Publications by authors named "Kirsten Nielsen"

132 Publications

Docusate-Based Ionic Liquids of Anthelmintic Benzimidazoles Show Improved Pharmaceutical Processability, Lipid Solubility, and Activity against .

ACS Infect Dis 2021 09 1;7(9):2637-2649. Epub 2021 Sep 1.

Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawai'i at Hilo, Hilo, Hawaii 96720, United States.

As the existing therapeutic modalities for the treatment of cryptococcal meningitis (CM) have suboptimal efficacy, repurposing existing drugs for the treatment of CM is of great interest. The FDA-approved anthelmintic benzimidazoles, albendazole, mebendazole, and flubendazole, have demonstrated potent but variable activity against , the predominant fungal species responsible for CM. We performed molecular docking studies to ascertain the interaction of albendazole, mebendazole, and flubendazole with a β-tubulin structure, which revealed differential binding interactions and explained the different efficacies reported previously and observed in this investigation. Despite their promising efficacy, the repurposing of anthelmintic benzimidazoles for oral CM therapy is significantly hampered due to their high crystallinity, poor pharmaceutical processability, low and pH-dependent solubility, and drug precipitation upon entering the intestine, all of which result in low and variable oral bioavailability. Here, we demonstrate that the anthelmintic benzimidazoles can be transformed into partially amorphous low-melting ionic liquids (ILs) with a simple metathesis reaction using amphiphilic sodium docusate as a counterion. efficacy studies on a laboratory reference and a clinical isolate of showed 2- to 4-fold lower IC values for docusate-based ILs compared to the pure anthelmintic benzimidazoles. Furthermore, using a strain with green fluorescent protein (GFP)-tagged β-tubulin and albendazole and its docusate IL as model candidates, we showed that the benzimidazoles and their ILs reduce the viability of by interfering with its microtubule assembly. Unlike pure anthelmintic benzimidazoles, the docusate-based ILs showed excellent solubility in organic solvents and >30-fold higher solubility in bioavailability-enhancing lipid vehicles. Finally, the docusate ILs were successfully incorporated into SoluPlus, a self-assembling biodegradable polymer, which upon dilution with water formed polymeric micelles with a size of <100 nm. Thus, the development of docusate-based ILs represents an effective approach to improve the physicochemical properties and potency of anthelmintic benzimidazoles to facilitate their repurposing and preclinical development for CM therapy.
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http://dx.doi.org/10.1021/acsinfecdis.1c00063DOI Listing
September 2021

ATI-2307 Exhibits Equivalent Antifungal Activity in Clinical Isolates With High and Low Fluconazole IC.

Front Cell Infect Microbiol 2021 23;11:695240. Epub 2021 Jun 23.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, United States.

Half maximal inhibitory concentrations (IC) to the experimental drug ATI-2307 and complete inhibition (IC) of the common clinically used antifungal drug amphotericin B were determined by microbroth dilution assay for a collection of 69 clinical isolates of from Uganda that had high fluconazole IC values. The majority of the clinical isolates tested had fluconazole IC at or above 8 µg/mL, but were susceptible to both amphotericin B (IC ≤1 μg/mL) and ATI-2307 (IC50 ≤0.0312 µg/mL). No correlation between increased fluconazole minimum inhibitory concentration (MIC) and ATI-2307 or amphotericin B MIC was observed, suggesting that the cellular changes impacting fluconazole susceptibility did not impact the effectiveness of ATI-2307. Our results suggest that ATI-2307 is a promising new antifungal drug for use in the context of high fluconazole or other antifungal drug MICs and/or in combination drug therapy regimens.
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http://dx.doi.org/10.3389/fcimb.2021.695240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262267PMC
July 2021

Risk of coronary artery disease after adjuvant radiotherapy in 29,662 early breast cancer patients: A population-based Danish Breast Cancer Group study.

Radiother Oncol 2021 04 27;157:106-113. Epub 2021 Jan 27.

Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark; Department of Oncology, Aarhus University Hospital, Denmark; Danish Center for Particle Therapy, Aarhus, Denmark.

Purpose: Radiotherapy (RT) for early breast cancer (BC) reduces the risk of recurrence and improves overall survival. However, thoracic RT may cause some incidental RT dose to the heart with subsequent risk of heart disease. During 2000-2010, CT-based RT planning was gradually introduced. The aim of this study was to investigate the risk of cardiac events in left-sided compared with right-sided BC patients treated during a non-CT-based (1999-2007) vs a CT-based period (2008-2016).

Material And Methods: Information on BC and cardiac events among Danish women was obtained from population-based medical registers. Patients diagnosed with BC during 1999-2016, were included. A cardiac event was defined as coronary artery disease or severe valvular heart disease.

Results: Among 29,662 patients, 22,056 received RT. For those irradiated during the non-CT-based period, the 10-year cumulative risk of cardiac event was 1.7% (95% CI 1.4-2.0) at median follow-up of 11.1 years. The incidence rate ratio (IRR) for cardiac event in left-sided vs right-sided patients was 1.44 (1.07-1.94) and a trend towards worse outcome was seen within the first 10 years after RT and approached statistical significance with longer follow-up. Among patients irradiated during the CT-based period, the 10-year cumulative risk of cardiac event was 2.1% (1.8-2.4) at median 6.8 years follow-up. The IRR for cardiac event in left-sided vs right-sided patients was 0.90 (0.69-1.16) and no trend towards worse outcome within the first 10 years was observed.

Conclusion: This study confirmed a higher risk of cardiac events in left-sided vs right-sided BC patients irradiated during a non-CT-based period. For patients irradiated during a CT-based period, no increased risk of cardiac events in left-sided vs right-sided patients was observed within the first 10 years after RT, whilst information on cardiac events beyond 10 years after RT was limited.
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http://dx.doi.org/10.1016/j.radonc.2021.01.010DOI Listing
April 2021

Analysis and modeling of environmental prevalence in Minnesota using soil collected to compare basal and outbreak levels.

Appl Environ Microbiol 2020 Dec 18. Epub 2020 Dec 18.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA

Outbreaks of blastomycosis, caused by the fungus , occur in endemic areas of the United States and Canada but the geographic range of blastomycosis is expanding. Previous studies inferred the location of through epidemiologic data associated with outbreaks because culture of from the environment is often unsuccessful. In this study, we used a culture-independent, PCR-based method to identify DNA in environmental samples using the BAD1 promoter region. We tested 250 environmental samples collected in Minnesota, either associated with blastomycosis outbreaks or environmental samples collected from high- and low-endemic regions to determine basal prevalence of in the environment. We identified a fifth BAD1 promoter haplotype of prevalent in Minnesota. Ecological niche analysis identified latitude, longitude, elevation, and site classification as environmental parameters associated with the presence of Using this analysis, a Random Forest model predicted presence in basal environmental samples with 75% accuracy. These data support use of culture-independent, PCR-based environmental sampling to track spread into new regions and to characterize the unknown environmental niche. Upon inhalation of spores from the fungus from the environment, humans and animals can develop the disease blastomycosis. Based on disease epidemiology, is known to be endemic in the United States and Canada around the Great Lakes and in the Ohio and Mississippi River Valleys but is starting to emerge in other areas. is extremely difficult to culture from the environment so little is known about the environmental reservoirs for this pathogen. We used a culture-independent PCR-based assay to identify the presence of DNA in soil samples from Minnesota. By combining molecular data with ecological niche modeling, we were able to predict the presence of in environmental samples with 75% accuracy and to define characteristics of the environmental niche. Importantly, we showed the effectiveness of using a PCR-based assay to identify in environmental samples.
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http://dx.doi.org/10.1128/AEM.01922-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090874PMC
December 2020

The interplay of phenotype and genotype in Cryptococcus neoformans disease.

Biosci Rep 2020 10;40(10)

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, U.S.A.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningitis primarily in immunocompromised individuals. In order to survive and proliferate during infection, C. neoformans must adapt to a variety of stresses it encounters within the host. Patient outcome depends on the interaction between the pathogen and the host. Understanding the mechanisms that C. neoformans uses to facilitate adaptation to the host and promote pathogenesis is necessary to better predict disease severity and establish proper treatment. Several virulence phenotypes have been characterized in C. neoformans, but the field still lacks a complete understanding of how genotype and phenotype contribute to clinical outcome. Furthermore, while it is known that C. neoformans genotype impacts patient outcome, the mechanisms remain unknown. This lack of understanding may be due to the genetic heterogeneity of C. neoformans and the extensive phenotypic variation observed between and within isolates during infection. In this review, we summarize the current understanding of how the various genotypes and phenotypes observed in C. neoformans correlate with human disease progression in the context of patient outcome and recurrence. We also postulate the mechanisms underlying the genetic and phenotypic changes that occur in vivo to promote rapid adaptation in the host.
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http://dx.doi.org/10.1042/BSR20190337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569153PMC
October 2020

Prevention, Detection, and Management of Heart Failure in Patients Treated for Breast Cancer.

Curr Heart Fail Rep 2020 12 26;17(6):397-408. Epub 2020 Sep 26.

Department of Cardiology, Oslo University Hospital, Postbox 4950, Ullevål, Nydalen, 0424, Oslo, Norway.

Purpose Of Review: Long-term survival has increased significantly in breast cancer patients, and cardiovascular side effects are surpassing cancer-related mortality. We summarize risk factors, prevention strategies, detection, and management of cardiotoxicity, with focus on left ventricular dysfunction and heart failure, during breast cancer treatment.

Recent Findings: Baseline treatment of cardiovascular risk factors is recommended. Anthracycline and trastuzumab treatment constitute a substantial risk of developing cardiotoxicity. There is growing evidence that this can be treated with beta blockers and angiotensin antagonists. Early detection of cardiotoxicity with cardiac imaging and circulating cardiovascular biomarkers is currently evaluated in clinical trials. Chest wall irradiation accelerates atherosclerotic processes and induces fibrosis. Immune checkpoint inhibitors require consideration for surveillance due to a small risk of severe myocarditis. Cyclin-dependent kinases4/6 inhibitors, cyclophosphamide, taxanes, tyrosine kinase inhibitors, and endocrine therapy have a lower-risk profile for cardiotoxicity. Preventive and management strategies to counteract cancer treatment-related left ventricular dysfunction or heart failure in breast cancer patients should include a comprehensive cardiovascular risk assessment and individual clinical evaluation. This should include both patient and treatment-related factors. Further clinical trials especially on early detection, cardioprevention, and management are urgently needed.
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http://dx.doi.org/10.1007/s11897-020-00486-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683437PMC
December 2020

Tricuspid Annular Plane Systolic Excursion is a Predictor of Mortality for Septic Shock.

Intern Med J 2020 Jul 2. Epub 2020 Jul 2.

Department of Critical Care Medicine, Division of Anesthesiology and Critical Care, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit #112, Houston, Texas, 77030, USA.

Objective: Cardiac dysfunction is a common sequela in patients with sepsis and multi-organ dysfunction. Echocardiography is commonly used in the investigation of circulatory failure. We aimed to evaluate the prognostic value of echocardiographic parameters in patients with septic shock.

Methods: This study was a retrospective trial. We included patients who were admitted to ICU with septic shock. The patients' echocardiograms, clinical data, and outcomes were obtained from their medical records. Associations between echo-cardiogram variables and mortality were assessed using logistic regression, controlled for age, sex, BMI, and the interval between the ICU admission and echocardiogram. The utility of statistically significant echocardiogram variables to predict mortality were assessed using receiver operating characteristic (ROC) curves.

Results: The outcomes presented that Tricuspid Annular Plane Systolic Excursion(TAPSE) was statistically significantly associated with both ICU (p = 0.02) and 90-day (p = 0.001) mortality. From the ROC curves, TAPSE emerged a significant and moderate predictor for 90-day (area under curve (AUC) = 0.69, 95% CI = 0.565-0.814) and in-ICU mortality (AUC = 0.762, 95% CI = 0.652-0.871). The optimal cut-off for TAPSE was 2.1 cm for both 90-day mortality (sensitivity of 80% and specificity and 58%) and in-ICU mortality (sensitivity of 69% and specificity of 77%).

Conclusion: TAPSE was associated with increased mortality in those with sepsis and suspicion of cardiac dysfunction. This is a hypothesis generating paper that an association may be present and requires significant more work with expansion to the entire population base. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.14957DOI Listing
July 2020

A titanic drug resistance threat in Cryptococcus neoformans.

Curr Opin Microbiol 2019 12 22;52:158-164. Epub 2019 Nov 22.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, 55455 USA. Electronic address:

Increasing resistance to frontline antifungals is a growing threat to global health. In the face of high rates of relapse for patients with cryptococcal meningitis and frequent drug resistance in clinical isolates, recent insights into Cryptococcus neoformans morphogenesis and genome plasticity take on new and urgent meaning. Here we review the state of the understanding of mechanisms of drug resistance in the context of host-relevant changes in Cryptococcus morphology and cell ploidy.
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http://dx.doi.org/10.1016/j.mib.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941473PMC
December 2019

Does socially differentiated cardiac rehabilitation affect the use of healthcare services after myocardial infarction? A 10-year follow-up study.

BMJ Open 2019 10 28;9(10):e030807. Epub 2019 Oct 28.

Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.

Objective: To examine the long-term effect of a socially differentiated cardiac rehabilitation (CR) intervention tailored to reduce social inequalities in health regarding use of healthcare services in general practice and hospital among socially vulnerable patients admitted with first-episode myocardial infarction (MI).

Design: A prospective cohort study with 10 years' follow-up.

Setting: Department of cardiology at a university hospital in Denmark between 2000 and 2004.

Participants: Patients <70 years admitted with first-episode MI categorised as socially vulnerable (n=208) or non-socially vulnerable (n=171) based on educational level and social network.

Intervention: A socially differentiated CR intervention. The intervention consisted of standard CR and expanded CR with focus on cross-sectional collaboration.

Main Outcome Measures: Participation in annual chronic care consultations in general practice, contacts to general practice, all-cause hospitalisations and cardiovascular readmissions.

Results: At 2-year and 5-year follow-up, socially vulnerable patients receiving expanded CR participated significantly more in annual chronic care consultations (p=0.02 and p<0.01) but at 10-year follow-up, there were no significant differences in annual chronic care consultations (p=0.13). At 10-year follow-up, socially vulnerable patients receiving standard CR had significantly more contacts to general practice (p=0.03). At 10-year follow-up, there were no significant differences in the proportion of socially vulnerable patients receiving expanded CR in the mean number of all-cause hospitalisations and cardiovascular readmissions (p>0.05).

Conclusions: The present study found no persistent association between the socially differentiated CR intervention and use of healthcare services in general practice and hospital in patients admitted with first-episode MI during a 10-year follow-up.
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http://dx.doi.org/10.1136/bmjopen-2019-030807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830639PMC
October 2019

Identification of Pathogen Genomic Differences That Impact Human Immune Response and Disease during Cryptococcus neoformans Infection.

mBio 2019 07 16;10(4). Epub 2019 Jul 16.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA

Patient outcomes during infection are due to a complex interplay between the quality of medical care, host immunity factors, and the infecting pathogen's characteristics. To probe the influence of pathogen genotype on human survival, immune response, and other parameters of disease, we examined isolates collected during the Cryptococcal Optimal Antiretroviral Therapy (ART) Timing (COAT) Trial in Uganda. We measured human participants' survival, meningitis disease parameters, immunologic phenotypes, and pathogen growth characteristics. We compared those clinical data to whole-genome sequences from 38  isolates of the most frequently observed sequence type (ST), ST93, in our Ugandan participant population and to sequences from an additional 18 strains of 9 other sequence types representing the known genetic diversity within the Ugandan clinical isolates. We focused our analyses on 652 polymorphisms that were variable among the ST93 genomes, were not in centromeres or extreme telomeres, and were predicted to have a fitness effect. Logistic regression and principal component analysis identified 40 candidate genes and 3 hypothetical RNAs associated with human survival, immunologic response, or clinical parameters. We infected mice with 17 available KN99α gene deletion strains for these candidate genes and found that 35% (6/17) directly influenced murine survival. Four of the six gene deletions that impacted murine survival were novel. Such bedside-to-bench translational research identifies important candidate genes for future studies on virulence-associated traits in human infections. Even with the best available care, mortality rates in cryptococcal meningitis range from 20% to 60%. Disease is often due to infection by the fungus and involves a complex interaction between the human host and the fungal pathogen. Although previous studies have suggested genetic differences in the pathogen impact human disease, it has proven quite difficult to identify the specific genes that impact the outcome of the human infection. Here, we take advantage of a Ugandan patient cohort infected with closely related strains to examine the role of pathogen genetic variants on several human disease characteristics. Using a pathogen whole-genome sequencing approach, we showed that 40  genes are associated with human disease. Surprisingly, many of these genes are specific to and have unknown functions. We also show deletion of some of these genes alters disease in a mouse model of infection, confirming their role in disease. These findings are particularly important because they are the first to identify genes associated with human cryptococcal meningitis and lay the foundation for future studies that may lead to new treatment strategies aimed at reducing patient mortality.
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http://dx.doi.org/10.1128/mBio.01440-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635531PMC
July 2019

Medication adherence, biological and lifestyle risk factors in patients with myocardial infarction: a ten-year follow-up on socially differentiated cardiac rehabilitation.

Scand J Prim Health Care 2019 Jun 23;37(2):182-190. Epub 2019 May 23.

a Section for Clinical Social Medicine and Rehabilitation Department of Public Health , Aarhus University , Aarhus , Denmark.

There is strong evidence that medication adherence and lifestyle changes are essential in patients undergoing secondary cardiovascular disease prevention. Cardiac rehabilitation (CR) increases medication adherence and improves lifestyle changes. Patients with cardiac diseases and a low educational level and patients with little social support are less responsive to improve medication adherence and to adapt lifestyle changes. The aim of the present study was to investigate the long-term effects of a socially differentiated CR intervention on medication adherence as well as changes in biological and lifestyle risk factors at two- five- and ten-year follow-up. A prospective cohort study. The cardiac ward at Aarhus University Hospital, Denmark. A socially differentiated CR intervention in addition to the standard CR program. Patients admitted with first-episode myocardial infarction between 2000 and 2004,  379. Patients were defined as socially vulnerable or non-socially vulnerable according to their educational level and extent of social network. Primary outcome was medication adherence to antithrombotics, beta-blockers, statins and angiotensin-converting enzyme inhibitors. Secondary outcomes were biological and lifestyle risk factors defined as; total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glycated hemoglobin, blood pressure and smoking status. No significant long-term effect of the intervention was found. The results indicate a non-significant effect of the intervention. However, it was found that equality in health was improved in the study population except concerning smoking. General practitioners manage to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status. Key points The socially differentiated intervention did not significantly improve medication adherence or biological and lifestyle risk factors. Despite the non-significant effect of the intervention, equality in health was improved except concerning smoking. General practitioners managed to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status.
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http://dx.doi.org/10.1080/02813432.2019.1608046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566981PMC
June 2019

Standard complication screening information can be used for risk assessment for first time foot ulcer among patients with type 1 and type 2 diabetes.

Diabetes Res Clin Pract 2019 May 18;151:177-186. Epub 2019 Apr 18.

Steno Diabetes Center Copenhagen, Niels Steensensvej 2, 2820 Gentofte, Denmark; Department of Dermatology and Copenhagen Woundhealing Center, Copenhagen Wound Healing Center, Copenhagen University Hospital Bispebjerg, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark.

Aim: Diabetic foot ulcer (DFU) is a major complication of both Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D); however research into risk factors for DFU does not separate between these two types. The purpose of the present investigation was to identify risk factors for development of first time DFU (FTDFU) over a period of 15 years in patients with T1D and T2D separately.

Methods: This retrospective cohort study included 25,220 feet from 5588 patients with T1D and 7113 patients with T2D treated in the period 2001-2015. Data on baseline characteristics and comorbidities were collected from electronic patient records. Influences of various risk factors for the development of FTDFU were assessed by hazard ratios (HR) from Cox proportional hazard regression models on time from enrolment to FTDFU diagnosis or end-of-follow-up.

Results: In T1D independent risk factors were male sex, age >60 years, high HbA1c, long diabetes duration, history of cardiovascular disease, macro-albuminuria, decreased visual acuity, advanced diabetic retinopathy, decreased/absent vibration sense, presence of patient reported symptoms of neuropathy, and absence of foot pulses. In T2D the independent risk factors were the same except age >60 years, a history of cardiovascular disease, and long diabetes duration.

Conclusions: This study documents that much of the standard clinical information obtained as part of the routine follow-up are also independent risk factors for development of FTDFU. This may be used to create a basis for in which patient and when prevention should be started.
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http://dx.doi.org/10.1016/j.diabres.2019.04.021DOI Listing
May 2019

Globally networked learning: Deepening Canadian and Danish nursing students' understanding of nursing, culture and health.

Nurse Educ Today 2019 May 22;76:228-233. Epub 2019 Feb 22.

School of Nursing, Gl. Struervej 1, Via University College, Holstebro DK-7500, Denmark. Electronic address:

Background: Providing intercultural learning experiences that assist students to develop cultural awareness and culturally safe nursing care is an important part of nursing education in Canada and Denmark. However, providing opportunities for students to study and travel to another country can be challenging given the strict requirements to meet entry-to-practice competencies and the timing of clinical placement courses. In an attempt to increase opportunities for students, an innovative strategy called Globally Networked Learning (GNL) that uses the internet and social media, was developed to enable Canadian and Danish nursing students to collaborate and complete a clinically oriented assignment.

Objectives: This study aims to explore three research questions. What are the students' experiences with GNL? How did GNL influence understanding of how culture, nursing care and health systems influence health outcomes? Can GNL support students to develop a global understanding of health and nursing?

Design: A qualitative study was conducted to explore the students' experiences and learning from their participation in GNL.

Setting: A school of nursing in Canada and one in Denmark were used as sites for this study, although the collaborative learning experience occurred online.

Participants: In total, 24 BScN nursing students completed GNL projects (12 from Canada and 12 from Denmark) and 15 students (six Canadian and nine Danish) participated in this study.

Results: Students reported very positive experiences with using GNL to complete an assignment that was structured to support inter-cultural learning. Completing the GNL assignment enhanced students' understanding of the global reach of nursing, how culture influences nursing practice and how considering cultural differences enabled them to learn from each other to improve their nursing practice at home.

Conclusions: GNL is a promising education strategy and plans for expanding GNL in nursing education are proposed.
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http://dx.doi.org/10.1016/j.nedt.2019.02.006DOI Listing
May 2019

The Mouse Inhalation Model of Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence.

Infect Immun 2019 03 23;87(5). Epub 2019 Apr 23.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA

Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet the factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with the clinical outcome, but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIV-infected cryptococcal meningitis patients infected with strains with the same multilocus sequence type (MLST). Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome was not associated with the patient CD4 count. Patient mortality was associated with higher cryptococcal antigen levels, the cerebrospinal fluid (CSF) fungal burden by quantitative culture, and low CSF fungal clearance. The virulence of a subset of clinical strains with the same sequence type was analyzed using a mouse inhalation model of cryptococcosis. We showed a strong association between human and mouse mortality rates, demonstrating that the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply , demonstrated by a high fungal burden in lung and brain tissues, was associated with mouse mortality. Mouse survival time was not associated with single virulence factors or ; rather, a trend in survival time correlated with a suite of traits. These observations show that MLST-derived genotype similarities between strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that assays do not fully reproduce conditions that influence virulence.
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http://dx.doi.org/10.1128/IAI.00046-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479045PMC
March 2019

Titan cell production in reshapes the cell wall and capsule composition during infection.

Cell Surf 2018 Mar 16;1:15-24. Epub 2018 Feb 16.

Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, USA.

is a human fungal pathogen that often causes infections in immunocompromised individuals. Upon inhalation into the lungs differentiates into cells with altered size and morphology, including production of large titan cells. Titan cells possess thickened cell wall and dense, cross-linked capsule when compared to grown cells. In addition, titan cells have increased cell wall chitin that is associated with a detrimental anti-inflammatory immune response. Here we examined the cell wall and capsule composition of , typical-sized and titan cells using High Performance Liquid Chromatography (HPLC). The monomer composition of cell wall polysaccharides showed that cells contained more glucosamine and less glucose than cells, suggesting alteration in abundance of both chitin and glucans, respectively. Low levels of galactosamine were also detected in carbohydrates from both and cells. Within the cell population, differences in the proportions of cell wall and capsule monomers between typical and titan cells were also observed. Taken together, these results demonstrate that reshapes its cell wall and capsule composition during infection. These cell wall and capsule alterations likely help escape recognition by, and allow modulation of, the host immune system.
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http://dx.doi.org/10.1016/j.tcsw.2017.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095662PMC
March 2018

Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators.

PLoS Pathog 2018 05 18;14(5):e1006982. Epub 2018 May 18.

Institut Pasteur, Molecular Mycology Unit, Département de Mycologie, Paris, France.

The pathogenic fungus Cryptococcus neoformans exhibits morphological changes in cell size during lung infection, producing both typical size 5 to 7 μm cells and large titan cells (> 10 μm and up to 100 μm). We found and optimized in vitro conditions that produce titan cells in order to identify the ancestry of titan cells, the environmental determinants, and the key gene regulators of titan cell formation. Titan cells generated in vitro harbor the main characteristics of titan cells produced in vivo including their large cell size (>10 μm), polyploidy with a single nucleus, large vacuole, dense capsule, and thick cell wall. Here we show titan cells derived from the enlargement of progenitor cells in the population independent of yeast growth rate. Change in the incubation medium, hypoxia, nutrient starvation and low pH were the main factors that trigger titan cell formation, while quorum sensing factors like the initial inoculum concentration, pantothenic acid, and the quorum sensing peptide Qsp1p also impacted titan cell formation. Inhibition of ergosterol, protein and nucleic acid biosynthesis altered titan cell formation, as did serum, phospholipids and anti-capsular antibodies in our settings. We explored genetic factors important for titan cell formation using three approaches. Using H99-derivative strains with natural genetic differences, we showed that titan cell formation was dependent on LMP1 and SGF29 genes. By screening a gene deletion collection, we also confirmed that GPR4/5-RIM101, and CAC1 genes were required to generate titan cells and that the PKR1, TSP2, USV101 genes negatively regulated titan cell formation. Furthermore, analysis of spontaneous Pkr1 loss-of-function clinical isolates confirmed the important role of the Pkr1 protein as a negative regulator of titan cell formation. Through development of a standardized and robust in vitro assay, our results provide new insights into titan cell biogenesis with the identification of multiple important factors/pathways.
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http://dx.doi.org/10.1371/journal.ppat.1006982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959062PMC
May 2018

[Management of cardiovascular complications secondary to medical treatment of cancer].

Ugeskr Laeger 2018 Feb;180(7)

As the prognoses of both heart and cancer patients have improved along with a longer life expectancy in the general population, the prevalence of both heart- and cancer diseases is increasing. Thus, a larger proportion of cancer patients will have cardiovascular co-morbidity and an increased risk of cardiovascular complications during and after cancer treatment. In this article, the current knowledge on the prevention, monitoring and treatment of cardiotoxicity induced by medical anti-cancer treatment with focus on anthracyclines, trastuzumab and 5-fluorouracil is described.
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February 2018

Expanded cardiac rehabilitation in socially vulnerable patients with myocardial infarction: a 10-year follow-up study focusing on mortality and non-fatal events.

BMJ Open 2018 01 23;8(1):e019307. Epub 2018 Jan 23.

Department of Cardiology, Danish Centre for Inequality in Health, Aalborg University Hospital, Aalborg, Denmark.

Objective: Cardiac rehabilitation (CR) has been shown to reduce cardiovascular risk. A research project performed at a university hospital in Denmark offered an expanded CR intervention to socially vulnerable patients. One-year follow-up showed significant improvements concerning medicine compliance, lipid profile, blood pressure and body mass index when compared with socially vulnerable patients receiving standard CR. The aim of the study was to perform a long-term follow-up on the socially differentiated CR intervention and examine the impact of the intervention on all-cause mortality, cardiovascular mortality, non-fatal recurrent events and major cardiac events (MACE) 10 years after.

Design: Prospective cohort study.

Setting: The cardiac ward at a university hospital in Denmark from 2000 to 2004.

Participants: 379 patients aged <70 years admitted with first episode myocardial infarction (MI). The patients were defined as socially vulnerable or non-socially vulnerable according to their educational level and their social network. A complete follow-up was achieved.

Intervention: A socially differentiated CR intervention. The intervention consisted of standard CR and additionally a longer phase II course, more consultations, telephone follow-up and a better handover to phase III CR in the municipal sector, in general practice and in the patient association.

Main Outcome Measures: All-cause mortality, cardiovascular mortality, non-fatal recurrent events and MACE.

Results: There was no significant difference in all-cause mortality (OR: 1.29, 95% CI 0.58 to 2,89), cardiovascular mortality (OR: 0.80, 95% CI 0.31 to 2.09), non-fatal recurrent events (OR:1.62, 95% CI 0.67 to 3.92) or MACE (OR: 1.31, 95% CI 0.53 to 2.42) measured at 10-year follow-up when comparing the expanded CR intervention to standard CR.

Conclusions: Despite the significant results of the socially differentiated CR intervention at 1-year follow-up, no long-term effects were seen regarding the main outcome measures at 10-year follow-up. Future research should focus on why it is not possible to lower the mortality and morbidity significantly among socially vulnerable patients admitted with first episode MI.
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http://dx.doi.org/10.1136/bmjopen-2017-019307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786137PMC
January 2018

Morphology Changes in Human Fungal Pathogens upon Interaction with the Host.

J Fungi (Basel) 2017 1;3(4). Epub 2017 Dec 1.

Department of Microbiology and Immunity, Medical School, University of Minnesota, 689 23rd Ave SE, Minneapolis, MN 55455, USA.

Morphological changes are a very common and effective strategy for pathogens to survive in the mammalian host. During interactions with their host, human pathogenic fungi undergo an array of morphological changes that are tightly associated with virulence. switches between yeast cells and hyphae during infection. Thermally dimorphic pathogens, such as and species transform from hyphal growth to yeast cells in response to host stimuli. and species produce spherules and cysts, respectively, which allow for the production of offspring in a protected environment. Finally, species suppress hyphal growth and instead produce an array of yeast cells-from large polyploid titan cells to micro cells. While the morphology changes produced by human fungal pathogens are diverse, they all allow for the pathogens to evade, manipulate, and overcome host immune defenses to cause disease. In this review, we summarize the morphology changes in human fungal pathogens-focusing on morphological features, stimuli, and mechanisms of formation in the host.
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http://dx.doi.org/10.3390/jof3040066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753168PMC
December 2017

Adaptive Immunity to Infections.

J Fungi (Basel) 2017 21;3(4). Epub 2017 Nov 21.

Department of Microbiology and Immunology, Medical School, University of Minnesota, 689 23rd Ave SE, Minneapolis, MN 55455, USA.

The / species complex is a group of fungal pathogens with different phenotypic and genotypic diversity that cause disease in immunocompromised patients as well as in healthy individuals. The immune response resulting from the interaction between and the host immune system is a key determinant of the disease outcome. The species causes the majority of human infections, and therefore almost all immunological studies focused on infections. Thus, this review presents current understanding on the role of adaptive immunity during infections both in humans and in animal models of disease.
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http://dx.doi.org/10.3390/jof3040064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753166PMC
November 2017

Importance of Resolving Fungal Nomenclature: the Case of Multiple Pathogenic Species in the Genus.

mSphere 2017 Jul-Aug;2(4). Epub 2017 Aug 30.

Department of Bacteriology and Mycology, Tropical Medicine Institute Pedro Kouri, Havana, Cuba.

Cryptococcosis is a major fungal disease caused by members of the and species complexes. After more than 15 years of molecular genetic and phenotypic studies and much debate, a proposal for a taxonomic revision was made. The two varieties within were raised to species level, and the same was done for five genotypes within . In a recent perspective (K. J. Kwon-Chung et al., mSphere 2:e00357-16, 2017, https://doi.org/10.1128/mSphere.00357-16), it was argued that this taxonomic proposal was premature and without consensus in the community. Although the authors of the perspective recognized the existence of genetic diversity, they preferred the use of the informal nomenclature " species complex" and " species complex." Here we highlight the advantage of recognizing these seven species, as ignoring these species will impede deciphering further biologically and clinically relevant differences between them, which may in turn delay future clinical advances.
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http://dx.doi.org/10.1128/mSphere.00238-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577652PMC
August 2017

Evaluation of trypan blue stain in a haemocytometer for rapid detection of cerebrospinal fluid sterility in HIV patients with cryptococcal meningitis.

BMC Microbiol 2017 Aug 22;17(1):182. Epub 2017 Aug 22.

Infectious Diseases Institute, College of Health Sciences, Makerere University, P.O.BOX 22418, Kampala, Uganda.

Background: Quantitative culture is the most common method to determine the fungal burden and sterility of cerebrospinal fluid (CSF) among persons with cryptococcal meningitis. A major drawback of cultures is a long turnaround-time. Recent evidence demonstrates that live and dead Cryptococcus yeasts can be distinguished using trypan blue staining. We hypothesized that trypan blue staining combined with haemocytometer counting may provide a rapid estimation of quantitative culture count and detection of CSF sterility. To test this, we evaluated 194 CSF specimens from 96 HIV-infected participants with cryptococcal meningitis in Kampala, Uganda. Cryptococcal meningitis was diagnosed by CSF cryptococcal antigen (CRAG). We stained CSF with trypan blue and quantified yeasts using a haemocytometer. We compared the haemocytometer readings versus quantitative Cryptococcus CSF cultures.

Results: Haemocytometer counting with trypan blue staining had a sensitivity of 98% (64/65), while CSF cultures had a sensitivity of 95% (62/65) with reference to CSF CRAG for diagnostic CSF specimens. For samples that were positive in both tests, the haemocytometer had higher readings compared to culture. For diagnostic specimens, the median of log transformed counts were 5.59 (n = 64, IQR = 5.09 to 6.05) for haemocytometer and 4.98 (n = 62, IQR = 3.75 to 5.79) for culture; while the overall median counts were 5.35 (n = 189, IQR = 4.78-5.84) for haemocytometer and 3.99 (n = 151, IQR = 2.59-5.14) for cultures. The percentage agreement with culture sterility was 2.4% (1/42). Counts among non-sterile follow-up specimens had a median of 5.38 (n = 86, IQR = 4.74 to 6.03) for haemocytometer and 2.89 (n = 89, IQR = 2.11 to 4.38) for culture. At diagnosis, CSF quantitative cultures correlated with haemocytometer counts (R = 0.59, P < 0.001). At 7-14 days, quantitative cultures did not correlate with haemocytometer counts (R = 0.43, P = 0.4).

Conclusion: Despite a positive correlation, the haemocytometer counts with trypan blue staining did not predict the outcome of quantitative cultures in patients receiving antifungal therapy.
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http://dx.doi.org/10.1186/s12866-017-1093-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567638PMC
August 2017

AIDS-Related Mycoses: Current Progress in the Field and Future Priorities.

Trends Microbiol 2017 06 25;25(6):428-430. Epub 2017 Apr 25.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, 55455, USA.

Opportunistic fungal infections continue to take an unacceptably heavy toll on the most disadvantaged living with HIV-AIDS, and are a major driver for HIV-related deaths. At the second EMBO Workshop on AIDS-Related Mycoses, clinicians and scientists from around the world reported current progress and key priorities for improving outcomes from HIV-related mycoses.
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http://dx.doi.org/10.1016/j.tim.2017.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549875PMC
June 2017

Short and long term radiation induced cardiovascular disease in patients with cancer.

Clin Cardiol 2017 Apr 31;40(4):255-261. Epub 2017 Jan 31.

Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Radiation-induced cardiovascular disease is well described as a late effect in cancer patients treated with radiation therapy. Advancements in surgery, radiotherapy, and chemotherapy have led to an increasing number of cancer survivors with resultant long-term side effects related to their cancer treatments. In this review, we describe the short- and long-term cardiovascular consequences of mediastinal radiotherapy and discuss the optimal cardiovascular assessments and diagnostic tools in asymptomatic and symptomatic patients.
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http://dx.doi.org/10.1002/clc.22634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589645PMC
April 2017

MLST-Based Population Genetic Analysis in a Global Context Reveals Clonality amongst Cryptococcus neoformans var. grubii VNI Isolates from HIV Patients in Southeastern Brazil.

PLoS Negl Trop Dis 2017 01 18;11(1):e0005223. Epub 2017 Jan 18.

Infectious Disease Department, Triangulo Mineiro Federal University, Uberaba, Brazil.

Cryptococcosis is an important fungal infection in immunocompromised individuals, especially those infected with HIV. In Brazil, despite the free availability of antiretroviral therapy (ART) in the public health system, the mortality rate due to Cryptococcus neoformans meningitis is still high. To obtain a more detailed picture of the population genetic structure of this species in southeast Brazil, we studied 108 clinical isolates from 101 patients and 35 environmental isolates. Among the patients, 59% had a fatal outcome mainly in HIV-positive male patients. All the isolates were found to be C. neoformans var. grubii major molecular type VNI and mating type locus alpha. Twelve were identified as diploid by flow cytometry, being homozygous (AαAα) for the mating type and by PCR screening of the STE20, GPA1, and PAK1 genes. Using the ISHAM consensus multilocus sequence typing (MLST) scheme, 13 sequence types (ST) were identified, with one being newly described. ST93 was identified from 81 (75%) of the clinical isolates, while ST77 and ST93 were identified from 19 (54%) and 10 (29%) environmental isolates, respectively. The southeastern Brazilian isolates had an overwhelming clonal population structure. When compared with populations from different continents based on data extracted from the ISHAM-MLST database (mlst.mycologylab.org) they showed less genetic variability. Two main clusters within C. neoformans var. grubii VNI were identified that diverged from VNB around 0.58 to 4.8 million years ago.
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http://dx.doi.org/10.1371/journal.pntd.0005223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242430PMC
January 2017

Different Lymphocyte Populations Direct Dichotomous Eosinophil or Neutrophil Responses to Pulmonary Cryptococcus Infection.

J Immunol 2017 02 9;198(4):1627-1637. Epub 2017 Jan 9.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455;

Many pulmonary infections elicit lymphocyte responses that lead to an accumulation of granulocytes in the lungs. A variety of lymphocytes are capable of directing eosinophils or neutrophils to the lungs, but the contribution of each subset remains enigmatic. In this study, we used a murine model to examine lymphocyte subsets that ultimately drive the eosinophil or neutrophil response to infection with the fungal pathogen Cryptococcus neoformans. We show that granulocytes are produced in the bone marrow, released into the blood stream, and accumulate in the lungs under the instruction of lung parenchymal lymphocytes. The eosinophils that populated the lungs of wild-type animals were highly dependent on Th cells or IL-5. Surprisingly, infected mice with Th cell impairment experienced a compensatory neutrophil response that required IL-17A. This unexpected swing in the response prompted us to investigate the ability of different lymphocyte subsets to produce this dichotomous eosinophilia or neutrophilia. We used mice with lymphocyte deficiencies to determine which of the remaining IL-5- or IL-17A-producing lymphocyte subsets dominated the neutrophil or eosinophil response. Finally, skewing the response toward neutrophil-inducing lymphocytes correlated with accelerated disease. Our data collectively demonstrate that the predominance of a lymphocyte subset determines the functional consequences of an immune response to pulmonary fungal infection that can ultimately affect disease.
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http://dx.doi.org/10.4049/jimmunol.1600821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296217PMC
February 2017

Transcatheter left atrial appendage occlusion in patients with atrial fibrillation and a high bleeding risk using aspirin alone for post-implant antithrombotic therapy.

EuroIntervention 2017 Apr;12(17):2075-2082

Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.

Aims: The aim of the study was to evaluate the safety and efficacy of left atrial appendage occlusion (LAAO) with the AMPLATZER Cardiac Plug (ACP) or Amulet using aspirin alone (ASA) as post-implantation antithrombotic treatment.

Methods And Results: This was a single-centre, prospective, non-randomised study on LAAO with the ACP or Amulet in a consecutive cohort (n=110) treated by ASA alone post implantation. The primary outcome was device-related thrombosis, while secondary outcomes were ischaemic stroke or major bleeding. Clinical follow-up was conducted after six weeks and 12 months with TEE and cardiac CT. One hundred and seven patients were included in the analysis. Three patients were excluded due to a mechanical valve prosthesis. CHA2DS2-VASc score was 4.4±1.6 and HAS-BLED 4.1±1.1. Successful implantation was obtained in all patients with a periprocedural complication rate of 4.6%. Median follow-up was 2.3 years, with a total of 265 patient-years. Device-related thrombosis was detected in 2/107 (1.9%) cases. Stroke occurred in 6/107 patients, with an annualised rate of 2.3%, which is a 61% risk reduction compared to the predicted rate. Annual risk of major bleeding was reduced by 57%.

Conclusions: LAAO with the ACP or Amulet was safely performed with ASA monotherapy after implantation without an increased risk of device-related thrombosis or stroke.
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http://dx.doi.org/10.4244/EIJ-D-16-00726DOI Listing
April 2017

It's not all about us: evolution and maintenance of Cryptococcus virulence requires selection outside the human host.

Yeast 2017 04 12;34(4):143-154. Epub 2017 Jan 12.

Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA.

Cryptococcus is predominantly an AIDS-related pathogen that causes significant morbidity and mortality in immunocompromised patients. Research studies have historically focused on understanding how the organism causes human disease through the use of in vivo and in vitro model systems to identify virulence factors. Cryptococcus is not an obligate pathogen, however, as human-human transmission is either absent or rare. Selection in the environment must thus be invoked to shape the evolution of this taxa, and directly influences genotypic and trait diversity. Importantly, the evolution and maintenance of pathogenicity must also stem directly from environmental selection. To that end, here we examine abiotic and biotic stresses in the environment, and discuss how they could shape the factors that are commonly identified as important virulence traits. We identify a number of important unanswered questions about Cryptococcus diversity and evolution that are critical for understanding this deadly pathogen, and discuss how implementation of modern sampling and genomic tools could be utilized to answer these questions. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/yea.3222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528103PMC
April 2017

[Cardiovascular complications following thoracic radiotherapy in patients with cancer].

Ugeskr Laeger 2016 Sep;178(39)

Cardiovascular complications following thoracic radiotherapy in patients with cancer are well described. Advancements in surgery, radiotherapy and systemic treatments have led to an increasing number of cancer survivors and thus an increasing number of patients with long-term side effects of their cancer treatments. This article describes the short- and long-term cardiovascular morbidity and mortality following thoracic radiotherapy and further, optimal cardiovascular assessments and diagnostic tools in asymptomatic and symptomatic patients.
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September 2016
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