Publications by authors named "Christian Mueller"

744 Publications

Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.

Proc Natl Acad Sci U S A 2021 Jul;118(28)

Division of Cardiothoracic Surgery, Department of Surgery, Transplant and Stem Cell Immunobiology Laboratory, University of California, San Francisco, CA 94143;

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
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http://dx.doi.org/10.1073/pnas.2022091118DOI Listing
July 2021

Item Response Theory for Psychometric Properties of the SNOT-22 (22-Item Sinonasal Outcome Test).

Otolaryngol Head Neck Surg 2021 Jun 29:1945998211018383. Epub 2021 Jun 29.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.

Objective: The SNOT-22 (22-item Sinonasal Outcome Test) is a high-quality outcome measure that assesses chronic rhinosinusitis-specific quality of life. The aim of this study was to gain greater insight into the information provided by the SNOT-22 by determining its item-based psychometric properties.

Study Design: Retrospective cohort study.

Setting: Tertiary care academic centers.

Methods: This study used a previously described data set of the SNOT-22 completed by 800 patients with chronic rhinosinusitis. Item response theory graded response models were used to determine parameters reflecting item discrimination, difficulty, and information provided by each item toward the SNOT-22 subdomain to which it belonged.

Results: The unconstrained graded response model fitted the SNOT-22 data best. Item discrimination parameters and total information provided showed the greatest variability within the nasal subdomain, and the item related to sense of smell/taste demonstrated the lowest discrimination and provided the least amount of information overall. The dizziness item provided disparately lower total information and discrimination in the otologic/facial pain subdomain. Items in the sleep and emotional subdomains generally provided high discrimination. While items in the nasal, sleep, and otologic/facial pain subdomains spanned all levels of difficulty, emotional subdomain items covered higher levels of difficulty, indicating greater information provided at higher levels of disease severity.

Conclusion: The item-specific psychometric properties of the SNOT-22 support it as a high-quality instrument. Our results suggest the need and possibility for revision of the smell/taste dysfunction item, for example its wording, to improve its ability to discriminate among the different levels of disease burden.
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http://dx.doi.org/10.1177/01945998211018383DOI Listing
June 2021

Cardiovascular biomarkers in COVID-19.

Eur Heart J Acute Cardiovasc Care 2021 Jun;10(5):473-474

Department of Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1093/ehjacc/zuab037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245137PMC
June 2021

Readmission following both cardiac and non-cardiac acute dyspnoea is associated with a striking risk of death.

ESC Heart Fail 2021 Jun 10. Epub 2021 Jun 10.

Clinic of Cardiac and Vascular Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.

Aims: Readmission and mortality are the most common and often combined endpoints in acute heart failure (AHF) trials, but an association between these two outcomes is poorly investigated. The aim of this study was to determine whether unplanned readmission is associated with a greater subsequent risk of death in patients with acute dyspnoea due to cardiac and non-cardiac causes.

Methods And Results: Derivation cohort (1371 patients from the LEDA study) and validation cohort (1986 patients from the BASEL V study) included acute dyspnoea patients admitted to the emergency department. Cox regression analysis was used to determine the association of 6 month readmission and the risk of 1 year all-cause mortality in AHF and non-AHF patients and those readmitted due to cardiovascular and non-cardiovascular causes. In the derivation cohort, 666 (49%) of patients were readmitted at 6 months and 282 (21%) died within 1 year. Six month readmission was associated with an increased 1 year mortality risk in both the derivation cohort [adjusted hazard ratio (aHR) 3.0 (95% confidence interval, CI 2.2-4.0), P < 0.001] and the validation cohort (aHR 1.8, 95% CI 1.4-2.2, P < 0.001). The significant association was similarly observed in AHF (aHR 3.2, 95% CI 2.1-4.9, P < 0.001) and other causes of acute dyspnoea (aHR 2.9, 95% CI 1.9-4.5, P < 0.001), and it did not depend on the aetiology [aHR 2.2, 95% CI 1.6-3.1 for cardiovascular readmissions; aHR 4.1, 95% CI 2.9-5.7 for non-cardiovascular readmissions (P < 0.001 for both)] or timing of readmission. CONCLUSION​S: Our study demonstrated a long-lasting detrimental association between readmission and death in AHF and non-AHF patients with acute dyspnoea. These patients should be considered 'vulnerable patients' that require personalized follow-up for an extended period.
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http://dx.doi.org/10.1002/ehf2.13369DOI Listing
June 2021

Portable HEPA Purifiers to Eliminate Airborne SARS-CoV-2: A Systematic Review.

Otolaryngol Head Neck Surg 2021 Jun 8:1945998211022636. Epub 2021 Jun 8.

Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Objective: Current epidemiologic predictions of COVID-19 suggest that SARS-CoV-2 mitigation strategies must be implemented long-term. In-office aerosol-generating procedures pose a risk to staff and patients while necessitating examination room shutdown to allow aerosol decontamination by indwelling ventilation. This review summarizes the current state of knowledge on portable high-efficiency particulate air (HEPA) purifiers' effectiveness in eliminating airborne SARS-CoV-2 from indoor environments.

Data Sources: Medline, Embase, Cochrane Databases, and the World Health Organization's COVID-19 Global Literature on Coronavirus Disease.

Review Methods: Data sources were systematically searched for original English-language published studies indexed up to January 14, 2021 per the following search strategy: ("HEPA" OR "High-efficiency" OR "High-efficiency particulate air" OR "Efficiency particulate" OR "Purifier" OR "Filter" OR "Cleaner" OR "Filtration") AND ("COVID" OR "COVID-19" OR "SARS-CoV-2" OR "Coronavirus"). Additional relevant studies were identified by searching the reference lists of included articles.

Results: Eleven published studies have evaluated the effectiveness of portable HEPA purifiers in eliminating airborne SARS-CoV-2 with relevantly sized surrogate particles. Ten studies evaluated aerosols and submicron particles similar in size to SARS-CoV-2 virions. In all studies, portable HEPA purifiers were able to significantly reduce airborne SARS-CoV-2-surrogate particles. The addition of portable HEPA purifiers augmented other decontamination strategies such as ventilation.

Conclusion: Experimental studies provide evidence for portable HEPA purifiers' potential to eliminate airborne SARS-CoV-2 and augment primary decontamination strategies such as ventilation. Based on filtration rates, additional air exchanges provided by portable HEPA purifiers may be calculated and room shutdown times potentially reduced after aerosol-generating procedures.
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http://dx.doi.org/10.1177/01945998211022636DOI Listing
June 2021

Long-term beta-blocker treatment in stable patients after myocardial infarction: a potential impact due to changes in the diagnosis of myocardial infarction?

Eur Heart J 2021 May 23. Epub 2021 May 23.

Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, University of Basel, Spitalstrasse 2, 4056 Basel, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehab257DOI Listing
May 2021

Prognostic Utility of a Modified HEART Score When Different Troponin Cut-points Are Used.

Crit Pathw Cardiol 2021 May 12. Epub 2021 May 12.

Heart and Vascular Institute, Henry Ford Health System, Detroit, MI, USA Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, USA Depar Medizinische Klinik III, Universitätsklinikum Heidelberg, Heidelberg, Germany Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA Department of Medicine, Inova Heart and Vascular Institute, Falls Church, VA, USA Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Department of Emergency Medicine, Cantonal Hospital Lucerne, Switzerland Manchester University NHS Foundation Trust, Manchester, United Kingdom Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA Cardiology and Cardiovascular Research Institute Basel, University Hospital Basel, Switzerland.

Background: Although the recommended cut-point for cardiac troponin (cTn) is the 99th percentile, many institutions use cut-points that are multiples higher than the 99th percentile for diagnosing acute myocardial infarction (AMI). Prior studies have shown that patients with a HEART score (HS) ≤ 3 and normal serial cTn values (modified HS) are at low risk for adverse events. This study aimed to evaluate the prognostic utility of the HS when various cTn cut-points are used.

Methods: This was a sub-study of TRAPID-AMI, a multicenter, international trial evaluating a rapid rule-out AMI study using high sensitivity cTnT (hs-cTnT). 1,282 patients were evaluated for AMI from 12 centers in Europe, United States of America, and Australia from 2011-2013. Blood samples of hs-cTnT were collected at presentation and 2 hours, and each patient had a HS calculated. The US Food and Drug Administration approved 99th percentile for hs-cTnT (19 ng/L) was used.

Results: There were 213 (17%) AMIs. Within 30 days, there were an additional 2 AMIs and 8 deaths. The adverse event rates at 30 days (death/AMI) for a HS ≤ 3 and non-elevated hs-cTnT over 2 hours using increasing hs-cTnT cut-points ranged from 0.6% to 5.1%.

Conclusions: Using the recommended 99th percentile cut-point for hs-cTnT, the combination of a HS ≤ 3 with non-elevated hs-cTnT values over 2 hours identifies a low-risk cohort who can be considered for discharge from the emergency department without further testing. The prognostic utility of this strategy is greatly lessened as higher hs-cTnT cut-points are used.
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http://dx.doi.org/10.1097/HPC.0000000000000262DOI Listing
May 2021

Retronasal olfactory testing in early diagnosed and suspected COVID-19 patients: a 7-week follow-up study.

Eur Arch Otorhinolaryngol 2021 May 13. Epub 2021 May 13.

Department of Otorhinolaryngology, Head and Neck Surgery, Vienna General Hospital, Medical University of Vienna, 1090, Vienna, Austria.

Objectives: Olfactory dysfunction (OD) constitutes a major symptom in Coronavirus Disease 2019 (COVID-19). Yet, most data on smell loss rely on the evaluation of orthonasal olfactory performance. Therefore, we aimed to assess retronasal olfactory function (ROF) over a period of several weeks in proven and suspected COVID-19 patients.

Methods: One hundred and one subjects with suspected or laboratory-proven COVID-19 participated in this study. In patients with OD no longer than 4 weeks after initial symptom onset, ROF was measured with the 7-item Candy Smell Test ten times over 7 weeks.

Results: Olfactory function was decreased in the investigated patients and remained decreased over the course of 7 weeks. One-way repeated-measures ANOVA revealed no significant difference of ROF between different measurement time points. However, self-assessment of smell and flavour improved significantly (p = 0.013 and p = 0.043), but did not show complete recovery.

Conclusion: The current investigation revealed significant improvements in subjective smell and flavour perception over the course of 7 weeks in proven and suspected COVID-19 patients suffering from acute OD. However, objectively measured ROF based on a screening test revealed no improvements within the same time period.
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http://dx.doi.org/10.1007/s00405-021-06826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118104PMC
May 2021

Downstream Consequences of Implementing High-Sensitivity Cardiac Troponin: Why Indication and Education Matter.

J Am Coll Cardiol 2021 Jun 3;77(25):3180-3183. Epub 2021 May 3.

Cardiovascular Research Institute Basel (CRIB), Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland; Division of Cardiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.1016/j.jacc.2021.04.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091426PMC
June 2021

From Multi-Modal Property Dataset to Robot-Centric Conceptual Knowledge About Household Objects.

Front Robot AI 2021 15;8:476084. Epub 2021 Apr 15.

Institute for Computer Science, Technische Universität Bergakademie Freiberg, Freiberg, Germany.

Conceptual knowledge about objects is essential for humans, as well as for animals, to interact with their environment. On this basis, the objects can be understood as tools, a selection process can be implemented and their usage can be planned in order to achieve a specific goal. The conceptual knowledge, in this case, is primarily concerned about the physical properties and functional properties observed in the objects. Similarly tool-use applications in robotics require such conceptual knowledge about objects for among other purposes. State-of-the-art methods employ a top-down approach where hand-crafted symbolic knowledge, which is defined from a human perspective, is grounded into sensory data afterwards. However, due to different sensing and acting capabilities of robots, a robot's conceptual understanding of objects (e.g., light/heavy) will vary and therefore should be generated from the robot's perspective entirely, which entails robot-centric conceptual knowledge about objects. A similar bottom-up argument has been put forth in cognitive science that humans and animals alike develop conceptual understanding of objects based on their own perceptual experiences with objects. With this goal in mind, we propose an extensible property estimation framework which consists of estimations methods to obtain the quantitative measurements of physical properties (rigidity, weight, etc.) and functional properties (containment, support, etc.) from household objects. This property estimation forms the basis for our second contribution: Generation of robot-centric conceptual knowledge. Our approach employs unsupervised clustering methods to transform numerical property data into symbols, and Bivariate Joint Frequency Distributions and Sample Proportion to generate conceptual knowledge about objects using the robot-centric symbols. A preliminary implementation of the proposed framework is employed to acquire a dataset comprising six and four properties of 110 household objects. This Robot-Centric dataSet (RoCS) is used to evaluate the framework regarding the property estimation methods and the semantics of the considered properties within the dataset. Furthermore, the dataset includes the derived robot-centric conceptual knowledge using the proposed framework. The application of the conceptual knowledge about objects is then evaluated by examining its usefulness in a tool substitution scenario.
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http://dx.doi.org/10.3389/frobt.2021.476084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082111PMC
April 2021

Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.

Neurobiol Dis 2021 Jul 20;155:105368. Epub 2021 Apr 20.

Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Parkinson's disease (PD) is the most common form of neurodegenerative movement disorder, associated with profound loss of dopaminergic neurons from the basal ganglia. Though loss of dopaminergic neuron cell bodies from the substantia nigra pars compacta is a well-studied feature, atrophy and loss of their axons within the nigrostriatal tract is also emerging as an early event in disease progression. Genes that drive the Wallerian degeneration, like Sterile alpha and toll/interleukin-1 receptor motif containing (Sarm1), are excellent candidates for driving this axon degeneration, given similarities in the morphology of axon degeneration after axotomy and in PD. In the present study we assessed whether Sarm1 contributes to loss of dopaminergic projections in mouse models of PD. In Sarm1 deficient mice, we observed a significant delay in the degeneration of severed dopaminergic axons distal to a 6-OHDA lesion of the medial forebrain bundle (MFB) in the nigrostriatal tract, and an accompanying rescue of morphological, biochemical and behavioural phenotypes. However, we observed no difference compared to controls when striatal terminals were lesioned with 6-OHDA to induce a dying back form of neurodegeneration. Likewise, when PD phenotypes were induced using AAV-induced alpha-synuclein overexpression, we observed similar modest loss of dopaminergic terminals in Sarm1 knockouts and controls. Our data argues that axon degeneration after MFB lesion is Sarm1-dependent, but that other models for PD do not require Sarm1, or that Sarm1 acts with other redundant genetic pathways. This work adds to a growing body of evidence indicating Sarm1 contributes to some, but not all types of neurodegeneration, and supports the notion that while axon degeneration in many context appears morphologically similar, a diversity of axon degeneration programs exist.
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http://dx.doi.org/10.1016/j.nbd.2021.105368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292971PMC
July 2021

A Concept for the Reduction of Mucosal SARS-CoV-2 Load using Hypochloric Acid Solutions.

Drug Res (Stuttg) 2021 Jul 22;71(6):348-350. Epub 2021 Apr 22.

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

During the next few months or years, vaccination against SARS-CoV-2 infection will significantly reduce the morbidity and mortality of COVID-19. However, additional measures are needed to protect those who are still not immunized. This is even more important in view of new viral mutations that result in increased transmission rates. We propose that the use of long-standing medicinal solutions based on hypochloric acid (HOCl) and intended for application on wounds may be effective as a gargling solution or nasal irrigation in blocking transmission of the virus. Here, we propose the use of HOCl-containing solutions for blocking the transmission of SARS-CoV-2 in combination with other prevention measures. This may constitute another important cornerstone in the fight against the COVID-19 pandemic.
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http://dx.doi.org/10.1055/a-1467-5956DOI Listing
July 2021

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction.

JAMA Cardiol 2021 Jul;6(7):771-780

Cardiovascular Research Institute Basel and Department of Cardiology, University Hospital Basel, University of Basel, Basel, Switzerland.

Importance: Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy.

Objective: To test the hypothesis that novel cardiovascular biomarkers quantifying different pathophysiological pathways involved in T2MI and/or T1MI may aid physicians in the rapid discrimination of T2MI vs T1MI.

Design, Setting, And Participants: This international, multicenter prospective diagnostic study was conducted in 12 emergency departments in 5 countries (Switzerland, Spain, Italy, Poland, and the Czech Republic) with patients presenting with acute chest discomfort to the emergency departments. The study quantified the discrimination of hs-cTn T, hs-cTn I, and 17 novel cardiovascular biomarkers measured in subsets of consecutively enrolled patients against a reference standard (final diagnosis), centrally adjudicated by 2 independent cardiologists according to the fourth universal definition of MI, using all information, including cardiac imaging and serial measurements of hs-cTnT or hs-cTnI.

Results: Among 5887 patients, 1106 (18.8%) had an adjudicated final diagnosis of MI; of these, 860 patients (77.8%) had T1MI, and 246 patients (22.2%) had T2MI. Patients with T2MI vs those with T1MI had lower concentrations of biomarkers quantifying cardiomyocyte injury hs-cTnT (median [interquartile range (IQR)], 30 (17-55) ng/L vs 58 (28-150) ng/L), hs-cTnI (median [IQR], 23 [10-83] ng/L vs 115 [28-576] ng/L; P < .001), and cardiac myosin-binding protein C (at presentation: median [IQR], 76 [38-189] ng/L vs 257 [75-876] ng/L; P < .001) but higher concentrations of biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress (median [IQR] values: C-terminal proendothelin 1, 97 [75-134] pmol/L vs 68 [55-91] pmol/L; midregional proadrenomedullin, 0.97 [0.67-1.51] pmol/L vs 0.72 [0.53-0.99] pmol/L; midregional pro-A-type natriuretic peptide, 378 [207-491] pmol/L vs 152 [90-247] pmol/L; and growth differentiation factor 15, 2.26 [1.44-4.35] vs 1.56 [1.02-2.19] ng/L; all P < .001). Discrimination for these biomarkers, as quantified by the area under the receiver operating characteristics curve, was modest (hs-cTnT, 0.67 [95% CI, 0.64-0.71]; hs-cTn I, 0.71 [95% CI, 0.67-0.74]; cardiac myosin-binding protein C, 0.67 [95% CI, 0.61-0.73]; C-terminal proendothelin 1, 0.73 [95% CI, 0.63-0.83]; midregional proadrenomedullin, 0.66 [95% CI, 0.60-0.73]; midregional pro-A-type natriuretic peptide, 0.77 [95% CI, 0.68-0.87]; and growth differentiation factor 15, 0.68 [95% CI, 0.58-0.79]).

Conclusions And Relevance: In this study, biomarkers quantifying myocardial injury, endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in early, noninvasive diagnosis of T2MI.
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http://dx.doi.org/10.1001/jamacardio.2021.0669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060883PMC
July 2021

Annual trends in Google searches provides insights related to rhinosinusitis exacerbations.

Eur Arch Otorhinolaryngol 2021 Apr 20. Epub 2021 Apr 20.

Department of Otorhinolaryngology, Head and Neck Surgery, Vienna General Hospital (AKH), Medical University of Vienna, Vienna, Austria.

Purpose: Temporal trends of disease-specific internet searches may provide novel insights into seasonal dynamics of disease burden and, by extension, disease pathophysiology. The aim of this study was to define the temporal trends in rhinosinusitis-specific internet searches.

Methods: This was a cross sectional analysis of search volume for predefined search terms. Google trends was used to explore the volume of searches for five specific search terms related to rhinosinusitis: nose, mucus, sinus, sinusitis, chronic sinusitis, which were entered into Google web search between 2004 and 2019. Results were analyzed within search "context" which included temporally associated related searches. Relative search volume (RSV) was analyzed for English and non-English speaking countries from the Northern and Southern hemispheres. Analysis of seasonality was performed using the cosinor model.

Results: The five specific search terms were most related to rhinosinusitis-related search contexts, indicating that they were appropriately reflective of internet queries by patients for rhinosinusitis. The RSV for rhinosinusitis-related terms and more general search terms increased with each passing year indicating constant interest in rhinosinusitis. Cosinor time series analysis revealed inquiry peaks in winter months for all five specific rhinosinusitis-related search terms independent from the hemisphere.

Conclusion: Over a 15-year period, Google searches with rhinosinusitis-specific search terms consistently peaked during the winter around the world. These findings indirectly support the model of viral infection or exposure as the predominant cause of acute rhinosinusitis and acute exacerbations of chronic rhinosinusitis.
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http://dx.doi.org/10.1007/s00405-021-06806-5DOI Listing
April 2021

External Validation and Extension of a Clinical Score for the Discrimination of Type 2 Myocardial Infarction.

J Clin Med 2021 Mar 18;10(6). Epub 2021 Mar 18.

Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.

Background: The early non-invasive discrimination of Type 2 versus Type 1 Myocardial Infarction (T2MI, T1MI) is a major unmet clinical need. We aimed to externally validate a recently derived clinical score (Neumann) combing female sex, no radiating chest pain, and high-sensitivity cardiac troponin I (hs-cTnI) concentration ≤40.8 ng/L.

Methods: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. The final diagnoses of T2MI and T1MI were centrally adjudicated by two independent cardiologists using all information including cardiac imaging and serial measurements of hs-cTnT/I according to the fourth universal definition of MI. Model performance for T2MI diagnosis was assessed by formal tests and graphical means of discrimination and calibration.

Results: Among 6684 enrolled patients, MI was the adjudicated final diagnosis in 1079 (19%) patients, of which 242 (22%) had T2MI. External validation of the Neumann Score showed a moderate discrimination (C-statistic 0.67 (95%CI 0.64-0.71)). Model calibration showed underestimation of the predicted probabilities of having T2MI for low point scores. Model extension by adding the binary variable heart rate >120/min significantly improved model performance (C-statistic 0.73 (95% CI 0.70-0.76, < 0.001) and had good calibration. Patients with the highest score values of 3 (Neumann Score, 9.9%) and 5 (Extended Neumann Score, 3.3%) had a 53% and 91% predicted probability of T2MI, respectively.

Conclusion: The Neumann Score provided moderate discrimination and suboptimal calibration. Extending the Neumann Score by adding heart rate >120/min improved the model's performance.
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http://dx.doi.org/10.3390/jcm10061264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003225PMC
March 2021

Decongestion discriminates risk for one-year mortality in patients with improving renal function in acute heart failure.

Eur J Heart Fail 2021 Jul 15;23(7):1122-1130. Epub 2021 Apr 15.

School of Medicine, University College Dublin, Dublin, Ireland.

Aims: Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion.

Methods And Results: We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B-type natriuretic peptide (BNP), and 1-year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% were men, 72% were white, and median admission eGFR was 49 mL/min/1.73 m . IRF patients had more severe heart failure reflected by lower admission eGFR, higher blood urea nitrogen, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher 1-year mortality (25%) than non-IRF patients (15%) (P < 0.01). However, this relationship differed by BNP trajectory (P-interaction = 0.03). When stratified by BNP change, non-IRF patients and IRF patients with decreasing BNP had lower 1-year mortality than either non-IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality [adjusted hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.7-1.5] while BNP was (adjusted HR 0.5, 95% CI 0.3-0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality.

Conclusion: Improving renal function is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than IRF.
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http://dx.doi.org/10.1002/ejhf.2179DOI Listing
July 2021

Cortical volume reductions as a sign of secondary cerebral and cerebellar impairment in patients with degenerative cervical myelopathy.

Neuroimage Clin 2021 13;30:102624. Epub 2021 Mar 13.

Department of Neurosurgery, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address:

This study investigated supra- and infratentorial structural gray and white matter (GM, WM) alterations in patients with degenerative cervical myelopathy (DCM) as an indicator of secondary harm due to chronic cervical cord compression and micro trauma. With MRI-based anatomical assessment and subsequent voxel-based morphometry analyses, pre- and postoperative volume alterations in the primary motor cortex (MI), the primary somatosensory cortex (SI), the supplementary motor area (SMA), and the cerebellum were analyzed in 43 DCM patients and 20 controls. We assessed disease-related symptom severity by the modified Japanese Orthopaedic Association scale (mJOA). The study also explored symptom severity-based brain volume alterations as well as their association with clinical status. Patients had lower mJOA scores (p = .000) and lower GM volume than controls in SI (p = .016) and cerebellar regions (p = .001). Symptom severity-based subgroup analyses revealed volume reductions in almost all investigated GM ROIs (MI: p = .001; CB: p = .040; SMA: p = .007) in patients with severe clinical symptoms as well as atrophy already present in patients with moderate symptom severity. Clinical symptoms in DCM were associated with cortical and cerebellar volume reduction. GM volume alterations may serve as an indicator of both disease severity and ongoing disease progression in DCM, and should be considered in further patient care and treatment monitoring.
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http://dx.doi.org/10.1016/j.nicl.2021.102624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025145PMC
March 2021

Incidence and outcomes of perioperative myocardial infarction/injury diagnosed by high-sensitivity cardiac troponin I.

Clin Res Cardiol 2021 Mar 25. Epub 2021 Mar 25.

Department of Cardiology and Cardiovascular Research Institute Basel (CRIB), University Hospital Basel, University of Basel, Spitalstrasse 2, CH-4056, Basel, Switzerland.

Background:  Perioperative myocardial infarction/injury (PMI) diagnosed by high-sensitivity troponin (hs-cTn) T is frequent and a prognostically important complication of non-cardiac surgery. We aimed to evaluate the incidence and outcome of PMI diagnosed using hs-cTnI, and compare it to PMI diagnosed using hs-cTnT.

Methods: We prospectively included 2455 patients at high cardiovascular risk undergoing 3111 non-cardiac surgeries, for whom hs-cTnI and hs-cTnT concentrations were measured before surgery and on postoperative days 1 and 2. PMI was defined as a composite of perioperative myocardial infarction (PMI) and perioperative myocardial injury (PMI), according to the Fourth Universal Definition of Myocardial Infarction. All-cause mortality was the primary endpoint.

Results: Using hs-cTnI, the incidence of overall PMI was 9% (95% confidence interval [CI] 8-10%), including PMI 2.6% (95% CI 2.0-3.2) and PMI 6.1% (95% CI 5.3-6.9%), which was lower versus using hs-cTnT: overall PMI 15% (95% CI 14-16%), PMI 3.7% (95% CI 3.0-4.4) and PMI 11.3% (95% CI 10.2-12.4%). All-cause mortality occurred in 52 (2%) patients within 30 days and 217 (9%) within 1 year. Using hs-cTnI, both PMI and PMI were independent predictors of 30-day all-cause mortality (adjusted hazard ratio [aHR] 2.5 [95% CI 1.1-6.0], and aHR 2.8 [95% CI 1.4-5.5], respectively) and, 1-year all-cause mortality (aHR 2.0 [95% CI 1.2-3.3], and aHR 1.8 [95% CI 1.2-2.7], respectively). Overall, the prognostic impact of PMI diagnosed by hs-cTnI was comparable to the prognostic impact of PMI using hs-cTnT.

Conclusions: Using hs-cTnI, PMI is less common versus using hs-cTnT. Using hs-cTnI, both PMI and PMI remain independent predictors of 30-day and 1-year mortality.
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http://dx.doi.org/10.1007/s00392-021-01827-wDOI Listing
March 2021

The management of secondary mitral regurgitation in patients with heart failure: a joint position statement from the Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), and European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Eur Heart J 2021 Mar 18. Epub 2021 Mar 18.

Department of Cardiology, Inselspital, University of Bern, Bern, Switzerland.

Secondary (or functional) mitral regurgitation (SMR) occurs frequently in chronic heart failure (HF) with reduced left ventricular (LV) ejection fraction, resulting from LV remodelling that prevents coaptation of the valve leaflets. Secondary mitral regurgitation contributes to progression of the symptoms and signs of HF and confers worse prognosis. The management of HF patients with SMR is complex and requires timely referral to a multidisciplinary Heart Team. Optimization of pharmacological and device therapy according to guideline recommendations is crucial. Further management requires careful clinical and imaging assessment, addressing the anatomical and functional features of the mitral valve and left ventricle, overall HF status, and relevant comorbidities. Evidence concerning surgical correction of SMR is sparse and it is doubtful whether this approach improves prognosis. Transcatheter repair has emerged as a promising alternative, but the conflicting results of current randomized trials require careful interpretation. This collaborative position statement, developed by four key associations of the European Society of Cardiology-the Heart Failure Association (HFA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association of Cardiovascular Imaging (EACVI), and European Heart Rhythm Association (EHRA)-presents an updated practical approach to the evaluation and management of patients with HF and SMR based upon a Heart Team approach.
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http://dx.doi.org/10.1093/eurheartj/ehab086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014526PMC
March 2021

Systemic corticosteroids in coronavirus disease 2019 (COVID-19)-related smell dysfunction: an international view.

Int Forum Allergy Rhinol 2021 07 16;11(7):1041-1046. Epub 2021 Mar 16.

Smell and Taste Clinic, Department of Otorhinolaryngology, TU Dresden, Dresden, Germany.

The frequent association between coronavirus disease 2019 (COVID-19) and olfactory dysfunction is creating an unprecedented demand for a treatment of the olfactory loss. Systemic corticosteroids have been considered as a therapeutic option. However, based on current literature, we call for caution using these treatments in early COVID-19-related olfactory dysfunction because: (1) evidence supporting their usefulness is weak; (2) the rate of spontaneous recovery of COVID-19-related olfactory dysfunction is high; and (3) corticosteroids have well-known potential adverse effects. We encourage randomized placebo-controlled trials investigating the efficacy of systemic steroids in this indication and strongly emphasize to initially consider smell training, which is supported by a robust evidence base and has no known side effects.
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http://dx.doi.org/10.1002/alr.22788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251281PMC
July 2021

Cardiovascular biomarkers in patients with COVID-19.

Eur Heart J Acute Cardiovasc Care 2021 May;10(3):310-319

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

The coronavirus disease 2019 (COVID-19) pandemic has increased awareness that severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) may have profound effects on the cardiovascular system. COVID-19 often affects patients with pre-existing cardiac disease, and may trigger acute respiratory distress syndrome (ARDS), venous thromboembolism (VTE), acute myocardial infarction (AMI), and acute heart failure (AHF). However, as COVID-19 is primarily a respiratory infectious disease, there remain substantial uncertainty and controversy whether and how cardiovascular biomarkers should be used in patients with suspected COVID-19. To help clinicians understand the possible value as well as the most appropriate interpretation of cardiovascular biomarkers in COVID-19, it is important to highlight that recent findings regarding the prognostic role of cardiovascular biomarkers in patients hospitalized with COVID-19 are similar to those obtained in studies for pneumonia and ARDS in general. Cardiovascular biomarkers reflecting pathophysiological processes involved in COVID-19/pneumonia and its complications have a role evaluating disease severity, cardiac involvement, and risk of death in COVID-19 as well as in pneumonias caused by other pathogens. First, cardiomyocyte injury, as quantified by cardiac troponin concentrations, and haemodynamic cardiac stress, as quantified by natriuretic peptide concentrations, may occur in COVID-19 as in other pneumonias. The level of those biomarkers correlates with disease severity and mortality. Interpretation of cardiac troponin and natriuretic peptide concentrations as quantitative variables may aid in risk stratification in COVID-19/pneumonia and also will ensure that these biomarkers maintain high diagnostic accuracy for AMI and AHF. Second, activated coagulation as quantified by D-dimers seems more prominent in COVID-19 as in other pneumonias. Due to the central role of endothelitis and VTE in COVID-19, serial measurements of D-dimers may help physicians in the selection of patients for VTE imaging and the intensification of the level of anticoagulation from prophylactic to slightly higher or even therapeutic doses.
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http://dx.doi.org/10.1093/ehjacc/zuab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989520PMC
May 2021

Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy;

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the gene encoding AAT and the common mutant Z allele of encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR-34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.
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http://dx.doi.org/10.1073/pnas.2025242118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958360PMC
March 2021

External validation of the clinical chemistry score.

Clin Biochem 2021 May 23;91:16-25. Epub 2021 Feb 23.

Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, University of Basel, Switzerland; GREAT Network. Electronic address:

Background: Combining high-sensitivity cardiac troponin (hs-cTn) with estimated glomerular filtration rate and glucose within the Clinical Chemistry Score (CCS) could help in the assessment of patients with suspected acute myocardial infarction (AMI).

Methods: In patients presenting with suspected AMI to the emergency department, we aimed to externally validate the performance of the CCS in a prospective international multicenter study and to directly compare the diagnostic and prognostic performance of the CCS with hs-cTnT and hs-cTnI baseline levels alone using a single cut-off approach. The diagnostic endpoint was diagnostic accuracy for AMI as centrally adjudicated by two independent cardiologists including cardiac imaging and serial hs-cTnT/I measurements. The prognostic endpoint was 30-day AMI or death.

Results: AMI was the final diagnosis in 620/3827 patients (16.2%) adjudicated with hs-cTnT and 599 patients (15.7%) adjudicated with hs-cTnI. The CCS resulted in high diagnostic accuracy for AMI and prognostic accuracy for 30-days AMI/death as quantified by the area under the receiver-operating characteristic curve (AUC), using hs-cTnT 0.90 (95%CI 0.89-0.91) and 0.89 (95%CI 0.88-0.90), using hs-cTnI 0.91 (95%Cl 0.90-0.92) and 0.90 (95%CI 0.89-0.91) respectively. E.g. a CCS of 0 points resulted in a sensitivity of 99.8% (95%CI 99.1-100%) for rule-out of index AMI and 99.5% (95%CI 98.5-100%) for AMI/death at 30 days for hs-cTnT and 99.8% (95%CI 98.9-100%) and 99.6% (95%CI 98.6-100%) using hs-cTnI. Overall, the single hs-cTnT/I measurement approach provided comparable diagnostic (sensitivity 99.5-99.7%) and prognostic (sensitivity 98.9-99.5%) performance versus the CCS.

Interpretation: The CCS provided high diagnostic and prognostic performance also in this independent large validation cohort. A single hs-cTnT/I measurement approach for rule-out MI yielded similar estimates.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.02.006DOI Listing
May 2021