA, targeting the genetic markers N1, N2 and RdRp, and for two faecal indicators, Pepper Mild Mottle Virus and crAssphage. We calculated the weekly SARS-CoV-2 RNA concentration in the wastewater from each sampling site and monitored it in view of the results from individual testing, at the national and regional levels. We attempted to use wastewater results to identify potential local outbreaks, and we sequenced positive wastewater samples using Nanopore sequencing to monitor the circulation of viral variants in Denmark. The system reached its full implementation by October 2021 and covered up to 86.4 % of the Danish population. The system allowed for monitoring of the national and regional trends of SARS-CoV-2 infections in Denmark. However, the system contribution to the identification of potential local outbreaks was limited by the extensive information available from clinical testing. The sequencing of wastewater samples identified relevant variants of concern, in line with results from sequencing of human samples. Amidst the COVID-19 pandemic, Denmark implemented a nationwide SARS-CoV-2 wastewater-based surveillance system that integrated routine surveillance from individual testing. Today, while testing for COVID-19 at the community level has been discontinued, the system is on the frontline to monitor the occurrence and spread of SARS-CoV-2 in Denmark., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort., Methods: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD])., Results: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350 cells/μl or less (vs. 351-500 cells/μl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05)., Conclusion: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronary computed tomography angiography (CCTA)-derived quantitative flow ratio (CT-QFR) is an on-site non-invasive technique estimating invasive fractional flow reserve (FFR). This study assesses the diagnostic performance of using most distal CT-QFR versus lesion-specific CT-QFR approach for identifying hemodynamically obstructive coronary artery disease (CAD)., Methods: Prospectively enrolled de novo chest pain patients (n ​= ​445) with ≥50 ​% visual diameter stenosis on CCTA were referred for invasive evaluation. On-site CT-QFR was analyzed post-hoc blinded to angiographic data and obtained as both most distal (MD-QFR) and lesion-specific CT-QFR (LS-QFR). Abnormal CT-QFR was defined as ≤0.80. Hemodynamically obstructive CAD was defined as invasive FFR ≤0.80 or ≥70 ​% diameter stenosis by 3D-quantitative coronary angiography., Results: In total 404/445 patients had paired CT-QFR and invasive analyses of whom 149/404 (37 ​%) had hemodynamically obstructive CAD. MD-QFR and LS-QFR classified 188 (47 ​%) and 165 (41 ​%) patients as abnormal, respectively. Areas under the receiver-operating characteristic curve for MD-QFR was 0.83 vs. 0.85 for LS-QFR, p ​= ​0.01. Sensitivities for MD-QFR and LS-QFR were 80 ​% (95%CI: 73-86) vs. 77 ​% (95%CI: 69-83), p ​= ​0.03, respectively, and specificities were 73 ​% (95%CI: 67-78) vs. 80 ​% (95%CI: 75-85), p ​< ​0.01, respectively. Positive predictive values for MD-QFR and LS-QFR were 63 ​% vs. 69 ​%, p ​< ​0.01, respectively, and negative predictive values for MD-QFR and LS-QFR were 86 ​% vs. 85 ​%, p ​= ​0.39, respectively)., Conclusion: Using a lesion-specific CT-QFR approach has superior discrimination of hemodynamically obstructive CAD compared to a most distal CT-QFR approach. CT-QFR identified most cases of hemodynamically obstructive CAD while a normal CT-QFR excluded hemodynamically obstructive CAD in the majority of patients., Competing Interests: Declaration of competing interest Morten Bøttcher reports advisory board participation for NOVO Nordisk, Astra-Zeneca, Pfizer, Boeringer Ingelheim, Bayer, Sanofi, Novartis, Amgen, CLS-Behring, Acarix and MEDtrace. William Wijns reports senior advisor Rede Optimus Research and Corrib Core Laboratory, co-founder Argonauts Partners, an innovation facilitator. Shengxian Tu reports consultancy and research grants from Pulse Medical., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To develop a tool including exercise electrocardiography (ExECG) for patient-specific clinical likelihood estimation of patients with suspected obstructive coronary artery disease (CAD)., Methods: An ExECG-weighted clinical likelihood (ExECG-CL) model was developed in a training cohort of patients with suspected obstructive CAD undergoing ExECG. Next, the ExECG-CL model was applied in a CAD validation cohort undergoing ExECG and clinically driven invasive coronary angiography and a prognosis validation cohort and compared with the risk factor-weighted clinical likelihood (RF-CL) model for obstructive CAD discrimination and prognostication, respectively.In the CAD validation cohort, obstructive CAD was defined as >50% diameter stenosis on invasive coronary angiography. For prognosis, the endpoint was non-fatal myocardial infarction and death., Results: The training cohort consisted of 1214 patients (mean age 57 years, 57% males). In the CAD (N=408; mean age 55 years, 53% males) and prognosis validation (N=3283; mean age 57 years, 57% males) cohorts, 11.8% patients had obstructive CAD and 4.4% met the endpoint. In the CAD validation cohort, discrimination of obstructive CAD was similar between the ExECG-CL and RF-CL models: area under the receiver-operating characteristic curves 83.1% (95% CIs 77.5% to 88.7%) versus 80.7% (95% CI 74.6% to 86.8%), p=0.14. In the ExECG-CL model, more patients had very low (≤5%) clinical likelihood of obstructive CAD compared with the RF-CL (42.2% vs 36.0%, p<0.01) where obstructive CAD prevalence and event risk remained low., Conclusions: ExECG incorporated into a clinical likelihood model improves reclassification of patients to a very low clinical likelihood group with very low prevalence of obstructive CAD and favourable prognosis., Competing Interests: Competing interests: SES and MB acknowledge support from Acarix in form of an institutional research grant. MB discloses advisory board participation for NOVO Nordisk, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Sanofi, and Acarix outside of submitted work. SES is a part-time consultant and minor shareholders in Acarix. JK discloses speaker fees from GE Healthcare, Merck, Lundbeck, Boehringer-Ingelheim, Bayer and Pfizer and study protocol consultant fees from GE Healthcare and AstraZeneca outside of submitted work. KN acknowledges support from the NIH (NIH R01- HL141712; NIH R01 - HL146754), and reports unrestricted institutional research support from Siemens Healthineers, Bayer, HeartFlow Inc, Novartis unrelated to this work, consulting for Siemens Medical Solutions USA and Novartis, and equity in Lumen Therapeutics., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Guidelines propose the inclusion of quantitative measurements from 82 Rubidium positron emission tomography (RbPET) to discriminate obstructive coronary artery disease (CAD). However, the effect on diagnostic accuracy is unknown. The aim was to investigate the optimal RbPET reading algorithm for improved identification of obstructive CAD., Methods: Prospectively enrolled patients (N=400) underwent RbPET and invasive coronary angiography with fractional flow reserve and quantitative coronary angiography. Quantitative measurements (myocardial blood flow (MBF), MBF reserve, transient ischemic dilatation) by RbPET were step-wisely added to a qualitative assessment by the summed stress score based on their diagnostic accuracy of obstructive CAD by invasive coronary angiography-fractional flow reserve. Prespecified cutoffs were summed stress score ≥4, hyperemic MBF 2.00 mL/g per min, and MBF reserve 1.80, respectively. Hemodynamically obstructive CAD was defined as >90% diameter stenosis or invasive coronary angiography-fractional flow reserve ≤0.80, and sensitivity analyses included a clinically relevant reference of anatomically severe CAD (>70% diameter stenosis by invasive coronary angiography-quantitative coronary angiography)., Results: Hemodynamically obstructive CAD was present in 170/400 (42.5%) patients. Stand-alone summed stress score showed a sensitivity and specificity of 57% and 93%, respectively, while hyperemic MBF showed similar sensitivity (61%, P =0.57) but lower specificity (85%, P =0.008). With increased discrimination by receiver-operating characteristic curves (0.78 versus 0.85; P <0.001), combining summed stress score, MBF and MBF reserve showed the highest sensitivity of 77% but lower specificity of 74% ( P <0.001 for both comparisons). Against anatomically severe CAD, all measures independently yielded high discrimination ≥0.90 with increased sensitivity and lower specificity by additional quantification., Conclusions: The inclusion of quantitative measurements to a RbPET read increases in the identification of obstructive CAD., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481712., Competing Interests: Disclosures Dr Rasmussen acknowledges support in terms of a research grant (PD5Y-2023001-DCA) from the Danish Cardiovascular Academy, which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and The Danish Heart Foundation. Dr Winther acknowledges support from the Novo Nordisk Foundation Clinical Emerging Investigator grant (NNF21OC0066981). Dr Bøttcher disclose advisory board participation for NOVO Nordisk, Astra-Zeneca, Pfizer, Boeringer Ingelheim, Bayer, Sanofi, Novartis, AMGEN, CLS-Behring, and Acarix. The other authors report no conflicts.