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Background: Quantitative flow ratio (QFR) is a tool for physiological lesion assessment based on invasive coronary angiography.Aims: We aimed to assess the reproducibility of QFR computed from the same angiograms as assessed by multiple observers from different, international sites.Methods: We included 50 patients previously enrolled in dedicated QFR studies. QFR was computed twice, one month apart by five blinded observers. The main analysis was the coefficient of variation (CV) as a measure of infra- and inter-observer reproducibility. Key secondary analysis was the identification of clinical and procedural characteristics predicting reproducibility.Results: The intra-observer CV ranged from 2.3% (1.5-2.8) to 10.2% (6.6-12.0) among the observers. The inter-observer CV was 9.4% (8.0-10.5). The QFR observer, low angiographic quality, and low fractional flow reserve (FFR) were independent predictors of a large absolute difference between repeated QFR measurements defined as a difference larger than the median difference (>0.03).Conclusions: The inter- and intra-observer reproducibility for QFR computed from the same angiograms ranged from high to poor among multiple observers from different sites with an average agreement of 0.01 +/--0.08 for repeated measurements. The reproducibility was dependent on the observer, angiographic quality and the coronary artery stenosis severity as assessed by FFR.

Crown-of-thorns sea stars (Acanthaster sp.) are among the most studied coral reef organisms, owing to their propensity to undergo major population irruptions, which contribute to significant coral loss and reef degradation throughout the Indo-Pacific. However, there are still important knowledge gaps pertaining to the biology, ecology, and management of Acanthaster sp. Renewed efforts to advance understanding and management of Pacific crown-of-thorns sea stars (Acanthaster sp.) on Australia’s Great Barrier Reef require explicit consideration of relevant and tractable knowledge gaps. Drawing on established horizon scanning methodologies, this study identified contemporary knowledge gaps by asking active and/or established crown-of-thorns sea star researchers to pose critical research questions that they believe should be addressed to improve the understanding and management of crown-of-thorns sea stars on the Great Barrier Reef. A total of 38 participants proposed 246 independent research questions, organized into 7 themes: feeding ecology, demography, distribution and abundance, predation, settlement, management, and environmental change. Questions were further assigned to 48 specific topics nested within the 7 themes. During this process, redundant questions were removed, which reduced the total number of distinct research questions to 172. Research questions posed were mostly related to themes of demography (46 questions) and management (48 questions). The dominant topics, meanwhile, were the incidence of population irruptions (16 questions), feeding ecology of larval sea stars (15 questions), effects of elevated water temperature on crown-of-thorns sea stars (13 questions), and predation on juveniles (12 questions). While the breadth of questions suggests that there is considerable research needed to improve understanding and management of crown-of-thorns sea stars on the Great Barrier Reef, the predominance of certain themes and topics suggests a major focus for new research while also providing a roadmap to guide future research efforts.

Objectives: The aim of this study was to assess clinical outcomes after combined pressure and flow assessment of coronary lesions. Background: Although fractional flow reserve (FFR) remains the invasive reference standard for revascularization, approximately 40% of stenoses have discordant coronary flow reserve (CFR). Optimal treatment for these disagreements remains unclear. Methods: A total of 455 subjects with 668 lesions were enrolled from 12 sites in 6 countries. Only lesions with reduced FFR and CFR underwent revascularization; all other combinations received initial medical therapy. Results: Fourteen percent of lesions had FFR ≤0.8 but CFR ≥2.0 while 23% of lesions had FFR >0.8 but CFR 0.8 and CFR ≥2.0 (6.2% event rate) exceeded the prespecified +10% noninferiority margin (P = 0.090). Target vessel failure models using both continuous FFR and continuous CFR found that only higher FFR was associated with reduced target vessel failure (Cox P = 0.007) after initial medical treatment. Central core laboratory review accepted 69.8% of all tracings with mean differences of 0.8 and CFR ≥2.0. These results do not support using invasive CFR ≥2.0 to defer revascularization for lesions with reduced FFR if the patient would otherwise be a candidate on the basis of the entire clinical scenario and treatment preference.

Background Managing low back pain (LBP) often involves MRI despite the fact that international guidelines do not recommend routine imaging. To allow us to explore the topic and use this knowledge in further research, a reliable method to review the MRI referrals is needed. Consequently, this study aimed to assess the inter-rater reliability of a method evaluating lumbar spine MRI referrals’ appropriateness. Methods Four inexperienced students (chiropractic master’s students) and a senior clinician (chiropractor) were included as independent raters in this inter-rater reliability study. Lumbar spine MRI referrals from primary care on patients (> 18 years) with LBP with or without leg pain were included. The referrals were classified using a modified version of the American College of Radiology (ACR) imaging appropriateness criteria for LBP. Categories of appropriate referrals included; fractures, cancer, previous surgery, candidate for surgery or suspicion of cauda equina. Inappropriate referrals included lacking information on previous non-surgical treatment, no word on non-surgical treatment duration, or “other reasons” for inappropriate referrals. After two rounds of training and consensus sessions, 50 lumbar spine MRI referrals were reviewed independently by the five raters. Inter-rater reliability was quantified using unweighted Kappa statistics, and the observed agreement was calculated with both a pairwise comparison and an overall five-rater comparison. Results Inter-rater reliability was substantial, with a Kappa value for appropriate vs. inappropriate referrals of 0.76 (95% CI: 0.55–0.89). When six and eight subcategories were evaluated, the Kappa values were 0.77 (95% CI: 0.58–0.91) and 0.82 (95% CI: 0.72–0.92), respectively. The overall percentage of agreement for appropriate and inappropriate referrals was 92% and ranged from 88 to 98% for the pairwise comparisons of the five raters’ results. For the six and eight subcategories, the overall agreement was 92 and 88%, respectively, ranging from 88 to 98% and 84–92%, respectively, for the pairwise comparisons. Conclusion The inter-rater reliability of the evaluation of the appropriateness of lumbar spine MRI referrals, according to the modified ACR-appropriateness criteria, was found to range from substantial to almost perfect and can be used for research and quality assurance purposes.

Background Permanent drug-eluting stents are associated with a steady increase of late complications attributed to persistent inflammation and poor vessel remodelling. Bioresorbable scaffolds have been developed to overcome such long-term limitations by providing temporary vessel support and disappearing thereafter. We aimed to assess the long-term outcomes of an absorbable metallic scaffold at 5 years. Methods BIOSOLVE-II is an international, multi-centre, first-in-human study assessing the safety and performance of the sirolimus-eluting absorbable metal scaffold DREAMS 2G (commercial name Magmaris) in patients with a maximum of two de novo lesions. After 3 years, follow-up was extended to 5 years with the endpoints target lesion failure and rate of definite or probable stent thrombosis . Results 123 patients with 123 lesions were enrolled. Lesions were 12.6 ± 4.5 mm long and 2.7 ± 0.4 mm in diameter, 43.4% were class B2/C lesions, and calcification was moderate to severe in 10.6%. At 5 years, 5.4% of patients had stable angina and 94.6% had no symptoms or ischemia . Target lesion failure rate was 8.0% [95% CI:4.2;14.9], reflecting 2 cardiac deaths, 2 target-vessel myocardial infarction, and 6 clinically-driven target lesion revascularizations . Only one target lesion failure occurred beyond 3 years; a target-vessel myocardial infarction with clinically-driven TLR on post-procedure day 1157. One additional non-cardiac death beyond 3 years due to renal failure was reported on day 1777. No definite or probable scaffold thrombosis was observed. Conclusion The Magmaris scaffold showed favourable long-term safety and clinical performance with low target lesion failure rates and absence of definite or probable scaffold thrombosis throughout 5 years. Annotated table of contents BIOSOLVE-II is a prospective, multi-centre, first-in-man trial enrolling 123 patients with de novo coronary artery lesions. Target lesion failure rate at 5 years was low (8.0%), including 2 cardiac deaths, 2 target-vessel myocardial infarction and 6 clinically-driven target lesion revascularizations. No definite or probable scaffold thrombosis was observed.

Introduction: The predictors of stent treatment failure and their importance 10 years after treatment with drug-eluting stents (DESs) have not been reported in detail. Methods: Data were retrieved from the SORT-OUT II database encompassing 2,849 non-left main coronary lesions in 2,073 unselected all-comer patients treated with first-generation DES and followed clinically for 10 years. Stent treatment failure (STF) was defined as definite or probable stent thrombosis, target lesion revascularization (TLR), or >70% restenosis left untreated. Target lesion failure (TLF) was defined as cardiac death, target vessel myocardial infarction, or TLR. Characteristics predicting higher hazard ratios (HRs) were identified by the multivariate Cox regression analysis. Results: A stent diameter ≤2.5 versus ≥3.5 mm had STF 23.3 versus 11.8% and TLF 27.9 versus 18.8%. Stent length 40 mm had STF 13.0 versus 29.0% and TLF 18.7 versus 34.6%. In multivariate analysis, decreasing stent diameter (HR: 1.24 [3.0 mm] to 2.12 [2.25 mm], reference ≥3.5 mm) and increasing stent length (HR: 1.15 [20–30 mm] to 2.07 [>40 mm], reference Conclusions: Ten-year outcomes show large variations depending on the stent size and a few patient and lesion characteristics. The calculation of a PS from these unambiguous variables may be used to improve the risk estimate in individual lesions and patients.

OBJECTIVES: To study safety and performance of the MANTA Vascular closure device (VCD) under real world conditions in 10 centers.BACKGROUND: The MANTA is a novel plug-based device for large bore arteriotomy closure.METHODS: We included all eligible patients who underwent transfemoral large bore percutaneous procedures. Exclusion criteria were per operator's discretion and included severe calcification or marked tortuosity of the access vessel, presence of marked obesity/cachexia or a systolic blood pressure above 180 mmHg. The primary performance endpoint was time to hemostasis. Primary and secondary safety endpoints were major and minor access site related vascular complications up to 30 days, respectively. Vascular complications were adjudicated by an independent clinical event committee according to VARC-2 criteria. We performed multivariable logistic regression to estimate the effect of baseline and procedural characteristics on any and major vascular complications.RESULTS: Between February 2018 and July 2019 500 patients were enrolled undergoing Transcatheter aortic valve replacement (TAVR, N = 496), Balloon aortic valvuloplasty (BAV, N = 2), Mechanical circulatory support (MCS, N = 1) or Endovascular aneurysm repair (EVAR, N = 1). Mean age was 80.8 ± 6.6 years with a median STS-score of 2.7 [IQR 2.0-4.3] %. MANTA access site complications were major in 20 (4%) and minor in 28 patients (5.6%). Median time to hemostasis was 50 [IQR 20-120] sec. Severe femoral artery calcification, scar presence in groin, longer procedure duration, female gender and history of hypertension were independent predictors for vascular complications.CONCLUSION: In this study, MANTA appeared to be a safe and effective device for large bore access closure under real-world conditions.

Offering a variety of activities and events is considered a central part of many public libraries today. Under the term public library programmes, this article presents the findings from an empirical study of the development of publicly available and publicly announced activities and events offered within or in relation to Danish public libraries over a sixty-year period. The aim of the study was to enrich our understanding of these library services from a historical perspective focussing on describing development. Inspired by Historical Case Study (HCS), the study was designed as a diachronic analysis of a broad variety of empirical source materials collected from two case libraries, documenting programmes offered between 1960 and 2020, including interviews with programming librarians. From analysing the source materials, a development is described which shows that while the different types of programmes offered throughout the period have been somewhat consistent, their format and content have expanded in parallel with the expansion of the public library, its collections and services. At the same time, the reasoning behind offering programmes can be described as a development from programmes considered as a means to an end (e.g. education, publicity or community building) to programmes also considered as ends in themselves. By supporting and enriching the knowledge on programmes as services, this study provides an empirical foundation for discussions and debates about the role and function of public library programmes as part of the public library in the future as well as rich empirical examples for further research.

The risk of dementia seems to be established already early in life, which leads to the question if overweight early in life is an important risk factor for dementia as it appears to be later in life. We examined the association between body mass index (BMI) at entry to adult life and subsequent risk of dementia in men and assessed whether the relationship differed by levels of intelligence and education. The study population consisted of 377,598 Danish men born 1939–1959 with measures of height, weight, intelligence test score (ITS), and educational level (EL) at conscript board examinations around the age of 19 years. Dementia outcomes were obtained from National Patient and Prescription Registries between 1969 and 2016. The association between BMI and dementia was analysed using Cox proportional hazard regression including interactions between BMI and ITS and EL, respectively. During the follow-up through age 77 years, 6144 (1.6%) developed dementia. The frequency was highest in men with lowest BMI, lowest ITS and lowest EL. Young adult BMI below the mean of 21.8 kg/m2 was inversely associated with subsequent dementia, whereas there was no association with higher levels of BMI. Adjustment for young adult ITS and EL attenuated the risk estimates slightly, and interaction analyses showed that the shape of the association between BMI and dementia was unaffected by the levels of ITS and EL. Regardless of levels of ITS and EL, young adult BMI below the mean is inversely associated with subsequent dementia, whereas there is no association with higher levels of BMI.

PURPOSE: Exercise increases pressure pain thresholds (PPT) in pain-free individuals, known as exercise-induced hypoalgesia (EIH). Positive preexercise information can elicit higher EIH responses, but the effect of positive versus negative preexercise information on EIH is unknown. The primary aim of this randomized controlled trial was to compare EIH at the exercising thigh muscle after an isometric squat exercise between individuals receiving positive versus negative preexercise information about the effect of exercise on pain. Secondary aims were to compare EIH at nonexercising muscles between groups, and to investigate the relationship between participants' expectations and EIH.METHODS: Eighty-three participants were randomly assigned to brief positive (n = 28), neutral (n = 28) or negative (n = 27) verbal information. The neutral information group was included in the study as a reference group. Pressure pain thresholds at the thigh and trapezius muscles were assessed before and after the intervention (i.e., preexercise information+squat exercise). Expectations of pain relief were assessed using a numerical rating scale (-10 [most negative] to 10 [most positive]).RESULTS: Change in quadriceps and trapezius PPT after the squat exercise showed a large difference between the positive and negative information groups (quadriceps, 102 kPa; 95% confidence interval, 55-150; effect size, 1.2; trapezius, 41 kPa; 95% confidence interval, 16-65; effect size:, 0.9). The positive information group had a 22% increase in quadriceps PPT whereas the negative information group had a 4% decrease. A positive correlation was found between expectations and increase in PPT.CONCLUSIONS: Negative preexercise information caused hyperalgesia after the wall squat exercise, whereas positive or neutral preexercise information caused hypoalgesia. Positive preexercise information did not change the magnitude of EIH compared with neutral information.

In this paper, active filters are embedded in the grid-connected converter control of Type-IV wind turbines to reduce harmonic voltage amplification in offshore wind power plants (WPPs). The extra element theorem is employed to tune the active filters and determine the stability margin. Active filter tunings that satisfactorily reduce harmonic voltage amplification yet provide sufficient stability margin in the augmented system are identified. A running example is performed on a 270 MW offshore WPP comprised of 3-MW wind turbines implemented in real-time simulation as hardware-in-the-loop. Both converter and grid voltage harmonics are suppressed at WPP buses to below the stipulated planning levels.

Objectives This study was designed to compare head-to-head fractional flow reserve (FFR) derived from coronary computed tomography angiography (CTA) (FFRCT) and cardiac magnetic resonance (CMR) stress perfusion imaging for prediction of standard-of-care–guided coronary revascularization in patients with stable chest pain and obstructive coronary artery disease by coronary CTA. Background FFRCT is a novel modality for noninvasive functional testing. The clinical utility of FFRCT compared to CMR stress perfusion imaging in symptomatic patients with coronary artery disease is unknown. Methods Prospective study of patients (n=110) with stable angina pectoris and 1 or more coronary stenosis ≥50% by coronary CTA. All patients underwent invasive coronary angiography. Revascularization was FFR-guided in stenoses ranging from 30% to 90%. FFRCT ≤0.80 in 1 or more coronary artery or a reversible perfusion defect (≥2 segments) by CMR categorized patients with ischemia. FFRCT and CMR were analyzed by core laboratories blinded for patient management. Results A total of 38 patients (35%) underwent revascularization. Per-patient diagnostic performance for identifying standard-of-care–guided revascularization, (95% confidence interval) yielded a sensitivity of 97% (86 to 100) for FFRCT versus 47% (31 to 64) for CMR, p 0.05, respectively. Conclusions In patients with stable chest pain referred to invasive coronary angiography based on coronary CTA, FFRCT and CMR yielded similar overall diagnostic accuracy. Sensitivity for prediction of revascularization was highest for FFRCT, whereas specificity was highest for CMR.

PurposeAs a research topic within the field of LIS, programs in public libraries are underexplored, and the question of user fees for programs has not previously been addressed.Design/methodology/approachThis article compares data collected from two individually conducted studies of public library programs in North America and Denmark to enrich our understanding of user fees in relation to programs.FindingsThe comparative analysis shows both similarities and deviations regarding the levying of fees for library programs. While paying a fee to attend a program is rather normal in Denmark, it is more of a fringe idea in North America.Research limitations/implicationsBy exploring a previously understudied facet of contemporary public librarianship, this article opens up new avenues for inquiry regarding how the relative accessibility and availability of programs relate to theoretical discussions about programs as public library services.Practical implicationsThis article provides library managers with needed information about how to conceptualize the roles of programs as public library services.Social implicationsAs programming surges to the fore in contemporary public librarianship, the levying of user fees has social implications in terms of social equity and the public library ethos of free and equal access for all.Originality/valueThis article is the first study of user fees for public library programs, as well as among the first cross-national comparisons of programming as a dimension of public librarianship.

Among the disabled workforce, many are engaged in part-time work. However, research regarding the relationship between disability and part-time work has only partially elucidated how people with disabilities who are in receipt of partial or graded disability pensions perceive and handle the combination of part-time work with their pension payments. This article addresses the narrated strategies employed by people with disabilities in managing part-time employment, drawing on interview data from 10 Norwegian citizens who worked part-time in addition to receiving a graded disability pension. The findings illustrate that flexibility and visibility are specific strategies that our informants implement when health issues and reduced working hours result in weakened connections to the workplace. The article demonstrates how the discourses around paid employment facilitate these strategies. By providing insight into people's narrated experiences of engaging in part-time work with disabilities, the article offers significant recommendations into the conditions necessary for people with disabilities to remain employed while also in receipt of graded disability pensions.

We compared 10-year clinical outcomes in diabetes and nondiabetes patients treated with Endeavor zotarolimus-eluting (ZES) or Cypher sirolimus-eluting coronary stents (SES). A total of 1,162 patients were randomized to ZES (169 with diabetes) and 1,170 patients were randomized to SES (168 with diabetes). Patients were further stratified by diabetes status at the time of inclusion. A subgroup of patients with diabetes (n = 88) underwent angiographic re-evaluation 10 months after stent implantation. End points included a combined end point of death or myocardial infarction, and the individual end points of death, myocardial infarction, and revascularization. In patients with diabetes, we found no difference in the combined end point (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.53 to 1.24), death (OR 0.80, 95% CI 0.51 to 1.25), or in MI (OR 1.07, 95% CI 0.60 to 1.91). However, diabetics with ZES more frequently underwent coronary revascularization compared with SES patients (OR 1.93, 95% CI 1.05 to 3.66). In patients without diabetes, ZES and SES had similar 10-year rates of all end points (death: OR 1.13, 95% CI 0.93 to 1.39; MI: OR 0.80, 95% CI 0.61 to 1.05; revascularization: OR 0.81, 95% CI 0.61 to 1.09). Landmark analysis from 5 to 10 years showed no difference in outcomes between SES and ZES in either subgroup. In conclusion, at 10 years, SES and ZES performed similarly in patients with and without diabetes. Although coronary revascularization was more prevalent in diabetes patients with ZES, this may, in part, have been related to the angiographic follow-up that was offered to a subgroup of diabetes patients.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking.METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed.RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group.CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

BACKGROUND: There are limited data on the association of membranous septum (MS) morphology and transcatheter heart valve (THV) implantation depth, and the development of new conduction abnormalities (CA) after transcatheter aortic valve implantation (TAVI). AIMS: The aim of this study was to describe the morphology of the MS and predict the risk of new CA after TAVI based on the MS morphology and THV implantation depth. METHODS: Based on preprocedural CT scans, the MS depth was measured for every 25% of the entire MS width in 272 TAVI patients without preprocedural bundle branch block (BBB) or pacemaker. Post-procedural CT scans for THV implantation depth assessment were available in 130 of these patients. RESULTS: The MS depth was a median of 2.5 mm (IQR 1.4-3.8) deeper at the posterior edge when compared to the anterior edge of the MS. New CA developed in 7.1% of patients in whom the THV did not cross the lower MS border at its anterior edge (3.6% with new BBB and high degree CA, respectively), in 18.8% of patients (15.6% with new BBB and 3.1% with new high-degree CA) where the THV overlapped the lower MS border by

BACKGROUND:Investigating the effect of newly approved oncological drugs in the real-world is warranted. With emerging novel treatments rapidly being approved for urothelial tract cancers, we aimed to assess real-world data, regarding effect and safety, during the first year after approval of pembrolizumab in Denmark for patients with locally advanced and unresectable or metastatic urothelial tract cancer (mUTC) in the first- and second-line setting.MATERIALS AND METHOD:At the six oncological departments treating mUTC in Denmark, we identified all mUTC patients receiving pembrolizumab during the first year after approval, between March 1, 2018 and February 28, 2019. A retrospective data collection was conducted from January to June 2020. Patient characteristics matching that of the relevant clinical trials for pembrolizumab in first- and second-line treatment-setting, overall survival (OS), progression-free survival (PFS), toxicity and tumor response were assessed.RESULTS:139 patients were identified, 53 in first-line treatment, 77 in second-line, and 9 receiving third or later lines of treatment. The population was characterized by a majority of males (70%), most patients had ECOG PS 0–1 (60.4%) and primary tumor in the bladder was predominant (90.6%). The overall response rate (ORR) in first-line was 30.2%, PFS was 3,5 months (95%CI 2,3–7,9 months) and OS 9,2 months (95%CI 7,0–20.9 months). For second-line treatment the ORR was 27,3%, PFS 2,9 months (95%CI 2,5–5,3) and OS 9.1 months (95%CI 5,4–12,8 months). Toxicity was comparable to clinical trials without any new toxicities registered.CONCLUSION:Real-world data on response rates, OS, PFS and toxicity for patients with mUTC receiving pembrolizumab in first- and second-line, shows comparable results to clinical trials. This study further establishes immunotherapy as an effective and tolerable treatment for mUTC. BACKGROUND: Investigating the effect of newly approved oncological drugs in the real-world is warranted. With emerging novel treatments rapidly being approved for urothelial tract cancers, we aimed to assess real-world data, regarding effect and safety, during the first year after approval of pembrolizumab in Denmark for patients with locally advanced and unresectable or metastatic urothelial tract cancer (mUTC) in the first- and second-line setting. MATERIALS AND METHOD: At the six oncological departments treating mUTC in Denmark, we identified all mUTC patients receiving pembrolizumab during the first year after approval, between March 1, 2018 and February 28, 2019. A retrospective data collection was conducted from January to June 2020. Patient characteristics matching that of the relevant clinical trials for pembrolizumab in first- and second-line treatment-setting, overall survival (OS), progression-free survival (PFS), toxicity and tumor response were assessed. RESULTS: 139 patients were identified, 53 in first-line treatment, 77 in second-line, and 9 receiving third or later lines of treatment. The population was characterized by a majority of males (70%), most patients had ECOG PS 0-1 (60.4%) and primary tumor in the bladder was predominant (90.6%). The overall response rate (ORR) in first-line was 30.2%, PFS was 3,5 months (95%CI 2,3-7,9 months) and OS 9,2 months (95%CI 7,0-20.9 months). For second-line treatment the ORR was 27,3%, PFS 2,9 months (95%CI 2,5-5,3) and OS 9.1 months (95%CI 5,4-12,8 months). Toxicity was comparable to clinical trials without any new toxicities registered. CONCLUSION: Real-world data on response rates, OS, PFS and toxicity for patients with mUTC receiving pembrolizumab in first- and second-line, shows comparable results to clinical trials. This study further establishes immunotherapy as an effective and tolerable treatment for mUTC.

BACKGROUND: The optimal revascularisation strategy for patients with left main coronary artery disease is uncertain. We therefore aimed to evaluate long-term outcomes for patients treated with percutaneous coronary intervention (PCI) with drug-eluting stents versus coronary artery bypass grafting (CABG).METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane database using the search terms "left main", "percutaneous coronary intervention" or "stent", and "coronary artery bypass graft*" to identify randomised controlled trials (RCTs) published in English between database inception and Aug 31, 2021, comparing PCI with drug-eluting stents with CABG in patients with left main coronary artery disease that had at least 5 years of patient follow-up for all-cause mortality. Two authors (MSS and BAB) identified studies meeting the criteria. The primary endpoint was 5-year all-cause mortality. Secondary endpoints were cardiovascular death, spontaneous myocardial infarction, procedural myocardial infarction, stroke, and repeat revascularisation. We used a one-stage approach; event rates were calculated by use of the Kaplan-Meier method and treatment group comparisons were made by use of a Cox frailty model, with trial as a random effect. In Bayesian analyses, the probabilities of absolute risk differences in the primary endpoint between PCI and CABG being more than 0·0%, and at least 1·0%, 2·5%, or 5·0%, were calculated.FINDINGS: Our literature search yielded 1599 results, of which four RCTs-SYNTAX, PRECOMBAT, NOBLE, and EXCEL-meeting our inclusion criteria were included in our meta-analysis. 4394 patients, with a median SYNTAX score of 25·0 (IQR 18·0-31·0), were randomly assigned to PCI (n=2197) or CABG (n=2197). The Kaplan-Meier estimate of 5-year all-cause death was 11·2% (95% CI 9·9-12·6) with PCI and 10·2% (9·0-11·6) with CABG (hazard ratio 1·10, 95% CI 0·91-1·32; p=0·33), resulting in a non-statistically significant absolute risk difference of 0·9% (95% CI -0·9 to 2·8). In Bayesian analyses, there was an 85·7% probability that death at 5 years was greater with PCI than with CABG; this difference was more likely than not less than 1·0% (INTERPRETATION: Among patients with left main coronary artery disease and, largely, low or intermediate coronary anatomical complexity, there was no statistically significant difference in 5-year all-cause death between PCI and CABG, although a Bayesian approach suggested a difference probably exists (more likely than not FUNDING: No external funding.

Objective: We explored the comparability of anxiety measures from register- and survey-based data including analyses of prevalence and associations with selected psychiatric and somatic diseases. Methods: We measured anxiety using Danish registers (hospital diagnosis and anxiolytic drug prescriptions), self-reports, symptom checklist (SCL) scores, and a clinical interview in 7493 adults with mean age 52 (SD 13.3) years who participated in a health survey between 2012 and 2015. We estimated the prevalence of anxiety, agreement between different measures and performed quantitative bias analysis. Results: The lifetime prevalence of hospital diagnosed anxiety, anxiolytic drug prescriptions, and self-reported anxiety were 4.4%, 6.2%, and 5.1%, respectively, after adjusting for selective participation. The agreement between the different anxiety measures was low. Thus, 25% with an anxiety diagnosis and 20% with anxiolytic drug prescriptions also had a high SCL score. Anxiolytic drugs were the only measure significantly associated with higher odds of heart disease. Hospital diagnosis and self-reported anxiety were associated with depression with odds ratio (OR) above 15, whereas anxiolytic drug prescriptions were less strongly associated (OR = 2.2(95% confidence interval: 1.26–3.91)). The risk estimates attenuated considerably when correcting for measurement error, whereas the ORs became slightly higher when the selective participation in the survey was accounted for. Conclusion: Anxiety diagnosed in hospitals and self-reported anxiety showed low level of agreement but provide comparable results regarding frequency measures and associations with disease outcomes.

Purpose Data regarding vessel healing by optical coherence tomography (OCT) after everolimus-eluting bioresorbable scaffolds (BRS) or everolimus-eluting metallic stent (EES) implantation in acute myocardial infarction (AMI) patients is scarce. We compared OCT findings after BRS or EES implantation in patients with AMI enrolled in a randomized trial. Methods In ISAR-Absorb MI, AMI patients were randomized to BRS or EES implantation, with 6–8 month angiographic follow-up. This analysis includes patients who underwent OCT during surveillance angiography. Tissue characterization was done using grey-scale signal intensity analysis. The association between OCT findings and target lesion failure (TLF) at 2 years was investigated. Results OCT was analyzed in 103 patients (2237 frames, 19,827 struts) at a median of 216 days post-implantation. Of these, 70 were treated with BRS versus 32 with EES. Pre-(92.8 vs. 68.7%, p = 0.002) and post-dilation (51.4 vs. 12.5%, p At two-years, 8 (7.8%) patients experienced TLF. Mean neointimal area [0.61 (0.21, 1.33) vs. 0.41 (0.11, 0.75) mm2, p = 0.03] and mean neointimal coverage [106.1 (65.2, 214.8) vs. 80.5 (53.5, 122.1) µm, p Conclusions In selected patients who underwent OCT surveillance 6–8 months after coronary intervention for AMI with differing implantation characteristics depending on the device type used, vessel healing was more advanced in BRS compared with EES, particularly in the STEMI subgroup.

Drug-related problems are important causes of patient harm and increased healthcare costs. To assist general practitioners in prioritizing patients in need of a critical medication review, we aimed to assess the ability of the Medication Risk Score (MERIS) to stratify patients with polypharmacy in general practice according to their risk of drug-related problems. We conducted a cross-sectional multi-centre external validation study. Patients receiving more than five concomitant medications (polypharmacy) were eligible. The outcome was potentially serious drug-related problems as evaluated by expert consensus. Performance was assessed in terms of calibration and discrimination indices. Of 497 patients, 489 were included in the main analysis. The median age (interquartile range) was 70.5 years (60-79). In total, 372 potentially serious drug-related problems were observed in 253 patients (52%). The MERIS was well calibrated above a score level of 10. The area under the receiver operating characteristic curve was 0.70 (95% confidence interval: 0.65-0.74). The performance of the MERIS was fair in patients with polypharmacy in general practice. Given the scale of drug-related problems and the lack of efficient prioritization tools in this setting, the MERIS could be a useful risk indicator to complement usual practice.

AIMS: CT-QFR is a novel coronary computed tomography angiography (CTA) based method for on-site evaluation of patients with suspected obstructive coronary artery disease (CAD). We compared the diagnostic performance of CT-QFR with myocardial perfusion scintigraphy (MPS) and cardiovascular magnetic resonance (CMR) as second-line tests in patients with suspected obstructive CAD after coronary CTA.METHODS AND RESULTS: Paired analysis of CT-QFR and MPS or CMR, with an invasive FFR-based classification as reference standard. Symptomatic patients with >50% diameter stenosis on coronary CTA were randomized to MPS or CMR and referred for invasive coronary angiography. The rate of coronary CTA not feasible for CT-QFR analysis was 17%. Paired patient-level data were available for 118 patients in the MPS group and 113 in the CMR group, respectively. Patient-level diagnostic accuracy was better for CT-QFR than for both MPS ((82.2% (95%CI 75.2-89.2) vs. 70.3% (95%CI 62.0-78.7), p=0.029) and CMR ((77.0% (95%CI 69.1-84.9) vs. 65.5% (95%CI 56.6-74.4), p=0.047). Following a positive coronary CTA and with the intention-to diagnose, CT-QFR, CMR and MPS were equally suitable as rule-in and rule-out modalities.CONCLUSIONS: The diagnostic performance of CT-QFR as second-line test was at least similar to MPS and CMR for the evaluation of obstructive coronary artery disease in symptomatic patients presenting with ≥50% diameter stenosis on coronary CTA.

Objectives To compare the early vascular healing of ruptured plaques (RP) and non-ruptured plaques (NRP) one month after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI), using optical coherence tomography (OCT). Background Vascular healing and strut coverage are important factors in reducing the risk of stent thrombosis after PCI. Influence of underlying lesion characteristics and differences in healing response between RP and NRP are unknown. Methods Twenty-six STEMI-patients underwent PCI and implantation of a polymer-free drug-coated Biofreedom stent (BF-BES). OCT was performed pre-PCI, post-PCI and at 1-month follow-up. The patients were divided into two groups: RP=15 and NRP=11. OCT analyses of culprit lesion, post stent implantation at baseline and follow-up were performed to determine the difference in vascular healing based on presence of uncovered and/or malapposed stent struts and intraluminal filling defects. Results The stent coverage did not differ significantly between the two groups at 1-month follow-up with percentage of uncovered struts: RP 26.5% [IQR 15.0-49.0] and NRP 28.1% [IQR 15.5-38.8] for NRP (p=0.78). At 1-month, RP showed an increased percentage of late acquired malapposed struts (1.4% [IQR 0.8-2.4] vs. 0.0% [IQR 0.0-1.4], p=0.03) and a larger total malapposition area (1.3 mm2 [IQR 0.4-2.5] vs. 0.0 mm2 [IQR 0.0-0.9], p=0.01), compared to NRP. Conclusion Three out of four struts were covered within one month after stenting. The vascular healing was comparable in RP and NRP on stent coverage. However, RP had more and larger late acquired malapposition areas. Condensed abstract In 26 patients with ST-segment elevation myocardial infarction optical coherence tomography was performed before and after implantation of a Biofreedom (BF-BES) polymer-free drug-coated stent, and after one month. Lesion morphology was determined and divided into two groups: ruptured plaques (RP) or non-ruptured plaques (NRP). The stent coverage did not differ significantly between the two groups at 1-month follow-up with percentage of uncovered struts: RP 26.5% [IQR 15.0-49.0] and NRP 28.1% [IQR 15.5-38.8] for NRP (p=0.78). Culprit lesions with RP had more and larger areas of late acquired malapposed struts compared to lesions with NRP.

Recent studies have highlighted the efficacy of and willingness to use pre-exposure prophylaxis (PrEP) to prevent HIV infection among people who inject drugs (PWID), however knowledge of real-world applicability is limited. We aimed to quantify the real-world eligibility for HIV-PrEP among HIV-negative PWID in Montreal, Canada (n = 718). Eligibility was calculated according to US Centers for Disease Control and Prevention (CDC) guidelines and compared to risk of HIV acquisition according to the assessing the risk of contracting HIV (ARCH-IDU) risk screening tool. Over one-third of participants (37%) were eligible for HIV PrEP, with 1/3 of these eligible due to sexual risk alone. Half of participants were considered high risk of HIV acquisition according to ARCH-IDU, but there was poor agreement between the two measures. Although a large proportion of PWID were eligible for HIV-PrEP, better tools that are context- and location-informed are needed to identify PWID at higher risk of HIV acquisition.

A patient with chest pain and inferoseptal ischemia at Rubidium-82 Positron Emission Tomography (82RbPET) was revascularized in a stenosis in the LAD/D1 bifurcation, while a CTO RCA was left untreated. One-year follow-up with Seattle Angina Questionnaire and repeat 82RbPET revealed symptom relief and improved inferoseptal perfusion likely through LAD collateralization.

BACKGROUND: The aim of this study was to compare the 12-month clinical outcomes of patients treated with Magmaris or Orsiro. Second generation drug-eluting absorbable metal scaffold Magmaris (Dreams 2G) has proved to be safe and effective in the BIOSOLVE-II study. Similarly, biodegradable polymer sirolimus-eluting stent, Orsiro has shown notable clinical results even in all-comer populations.METHODS: Magmaris group patients were taken from the BIOSOLVE-II and BIOSOLVE-III trials, while the patients from Orsiro group were enrolled in BIOFLOW-II trial. The primary outcome was explored using a time-to-event assessment of the unadjusted clinical outcomes for target lesion failure (TLF) at 12 months, followed by a multivariate analysis adjusting for all the significantly different covariates between the groups.RESULTS: The study population consisted of 482 patients (521 lesions), 184 patients (189 lesions) in Magmaris group and 298 patients (332 lesions) in Orsiro group. The mean age was 65.5 ± 10.8 and 62.7 ± 10.4 years in Magmaris and Orsiro groups, respectively (p = 0.005). Magmaris and Orsiro unadjusted TLF rates were 6.0 and 6.4% with no significant difference between the groups (p = 0.869). In the multivariate analysis, there were no meaningful differences between Magmaris and Orsiro groups. Finally, none of the groups presented device thrombosis cases at 12 months.CONCLUSION: At 12 months there were no significant differences between Magmaris and Orsiro groups neither in the unadjusted assessment nor in the multivariate analysis for target lesion failure. These results should be taken as hypothesis generating and may warrant a head to head comparison on a randomized fashion.

Highly nutritional microalgal species are extensively used in aquaculture as live feedstock. Due to difficulties in maintaining microalgae in axenic conditions, they represent a potential pathogen carrier and disease vector in aquaculture ponds. Photodynamic therapy (PDT) via singlet oxygen (1O2) production is a promising sterilization technique in aquaculture. Here, we report on the sensitivity of aquaculture-relevant microalgae towards 1O2 generated by the cationic photosensitizer TMPyP. Possible PDT sterilization protocols of contaminated microalgae cultures were evaluated using the luminescent bacterium Vibrio campbellii ISO7 as a model aquaculture pathogen. Species-specific sensitivity of microalgae to TMPyP-mediated PDT was demonstrated and found to be strongly influenced by the nature and architecture of their respective cell wall. While cytotoxicity was not evident against Nannochloropsis oculata, toxicity of 1O2 was dose-, time- and light activation-dependent against Tisochrysis lutea, Tetraselmis chui, Chaetoceros muelleri and Picochlorum atomus. The 1O2-resilient N. oculata was sterilized when incubated under light in the presence of V. campbellii ISO7 (up to 107 CFU mL−1) and 20 μM TMPyP; hence, TMPyP-based PDT sterilization of N. oculata could be suitable for aquaculture hatcheries. This study also suggests that PDT using cationic porphyrins such as TMPyP holds potential as an algicidal treatment in aquaria and aquaculture systems (but more research using opportunistic and toxic species is needed for confirmation).

As direct-acting antiviral (DAA) therapy costs fall and eligibility criteria are relaxed, people who inject drugs (PWID) will increasingly become eligible for HCV treatment. Yet eligibility does not necessarily equate to access. Amidst efforts to expand treatment uptake in this population, we seek to synthesise and clarify the conceptual underpinnings of access to health care for PWID, with a view to informing research and practice. Integrating dominant frameworks of health service utilisation, care seeking processes, and ecological perspectives on health promotion, we present a comprehensive theoretical framework to understand, investigate and intervene upon barriers and facilitators to HCV care for PWID. Built upon the concept of Candidacy, the framework describes access to care as a continually negotiated product of the alignment between individuals, health professionals, and health systems. Individuals must identify themselves as candidates for services and then work to stake this claim; health professionals serve as gatekeepers, adjudicating asserted candidacies within the context of localised operating conditions; and repeated interactions build experiential knowledge and patient-practitioner relationships, influencing identification and assertion of candidacy over time. These processes occur within a complex social ecology of interdependent individual, service, system, and policy factors, on which other established theories provide guidance. There is a pressing need for a deliberate and nuanced theory of health care access to complement efforts to document the HCV ‘cascade of care’ among PWID. We offer this framework as an organising device for observational research, intervention, and implementation science to expand access to HCV care in this vulnerable population. Using practical examples from the HCV literature, we demonstrate its utility for specifying research questions and intervention targets across multiple levels of influence; describing and testing plausible effect mechanisms; and identifying potential threats to validity or barriers to research translation.

Background Multiple barriers for accessing hepatitis C virus (HCV) treatment were identified during the interferon-based (IFN) treatment era for people who inject drugs (PWID). Whether these barriers persist since the introduction of IFN-free direct-acting antiviral (DAA) agents in Canada remains to be documented. This study examined temporal trends in HCV treatment initiation and associated factors during the transition from INF-based to all-oral DAA regimens. Methods The study population was drawn from a prospective cohort of PWID in Montreal, Canada. At three-month/one-year intervals between 2011 and 2017, participants with chronic HCV infection completed an interviewer-administered questionnaire on socio-demographic characteristics, drug use and health service utilisation, including HCV treatment. Time-updated Cox multivariate regression models, stratified by DAA + INF (2011-2013) and all-oral DAA (2014–2017) availability periods, were conducted to examine associations between time to HCV treatment initiation and associated barriers and facilitators. Results Of 308 participants (85% male, median age 42 [IQR: 33, 50]), 80 (26%) initiated HCV treatment during 915 person-years (PY). Incidence rates increased from 1.6 /100 PY (95%CI:0.9–2.6) in 2011 to 12.7 (10.6–15.1) in 2017 (p-trend = 0.0012). In multivariate analyses, visiting a primary care physician (2011–2013: aHR = 3.63[1.21–10.9]; 2014–2017: 2.52[1.10–5.77]) and frequent injection (0.23[0.05–0.99] and 0.49[0.24–0.99]) were consistently associated with treatment initiation. Participants aged >40 (2.27[1.24–4.13]), receiving opioid agonist therapy (OAT) (2.17[1.19–3.94]), and reporting prior HCV treatment (3.00[1.75–5.15]) were more likely to initiate treatment in the all-oral DAA period. Conclusion Treatment initiation increased between 2011 and 2017, but still remains low among PWID. Primary care visiting was a key facilitator regardless of the period, while engagement in OAT and health services, indicated by prior HCV treatment, increased the likelihood of treatment initiation in the DAA era. These findings suggest that access to health services is essential but not enough to scale up treatment in this population.

OBJECTIVES: To estimate the association between fetal congenital heart defects (CHDs) and measures of brain size throughout pregnancy, from the end of the first trimester to birth.STUDY DESIGN: The cohort consisted of all fetuses scanned in Western Denmark in 2012 and 2013. Anthropometric measures in fetuses with isolated CHDs diagnosed within 12 months after birth were compared with those in the fetuses without CHDs. Z-scores standardized to gestational age were calculated for first trimester biparietal diameter, second trimester head circumference, fetal weight, birthweight, head circumference, and placental weight.RESULTS: We obtained data from 63 349 pregnancies and identified 295 fetuses with isolated CHDs (major n = 145; minor n = 150). The first trimester mean biparietal diameter Z-scores were not different between those with and those without CHDs. The head circumference mean Z-score difference was -0.13 (95% CI, -0.24 to -0.01; P = .03) in the second trimester and -0.22 (95% CI, -0.35 to -0.09; P < .001) at birth. Fetuses with univentricular physiology or tetralogy of Fallot showed the most pronounced compromise in cerebral size.CONCLUSIONS: Our results suggest that the brain alterations inducing an increased risk of impaired neurodevelopment in children with CHDs begin during pregnancy. Although fetuses with univentricular physiology or tetralogy of Fallot exhibited the most pronounced compromise in cerebral size, we recommend neurodevelopmental follow-up for all children with CHDs.

We aimed to identify factors influencing the sensitivity of perfusion imaging after an initial positive coronary computed tomography angiography (CCTA) using invasive coronary angiography (ICA) with conditional fractional flow reserve (FFR) as reference. Secondly we aimed to identify factors associated with revascularisation and to evaluate treatment outcome after ICA. We analysed 292 consecutive patients with suspected significant coronary artery disease (CAD) at CCTA, who underwent perfusion imaging with either cardiac magnetic resonance (CMR) or myocardial perfusion scintigraphy (MPS) followed by ICA with conditional FFR. Stratified analysis and uni- and multiple logistic regression analyses were performed to identify predictors of diagnostic agreement between perfusion scans and ICA and predictors of revascularisation. Myocardial ischemia evaluated with perfusion scans was present in 65/292 (22%) while 117/292 (40%) had obstructive CAD evaluated by ICA. Revascularisation rate was 90/292 (31%). The overall sensitivity for perfusion scans was 39% (30–48), specificity 89% (83–93), PPV 69% (57–80) and NPV 68% (62–74). Stratified analysis showed higher sensitivities in patients with multi-vessel disease at CCTA 49% (37–60) and typical chest pain 50% (37–60). Predictors of revascularisation were multi-vessel disease by CCTA (OR 3.51 [1.91–6.48]) and a positive perfusion scan (OR 4.69 [2.49–8.83]). The sensitivity for perfusion scans after CCTA was highest in patients with typical angina and multiple lesions at CCTA and predicted diagnostic agreement between perfusion scans and ICA. Abnormal perfusion and multi vessel disease at CCTA predicted revascularisation.

Objectives The aim of this study was to compare the thin-strut biodegradable-polymer everolimus-eluting platinum-chromium stent (EES) with the biodegradable-polymer biolimus-eluting stainless-steel stent (BES). Background Currently available drug-eluting coronary stents have been refined to reduce the risk for coronary events following implantation. Methods This randomized, multicenter, all-comers, noninferiority trial was undertaken at 3 sites in western Denmark. Patients with clinical indications for percutaneous coronary intervention were eligible for inclusion. Patients were randomly assigned (1:1) to either EES or BES. The primary endpoint, target lesion failure, was a composite of safety (cardiac death and myocardial infarction not clearly attributable to a nontarget lesion) and efficacy (target lesion revascularization) at 12 months, analyzed using intention-to-treat principles. The trial was powered to assess target lesion failure noninferiority of the EES compared with the BES with a predetermined noninferiority margin of 3%. Results A total of 1,385 patients were assigned to treatment with EES and 1,369 patients to treatment with BES. The analysis showed that 55 patients (4.0%) assigned to the EES and 60 (4.4%) assigned to the BES met the primary endpoint (absolute risk difference 0.4%; upper limit of 1-sided 95% confidence interval: 1.7%; p Conclusions At 1-year follow-up, the EES was found to be noninferior to the BES with respect to target lesion failure. (Everolimus-eluting SYNERGY Stent Versus Biolimus-Eluting Biomatrix NeoFlex Stent—SORT-OUT VIII; NCT02093845)

OBJECTIVES To evaluate the cost-effectiveness and safety of simultaneous hybrid coronary revascularization (sHCR) compared to conventional coronary artery bypass grafting (CABG) in elective patients with multivessel coronary artery disease. METHODS Cost–utility analysis of a prospective cohort follow-up study comparing per protocol 50 sHCR patients to 50 contemporaneous matched patients undergoing CABG. Resource utilization data and health-related quality of life were collected prospectively, and the cumulative 1-year costs were assessed from the Danish health sector perspective. Effectiveness was measured by quality-adjusted life years using EuroQol-5D. Probabilistic sensitivity analyses using bootstrapping were conducted. Secondary safety measures including early clinical outcomes and freedom from major adverse cardiac or cerebrovascular events at 1 year were assessed. RESULTS The clinical trial was discontinued prematurely due to safety reasons after inclusion of 50 patients (24 sHCR; 26 CABG), as the chest tube output and the risk of postoperative pleural effusions requiring thoracocentesis were significantly increased following sHCR compared with CABG. Based on 48 patients available for 1-year follow-up, both treatment strategies were similarly effective (quality-adjusted life year difference between the groups −0.019), with a net cost difference in favour of conventional CABG estimated to be €2173 per patient. Exclusion of 1 outlier patient with chronic renal failure and deep sternal wound infection in the sHCR group resulted in an equalization of the total 1-year costs. CONCLUSIONS At 1 year, sHCR was less cost-effective than conventional CABG and associated with higher chest tube output and a higher risk of postoperative pleural effusions requiring thoracocentesis. Clinical trial registration NCT01496664.

Introduction Promoting active transport offers the potential to increase population physical activity levels. Compensation theories state that above-average physical activity in one activity is compensated in later activities; a mechanism that results in stable levels of total physical activity. Little is known about possible compensation of transport physical activity among older adults. Methods GPS (Global Positioning System) and accelerometer data collected among older adults (65+) were pooled from four cohorts in Canada, Luxembourg, and France (n=636, collected between 2012 and 2016). Physical activity was measured as total volume of physical activity for trips and non-trip activities. Robust linear regressions on person-centered data were used to test within-person associations between transport and total physical activity. Results 636 older adults – median age of 76 years, 49% women - provided accelerometer and GPS data for at least 4 days. 18% of the total volume of physical activity was related to transport. A positive association was found between physical activity during a trip and the physical activity during the next hour, among those with lower levels of regular physical activity. Negative associations - indicating partial compensation - were found between transport physical activity during a day, and both total physical activity during the next day and non-transport physical activity during the same day. No differences were found between the four study cohorts. Conclusions Transport physical activity is compensated partially by older adults during non-transport physical activity. Given the presence of compensation, we strongly recommend evaluations of transport interventions to measure and analyze both non-transport and transport physical activity.

Objectives The aim was to establish a contemporary scoring system to predict the outcome of chronic total occlusion coronary angioplasty. Background Interventional treatment of chronic total coronary occlusions (CTOs) is a developing subspecialty. Predictors of technical success or failure have been derived from datasets of modest size. A robust scoring tool could facilitate case selection and inform decision making. Methods The study analyzed data from the EuroCTO registry. This prospective database was set up in 2008 and includes >20,000 cases submitted by CTO expert operators (>50 cases/year). Derivation (n = 14,882) and validation (n = 5,745) datasets were created to develop a risk score for predicting technical failure. Results There were 14,882 patients in the derivation dataset (with 2,356 [15.5%] failures) and 5,745 in the validation dataset (with 703 [12.2%] failures). A total of 20.2% of cases were done retrogradely, and dissection re-entry was performed in 9.3% of cases. We identified 6 predictors of technical failure, collectively forming the CASTLE score (Coronary artery bypass graft history, Age (≥70 years), Stump anatomy [blunt or invisible], Tortuosity degree [severe or unseen], Length of occlusion [≥20 mm], and Extent of calcification [severe]). When each parameter was assigned a value of 1, technical failure was seen to increase from 8% with a CASTLE score of 0 to 1, to 35% with a score ≥4. The area under the curve (AUC) was similar in both the derivation (AUC: 0.66) and validation (AUC: 0.68) datasets. Conclusions The EuroCTO (CASTLE) score is derived from the largest database of CTO cases to date and offers a useful tool for predicting procedural outcome.

BACKGROUND: Coronary physiology is a routine diagnostic tool when assessing whether coronary revascularization is indicated. The iFR-SWEDEHEART trial demonstrated similar clinical outcomes when using instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) to guide revascularization. The objective of this analysis was to assess a cost-minimization analysis of iFR-guided compared with FFR-guided revascularization.METHODS: In this cost-minimization analysis we used a decision-tree model from a healthcare perspective with a time-horizon of one year to estimate the cost difference between iFR and FFR in a Nordic setting and a United States (US) setting. Treatment pathways and health care utilizations were constructed from the iFR-SWEDEHEART trial. Unit cost for revascularization and myocardial infarction in the Nordic setting and US setting were derived from the Nordic diagnosis-related group versus Medicare cost data. Unit cost of intravenous adenosine administration and cost per stent placed were based on the average costs from the enrolled centers in the iFR-SWEDEHEART trial. Deterministic and probabilistic sensitivity analyses were carried out to test the robustness of the result.RESULTS: The cost-minimization analysis demonstrated a cost saving per patient of $681 (95% CI: $641 - $723) in the Nordic setting and $1024 (95% CI: $934 - $1114) in the US setting, when using iFR-guided compared with FFR-guided revascularization. The results were not sensitive to changes in uncertain parameters or assumptions.CONCLUSIONS: IFR-guided revascularization is associated with significant savings in cost compared with FFR-guided revascularization.

The creation of macroscopic quantum systems represents a long-pursued goal for the quantum-technology com-munity as it might shed new light on the theory of quantum mechanics and find application in quantum information science. Feedback cooling provides an efficient strategy to such objective, as it enables motion control of massive objects coupled to a light field. Several successful approaches have been developed to achieve cooling into the ground state. The system we present consists of a SiN tethered membrane (trampoline) placed inside an optical cavity with a finesse of 15000. The mechanical motion at 132 kHz is imprinted into the phase of a probing laser beam at 1550 nm and then readout by homodyne detection. The measurement results are then used to modulate the amplitude of a cooling beam which steers the trampoline towards the ground state via radiation pressure force. Figure 1c shows the results obtained in our feedback cooling scheme, which allowed to reach a final phonon number occupancy of 4000 starting from room temperature.

Objectives:To compare early neurocognitive development in children born with and without isolated CHD using the Bayley Scales of Infant and Toddler Development (3rd edition) and the Ages and Stages Questionnaire (3rd edition).Methods:Recruitment took place before birth. Women expecting fetuses with and without CHD causing disturbances in the flow of oxygenated blood to the fetal brain were included in a prospective cohort study comprising fetal MRI (previously published) and neurodevelopmental follow-up. We now present the 18- and 36-month neurodevelopmental follow-up using the Bayley Scales according to age and the 6-month-above-age Ages and Stages Questionnaire in 15 children with and 27 children without CHD.Results:Children with CHD had, compared with the children without CHD, an increased risk of scoring ≤ 100 in the Bayley Scales cognition category at 18 and 36 -months; relative risk 1.7 (95% confidence interval (CI): 1.0–2.8) and 3.1 (CI: 1.2–7.5), respectively. They also achieved lower scores in the 6-month-above-age Ages and Stages Questionnaires (24 and 42 months) communication; mean z-score difference −0.72 (CI: −1.4; −0.1) and −1.06 (CI: −1.8; −0.3) and gross motor; mean z-score difference: −0.87 (CI: −1.7; −0.1) and −1.22 (CI: −2.4; −0.02) categories.Conclusions:The children with CHD achieved lower scores in the Bayley Scales cognition category and the Ages and Stages Questionnaire communication and gross motor categories possibly indicative of early neurodevelopmental deficiencies. We recommend early screening and monitoring for neurodevelopmental delays in children with CHD in order to improve further neurodevelopment and educational achievements.

Aims Recent technological advances enable diagnosing of obstructive coronary artery disease (CAD) from heart sound analysis with a high negative predictive value. However, the prognostic impact of this approach remains unknown. To investigate the prognostic value of heart sound analysis as two scores, the Acoustic-score and the CAD-score, in patients with suspected CAD which is treated according to standard of care. Methods and results Consecutive patients with angina symptoms referred for coronary computed tomography angiography (CTA) were enrolled. The Acoustic-score was developed from eight acoustic CAD-related features. This score was combined with risk factors to generate the CAD-score. A cut-off score >20 was pre-specified for both scores to indicate disease. If coronary CTA raised suspicion of obstructive CAD, patients were referred to invasive angiography and revascularized when indicated. Of 1675 enrolled patients, 1464 (87.4%) were included in this substudy. The combined primary endpoint was all-cause mortality and myocardial infarction (n = 26). Follow-up was 3.1 (2.7–3.4) years. Of patients with primary endpoints, the Acoustic-score was >20 in 25 (96%); the CAD-score was >20 in 22 (85%). In an unadjusted Cox analysis of the primary endpoints, the hazard ratio for scores >20 under current standard clinical care was 12.6 (1.7–93.2) for the Acoustic-score and 5.4 (1.9–15.7) for the CAD-score. The CAD-score contained prognostic information even after adjusting for lipid-lowering therapy initiation, stenosis at CTA, and early revascularization. Conclusion Heart sound analysis seems to carry prognostic information and may improve initial risk stratification of patients with suspected CAD. Clinicaltrials.org ID NCT02264717.

Background: Target lesion failure remains an issue with contemporary drug-eluting stents. Thus, the dual-therapy sirolimus-eluting and CD34+ antibody–coated Combo stent (DTS) was designed to further improve early healing. This study aimed to investigate whether the DTS is noninferior to the sirolimus-eluting Orsiro stent (SES) in an all-comers patient population. Methods: The SORT OUT X (Combo Stent Versus Orsiro Stent) trial, was a large-scale, randomized, multicenter, single-blind, 2-arm, noninferiority trial with registry-based follow-up. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, analyzed using intention-to-treat. The trial was powered for assessing target lesion failure noninferiority of the DTS compared with the SES with a predetermined noninferiority margin of 0.021. Results: A total of 3146 patients were randomized to treatment with the DTS (1578 patients; 2008 lesions) or SES (1568 patients; 1982 lesions). At 12 months, intention-to-treat analysis showed that 100 patients (6.3%) assigned the DTS and 58 patients (3.7%) assigned the SES met the primary end point (absolute risk difference, 2.6% [upper limit of 1-sided 95% CI, 4.1%]; P (noninferiority)=0.76). The SES was superior to the DTS (incidence rate ratios for target lesion failure, 1.74 [95% CI, 1.26–2.41]; P =0.00086). The difference was explained mainly by a higher incidence of target lesion revascularization in the DTS group compared with the SES group (53 [3.4%] vs. 24 [1.5%]; incidence rate ratio, 2.22 [95% CI, 1.37–3.61]; P =0.0012). Conclusions: The DTS did not confirm noninferiority to the SES for target lesion failure at 12 months in an all-comer population. The SES was superior to the DTS mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the 2 stent groups. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03216733.

Background: In coronary artery bypass grafting (CABG), the use of fractional flow reserve (FFR) is insufficiently investigated. Stenosis assessment usually relies on visual estimates of lesion severity. This study evaluated health-related quality of life (HRQoL) and angina after FFR- versus angiography-guided CABG. Methods: One hundred patients referred for CABG were randomized to FFR- or angiography-guided CABG. In the FFR group, lesions with FFR>0.80 were deferred, while the surgeon was blinded to the FFR values in the angiography group. Before and 6 months after CABG, HRQoL was assessed by the health state classifier EQ-5D of the EuroQoL 5-level instrument and angina status based on the Canadian Cardiovascular Society classification system were registered. Results: Six-month angiography included FFR evaluations of deferred lesions. In total, completed EQ-5D of the EuroQoL 5-level instrument questionnaires were available in 86 patients (43 in the FFR versus 43 in the angiography-guided group). HRQoL was significantly improved and angina significantly decreased from baseline to 6 months after CABG with no difference between the randomization groups. Graft failure rates and clinical outcomes were similar in both groups. Patients with graft failure or FFRP =0.004) and more angina compared with patients without graft failure or FFR≥0.80 at 6-month follow-up. Conclusions: FFR- versus angiography-guided CABG demonstrated similar improvements in HRQoL and angina 6 months after CABG. Graft failure or low FFR in deferred lesions were associated with low HRQoL and angina. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02477371

Background: Polygenic risk scores (PRSs) are associated with coronary artery disease (CAD), but the clinical potential of using PRSs at the single-patient level for risk stratification has yet to be established. We investigated whether adding a PRS to clinical risk factors (CRFs) improves risk stratification in patients referred to coronary computed tomography angiography on a suspicion of obstructive CAD. Methods: In this prespecified diagnostic substudy of the Dan-NICAD trial (Danish study of Non-Invasive testing in Coronary Artery Disease), we included 1617 consecutive patients with stable chest symptoms and no history of CAD referred for coronary computed tomography angiography. CRFs used for risk stratification were age, sex, symptoms, prior or active smoking, antihypertensive treatment, lipid-lowering treatment, and diabetes. In addition, patients were genotyped, and their PRSs were calculated. All patients underwent coronary computed tomography angiography. Patients with a suspected ≥50% stenosis also underwent invasive coronary angiography with fractional flow reserve. A combined end point of obstructive CAD was defined as a visual invasive coronary angiography stenosis >90%, fractional flow reserve 50% if fractional flow reserve measurements were not feasible. Results: The PRS was associated with obstructive CAD independent of CRFs (adjusted odds ratio, 1.8 [95% CI, 1.5–2.2] per SD). The PRS had an area under the curve of 0.63 (0.59–0.68), which was similar to that for age and sex. Combining the PRS with CRFs led to a CRF+PRS model with area under the curve of 0.75 (0.71–0.79), which was 0.04 more than the CRF model ( P =0.0029). By using pretest probability (pretest probability) cutoffs at 5% and 15%, a net reclassification improvement of 15.8% ( P =3.1×10 −4 ) was obtained, with a down-classification of risk in 24% of patients (211 of 862) in whom the pretest probability was 5% to 15% based on CRFs alone. Conclusions: Adding a PRS improved risk stratification of obstructive CAD beyond CRFs, suggesting a modest clinical potential of using PRSs to guide diagnostic testing in the contemporary clinical setting. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02264717.

OBJECTIVE: To evaluate the diagnostic performance of quantitative flow ratio (QFR) related to fractional flow reserve (FFR) and resting distal-to-aortic pressure ratio (resting Pd/Pa) concordance.BACKGROUND: QFR is a method for computation of FFR based on standard coronary angiography. It is unclear how QFR is performed in patients with discordance between FFR and resting pressure ratios (distal-to-aortic pressure ratio [Pd/Pa]).MATERIALS AND METHODS: The main comparison was the diagnostic performance of QFR with FFR as reference stratified by correspondence between FFR and resting Pd/Pa. Secondary outcome measures included distribution of clinical or procedural characteristics stratified by FFR and resting Pd/Pa correspondence.RESULTS: Four prospective studies matched the inclusion criteria. Analysis was performed on patient level data reaching a total of 759 patients and 887 vessels with paired FFR, QFR, and resting Pd/Pa. Median FFR was 0.85 (IQR: 0.77-0.90). Diagnostic accuracy of QFR with FFR as reference was higher if FFR corresponded to resting Pd/Pa: accuracy 90% (95% CI: 88-92) versus 72% (95% CI: 64-80), p CONCLUSION: Diagnostic performance of QFR with FFR as reference is reduced for lesions with discordant FFR (≤0.80) and resting Pd/Pa (≤0.92) measurements.

We investigate the importance of adult children and/or cohabitation with a partner for older hip fracture patients' probability of independent living, public home care use and hospital readmission. Data from 35,066 Swedish hip fracture patients between 2012 and 2017, aged 65 years, and living at home at the time of the fracture in the Swedish Registry for Hip Fracture Patients and Treatment were linked with national registers. We applied adjusted logistic regression models and Cox proportional hazard models. In total, 959 (4.0%) women and 817 (7.3%) men had no adult children, 13,384 (56.0%) women and 3,623 (32.5%) men had no cohabiting partner and 2,780 (11.6%) women and 1,389 (12.5%) men neither had a cohabiting partner nor adult children. In comparison with women and men who had both a cohabiting partner and adult children, those without a cohabiting partner (i.e. only adult children) and those who neither had a cohabiting partner nor adult children had significantly lower probabilities of returning home (at discharge and after 4 months). They also had a greater probability of both receiving home care and having an increase in the amount of home care they receive. Having a close next of kin and hospital readmission were not associated. In conclusion, absence of a close next of kin, specifically a cohabiting partner, reduces the chance of return to independent living and increases the use of home care after a hip fracture hospitalisation. The findings highlight the importance of family support for older adults living situation after a hip fracture.

Background Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). Methods PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. Findings Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17 women, 745 [83 men; median age 63 [IQR 55-70] years). Median follow-up was 3.7 (IQR 3.0-4.4) years. Adverse events within 4 years occurred in 112 (13.2 951.0-15.6) of 898 patients, with 66 (8.0 95.2-10.0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46.9[SD 15.9]). Highly lipidic lesions (851 [24 of 3500 lesions, present in 520 [59 of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2.27, 95.25-4.13) and nonculprit lesion-specific MACEs (7.83, 4.12-14.89). Large plaque burden (787 [22 of 3629 lesions, present in 530 [59 of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7.095.0-10.0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13.295.4-17.6). Interpretation Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. Copyright (C) 2021 Elsevier Ltd. All rights reserved. BackgroundNear-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs).MethodsPROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065.FindingsBetween June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55–70] years). Median follow-up was 3·7 (IQR 3·0–4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0–15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2–10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25–4·13) and non-culprit lesion-specific MACEs (7·83, 4·12–14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0–10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4–17·6).InterpretationCombined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes.FundingAbbott Vascular, Infraredx, and The Medicines Company.

This paper aims at investigating the impact of the COVID-19 crisis on the automotive sector in Central and Eastern Europe. It details the effects of the pandemic and subsequent lockdown measures on the activity in the sector. It also discusses the prospects for car sales in the short to medium run, potential spillover effects in the region, and new risks to the supply chains posed by the pandemic. It shows that disruptions to the supply chains had limited impact so far and that the sector has been mainly affected by low level of demand. Going forward, the pandemic might have a significant negative impact on investment capacity, while the transition to alternative powertrains and the digital transformation of the industry require large investment and restructuring. The long-term impact on CEE economies is highly uncertain, but will depend on the capacity to maintain a comparative advantage, while the sector transforms deeply.