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Background: Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function., Methods: We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT., Results: A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays., Conclusions: We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function., (© Association for Diagnostics & Laboratory Medicine 2024. 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: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans., Methods: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays., Results: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0-6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180-679 mL) autologous plasma, the concentration of cTn in participants' blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8-168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7-295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0-44.9) to 52.7 mL/min (95% CI, 42.2-57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2-95.0)., Conclusions: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury., Competing Interests: Dr Bundgaard received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Sanofi, BMS, and MSD. Dr Bundgaard owns stock or stock options in Novo Nordic. Dr Kamstrup reported a grant from Gangsted Fonden outside the present work. P.R.K. reported consulting fees from Novartis and Silence Therapeutics. Dr Kamstrup reported payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Physicians’ Academy for Cardiovascular Education, Novartis, and PCSK9 Forum. Dr Frikke-Schmidt reported grants or contracts outside the present work from Lundbeck Foundation, The Danish Heart Foundation, and Sygeforsikringen Denmark Research Fund. Dr Kjærgaard reports a grant or contract from Novo Nordisk Foundation outside the present work. Dr Holmvang reported personal payment or honoraria for lectures from Boehringer Ingelheim and payment or honoraria to her institution for lectures from Bayer. Dr Holmvang reported receiving support for travel from Abbott to her institution. Dr Bor reported receiving honoraria for a lecture from Bristol-Myers. Dr Thygesen reported participation on the Data Safety Monitoring Board of DANBLOCK (Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction) and REDUCE (Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction in the SWEDEHEART Registry). Dr Jaffe reported royalties or licenses and stock or stock options to RCE Technologies; consulting fees from Abbott, Roche, Beckman-Coulter, Radiometer, Siemens, Ortho Diagnostics, Spinship, and LuminaRx; and support for attending meetings and/or travel from the American Association for Clinical Chemistry. Dr Dahl reporting receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Grifols and Ciesi to himself and support for attending ERS Congress 2022 from Grifols.

Background: The influence of age on cardiac troponin is unclear and may vary between cardiac troponin T (cTnT) and I (cTnI). We aimed to compare the impact of age on the diagnostic and prognostic utility of cTnT and cTnI., Methods: This Danish nationwide, register-based cohort study included patients with at least one cardiac troponin (cTn) measurement from 2009 through June 2022, stratified into decades of age. We used peak cTn concentration during admission, dichotomized as positive/negative and normalized to the 99th percentile. Receiver operating characteristics for myocardial infarction (MI) and logistic regression were used to estimate the odds ratio (OR) for mortality at 1 year., Results: We included 541 817 patients; median age 66 years (interquartile range [IQR] 51-77) and 256 545 (47%) female. A total of 40 359 (7.4%) had an MI, and 59 800 (14.1%) patients died within 1 year of admission. The predictive ability of both cTns for MI were highest for patients 30 to 50 years. This was most pronounced for cTnT, the specificity of which fell from 83% among patients 40 to 49 years to 4% for patients ≥90 years. The prognostic ability of both cTns for 1-year mortality declined with age. cTnT had stronger prognostic ability for all age-groups; OR for a positive cTnT 28.4 (95% CI, 20.1-41.0) compared with 9.4 (95% CI, 5.0-16.7) for cTnI among patients <30 years., Conclusions: The predictive and prognostic ability of cTnT and cTnI declined with age. cTnT had a low specificity for MI in elderly patients. However, cTnT was the strongest prognostic marker among all age groups., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In SOT recipients previously vaccinated with at least three doses of BNT162b2, we investigated humoral responses to BNT162b2 booster doses. Anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) was measured using an in-house ELISA. Linear mixed models were fitted to investigate the change in the geometric mean concentration (GMC) of anti-SARS-CoV-2 RBD IgG after vaccination in participants with intervals of more or less than six months between the last two doses of vaccine. We included 107 SOT recipients vaccinated with a BNT162b2 vaccine. In participants with an interval of more than six months between the last two vaccine doses, we found a 1.34-fold change in GMC per month (95% CI 1.25-1.44), while we found a 1.09-fold change in GMC per month (95% CI 0.89-1.34) in participants with an interval of less than six months between the last two vaccine doses, resulting in a rate ratio of 0.82 (95% CI 0.66 to 1.01, p = 0.063). In conclusion, the administration of identical COVID-19 mRNA vaccine boosters within six months to SOT recipients may result in limited humoral immunogenicity of the last dose.

Background: Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice., Methods: This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds., Conclusions: The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Abstract: Diastolic dysfunction (DD) in heart failure is associated with increased myocardial cytosolic calcium and calcium-efflux through the sodium-calcium exchanger depends on the sodium gradient. Beta-3-adrenoceptor (β3-AR) agonists lower cytosolic sodium and have reversed organ congestion. Accordingly, β3-AR agonists might improve diastolic function, which we aimed to assess. In a first-in-man, randomized, double-blinded trial, we assigned 70 patients with HF with reduced ejection fraction, New York Heart Association II-III, and left ventricular ejection fraction <40% to receive the β3-AR agonist mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended heart failure therapy. We performed echocardiography and cardiac computed tomography and measured N-terminal probrain natriuretic peptide at baseline and follow-up. DD was graded per multiple renowned algorithms. Baseline and follow-up data were available in 57 patients (59 ± 11 years, 88% male, 49% ischemic heart disease). No clinically significant changes in diastolic measurements were found within or between the groups by echocardiography (E/e' placebo: 13 ± 7 to 13 ± 5, P = 0.21 vs. mirabegron: 12 ± 6 to 13 ± 8, P = 0.74, between-group follow-up difference 0.2 [95% CI, -3 to 4], P = 0.89) or cardiac computed tomography (left atrial volume index: between-group follow-up difference 9 mL/m 2 [95% CI, -3 to 19], P = 0.15). DD gradings did not change within or between the groups following 2 algorithms ( P = 0.72, P = 0.75). N-terminal probrain natriuretic peptide remained unchanged in both the groups ( P = 0.74, P = 0.64). In patients with HF with reduced ejection fraction, no changes were identified in diastolic measurements, gradings or biomarker after β3-AR stimulation compared with placebo. The findings add to the previous literature questioning the role of impaired Na + -Ca 2+ -mediated calcium export as a major culprit in DD. NCT01876433., Competing Interests: H. Bundgaard and H. Rasmussen are named inventors on a patent owned by Royal North Shore Hospital and the University of Sydney for the use of 𝛽3-AR agonists to treat heart failure. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: In the Partial Oral Treatment of Endocarditis (POET) trial, stabilized patients with left-sided infective endocarditis (IE) were randomized to oral step-down antibiotic therapy (PO) or conventional continued intravenous antibiotic treatment (IV), showing non-inferiority after 6 months. In this study, the first guideline-driven clinical implementation of the oral step-down POET regimen was examined., Methods: Patients with IE, caused by Staphylococcus aureus, Enterococcus faecalis, Streptococcus spp. or coagulase-negative staphylococci diagnosed between May 2019 and December 2020 were possible candidates for initiation of oral step-down antibiotic therapy, at the discretion of the treating physician. The composite primary outcome in patients finalizing antibiotic treatment consisted of embolic events, unplanned cardiac surgery, relapse of bacteraemia and all-cause mortality within 6 months., Results: A total of 562 patients [median age 74 years (IQR, interquartile range, 65-80), 70% males] with IE were possible candidates; PO was given to 240 (43%) patients and IV to 322 (57%) patients. More patients in the IV group had IE caused by S. aureus, or had an intra-cardiac abscess, or a pacemaker and more were surgically treated. The primary outcome occurred in 30 (13%) patients in the PO group and in 59 (18%) patients in the IV group (P = .051); in the PO group, 20 (8%) patients died vs. 46 (14%) patients in the IV group (P = .024). PO-treated patients had a shorter median length of stay [PO 24 days (IQR 17-36) vs. IV 43 days (IQR 32-51), P < .001]., Conclusions: After clinical implementation of the POET regimen almost half of the possible candidates with IE received oral step-down antibiotic therapy. Patients in the IV group had more serious risk factors for negative outcomes. At 6-month follow-up, there was a numerically but not statistically significant difference towards a lower incidence of the primary outcome, a lower incidence of all-cause mortality and a reduced length of stay in the PO group. Due to the observational design of the study, the lower mortality may to some extent reflect selection bias and unmeasured confounding. Clinical implementation of PO regimens seemed feasible and safe., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To accommodate waning COVID-19 vaccine immunity to emerging SARS-CoV-2 variants, variant-adapted mRNA vaccines have been introduced. Here, we examine serological responses to the BA.1 and BA.4-5 Omicron variant-adapted BNT162b2 COVID-19 vaccines in people with lymphoid malignancies. We included 233 patients with lymphoid malignancies (chronic lymphocytic B-cell leukemia: 73 (31.3%), lymphoma: 89 (38.2%), multiple myeloma/amyloidosis: 71 (30.5%)), who received an Omicron-adapted mRNA-based COVID-19 vaccine. IgG and neutralizing antibodies specific for the receptor-binding domain (RBD) of SARS-CoV-2 were measured using ELISA-based methods. Differences in antibody concentrations and neutralizing capacity and associations with risk factors were assessed using mixed-effects models. Over the period of vaccination with an Omicron-adapted COVID-19 vaccine, the predicted mean concentration of anti-RBD IgG increased by 0.09 log10 AU/mL/month (95% CI: 0.07; 0.11) in patients with lymphoid malignancies across diagnoses. The predicted mean neutralizing capacity increased by 0.9 percent points/month (95% CI: 0.2; 1.6). We found no associations between the increase in antibody concentration or neutralizing capacity and the variant included in the adapted vaccine. In conclusion, a discrete increase in antibody concentrations and neutralizing capacity was found over the course of Omicron-adapted vaccination in patients with lymphoid malignancies regardless of the adapted vaccine variant, indicating a beneficial effect of Omicron-adapted booster vaccination in this population.

We investigated the humoral response to the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine in patients with myasthenia gravis on or off immunosuppressants and compared this to the response in healthy individuals. The SARS-CoV-2 IgG response and neutralizing capacity were measured in 83 patients (57 on immunosuppressants) and 332 healthy controls at baseline, three weeks, and two and six months after the vaccine. We found that the proportion of positive humoral response was lower in patients on immunosuppressants vs. controls at three weeks and two months (p ≤ 0.001), but not at six months post-vaccination (p = 0.379)., Competing Interests: Declaration of Competing Interest The authors report no financial disclosures or conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Patients triaged as non-urgent in the emergency department constitute a diverse group with a low mortality rate assumed to be able to wait three hours for a physician. Little is known about the causes of death of non-urgent patients who die shortly after admission. We examined whether deaths among non-urgent patients were preventable., Method: Using data from the Copenhagen Triage Algorithm Study, we conducted a review of electronic medical records of all patients triaged as non-urgent who died within 30 days of presentation and constructed short summaries. These summaries were reviewed by two senior physicians who determined whether each death was expected or unexpected. The unexpected deaths were further assessed as unrelated or related to admission and if related as preventable or unpreventable. Any disagreements were settled by a third senior physician., Results: Among the patients triaged as non-urgent, 335 of 14,655 (2%) died within 30 days. When comparing biomarkers and age, the non-urgent patients resembled the patients in other triage categories who died within 30 days. Most deaths were expected or not preventable (96%). The preventable deaths (n = 13, 4%) were among older patients with comorbidities. Causes of death were sudden cardiac arrest (n = 3), infection (n = 4), kidney failure (n = 1), electrolyte derangement (n = 1) and unknown (n = 4)., Conclusion: Preventable deaths among non-urgent patients were rare and no overrepresentation was observed of specialties or diseases., Funding: Trygfonden., Clinicaltrials: gov:NCT02698319., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

The heterogeneity of the SARS-CoV-2 immune responses has become considerably more complex over time and diverse immune imprinting is observed in vaccinated individuals. Despite vaccination, following the emergence of the Omicron variant, some individuals appear more susceptible to primary infections and reinfections than others, underscoring the need to elucidate how immune responses are influenced by previous infections and vaccination. IgG, IgA, neutralizing antibodies and T-cell immune responses in 1,325 individuals (955 of which were infection-naive) were investigated before and after three doses of the BNT162b2 vaccine, examining their relation to breakthrough infections and immune imprinting in the context of Omicron. Our study shows that both humoral and cellular responses following vaccination were generally higher after SARS-CoV-2 infection compared to infection-naive. Notably, viral exposure before vaccination was crucial to achieving a robust IgA response. Individuals with lower IgG, IgA, and neutralizing antibody responses postvaccination had a significantly higher risk of reinfection and future Omicron infections. This was not observed for T-cell responses. A primary infection before Omicron and subsequent reinfection with Omicron dampened the humoral and cellular responses compared to a primary Omicron infection, consistent with immune imprinting. These results underscore the significant impact of hybrid immunity for immune responses in general, particularly for IgA responses even after revaccination, and the importance of robust humoral responses in preventing future infections., (© 2023. Springer Nature Limited.)

Objectives: End-stage renal disease is associated with a high risk of cardiovascular disease. We compared the concentration and prognostic ability of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) and cardiac myosin-binding protein C (cMyC) among stable hemodialysis patients., Methods: Patients were sampled before and after hemodialysis. We measured hs-cTnI, hs-cTnT and cMyC and used Cox regressions to assess the association between quartiles of concentrations and all-cause mortality and a combination of cardiovascular events and all-cause mortality during follow-up., Results: A total of 307 patients were included, 204 males, mean age 66 years (SD 14). Before dialysis, 299 (99 %) had a hs-cTnT concentration above the 99th percentile, compared to 188 (66 %) for cMyC and 35 (11 %) for hs-cTnI. Hs-cTnT (23 %, p<0.001) and hs-cTnI (15 %, p=0.049) but not cMyC (4 %, p=0.256) decreased during dialysis. Follow-up was a median of 924 days (492-957 days); patients in the 3rd and 4th quartiles of hs-cTnT (3rd:HR 3.0, 95 % CI 1.5-5.8, 4th:5.2, 2.7-9.8) and the 4th quartile of hs-cTnI (HR 3.8, 2.2-6.8) had an increased risk of mortality. Both were associated with an increased risk of the combined endpoint for patients in the 3rd and 4th quartiles. cMyC concentrations were not associated with risk of mortality or cardiovascular event., Conclusions: Hs-cTnT was above the 99th percentile in almost all patients. This was less frequent for hs-cTnI and cMyC. High cTn levels were associated with a 3-5-fold higher mortality. This association was not present for cMyC. These findings are important for management of hemodialysis patients., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Initial responses to coronavirus disease 2019 vaccination are impaired in patients with hematological malignancies. We investigated immune responses after three or four doses of BNT162b2 in patients with myeloid and lymphoid malignancies compared to controls, and identified risk factors for humoral and cellular nonresponse 1 year after first vaccination., Methods: In 407 hematological patients (45 myeloid, 362 lymphoid) and 98 matched controls, we measured immunoglobulin G (IgG) and neutralizing antibodies specific for the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline, 3 weeks, 2, 6, and 12 months, and interferon-γ release at 12 months., Results: In patients with lymphoid malignancies, SARS-CoV-2 receptor-binding domain IgG concentration and mean neutralizing capacity was lower than in controls at all time points. A diagnosis of chronic lymphocytic B-cell leukemia (CLL) or lymphoma was associated with humoral nonresponse at 12 months compared to having multiple myeloma/amyloidosis (p < .001 and p = .013). Compared to controls, patients with lymphoid malignancies had increased risk of cellular nonresponse. A lymphoma diagnosis was associated with lower risk of cellular nonresponse compared to patients with multiple myeloma/amyloidosis, while patients with CLL had comparable response rates to patients with multiple myeloma/amyloidosis (p = .037 and p = .280)., Conclusions: In conclusion, long-term humoral and cellular immune responses to BNT162b2 were impaired in patients with lymphoid malignancies., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: We investigated long-term durability of humoral and cellular immune responses to third dose of BNT162b2 in people with HIV (PWH) and controls., Methods: In 378 PWH with undetectable viral replication and 224 matched controls vaccinated with three doses of BNT162b2, we measured IgG-antibodies against the receptor binding domain of SARS-CoV-2 spike protein three months before third dose of BNT162b2, and four and eleven months after. In 178 PWH and 135 controls, the cellular response was assessed by interferon-γ (IFN-γ) release in whole blood four months after third dose. Differences in antibody or IFN-γ concentrations were assessed by uni- and multivariable linear regressions., Findings: Before the third dose the concentration of SARS-CoV-2 antibodies was lower in PWH than in controls (unadjusted geometric mean ratio (GMR): 0.68 (95% CI: 0.54-0.86, p = 0.002). We observed no differences in antibody concentrations between PWH and controls after four (0.90 (95% CI: 0.75-1.09), p = 0.285) or eleven months (0.89 (95% CI: 0.69-1.14), p = 0.346) after the third dose. We found no difference in IFN-γ concentrations four months after the third dose between PWH and controls (1.06 (95% CI: 0.71-1.60), p = 0.767)., Interpretation: We found no differences in antibody concentrations or cellular response between PWH and controls up to eleven months after third dose of BNT162b2. Our findings indicate that PWH with undetectable viral replication and controls have comparable immune responses to three doses of the BNT162b2 vaccine., Funding: This work was funded by the Novo Nordisk Foundation (NFF205A0063505, NNF20SA0064201), the Carlsberg Foundation (CF20-476 0045), the Svend Andersen Research Foundation (SARF2021), and Bio- and Genome Bank Denmark., Competing Interests: Declaration of interests LDH, LP-A, RBH, CBH, SRH, DLM, KF, JG, KG, SRO, RF-S, ES, LH, PG, and KI declare no conflicts of interests concerning this manuscript. MP-H has received travel grants from the Augustinus Foundation, the William Demant Foundation, the Copenhagen University Research Foundation, and Familien Hede Nielsen’s Foundation. MP-H has further received an independent research grant form Dagmar Marshall’s Foundation. HB has received an unrestricted grant from Kirsten and Freddy Johannsen’s Fund. CS has received honoraria from Gilead, ViiV Healthcare, and MSD, and was vice-chair of the British HIV Association. SDN has received unrestricted grants from the Novo Nordisk Foundation, and Dr. Sofus Carl Emil Friis and Wife Olga Doris Friis Scholarship. SDN has further received honoraria from Gilead and MSD and has served on advisory boards for Gilead, MSD, and GSK., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

With the increased sensitivity of the newest cardiac troponin assays, the risk of false positive cardiac troponin measurements has also increased. As summarised in this review, there are multiple possible causes of cardiac troponin release including several non-cardiac illnesses, particularly kidney disease. Further, there is a risk of analytical interference in which case repeated measurements with a different assay is a good tool. When there is a discrepancy between troponin measurement and clinical presentation of the patient, the clinician should consider the possibility of analytical interference.

Background: mRNA-based COVID-19 vaccines have short- and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied., Objectives: To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy., Methods: A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike glycoprotein-specific IgG and IgA, neutralizing capacity, and interferon-γ release from T cells stimulated with peptides of the SARS-CoV-2 spike glycoprotein., Results: The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-tumour necrosis factor (TNF) treatment compared with controls. Anti-TNF treatment was associated with lower IgG levels (β = -0.82, 95% confidence interval -1.38 to -0.25; P = 0.001). The median neutralizing index was lower in the anti-TNF group [50% inhibition (interquartile range [IQR] 37-89)] compared with controls [98% inhibition (IQR 96-99)]; P < 0.001. Cellular responses were numerically lowest in the anti-TNF group., Conclusions: Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity; however, the clinical implications are unknown., Competing Interests: Conflicts of interest H.B. has received lecture fees from Amgen, BMS, MSD and Sanofi-Avensis. C.Z. has been a scientific consultant, advisor, investigator and speaker for AbbVie, Almirall, Amgen, CSL, Eli Lilly, Janssen Cilag, LEO Pharma, MSD, Novartis, Regeneron, Takeda and UCB. L.S. has been a paid speaker for AbbVie, Eli Lilly and LEO Pharma, and has been a consultant or served on advisory boards with AbbVie, Admirall, Eli Lilly, Janssen Cilag, LEO Pharma, Novartis, Sanofi and UCB. She has served as an investigator for AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen Cilag, LEO Pharma, Novartis and Regeneron, and received research and educational grants from AbbVie, Janssen Cilag, LEO Pharma Novartis, Pfizer and Sanofi. A.K.-H., L.P.-A., R.F.A.-S., L.D.H., S.R.H., D.L.M., M.M.P.-H., K.F., C.B.H., R.B.H., J.R.M., J.J.A.A., R.F.-S., L.H., E.S., S.R.O., S.D.N., K.I. and P.G. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Diagnosing myocardial infarction is difficult during the initial phase. As, acute myocardial ischemia is associated with changes in metabolic pathways, metabolomics may provide ways of identifying early stages of ischemia. We investigated the changes in metabolites after induced ischemia in humans using nuclear magnetic resonance spectroscopy (NMR)., Methods: We included patients undergoing elective coronary angiography showing normal coronary arteries. These were randomized into 4 groups and underwent coronary artery occlusion for 0, 30, 60 or 90 s. Blood was collected over the next 3 h and analyzed using NMR. We used 2-way ANOVA of time from baseline- and treatment group to find metabolites that changed significantly following the intervention and principal component analysis (PCA) to investigate changes between the 90 s ischemia- and control groups at 15 and 60 min after intervention., Results: We included 34 patients. The most pronounced changes were observed in the lipid metabolism where 38 of 112 lipoprotein parameters (34%) showed a significant difference between the patients exposed to ischemia and the control group. There was a decrease in total plasma triglycerides over the first hour followed by a normalization. The principal component analysis showed a effects of the treatment after just 15 min. These effects were dominated by changes in high-density lipoprotein. An increase in lactic acid levels was detected surprisingly late, 1-2 h after the ischemia., Conclusion: We investigated the earliest changes in metabolites of patients undergoing brief myocardial ischemia and found that ischemia led to changes throughout the lipid metabolism as early as 15 min post-intervention., (© 2023. The Author(s).)

Knowledge about the effect of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on immunity reflected in the saliva is sparse. We examined the antibody response in saliva compared to that in serum 2 and 6 months after the first vaccination with the BNT162b2 vaccine. Four hundred fifty-nine health care professionals were included in a prospective observational study measuring antibody levels in saliva and corresponding serum samples at 2 and 6 months after BNT162b2 vaccination. Vaccinated, previously SARS-CoV-2-infected individuals (hybrid immunity) had higher IgG levels in saliva at 2 months than vaccinated, infection-naive individuals ( P  < 0.001). After 6 months, saliva IgG levels declined in both groups ( P  < 0.001), with no difference between groups ( P  = 0.37). Furthermore, serum IgG levels declined from 2 to 6 months in both groups ( P  < 0.001). IgG antibodies in saliva and serum correlated in individuals with hybrid immunity at 2 and 6 months (ρ = 0.58, P  = 0.001, and ρ = 0.53, P  = 0.052, respectively). In vaccinated, infection-naive individuals, a correlation was observed at 2 months (ρ = 0.42, P  < 0.001) but not after 6 months (ρ = 0.14, P  = 0.055). IgA and IgM antibodies were hardly detectable in saliva at any time point, regardless of previous infection. In serum, IgA was detected at 2 months in previously infected individuals. BNT162b2 vaccination induced a detectable IgG anti-SARS-CoV-2 RBD response in saliva at both 2 and 6 months after vaccination, being more prominent in previously infected than infection-naive individuals. However, a significant decrease in salivary IgG was observed after 6 months, suggesting a rapid decline in antibody-mediated saliva immunity against SARS-CoV-2, after both infection and systemic vaccination. IMPORTANCE Knowledge about the persistence of salivary immunity after SARS-CoV-2 vaccination is limited, and information on this topic could prove important for vaccine strategy and development. We hypothesized that salivary immunity would wane rapidly after vaccination. We measured anti-SARS-CoV-2 IgG, IgA, and IgM concentrations in saliva and serum in both previously infected and infection-naive individuals, 2 and 6 months after first vaccination with BNT162b2, in 459 hospital employees from Copenhagen University Hospital. We observed that IgG was the primary salivary antibody 2 months after vaccination in both previously infected and infection-naive individuals, but dropped significantly after 6 months. Neither IgA nor IgM was detectable in saliva at either time point. Findings indicate that salivary immunity against SARS-CoV-2 rapidly declines following vaccination in both previously infected and infection-naive individuals. We believe this study shines a light on the workings of salivary immunity after SARS-CoV-2 infection, which could prove relevant for vaccine development.

Introduction: We investigated humoral and T-cell responses within 12 months after first BNT162b2 vaccine in solid organ transplant (SOT) recipients and controls who had received at least three vaccine doses. Furthermore, we compared the immune response in participants with and without previous SARS-CoV-2 infection., Methods: We included adult liver, lung, and kidney transplant recipients, and controls were selected from a parallel cohort of healthcare workers., Results: At 12th-month, the IgG geometric mean concentrations (GMCs) (P<0.001), IgA GMCs (P=0.003), and median IFN-γ (P<0.001) were lower in SOT recipients than in controls. However, in SOT recipients and controls with previous infection, the neutralizing index was 99%, and the IgG, and IgA responses were comparable. After adjustment, female-sex (aOR: 3.6, P<0.009), kidney (aOR: 7.0, P= 0.008) or lung transplantation (aOR: 7.5, P= 0.014), and use of mycophenolate (aOR: 5.2, P=0.03) were associated with low IgG non response. Age (OR:1.4, P=0.038), time from transplantation to first vaccine (OR: 0.45, P<0.035), and previous SARS-CoV-2 infection (OR: 0.14, P<0.001), were associated with low IgA non response. Diabetes (OR:2.4, P=0.044) was associated with T-cell non response., Conclusion: In conclusion, humoral and T-cell responses were inferior in SOT recipients without previous SARS-CoV-2 infection but comparable to controls in SOT recipients with previous infection., Competing Interests: OR received a grant from Rigshospitalet related to this work, and a grant from AP Møller Fonden not related to this work. MP received a grant from Roche, non-financial support from Boehringer Ingelheim, personal fees from Mallinckrodt, Novartis, GSK, and Astra-Zeneca not related to this work. ZH received a grant from Independent Research Fund. SS reported other non-financial relations with Alexion, Hansa Biopharma, and Corline Biomedical, outside the submitted work. PG received grants from The Carlsberg Foundation, the Novo Nordisk Foundation and the Svend Andersen Foundation related to this work. SN received unrestricted research grants from Novo Nordisk Foundation and Independent Research Fund. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rezahosseini, Hamm, Heftdal, Pérez-Alós, Møller, Perch, Madsen, Hald, Hansen, Armenteros, Pries-Heje, Hasselbalch, Fogh, Frikke-Schmidt, Hilsted, Sørensen, Ostrowski, Harboe, Iversen, Bundgaard, Sørensen, Rasmussen, Garred and Nielsen.)

Background: Coronavirus disease 2019 (COVID-19) vaccines are implemented worldwide in efforts to curb the pandemic. This study investigates the risk of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction (RT-PCR) test following BNT162b2 vaccination in a large real-life population in Denmark., Methods: Vaccination status and positive SARS-CoV-2 RT-PCR results from adults in the Capital Region of Denmark (n = 1 549 488) were obtained from national registries. PCR testing was free and widely available. The number of positive PCR tests per individual at risk was calculated as weekly rates. Time to positive PCR test was modelled using Kaplan-Meier methods and hazard ratios (HRs) were calculated using Cox regression., Results: A total of 1 119 574 individuals received the first dose of BNT162b2 and 1 088 879 received a second dose of BNT162b2. Individuals were followed up to 8.7 months after first dose (median: 5.5 months; interquartile ratio: 4.1-8.7). Rates of PCR-confirmed SARS-CoV-2 infection 2-4 months after the second dose were 0.21, 0.33, and 0.36 per 1000 individuals per week at risk for July, August, and September, respectively. Four or more months after the second dose, the rates were 0.56, 0.76, and 0.53 per 1000 individuals per week at risk for July, August, and September, respectively. HR of SARS-CoV-2 infection after the second dose was 0.2 (95% confidence interval, .05-.48; P = .001) for individuals with 8 months' follow-up., Conclusions: Individuals who received 2 doses of the BNT162b2 COVID-19 vaccine had a low risk of breakthrough infection after up to 8 months of follow-up. However, there was a tendency toward higher rates with longer follow-up., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Responses to COVID-19 vaccination in patients with chronic pulmonary diseases are poorly characterised. We aimed to describe humoral responses following two doses of BNT162b2 mRNA COVID-19 vaccine and identify risk factors for impaired responses., Methods: Prospective cohort study including adults with chronic pulmonary diseases and healthcare personnel as controls (1:1). Blood was sampled at inclusion, 3 weeks, 2 and 6 months after first vaccination. We reported antibody concentrations as geometric means with 95% CI of receptor binding domain (RBD)-IgG and neutralising antibody index of inhibition of ACE-2/RBD interaction (%). A low responder was defined as neutralising index in the lowest quartile (primary outcome) or RBD-IgG <225 AU/mL plus neutralising index <25% (secondary outcome), measured at 2 months. We tested associations using Poisson regression., Results: We included 593 patients and 593 controls, 75% of all had neutralising index ≥97% at 2 months. For the primary outcome, 34.7% of patients (n=157/453) and 12.9% of controls (n=46/359) were low responders (p<0.0001). For the secondary outcome, 8.6% of patients (n=39/453) and 1.4% of controls (n=5/359) were low responders (p<0.001). Risk factors associated with low responder included increasing age (per decade, adjusted risk ratio (aRR) 1.17, 95% CI 1.03 to 1.32), Charlson Comorbidity Index (per point) (aRR 1.15, 95% CI 1.05 to 1.26), use of prednisolone (aRR 2.08, 95% CI 1.55 to 2.77) and other immunosuppressives (aRR 2.21, 95% CI 1.65 to 2.97)., Discussion: Patients with chronic pulmonary diseases established functional humoral responses to vaccination, however lower than controls. Age, comorbidities and immunosuppression were associated with poor immunological responses., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess the prevalence and severity of anaemia in patients with left-sided infective endocarditis (IE) and association with mortality., Methods: In the Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis trial, 400 patients with IE were randomised to conventional or partial oral antibiotic treatment after stabilisation of infection, showing non-inferiority. Haemoglobin (Hgb) levels were measured at randomisation. Primary outcomes were all-cause mortality after 6 months and 3 years. Patients who underwent valve surgery were excluded due to competing reasons for anaemia., Results: Out of 400 patients with IE, 248 (mean age 70.6 years (SD 11.1), 62 women (25.0%)) were medically managed; 37 (14.9%) patients had no anaemia, 139 (56.1%) had mild anaemia (Hgb <8.1 mmol/L in men and Hgb <7.5 mmol/L in women and Hgb ≥6.2 mmol/L) and 72 (29.0%) had moderate to severe anaemia (Hgb <6.2 mmol/L). Mortality rates in patients with no anaemia, mild anaemia and moderate to severe anaemia were 2.7%, 3.6% and 15.3% at 6-month follow-up and 13.5%, 20.1% and 34.7% at 3-year follow-up, respectively. Moderate to severe anaemia was associated with higher mortality after 6 months (HR 4.81, 95% CI 1.78 to 13.0, p=0.002) and after 3 years (HR 2.14, 95% CI 1.27 to 3.60, p=0.004) and remained significant after multivariable adjustment., Conclusion: Moderate to severe anaemia was present in 29% of patients with medically treated IE after stabilisation of infection and was independently associated with higher mortality within the following 3 years. Further investigations are warranted to determine whether intensified treatment of anaemia in patients with IE might improve outcome., Competing Interests: Competing interests: LK received speaker’s honorarium from Novo, Novartis, AstraZeneca and Boehringer, unrelated to this study. NEB received investigator-initiated grant from the Novo Nordisk Foundation and from the Region of Zealand, not related to this study. ELF has received independent research grant from Novo Nordisk Foundation, unrelated to this study. The other authors have nothing to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are a key factor in protecting against coronavirus disease 2019 (COVID-19). We examined longitudinal changes in seroprevalence in healthcare workers (HCWs) in Copenhagen and the protective effect of antibodies against SARS-CoV-2., Methods: In this prospective study, screening for antibodies against SARS-CoV-2 (ELISA) was offered to HCWs three times over 6 months. HCW characteristics were obtained by questionnaires. The study was registered at ClinicalTrials.gov, NCT04346186., Results: From April to October 2020 we screened 44 698 HCWs, of whom 2811 were seropositive at least once. The seroprevalence increased from 4.0% (1501/37 452) to 7.4% (2022/27 457) during the period (p < 0.001) and was significantly higher than in non-HCWs. Frontline HCWs had a significantly increased risk of seropositivity compared to non-frontline HCWs, with risk ratios (RRs) at the three rounds of 1.49 (95%CI 1.34-1.65, p < 0.001), 1.52 (1.39-1.68, p < 0.001) and 1.50 (1.38-1.64, p < 0.001). The seroprevalence was 1.42- to 2.25-fold higher (p < 0.001) in HCWs from dedicated COVID-19 wards than in other frontline HCWs. Seropositive HCWs had an RR of 0.35 (0.15-0.85, p 0.012) of reinfection during the following 6 months, and 2115 out of 2248 (95%) of those who were seropositive during rounds one or two remained seropositive after 4-6 months. The 133 of 2248 participants (5.0%) who seroreverted were slightly older and reported fewer symptoms than other seropositive participants., Conclusions: HCWs remained at increased risk of infection with SARS-CoV-2 during the 6-month period. Seropositivity against SARS-CoV-2 persisted for at least 6 months in the vast majority of HCWs and was associated with a significantly lower risk of reinfection., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: Cardiac troponin (cTn) is the biochemical gold standard for diagnosing myocardial infarction (MI). We compared the Siemens ADVIA Centaur High-Sensitivity (hs-cTnI) assay with the Siemens Ultra assay (cTnI-U)., Methods: Over 3 months cTnI-U and hs-cTnI were measured simultaneously at Herlev-Gentofte Hospital. Acute myocardial injury was diagnosed using the 4th universal definition. Disputed cases were adjudicated using clinical data. We compared diagnostic accuracy using area under the curve (AUC) of the receiver operating characteristic. Outliers in between-assay differences were defined as a factor-5 difference and ≥1 measurement >40 ng/L. Patients with outlier differences were invited for re-sampling and tested with serial dilution and heterophilic blocking tubes., Results: From the 18th January to the 20th April 2019, 4,369 samples on 2,658 patients were included. cTnI-U measured higher concentrations than hs-cTnI (mean 23%, -52-213%), resulting in a higher frequency of acute myocardial injury, 255 (9.6%) vs. 203 (7.6%), p<0.001. This remained significant after adjudication, 212 vs 197, p<0.001. AUC for the prediction of MI for was 0.963 for cTnI-U and 0.959 for hs-cTnI, p=0.001. Outlier differences were seen in 35 (1.2%) patients, primarily with elevated hs-cTnI (n=33, 94%). On two re-samplings (median 144 and 297 days since inclusion), 16 of 20 (80%) and 11 of 11 had sustained elevation of hs-cTnI. The samples showed no signs of heterophilic antibodies., Conclusions: Using hs-cTnI resulted in a subset of patients with large, discrepant elevations in concentration. These patients still had elevated hs-cTnI 6-10 months post admission but no heterophilic antibodies., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: People with HIV (PWH) are at increased risk of severe COVID-19. We aimed to determine humoral responses in PWH and controls who received two doses of BNT162b2., Methods: In 269 PWH and 538 age-matched controls, we measured IgG and neutralizing antibodies specific for the receptor-binding domain of SARS-CoV-2 at baseline, 3 weeks and 2 months after the first dose of BNT162b2., Results: IgG antibodies increased from baseline to 3 weeks and from 3 weeks to 2 months in both groups, but the concentrations of IgG antibodies were lower in PWH than that in controls at 3 weeks and 2 months (p = 0.025 and <0.001), respectively. The IgG titres in PWH with a humoral response at 2 months were 77.9% (95% confidence interval [62.5%-97.0%], age- and sex-adjusted p = 0.027) of controls., Conclusions: Reduced IgG antibody response to vaccination with BNT162b2 was found in PWH, and thus increased awareness of breakthrough infections in PWH is needed., (© 2021 The Association for the Publication of the Journal of Internal Medicine.)

SARS-CoV-2 vaccines are crucial in controlling COVID-19, but knowledge of which factors determine waning immunity is limited. We examined antibody levels and T-cell gamma-interferon release after two doses of BNT162b2 vaccine or a combination of ChAdOx1-nCoV19 and BNT162b2 vaccines for up to 230 days after the first dose. Generalized mixed models with and without natural cubic splines were used to determine immunity over time. Antibody responses were influenced by natural infection, sex, and age. IgA only became significant in naturally infected. A one-year IgG projection suggested an initial two-phase response in those given the second dose delayed (ChAdOx1/BNT162b2) followed by a more rapid decrease of antibody levels. T-cell responses correlated significantly with IgG antibody responses. Our results indicate that IgG levels will drop at different rates depending on prior infection, age, sex, T-cell response, and the interval between vaccine injections. Only natural infection mounted a significant and lasting IgA response., (© 2022. The Author(s).)

Background: Previous studies have indicated inferior responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in solid organ transplant (SOT) recipients. We examined the development of anti-receptor-binding domain (RBD) immunoglobulin G (IgG) after two doses of BNT162b2b in SOT recipients 6 months after vaccination and compared to that of immunocompetent controls., Methods: We measured anti-RBD IgG after two doses of BNT162b2 in 200 SOT recipients and 200 matched healthy controls up to 6 months after first vaccination. Anti-RBD IgG concentration and neutralizing capacity of antibodies were measured at first and second doses of BNT162b2 and 2 and 6 months after the first dose. T-cell responses were measured 6 months after the first dose., Results: In SOT recipients, geometric mean concentration (GMC) of anti-RBD IgG increased from first to second dose (1.14 AU/ml, 95% CI 1.08-1.24 to 11.97 AU/ml, 95% CI 7.73-18.77) and from second dose to 2 months (249.29 AU/ml, 95% CI 153.70-385.19). Six months after the first vaccine, anti-RBD IgG declined (55.85 AU/ml, 95% CI 36.95-83.33). At all time points, anti-RBD IgG was lower in SOT recipients than that in controls. Fewer SOT recipients than controls had a cellular response (13.1% vs. 59.4%, p < 0.001). Risk factors associated with humoral non-response included age [relative risk (RR) 1.23 per 10-year increase, 95% CI 1.11-1.35, p < 0.001], being within 1 year from transplantation (RR 1.55, 95% CI 1.30-1.85, p < 0.001), treatment with mycophenolate (RR 1.54, 95% CI 1.09-2.18, p = 0.015), treatment with corticosteroids (RR 1.45, 95% CI 1.10-1.90, p = 0.009), kidney transplantation (RR 1.70, 95% CI 1.25-2.30, p = 0.001), lung transplantation (RR 1.63, 95% CI 1.16-2.29, p = 0.005), and de novo non-skin cancer comorbidity (RR 1.52, 95% CI, 1.26-1.82, p < 0.001)., Conclusion: Immune responses to BNT162b2 are inferior in SOT recipients compared to healthy controls, and studies aiming to determine the clinical impact of inferior vaccine responses are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hamm, Møller, Pérez-Alós, Hansen, Pries-Heje, Heftdal, Hasselbalch, Fogh, Madsen, Almagro Armenteros, Knudsen, Poulsen, Frikke-Schmidt, Hilsted, Sørensen, Ostrowski, Harboe, Perch, Sørensen, Rasmussen, Bundgaard, Garred, Iversen and Nielsen.)

Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but being seronegative is observed in 1 to 9%. We aimed to investigate the risk factors associated with being seronegative following PCR-confirmed SARS-CoV-2 infection. In a prospective cohort study, we screened health care workers (HCW) in the Capital Region of Denmark for SARS-CoV-2 antibodies. We performed three rounds of screening from April to October 2020 using an enzyme-linked immunosorbent assay (ELISA) method targeting SARS-CoV-2 total antibodies. Data on all participants' PCR for SARS-CoV-2 RNA were captured from national registries. The Kaplan-Meier method and Cox proportional hazards models were applied to investigate the probability of being seronegative and the related risk factors, respectively. Of 36,583 HCW, 866 (2.4%) had a positive PCR before or during the study period. The median (interquartile range [IQR]) age of 866 HCW was 42 (31 to 53) years, and 666 (77%) were female. After a median of 132 (range, 35 to 180) days, 21 (2.4%) of 866 were seronegative. In a multivariable model, independent risk factors for being seronegative were self-reported asymptomatic or mild infection hazard ratio (HR) of 6.6 (95% confidence interval [CI], 2.6 to 17; P < 0.001) and body mass index (BMI) of ≥30, HR 3.1 (95% CI, 1.1 to 8.8; P = 0.039). Only a few (2.4%) HCW were not seropositive. Asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges. IMPORTANCE Most individuals seroconvert after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but negative serology is observed in 1 to 9%. We found that asymptomatic or mild infection as well as a BMI above 30 were associated with being seronegative. Since the presence of antibodies against SARS-CoV-2 reduces the risk of reinfection, efforts to protect HCW with risk factors for being seronegative may be needed in future COVID-19 surges.

Background: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic biomarker in cardiovascular disease but there is limited data for its use among patients undergoing dialysis., Methods: This was a cohort study of patients receiving maintenance hemodialysis from two Danish centers. Blood sampling and echocardiography were performed before and after a dialysis session. We calculated the area under the curve (AUC) for the receiver operating characteristics for diagnosing heart failure and Cox regressions for cardiovascular events and all-cause mortality., Results: Of the 306 patients, 284 (93%) had MR-proANP measurements both before and after dialysis. Median concentration was 642 pmol/L (IQR 419-858) before and 351 pmol/L (IQR 197-537) after dialysis, a mean decrease of 330 pmol/L (43%, CI 296-364, P < 0.001). MR-proANP concentration both before and after dialysis was negatively correlated to left ventricular ejection fraction with no difference in predictive ability for heart failure, AUC before and after dialysis were 0.60 (CI 0.50-0.70) and 0.61 (CI 0.51-0.71) (P = 0.40). Median follow-up was 32 months (IQR 31-33), during which 99 patients (32%) had a cardiovascular event and 110 (36%) died. A doubling of MR-proANP concentration was associated with a hazard ratio (HR) of 1.6 (CI 1.3-1.9) before and 1.7 (CI 1.4-2.0) after dialysis for mortality and a HR of 1.5 (CI 1.2-1.9) before and 1.4 (CI 1.2-1.7) after dialysis for cardiovascular events (all P < 0.001)., Conclusion: The MR-proANP concentration is elevated among patients undergoing hemodialysis and decreases during dialysis. MR-proANP concentration both before, after and intra-dialysis change strongly predicted cardiovascular events and all-cause mortality., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: To prospectively validate the CT-Valve score, a new risk score designed to identify patients with valvular heart disease at a low risk of coronary artery disease (CAD) who could benefit from multislice CT (MSCT) first instead of coronary angiography (CAG)., Methods: This was a prospective cohort study of patients referred for valve surgery in the Capital Region of Denmark and Odense University Hospital from the 1 February 2015 to the 1 February 2017. MSCT was implemented for patients with a CT-Valve score ≤7 at the referring physician's discretion. Patients with a history of CAD or chronic kidney disease were excluded. The primary outcome was the proportion of patients needing reevaluation with CAG after MSCT and risk of CAD among the patients determined to be low to intermediate risk., Results: In total, 1149 patients were included. The median score was 9 (IQR 3) and 339 (30%) had a score ≤7. MSCT was used for 117 patients. Of these 29 (25%) were reevaluated and 9 (7.7%) had CAD. Of the 222 patients with a score ≤7 that did not receive an MSCT, 14 (6%) had significant CAD. The estimated total cost of evaluation among patients with a score ≤7 before implementation was €132 093 compared with €79 073 after, a 40% reduction. Similarly, estimated total radiation before and after was 608 mSv and 362 mSv, a 41% reduction. Follow-up at a median of 32 months (18-48) showed no ischaemic events for patients receiving only MSCT., Conclusion: The CT-Valve score is a valid method for determining risk of CAD among patients with valvular heart disease. Using a score ≤7 as a cut-off for the use of MSCT is safe and cost-effective., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The optimal antibiotic treatment length for infective endocarditis (IE) is uncertain. International guidelines recommend treatment duration of up to 6 weeks for patients with left-sided IE but are primarily based on historical data and expert opinion. Efficacies of modern therapies, fast recovery seen in many patients with IE, and complications to long hospital stays challenge the rationale for fixed treatment durations in all patients., Objective: The objective was to conduct a noninferiority randomized controlled trial (acronym POET II) investigating the safety of accelerated (shortened) antibiotic therapy as compared to standard duration in patients with left-sided IE., Methods: The POET II trial is a multicenter, multinational, open-label, noninferiority randomized controlled trial. Patients with definite left-sided IE due to Streptococcus spp, Staphylococcus aureus, or Enterococcus faecalis will be eligible for enrolment. Each patient will be randomized to accelerated antibiotic treatment or standard-length treatment (1:1) following clinical stabilization as defined by clinical parameters, laboratory values, and transesophageal echocardiography findings. Accelerated treatment will be between 2 and 4 weeks, whereas standard-length treatment will be between 4 and 6 weeks, depending on microbiologic etiology, complications, need for valve surgery, and prosthetic versus native valve endocarditis. The primary outcome is a composite of all-cause mortality, unplanned cardiac surgery, relapse of bacteremia, or embolization within 6 months of randomization., Conclusions: The POET II trial will investigate the safety of accelerated antibiotic therapy for patients with left-sided IE caused by Streptococcus spp, Staphylococcus aureus, or Enterococcus faecalis. The results of the POET II trial will improve the evidence base of treatment recommendations, and clinical practice may be altered., Competing Interests: Declaration of competing interest Robert Horvath has received sponsorship for symposia from MSD. The other authors have nothing to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Coronary artery disease (CAD) is frequent in patients with newly diagnosed heart failure (HF). Multislice CT (MSCT) is a non-invasive alternative to coronary angiography (CAG) suggested for patients with a low-to-intermediate risk of CAD. No established definition of such patients exists. Our purpose was to develop a simple score to identify as large a group as possible with a suitable pretest risk of CAD., Methods: Retrospective study of patients in Denmark undergoing CAG due to newly diagnosed HF from 2010 to 2014. All Danish patients were registered in two databases according to geographical location. We used data from one registry and multiple logistic regression with backwards elimination to find predictors of CAD and used the derived OR to develop a clinical risk score called the CT-HF score, which was subsequently validated in the other database., Results: The main cohort consisted of 2171 patients and the validation cohort consisted of 2795 patients with 24% and 27% of patients having significant CAD, respectively. Among significant predictor, the strongest was extracardiac arteriopathy (OR 2.84). Other significant factors were male sex, smoking, hyperlipidaemia, diabetes mellitus, angina and age. A proposed cut-off of 9 points identified 61% of patients with a 15% risk of having CAD, resulting in an estimated savings of 15% of the cost and 21% of the radiation., Conclusions: A simple score based on clinical risk factors could identify HF patients with a low risk of CAD; these patients may have benefitted from MSCT as a gatekeeper for CAG., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Older patients is a complex group at increased risk of adverse outcomes compared to younger patients, which should be considered in the risk assessment performed in emergency departments. We evaluated whether the predictive ability of different risk assessment models for acutely admitted patients is affected by age., Methods: Cohort study of middle-aged and older patients. We investigated the accuracy in discriminating between survivors and non-survivors within 7 days of different risk assessment models; a traditional triage algorithm, a triage algorithm with clinical assessment, vital signs, routine biomarkers, and the prognostic biomarker soluble urokinase plasminogen activator receptor (suPAR)., Results: The cohort included 22,653 (53.2%) middle-aged patients (age 40-69 years), and 19,889 (46.8%) older patients (aged 70+ years). Death within 7 days occurred in 139 patients (0.6%) in middle-aged patients and 596 (3.0%) of the older patients. The models based on vital signs and routine biomarkers had the highest area under the curve (AUC), and both were significantly better at discriminating 7-day mortality in middle-aged patients compared to older patients; AUC (95% CI): 0.88 (0.84-0.91), 0.75 (0.72-0.78), P < 0.01, and 0.86 (0.82-0.90), 0.76 (0.73-0.78), P < 0.001. In a subgroup of the total cohort (6.400 patients, 15.0%), the suPAR level was available. suPAR had the highest AUC of all individual predictors with no significant difference between the age groups, but further research in this biomarker is required before it can be used., Conclusion: The predictive value was lower in older patients compared to middle-aged patients for all investigated models. Vital signs or routine biomarkers constituted the best models for predicting 7-day mortality and were better than the traditional triage model. Hence, the current risk assessment for short-term mortality can be strengthened, but modifications for age should be considered when constructing new risk assessment models in the emergency department.

Introduction: Triage systems with limited room for clinical judgment are used by emergency departments (EDs) worldwide. The Copenhagen Triage Algorithm (CTA) is a simplified triage system with a clinical assessment., Methods: The trial was a non-inferiority, two-center cluster-randomized crossover study where CTA was compared to a local adaptation of Adaptive Process Triage (ADAPT). CTA involves initial categorization based on vital signs with a final modification based on clinical assessment by an ED nurse. We used 30-day mortality with a non-inferiority margin at 0.5%. Predictive performance was compared using Receiver Operator Characteristics., Results: We included 45,347 patient visits, 23,158 (51%) and 22,189 (49%) were triaged with CTA and ADAPT respectively with a 30-day mortality of 3.42% and 3.43% (P = 0.996) a difference of 0.01% (95% CI: -0.34 to 0.33), which met the non-inferiority criteria. Mortality at 48 hours was 0.62% vs. 0.71%, (P = 0.26) and 6.38% vs. 6.61%, (P = 0.32) at 90 days for CTA and ADAPT. CTA triaged at significantly lower urgency level (P<0.001) and was superior in predicting 30-day mortality, Area under the curve: 0.67 (95% CI 0.65-0.69) compared to 0.64 for ADAPT (95% CI 0.62-0.66) (P = 0.03). There were no significant differences in rate of admission to the intensive care unit, length of stay, waiting time nor rate of readmission within 30 or 90 days., Conclusion: A novel triage system based on vital signs and a clinical assessment by an ED nurse was non-inferior to a traditional triage algorithm by short term mortality, and superior in predicting 30-day mortality., Trial Registration: Clinicaltrials.gov NCT02698319., Competing Interests: Dr. Torp-Pedersen reports grants and personal fees from Bayer, grants from Biotronic, outside the submitted work.

Background: Multislice computed tomography (MSCT) is a non-invasive, less expensive, low-radiation alternative to coronary angiography (CAG) prior to valvular heart surgery. MSCT has a high negative predictive value for coronary artery disease (CAD) but previous studies of patients with valvular disease have shown that MSCT, as the primary evaluation technique, lead to re-evaluation with CAG in about a third of cases and it is therefore not recommended. If a subgroup of patients with low- to intermediate risk of CAD could be identified and examined with MSCT, it could be cost-effective, reduce radiation and the risk of complications associated with CAG., Methods: The study cohort was derived from a national registry of patients undergoing CAG prior to valvular heart surgery. Using logistic regression, we identified significant risk factors for CAD and developed a risk score (CT-valve score). The score was validated on a similar cohort of patients from another registry., Results: The study cohort consisted of 2221 patients, 521 (23.5%) had CAD. The validation cohort consisted of 2575 patients, 771 (29.9%) had CAD. The identified risk factors were male sex, age, smoking, hyperlipidemia, hypertension, aortic valve disease, extracardiac arteriopathy, ejection fraction <30% and diabetes mellitus. CT-valve score could identify a third of the population with a risk about 10%., Conclusion: A score based on risk factors of CAD can identify patients that might benefit from using MSCT as a gatekeeper to CAG prior to heart valve surgery., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Fabry's disease is a rare X-linked genetic disorder characterized by reduced levels of the α-galactosidase A enzyme. It may present with a cardiac phenotype resembling hypertrophic cardiomyopathy. However, as a specific enzyme replacement therapy is available, it remains an important differential diagnoses in patients presenting with cardiac hypertrophy. In boys, onset has been reported in early childhood with complaints initially comprising neuropathic pain, reduced sweat production, and gastrointestinal symptoms. Later the cardiac, renal, and central nervous systems may become affected. Female mutation carriers may remain asymptomatic or present at a later age with varying symptoms and clinical manifestations due to random inactivation of the X chromosome in different organs., Case Presentation: Here we present a case of Fabry's disease diagnosed in the daughter of an elderly, Caucasian woman (81 years old) with late-onset cardiac conduction disease and heart failure. We discuss the implications of cascade screening relatives of elderly probands., Conclusions: Irrespective of the patient's age, physicians must be on the lookout for phenocopies when identifying patients with possibly inheritable cardiomyopathies. The specific - precise - diagnosis may be crucial for the patient as well as the relatives.

Background: Crowding in the emergency department (ED) is a well-known problem resulting in an increased risk of adverse outcomes. Effective triage might counteract this problem by identifying the sickest patients and ensuring early treatment. In the last two decades, systematic triage has become the standard in ED's worldwide. However, triage models are also time consuming, supported by limited evidence and could potentially be of more harm than benefit. The aim of this study is to develop a quicker triage model using data from a large cohort of unselected ED patients and evaluate if this new model is non-inferior to an existing triage model in a prospective randomized trial., Methods: The Copenhagen Triage Algorithm (CTA) study is a prospective two-center, cluster-randomized, cross-over, non-inferiority trial comparing CTA to the Danish Emergency Process Triage (DEPT). We include patients ≥16 years (n = 50.000) admitted to the ED in two large acute hospitals. Centers are randomly assigned to perform either CTA or DEPT triage first and then use the other triage model in the last time period. The CTA stratifies patients into 5 acuity levels in two steps. First, a scoring chart based on vital values is used to classify patients in an immediate category. Second, a clinical assessment by the ED nurse can alter the result suggested by the score up to two categories up or one down. The primary end-point is 30-day mortality and secondary end-points are length of stay, time to treatment, admission to intensive care unit, and readmission within 30 days., Discussion: If proven non-inferior to standard DEPT triage, CTA will be a faster and simpler triage model that is still able to detect the critically ill. Simplifying triage will lessen the burden for the ED staff and possibly allow faster treatment., Trial Registration: Clinicaltrials.gov: NCT02698319 , registered 24. of February 2016, retrospectively registered.