| 1. |
- Matuozzo, Daniela, et al.
(författare)
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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in~80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1×10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1×10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4×10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7×10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68×10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60years old.
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| 2. |
- Bingisser, Roland, et al.
(författare)
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Cardiac troponin : a critical review of the case for point-of-care testing in the ED
- 2012
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Ingår i: American Journal of Emergency Medicine. - : Elsevier BV. - 0735-6757 .- 1532-8171. ; 30:8, s. 1639-1649
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Forskningsöversikt (refereegranskat)abstract
- The measurement of cardiac troponin concentrations in the blood is a key element in the evaluation of patients with suspected acute coronary syndromes, according to current guidelines, and contributes importantly to the ruling in or ruling out of acute myocardial infarction. The introduction of point-of-care testing for cardiac troponin has the potential to reduce turnaround time for assay results, compared with central laboratory testing, optimizing resource use. Although, in general, many point-of-care cardiac troponin tests are less sensitive than cardiac troponin tests developed for central laboratory-automated analyzers, point-of-care systems have been used successfully within accelerated protocols for the reliable ruling out of acute coronary syndromes, without increasing subsequent readmission rates for this condition. The impact of shortened assay turnaround times with point-of-care technology on length of stay in the emergency department has been limited to date, with most randomized evaluations of this technology having demonstrated little or no reduction in this outcome parameter. Accordingly, the point-of-care approach has not been shown to be cost-effective relative to central laboratory testing. Modeling studies suggest, however, that reengineering overall procedures within the emergency department setting, to take full advantage of reduced therapeutic turnaround time, has the potential to improve the flow of patients through the emergency department, to shorten discharge times, and to reduce cost. To properly evaluate the potential contribution of point-of-care technology in the emergency department, including its costeffectiveness, future evaluations of point-of-care platforms will need to be embedded completely within a local decision-making structure designed for its use.
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| 3. |
- Bingisser, Roland, et al.
(författare)
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Measurement of natriuretic peptides at the point of care in the emergency and ambulatory setting : Current status and future perspectives
- 2013
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 166:4, s. 614-
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Tidskriftsartikel (refereegranskat)abstract
- The measurement of natriuretic peptides (NPs), B-type NP or N-terminal pro-B-type NP, can be an important tool in the diagnosis of acute heart failure in patients presenting to an Emergency Department (ED) with acute dyspnea, according to international guidelines. Studies and subsequent meta-analyses are mixed on the absolute value of routine NP assessment of ED patients. However, levels of NPs are likely to be used also to guide treatment and to assess risk of adverse outcomes in other patients at risk of developing heart failure, including those with pulmonary embolism or diabetes, or receiving chemotherapy. Natriuretic peptide levels, like other biomarkers, can now be measured at the point of care (POC). We have reviewed the current status of NP measurement together with the potential contribution of POC measurement of NPs to clinical care delivery in the emergency and other settings. Several POC systems for measuring NP levels are now available: these produce test results within 15 minutes and appear sufficiently sensitive and robust to be used routinely in diagnostic evaluations. Point-of-care systems could be used to assess NP levels in the ED and community outpatient settings to monitor the risk of acute heart failure. Furthermore, the use of protocol-driven POC testing of NP within the time frame of a patient consultation in the ED may facilitate and accelerate the throughput and disposition of at-risk patients. Appropriately designed clinical trials will be needed to confirm these potential benefits. It is also important that processes of care delivery are redesigned to take full advantage of the faster turnaround times provided by POC technology.
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| 4. |
- Marchal, Astrid, et al.
(författare)
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Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.
- 2024
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Ingår i: HGG advances. - 2666-2477. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing Tcell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.
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| 5. |
- Saeed, Kordo, et al.
(författare)
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The early identification of disease progression in patients with suspected infection presenting to the emergency department : A multi-centre derivation and validation study
- 2019
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. Methods: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. Results: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities. Conclusions: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.
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| 6. |
- Venge, Per, et al.
(författare)
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Equal clinical performance of a novel point-of-care cardiac troponin I (cTnI) assay with a commonly used high-sensitivity cTnI assay
- 2017
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Ingår i: Clinica Chimica Acta. - : ELSEVIER SCIENCE BV. - 0009-8981 .- 1873-3492. ; 469, s. 119-125
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Tidskriftsartikel (refereegranskat)abstract
- Background: Efficient rule-out of acute myocardial infarction (MI) facilitates early disposition of chest pain patients in emergency departments (ED). Point-of-care (POC) cardiac troponin (cTn) may improve patient throughput. We compared the diagnostic accuracy of a novel cTnI test (Minicare cTnI, Philips), with current POC cTnI (I-Stat, Abbott) and high-sensitivity central laboratory cTnI (hs-cTnI; Architect, Abbott) assays.Methods: The clinical performance of the assays were compared in samples from 450 patients from a previous clinical evaluation of Minicare cTnI.Results: Minicare cTnI correlated with Architect hs-cTnI (r(2) = 0.85, p < 0.0001) and I-Stat cTnI (r(2) = 0.93, p < 0.0001). Areas under the receiver operating characteristics curves were 0.87-0.91 at admission (p = ns) and 0.96-0.97 3 h after admission (p = ns). The negative predictive values (NPV) at admission were 95% ((92-97%, 95% CI) for Minicare cTnI and increased to 99% (97-100%) at 2-4 h, and similar to Architect hs-cTnI (98%, 96-100%), but higher than I-Stat cTnI (95%, 92-97%; p < 0.01). Negative likelihood ratios (LR) after 2-4 h were 0.06 (0.02-0.17, 95% CI) for Minicare cTnI, 0.11 (0.05-0.24) for Architect hs-cTnI (p = 0.02) and 0.28 (0.18-0.43) for I-Stat cTnI (p < 0.0001). The clinical concordances between Minicare cTnI and Architect hs-cTnI were 92% (admission) and 95% (2-4 h), with lower concordances between Minicare cTnI and I-Stat cTnI (83% and 78%, respectively; p = 0.007).Conclusions: The Minicare cTnI POC assay may become useful for prompt and safe ruling-out of AMI in ED patients with suspected AMI using a guideline supported 0/3 h sampling protocol.
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