Publications by authors named "Sanne Jensen"

55 Publications

Quality of life in pediatric patients with obsessive-compulsive disorder during and 3 years after stepped-care treatment.

Eur Child Adolesc Psychiatry 2021 Apr 21. Epub 2021 Apr 21.

Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Psychiatry, Denmark.

The present study aimed to investigate the long-term quality of life (QoL) in a large sample of pediatric obsessive-compulsive disorder (OCD) patients. The study included 220 pediatric OCD patients from the Nordic Long-term OCD Treatment Study (NordLOTS) who were evaluated at seven time points before, during, and after stepped-care treatment over a 3-year follow-up period. Data from three symptom severity trajectory classes formed the basis of the QoL evaluation: acute (n = 127, N = 147), slow (n = 46, N = 63), and limited responders (n = 47, N = 59). Patients' QoL was assessed using parent and child ratings of the revised Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL-R). QoL was analyzed by trajectory class using a random mixed effects model. The association between pre-treatment factors and long-term QoL was investigated across classes in a multivariate model. Three years after treatment, the acute responder class had reached QoL levels from a general population, whereas the limited responder class had not. The slow responder class reached norm levels for the child-rated QoL only. Higher levels of co-occurring externalizing symptoms before treatment were associated with lower parent-rated QoL during follow-up, while adolescence and higher levels of co-occurring internalizing symptoms were associated with lower child-rated QoL during follow-up. For some patients, residual OCD symptoms in the years after treatment, even at levels below assumed clinical significance, are associated with compromised QoL. Co-occurring symptoms could be part of the explanation. Assessing QoL after OCD treatment, beyond the clinician-rated symptom severity, could detect patients in need of further treatment and/or assessment. Trial registry: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com ; ISRCTN66385119.
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http://dx.doi.org/10.1007/s00787-021-01775-wDOI Listing
April 2021

Identification of Binding Sites on Human Serum Albumin for Somapacitan, a Long-Acting Growth Hormone Derivative.

Biochemistry 2020 04 30;59(14):1410-1419. Epub 2020 Mar 30.

Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Måløv, Denmark.

Somapacitan, a human growth hormone derivative that binds reversibly to albumin, was investigated for human serum albumin (HSA) and HSA domain binding. Isothermal titration calorimetry (ITC) binding profiles showed high-affinity binding (∼100-1000 nM) of one somapacitan molecule and low-affinity binding (∼1000-10000 nM) of one to two somapacitan molecules to HSA. The high-affinity site was identified in HSA domain III using size exclusion chromatography (SEC) and ITC. SEC studies showed that the neonatal Fc receptor shields one binding site for somapacitan, indicating its position in domain III. A crystal structure of somapacitan in complex with HSA optimized for neonatal Fc receptor binding, having four amino acid residue replacements, identified a low-affinity site in fatty acid-binding site 6 (domain II). Surface plasmon resonance (SPR) showed these replacements affect the kinetics of the high-affinity binding site. Furthermore, small-angle X-ray scattering and SPR brace two somapacitan-binding sites on HSA.
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http://dx.doi.org/10.1021/acs.biochem.0c00019DOI Listing
April 2020

Distinct trajectories of long-term symptom severity in pediatric obsessive-compulsive disorder during and after stepped-care treatment.

J Child Psychol Psychiatry 2020 09 17;61(9):969-978. Epub 2019 Nov 17.

Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Psychiatry, Aarhus, Denmark.

Background: First-line treatments for pediatric obsessive-compulsive disorder (OCD) include exposure-based cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs). No studies have thus far identified distinct classes and associated predictors of long-term symptom severity during and after treatment. Yet, these could form the basis for more personalized treatment in pediatric OCD.

Method: The study included 269 OCD patients aged 7-17 years from the Nordic Long-term OCD Treatment Study (NordLOTS). All participants received stepped-care treatment starting with 14 weekly sessions of manualized CBT. Nonresponders were randomized to either prolonged CBT or SSRIs. Symptom severity was assessed using the Children's Yale-Brown Obsessive-Compulsive Scale at seven time points from pre- to post-treatment and over a three-year follow-up. Latent class growth analysis (LCGA) was performed to identify latent classes of symptom severity trajectories. Univariate and multivariate analyses were used to detect differences between classes and identify predictors of trajectory class membership including several clinical and demographic variables.

Trial Registry: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com; ISRCTN66385119.

Results: Three LCGA classes were identified: (a) acute, sustained responders (54.6%); (b) slow, continued responders (23.4%); and (c) limited long-term responders (21.9%). Class membership was predicted by distinct baseline characteristics pertaining to age, symptom severity, contamination/cleaning and anxiety symptoms.

Conclusions: The LCGA suggests three distinct trajectory classes of long-term symptom severity during and after treatment in pediatric OCD with different clinical profiles at pretreatment. The results point to required clinical attention for adolescent patients with contamination/cleaning and anxiety symptoms who do not show convincing responses to first-line treatment even though they may have reached the established cutoff for treatment response.
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http://dx.doi.org/10.1111/jcpp.13155DOI Listing
September 2020

A Paradigm Shift: Sharing Patient Reported Outcome via a National Infrastructure.

Stud Health Technol Inform 2019 Aug;264:694-698

MEDIQ - Medical Informatics and Quality Development, Denmark.

Digital solutions transform the way clinical services can be provided and make it possible for patients to participate in decisions concerning their own treatment. With the aim to support a better and more efficient healthcare system in Denmark, it has been agreed among authorities and care providers to establish a national infrastructure for sharing data between hospitals, municipalities, general practitioners and patients and concurrently develop standardized national digital cross-sector questionnaires for the purpose. Sharing data via the national infrastructure enables proactive involvement through patient reported outcomes (PRO). The national infrastructure forms a paradigm shift 1) for collaboration by moving from a baton-passing workflow to sharing-based workflow and 2) for the development of digital cross-sector questionnaires. Cross-sector questionnaire definitions are stored in a national questionnaire repository, and are used in local PRO applications to capture the patients' responses.
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http://dx.doi.org/10.3233/SHTI190312DOI Listing
August 2019

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants.

Hepatology 2019 09 5;70(3):771-787. Epub 2019 Jun 5.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance-associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1-4, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156-RASs were not maintained. For genotypes 1 and 2, persistence of 156-RASs depended on genome-wide substitution networks, co-selected under continued PI treatment and identified by next-generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156-RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre-existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir/elbasvir and glecaprevir/pibrentasvir. In genotype 1 infected patients with treatment failure and 156-RASs, we observed genome-wide selection of substitutions under treatment. Conclusion: Comprehensive PI resistance profiling for HCV genotypes 1-6 revealed 156-RASs as key determinants of high-level resistance across clinically relevant PIs. We obtained in vitro proof of concept for persistence of highly fit genotype 1-3 156-variants, which might pose a threat to clinically relevant combination treatments.
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http://dx.doi.org/10.1002/hep.30647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772116PMC
September 2019

Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals.

AIDS 2019 07;33(8):1315-1325

Department of Infectious Diseases, Aarhus University Hospital.

Design: This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy.

Methods: We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety was assessed throughout the study. The primary outcome was reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, and time to viral rebound (viral load > 5000 copies/ml) after randomization into an analytical treatment interruption (ATI).

Results: A total of 12 individuals completed the treatment phase and nine completed the ATI. Adverse events were limited and consistent with previous reports for MGN1703. Although the dosing regimen led to potent T-cell activation and increased HIV-1-specific T-cell responses, there were no cohort-wide changes in persistent virus (total CD4 T cells viral DNA; P = 0.34). No difference in time to rebound was observed between the ATI arms (log rank P = 0.25). One of nine ATI participants, despite harboring a large replication-competent reservoir, controlled viremia for 150 days via both HIV-1-specific cellular and antibody-mediated immune responses.

Conclusion: A period of 24 weeks of MGN1703 treatment was safe and improved innate as well as HIV-1-specific adaptive immunity in HIV-1+ individuals. These findings support the incorporation of TLR9 agonism into combination HIV-1 cure strategies.

Trial Name And Registration: TLR9 Enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1B/2A trial; ClinicalTrials.gov NCT02443935.
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http://dx.doi.org/10.1097/QAD.0000000000002213DOI Listing
July 2019

Treatment Gains Are Sustainable in Pediatric Obsessive-Compulsive Disorder: Three-Year Follow-Up From the NordLOTS.

J Am Acad Child Adolesc Psychiatry 2020 02 14;59(2):244-253. Epub 2019 Feb 14.

Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Regional Centre for Child and Youth Mental Health and Child Welfare, Norwegian University of Science and Technology, Trondheim, Norway.

Objective: This study evaluated the long-term outcomes of a stepped care treatment for pediatric obsessive-compulsive disorder (OCD) and investigated whether response to first-step cognitive-behavioral therapy (CBT) is an important indicator of 3-year outcomes.

Method: This study is a part of the Nordic Long-term OCD Treatment Study (NordLOTS), in which 269 children and adolescents were treated with CBT. Nonresponders to CBT were randomized to extended treatment with continued CBT or pharmacotherapy with sertraline. Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) scores no higher than 15 and no higher than 10 were defined as treatment response and remission, respectively. Participants were assessed 2 and 3 years after first-step CBT. Linear mixed-effects models were used to analyze the outcomes.

Results: Intent-to-treat analyses showed a significant decrease in CY-BOCS total score from baseline (24.6) to 3-year follow-up (5.0; p = .001), with a mean decrease of 5.9 from after treatment to 3-year follow-up. Three years after treatment, 90% (n = 242) of participants were rated as responders and 73% were in clinical remission. The duration of treatment did not influence the symptom level at 3-year follow-up (p = .998) and no significant difference was found (p = .169) between the extended treatment conditions.

Conclusion: The results suggest that evidence-based treatment for pediatric OCD has long-term positive effects, whether a first step of manual-based CBT or extended treatment with CBT or sertraline. The improvements were maintained, and the symptoms decreased further during follow-up and were, after 3 years, similarly independent of treatment duration and form of extended treatment.

Clinical Trial Registration Information: Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com; ISRCTN66385119.
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http://dx.doi.org/10.1016/j.jaac.2019.01.010DOI Listing
February 2020

HCV genotype 1-6 NS3 residue 80 substitutions impact protease inhibitor activity and promote viral escape.

J Hepatol 2019 03 3;70(3):388-397. Epub 2018 Nov 3.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Electronic address:

Background & Aims: Protease inhibitors (PIs) are of central importance in the treatment of patients with chronic hepatitis C virus (HCV) infection. HCV NS3 protease (NS3P) position 80 displays polymorphisms associated with resistance to the PI simeprevir for HCV genotype 1a. We investigated the effects of position-80-substitutions on fitness and PI-resistance for HCV genotypes 1-6, and analyzed evolutionary mechanisms underlying viral escape mediated by pre-existing Q80K.

Methods: The fitness of infectious NS3P recombinants of HCV genotypes 1-6, with engineered position-80-substitutions, was studied by comparison of viral spread kinetics in Huh-7.5 cells in culture. Median effective concentration (EC50) and fold resistance for PIs simeprevir, asunaprevir, paritaprevir, grazoprevir, glecaprevir and voxilaprevir were determined in short-term treatment assays. Viral escape was studied by long-term treatment of genotype 1a recombinants with simeprevir, grazoprevir, glecaprevir and voxilaprevir and of genotype 3a recombinants with glecaprevir and voxilaprevir, next generation sequencing, NS3P substitution linkage and haplotype analysis.

Results: Among tested PIs, only glecaprevir and voxilaprevir showed pan-genotypic activity against the original genotype 1-6 culture viruses. Variants with position-80-substitutions were all viable, but fitness depended on the specific substitution and the HCV isolate. Q80K conferred resistance to simeprevir across genotypes but had only minor effects on the activity of the remaining PIs. For genotype 1a, pre-existing Q80K mediated accelerated escape from simeprevir, grazoprevir and to a lesser extent glecaprevir, but not voxilaprevir. For genotype 3a, Q80K mediated accelerated escape from glecaprevir and voxilaprevir. Escape was mediated by rapid and genotype-, PI- and PI-concentration-dependent co-selection of clinically relevant resistance associated substitutions.

Conclusions: Position-80-substitutions had relatively low fitness cost and the potential to promote HCV escape from clinically relevant PIs in vitro, despite having a minor impact on results in classical short-term resistance assays.

Lay Summary: Among all clinically relevant hepatitis C virus protease inhibitors, voxilaprevir and glecaprevir showed the highest and most uniform activity against cell culture infectious hepatitis C virus with genotype 1-6 proteases. Naturally occurring amino acid changes at protease position 80 had low fitness cost and influenced sensitivity to simeprevir, but not to other protease inhibitors in short-term treatment assays. Nevertheless, the pre-existing change Q80K had the potential to promote viral escape from protease inhibitors during long-term treatment by rapid co-selection of additional resistance changes, detected by next generation sequencing.
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http://dx.doi.org/10.1016/j.jhep.2018.10.031DOI Listing
March 2019

Establishing a Nation Wide Infrastructure for Systematic Use of Patient Reported Information.

Stud Health Technol Inform 2018 ;247:226-230

National Health Data Authority, Denmark.

In Denmark, we have set up a program to establish a nationwide infrastructure for Patient Reported Outcome (PRO) questionnaires. The effort is divided into an IT infrastructure part and a questionnaire development part. This paper describes how development and evaluation are closely knit together in the two tracks, as complexity is high in the PRO field and IT infrastructure, legal issues, various clinical workflows and the numerous stakeholders have to be taken into account concurrently. In the design process, we have thus used a participatory design approach to ensure a high level of active stakeholder involvement and capability of addressing all the relevant issues. In the next phases, we will apply the IT infrastructure in the planned full-scale evaluation of the questionnaires developed in the first phase, while we continue to develop new national questionnaires.
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June 2018

One-Year Outcome for Responders of Cognitive-Behavioral Therapy for Pediatric Obsessive-Compulsive Disorder.

J Am Acad Child Adolesc Psychiatry 2017 Nov 13;56(11):940-947.e1. Epub 2017 Sep 13.

Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Risskov, Denmark.

Objective: This study describes 1-year treatment outcomes from a large sample of cognitive-behavioral therapy (CBT) responders, investigates age as a possible moderator of these treatment outcomes, and evaluates clinical relapse at the 1-year follow-up.

Method: This study is the planned follow-up to the Nordic Long-term OCD [obsessive-compulsive disorder] Treatment Study (NordLOTS), which included 177 children and adolescents who were rated as treatment responders following CBT for OCD. Participants were assessed with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) at 6- and 12-month follow-up. Treatment response and remission were defined as CY-BOCS total scores ≤15 and ≤10, respectively. Linear mixed-effects models were used to analyze all outcomes.

Results: At 1 year, a total of 155 children and adolescents (87.6%) were available for follow-up assessment, with 142 of these (91.6%) rated below a total score of ≤15 on the CY-BOCS. At 1-year follow-up, 121 (78.1%) were in remission. On average, CY-BOCS total scores dropped by 1.72 points during the first year after terminating treatment (p = .001). A total of 28 participants (15.8%) relapsed (CY-BOCS ≥ 16) at either the 6- or 12-month assessment; only 2 patients required additional CBT.

Conclusion: Results suggest that manualized CBT in a community setting for pediatric OCD has durable effects for those who respond to an initial course of treatment; children and adolescents who respond to such treatment can be expected to maintain their treatment gains for at least 1 year following acute care. Clinical trial registration information- Nordic Long-term Obsessive-Compulsive Disorder (OCD) Treatment Study; www.controlled-trials.com; ISRCTN66385119.
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http://dx.doi.org/10.1016/j.jaac.2017.09.002DOI Listing
November 2017

Immunization with Clinical HIV-1 Env Proteins Induces Broad Antibody Dependent Cellular Cytotoxicity-Mediating Antibodies in a Rabbit Vaccination Model.

AIDS Res Hum Retroviruses 2018 02 17;34(2):206-217. Epub 2017 Nov 17.

1 Department of Virology and Special Microbial Diagnostic, Statens Serum Institut , Copenhagen, Denmark .

The induction of both neutralizing antibodies and non-neutralizing antibodies with effector functions, for example, antibody-dependent cellular cytotoxicity (ADCC), is desired in the search for effective vaccines against HIV-1. In the pursuit of novel immunogens capable of inducing an efficient antibody response, rabbits were immunized with selected antigens using different prime-boost strategies. We immunized 35 different groups of rabbits with Env antigens from clinical HIV-1 subtypes A and B, including immunization with DNA alone, protein alone, and DNA prime with protein boost. The rabbit sera were screened for ADCC activity using a GranToxiLux-based assay with human peripheral blood mononuclear cells as effector cells and CEM.NKR cells coated with HIV-1 envelope as target cells. The groups with the highest ADCC activity were further characterized for cross-reactivity between HIV-1 subtypes. The immunogen inducing the most potent and broadest ADCC response was a trimeric gp140. The ADCC activity was highest against the HIV-1 subtype corresponding to the immunogen. The ADCC activity did not necessarily reflect neutralizing activity in the pseudovirus-TZMbl assay, but there was an overall correlation between the two antiviral activities. We present a rabbit vaccination model and an assay suitable for screening HIV-1 vaccine candidates for the induction of ADCC-mediating antibodies in addition to neutralizing antibodies. The antigens and/or immunization strategies capable of inducing antibodies with ADCC activity did not necessarily induce neutralizing activity and vice versa. Nevertheless, we identified vaccine candidates that were able to concurrently induce both types of responses and that had ADCC activity that was cross-reactive between different subtypes. When searching for an effective vaccine candidate, it is important to evaluate the antibody response using a model and an assay measuring the desired function.
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http://dx.doi.org/10.1089/AID.2017.0140DOI Listing
February 2018

Clinical Simulation: A Protocol for Evaluation of Mobile Technology.

Stud Health Technol Inform 2017 ;241:179-184

University of Tasmania, Australia.

For mobile technology to be accepted at point of care in healthcare environments there is a need to demonstrate benefits whilst ameliorating the risks and challenges. To provide a standardised approach to evaluation of mobile technology a simulation protocol was developed to provide guidance for its use in healthcare environments. Simulated conditions provide the opportunity to assess intended and unintended consequences and identify potential workarounds when using technology. The protocol can also be used to demonstrate the importance of the development of digital professionalism by end-users prior to students entering the clinical practice setting. The mobile technology protocol was adapted from a health information systems protocol developed and used at the ITX Lab, Denmark for use in other simulation laboratories. Use case scenarios were developed to enable evaluation of mobile technology for mobile learning of nurses, nurse supervisors, students and patients. The scenarios can be used in a range of simulated environments including hospital bedside, outpatient clinic or community settings. A case study exemplar of a nurse and patient is included to demonstrate how the mobile technology protocol can be applied.
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April 2018

Clinical Simulation in the Development of eHealth: In-Situ and Laboratory Simulation.

Stud Health Technol Inform 2016 ;225:247-51

School of Health Information Science, University of Victoria, Canada.

Health information technology (IT) may improve patient safety and quality, but the application of new technology in health care may also increase patient safety hazards. The complexity of organizations, work practices and physical environments within the healthcare sector impacts the development and application of health IT. Clinical simulation can be used to evaluate technology in differing clinical contexts, throughout the software development life cycle in nursing informatics. Clinical simulation may be conducted in a range of settings varying from simulation laboratories to simulation in real settings. Clinical simulation supports involvement of context in pre-implementation design and evaluation of health IT involving real end-users as they use technology in realistic environments performing realistic tasks. The inclusion of clinical context is a powerful element of clinical simulation and enables visualization of technology in connection with clinical context without endangering patients.
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April 2017

Clinical Simulation as an Evaluation Method in Health Informatics.

Authors:
Sanne Jensen

Stud Health Technol Inform 2016 ;222:152-64

The Capital Region of Denmark, Copenhagen, Denmark.

Safe work processes and information systems are vital in health care. Methods for design of health IT focusing on patient safety are one of many initiatives trying to prevent adverse events. Possible patient safety hazards need to be investigated before health IT is integrated with local clinical work practice including other technology and organizational structure. Clinical simulation is ideal for proactive evaluation of new technology for clinical work practice. Clinical simulations involve real end-users as they simulate the use of technology in realistic environments performing realistic tasks. Clinical simulation study assesses effects on clinical workflow and enables identification and evaluation of patient safety hazards before implementation at a hospital. Clinical simulation also offers an opportunity to create a space in which healthcare professionals working in different locations or sectors can meet and exchange knowledge about work practices and requirement needs. This contribution will discuss benefits and challenges of using clinical simulation, and will describe how clinical simulation fits into classical usability studies, how patient safety may benefit by use of clinical simulation, and it will describe the different steps of how to conduct clinical simulation. Furthermore a case study is presented.
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January 2018

Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants: In Vitro Selection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle.

Antimicrob Agents Chemother 2016 06 23;60(6):3563-78. Epub 2016 May 23.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Hepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge about the determinants of PI resistance for the highly prevalent genotypes 2 to 6 remains limited. Using Huh7.5 cell culture-infectious HCV recombinants with genotype 1 to 6 NS3 protease, we identified protease positions 54, 155, and 156 as hot spots for the selection of resistance substitutions under treatment with the first licensed PIs, telaprevir and boceprevir. Treatment of a genotype 2 isolate with the newer PIs vaniprevir, faldaprevir, simeprevir, grazoprevir, paritaprevir, and deldeprevir identified positions 156 and 168 as hot spots for resistance; the Y56H substitution emerged for three newer PIs. Substitution selection also depended on the specific recombinant. The substitutions identified conferred cross-resistance to several PIs; however, most substitutions selected under telaprevir or boceprevir treatment conferred less resistance to certain newer PIs. In a single-cycle production assay, across genotypes, PI treatment primarily decreased viral replication, which was rescued by PI resistance substitutions. The substitutions identified resulted in differential effects on viral fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was due primarily to decreased replication. Most combinations of substitutions that were identified increased resistance or fitness. Combinations of resistance substitutions with fitness-compensating substitutions either rescued replication or compensated for decreased replication by increasing assembly. This comprehensive study provides insight into the selection patterns and effects of PI resistance substitutions for HCV genotypes 1 to 6 in the context of the infectious viral life cycle, which is of interest for clinical and virological HCV research.
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http://dx.doi.org/10.1128/AAC.02929-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879388PMC
June 2016

HIV-Specific CD8+ T Cell-Mediated Viral Suppression Correlates With the Expression of CD57.

J Acquir Immune Defic Syndr 2016 Jan;71(1):8-16

*Virus Research and Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institut, Copenhagen, Denmark;†Department of Infectious Diseases, Odense University Hospital, Odense, Denmark;‡Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark, Odense, Denmark;§Viro-immunology Research Unit, Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark; and‖Department of Infectious Diseases, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Background: Virus-specific CD8(+) T-cell responses are believed to play an important role in the control of HIV-1 infection; however, what constitutes an effective HIV-1 CD8(+) T-cell response remains a topic of debate. The ex vivo viral suppressive capacity was measured of CD8(+) T cells from 44 HIV-1-positive individuals. The phenotypic and cytokine profiles, and also the specificity of the CD8(+) T cells, were correlated with the suppression of HIV-1 replication. We also aimed to determine whether antiretroviral therapy (ART) had any positive effect on the HIV-1 suppressive CD8(+) T cells.

Method: Ex vivo suppression assay was used to evaluate the ability of CD8(+) T cells to suppress HIV-1 replication in autologous CD4(+) T cells. The CD107a, interferon-γ, interleukin-2, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1β (MIP-1β) responses to HIV-1 were evaluated by intracellular staining. The phenotypic profile of CD8(+) T cells was determined by whole blood staining.

Results: The expression of CD57 on effector CD8(+) T cells correlated with the suppression of HIV-1 replication and to the duration of ART. CD107a and tumor necrosis factor-α expression levels were significantly higher in individuals with ex vivo suppressive activity compared with individuals without suppressive activity.

Conclusions: Standard in vitro assays measuring one or several cytokines do not correlate with the functional viral suppressive capacity of CD8(+) T cells from HIV-1-positive individuals. The best correlation of viral suppression was found to be CD57 expression. CD57 expression correlated with the duration of ART, suggesting that ART restores the cytotoxic capacity of CD8(+) T lymphocytes.
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http://dx.doi.org/10.1097/QAI.0000000000000837DOI Listing
January 2016

HIV-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) -Mediating Antibodies Decline while NK Cell Function Increases during Antiretroviral Therapy (ART).

PLoS One 2015 22;10(12):e0145249. Epub 2015 Dec 22.

Virus Research & Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institut, Copenhagen, Denmark.

Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/μl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145249PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692281PMC
June 2016

Neutralizing Antibody Response and Antibody-Dependent Cellular Cytotoxicity in HIV-1-Infected Individuals from Guinea-Bissau and Denmark.

AIDS Res Hum Retroviruses 2016 May 7;32(5):434-42. Epub 2016 Jan 7.

1 Virus Research and Development Laboratory, Department of Microbiological Diagnostics and Virology, Statens Serum Institut , Copenhagen, Denmark .

The development of therapeutic and prophylactic HIV vaccines for African countries is urgently needed, but the question of what immunogens to use needs to be answered. One approach is to include HIV envelope immunogens derived from HIV-positive individuals from a geographically concentrated epidemic with more limited viral genetic diversity for a region-based vaccine. To address if there is a basis for a regional selected antibody vaccine, we have screened two regionally separate cohorts from Guinea-Bissau and Denmark for neutralizing antibody activity and antibody-dependent cellular cytotoxicity (ADCC) against local and nonlocal circulating HIV-1 strains. The neutralizing activity did not demonstrate higher potential against local circulating strains according to geography and subtype determination, but the plasma from Danish individuals demonstrated significantly higher inhibitory activity than that from Guinea-Bissau individuals against both local and nonlocal virus strains. Interestingly, an opposite pattern was observed with ADCC activity, where Guinea-Bissau individual plasma demonstrated higher activity than Danish plasma and was specifically against the local circulating subtype. Thus, on basis of samples from these two cohorts, no local-specific neutralizing activity was detected, but a local ADCC response was identified in the Guinea-Bissau samples, suggesting potential use of regional immunogens for an ADCC-inducing vaccine.
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http://dx.doi.org/10.1089/AID.2015.0118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845637PMC
May 2016

Initiation of Antiretroviral Therapy (ART) at Different Stages of HIV-1 Disease Is Not Associated with the Proportion of Exhausted CD8+ T Cells.

PLoS One 2015 1;10(10):e0139573. Epub 2015 Oct 1.

Virus Research & Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institut, Copenhagen, Denmark.

CD8+ T cell-restricted immunity is important in the control of HIV-1 infection, but continued immune activation results in CD8+ T cell dysfunction. Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution. Here, we evaluated whether restoration of CD8+ T cell function in HIV-1-infected individuals was dependent on early initiation of ART. HIV-specific CD107a, IFNγ, IL-2, TNFα and MIP-1β expression by CD8+ T cells and the frequency of CD8+ T cells expressing PD-1, 2B4 and CD160 were measured by flow cytometry. The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naïve individuals and similar to the frequency in HIV-uninfected controls. The expression of the three markers was similarly independent of when therapy was initiated. Individuals treated before seroconversion displayed an HIV-specific CD8+ T cell response that included all five functional markers; this was not observed in individuals treated after seroconversion or in ART-naïve individuals. In summary, ART appears to restore the total CD8+ T cell population to a less exhausted phenotype, independent of the time point of initiation. However, to preserve multifunctional, HIV-1-specific CD8+ T cells, ART might have to be initiated before seroconversion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0139573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591005PMC
June 2016

Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance.

Antimicrob Agents Chemother 2015 Dec 21;59(12):7426-36. Epub 2015 Sep 21.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Various protease inhibitors (PIs) currently are becoming available for treatment of hepatitis C virus (HCV). For genotype 1, substitutions at NS3 protease positions 155, 156, and 168 are the main determinants of PI resistance. For other genotypes, similar substitutions were selected during PI treatment but were not characterized systematically. To elucidate the impact of key PI resistance substitutions on genotypes 2 to 6, we engineered the substitutions R155A/E/G/H/K/Q/T, A156G/S/T/V, and D/Q168A/E/G/H/N/V into HCV recombinants expressing genotype 2 to 6 proteases. We evaluated viral fitness and sensitivity to nine PIs (telaprevir, boceprevir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, deldeprevir, and grazoprevir) in Huh7.5 cells. We found that most variants showed decreased fitness compared to that of the original viruses. Overall, R155K, A156G/S, and D/Q168A/E/H/N/V variants showed the highest fitness; however, genotype 4 position 168 variants showed strong fitness impairment. Most variants tested were resistant to several PIs. Resistance levels varied significantly depending on the specific substitution, genotype, and PI. For telaprevir and boceprevir, specific 155 and 156, but not 168, variants proved resistant. For the remaining PIs, most genotype 2, 4, 5, and 6, but not genotype 3, variants showed various resistance levels. Overall, grazoprevir (MK-5172) had the highest efficacy against original viruses and variants. This is the first comprehensive study revealing the impact of described key PI resistance substitutions on fitness and PI resistance of HCV genotypes 2 to 6. In conclusion, the studied substitutions induced resistance to a panel of clinically relevant PIs, including the newer PIs paritaprevir, deldeprevir, and grazoprevir. We discovered complex patterns of resistance, with the impact of substitutions varying from increased sensitivity to high resistance.
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http://dx.doi.org/10.1128/AAC.01953-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4649233PMC
December 2015

Clinical Simulation: For what and how can it be used in design and evaluation of health IT.

Authors:
Sanne Jensen

Stud Health Technol Inform 2015 ;215:217-28

Capital Region of Copenhagen, Copenhagen, Denmark.

The usability of health information technology (IT) is increasingly recognized as critically important to the development of systems that are both safe to use and acceptable to end-users. The substantial complexity of organizations, work practice and physical environments within the healthcare sector influences the development and application of health IT. When health IT is introduced in local clinical work practices, potential patient safety hazards and insufficient support of work practices need to be examined. Qualitative methods, such as clinical simulation, may be used to support Techno-Anthropologists design and evaluate new technology navigating in the intersection between people and technology and between various interests in forms of experts and stakeholders. This chapter will introduce the reader to clinical simulation, present the general guidelines and recommendation conducting simulations and describe a simulation lab in Copenhagen. Illustrative examples and references to specific projects will be part of the contribution.
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January 2018

Clinical simulation: A method for development and evaluation of clinical information systems.

J Biomed Inform 2015 Apr 12;54:65-76. Epub 2015 Feb 12.

Aalborg University, Department of Development and Planning, Vestre Havnepromenade 5, 9000 Aalborg, Denmark.

Use of clinical simulation in the design and evaluation of eHealth systems and applications has increased during the last decade. This paper describes a methodological approach for using clinical simulations in the design and evaluation of clinical information systems. The method is based on experiences from more than 20 clinical simulation studies conducted at the ITX-lab in the Capital Region of Denmark during the last 5 years. A ten-step approach to conducting simulations is presented in this paper. To illustrate the approach, a clinical simulation study concerning implementation of Digital Clinical Practice Guidelines in a prototype planning and coordination module is presented. In the case study potential benefits were assessed in a full-scale simulation test including 18 health care professionals. The results showed that health care professionals can benefit from such a module. Unintended consequences concerning terminology and changes in the division of responsibility amongst healthcare professionals were also identified, and questions were raised concerning future workflow across sector borders. Furthermore unexpected new possible benefits concerning improved communication, content of information in discharge letters and quality management emerged during the testing. In addition new potential groups of users were identified. The case study is used to demonstrate the potential of using the clinical simulation approach described in the paper.
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http://dx.doi.org/10.1016/j.jbi.2015.02.002DOI Listing
April 2015

HIV-specific ADCC improves after antiretroviral therapy and correlates with normalization of the NK cell phenotype.

J Acquir Immune Defic Syndr 2015 Feb;68(2):103-11

*Virus Research and Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institute, Copenhagen, Denmark; †Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; and ‡Viro-immunology Research Unit, Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Natural killer (NK) cell phenotype and function have recently gained much attention as playing crucial roles in antibody-dependent cellular cytotoxicity (ADCC). We investigated NK cell function, as measured by ADCC, in HIV-1-positive individuals before and 6 months after highly active antiretroviral therapy (HAART) initiation.

Method: The ability of antibodies and NK cells to mediate ADCC was investigated separately and in combination in an autologous model. The NK cell subset distribution and NK cell phenotype (ie, expression of maturation and activation markers within NK cell subsets) were analyzed.

Results: The ability of NK cells to mediate ADCC was significantly increased after only 6 months of HAART and was not explained by a normalization of NK cell subsets (CD56 CD16 and CD56 CD16 NK cells) but rather by normalization in the frequency of NK cells expressing CCR7 and CD27. For individuals with no increase in ADCC after 6 months of HAART, the frequency of NK cells expressing NKp46 was downregulated. The ability of antibodies to mediate ADCC alone and in combination in an autologous model was not improved.

Conclusions: HAART improves the ability of NK cells to mediate ADCC after 6 months. This improvement does not correlate with general immune restoration, as measured by CD4 T-cell counts, but rather to a decrease in the frequency of NK cells expressing CCR7 and CD27.
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http://dx.doi.org/10.1097/QAI.0000000000000429DOI Listing
February 2015

Boundary objects in clinical simulation and design of eHealth.

Health Informatics J 2016 06 9;22(2):248-64. Epub 2014 Oct 9.

University of Victoria, Canada.

Development and implementation of eHealth is challenging due to the complexity of clinical work practices and organizations. Standardizing work processes and documentation procedures is one way of coping with these challenges, and acceptance of these initiatives and acceptance of the clinical information system are vital for success. Clinical simulation may be used as "boundary objects" and help transferring of knowledge between groups of stakeholders and help to better understand needs and requirements in other parts of the organization. This article presents a case study about design of electronic documentation templates for nurses' initial patient assessment, where clinical simulation was used as a boundary object and thereby achieved mutual clinical agreement on the content. Results showed that meetings prior to and in between workshops allowed all communities of practice an opportunity to voice their point of view and affect the final result. Implications of considering clinical simulations as boundary objects are discussed.
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http://dx.doi.org/10.1177/1460458214551846DOI Listing
June 2016

Evaluation of a clinical simulation-based assessment method for EHR-platforms.

Stud Health Technol Inform 2014 ;205:925-9

IT, Medical Tech. and Telephony Services, The Capital Region of Denmark, Denmark.

In a procurement process assessment of issues like human factors and interaction between technology and end-users can be challenging. In a large public procurement of an Electronic health record-platform (EHR-platform) in Denmark a clinical simulation-based method for assessing and comparing human factor issues was developed and evaluated. This paper describes the evaluation of the method, its advantages and disadvantages. Our findings showed that clinical simulation is beneficial for assessing user satisfaction, usefulness and patient safety, all though it is resource demanding. The method made it possible to assess qualitative topics during the procurement and it provides an excellent ground for user involvement.
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May 2015

Differential sensitivity of 5'UTR-NS5A recombinants of hepatitis C virus genotypes 1-6 to protease and NS5A inhibitors.

Gastroenterology 2014 Mar 18;146(3):812-821.e4. Epub 2013 Nov 18.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Hvidovre Hospital and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background & Aims: Hepatitis C virus (HCV) therapy will benefit from the preclinical evaluation of direct-acting antiviral (DAA) agents in infectious culture systems that test the effects on different virus genotypes. We developed HCV recombinants comprising the 5' untranslated region-NS5A (5-5A) from genotypes 1-6 and 2a(JFH1) NS5B-3' untranslated region, and tested the effects of NS3 protease and NS5A inhibitors on these recombinants.

Methods: The HCV 5-5A recombinants with previously identified mutations in the NS3-helicase (F1464L), NS4A (A1672S), and NS5B (D2979G) were adapted and improved, by incorporating additional recovered mutations that increased their propagation in Huh7.5 cells. Concentration-response profiles were determined for each DAA agent in replicate infected Huh7.5 cells.

Results: Developed efficient 1a(H77), 1a(TN), 3a(S52), 4a(ED43), 5a(SA13), and 6a(HK6a) 5-5A recombinants did not require mutations after viral passage in the NS3 protease or NS5A domain-I regions targeted by the drugs. They were inhibited in a concentration-dependent manner by the NS3 protease inhibitors telaprevir, boceprevir, asunaprevir, simeprevir, vaniprevir, faldaprevir, and MK-5172 and by the NS5A inhibitor daclatasvir. The 1a(TN) 5-5A and JFH1-independent full-length viruses had similar levels of sensitivity to the DAA agents, validating the 5-5A recombinants as surrogates for full-length viruses in DAA testing. Compared with the 1a(TN) full-length virus, the 3a(S52) 5-5A recombinant was highly resistant to all protease inhibitors, and the 4a(ED43) recombinant was highly resistant to telaprevir and boceprevir, but most sensitive to other protease inhibitors. Compared with other protease inhibitors, MK-5172 had exceptional potency against all HCV genotypes. The NS5A inhibitor daclatasvir had the highest potency observed, but with genotype-dependent activity.

Conclusions: The mutations F1464L, A1672S, and D2979G permitted the development of efficient HCV recombinants comprising genotype-specific 5' untranslated region-NS5A (5-5A), which include the natural NS3 protease and NS5A domain-I drug targets. The robust replication of adapted 5-5A recombinants allowed for direct comparison of NS3 protease and NS5A inhibitors against HCV strains of genotypes 1-6.
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http://dx.doi.org/10.1053/j.gastro.2013.11.009DOI Listing
March 2014

Adapted J6/JFH1-based Hepatitis C virus recombinants with genotype-specific NS4A show similar efficacies against lead protease inhibitors, alpha interferon, and a putative NS4A inhibitor.

Antimicrob Agents Chemother 2013 Dec 23;57(12):6034-49. Epub 2013 Sep 23.

Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, and Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

To facilitate studies of hepatitis C virus (HCV) NS4A, we aimed at developing J6/JFH1-based recombinants with genotype 1- to 7-specific NS4A proteins. We developed efficient culture systems expressing NS4A proteins of genotypes (isolates) 1a (H77 and TN), 1b (J4), 2a (J6), 4a (ED43), 5a (SA13), 6a (HK6a), and 7a (QC69), with peak infectivity titers of ∼3.5 to 4.5 log10 focus-forming units per ml. Except for genotype 2a (J6), growth depended on adaptive mutations identified in long-term culture. Genotype 1a, 1b, and 4a recombinants were adapted by amino acid substitutions F772S (p7) and V1663A (NS4A), while 5a, 6a, and 7a recombinants required additional substitutions in the NS3 protease and/or NS4A. We demonstrated applicability of the developed recombinants for study of antivirals. Genotype 1 to 7 NS4A recombinants showed similar responses to the protease inhibitors telaprevir (VX-950), boceprevir (Sch503034), simeprevir (TMC435350), danoprevir (ITMN-191), and vaniprevir (MK-7009), to alpha interferon 2b, and to the putative NS4A inhibitor ACH-806. The efficacy of ACH-806 was lower than that of protease inhibitors and was not influenced by changes at amino acids 1042 and 1065 (in the NS3 protease), which have been suggested to mediate resistance to ACH-806 in replicons. Genotype 1a, 1b, and 2a recombinants showed viral spread under long-term treatment with ACH-806, without acquisition of resistance mutations in the NS3-NS4A region. Relatively high concentrations of ACH-806 inhibited viral assembly, but not replication, in a single-cycle production assay. The developed HCV culture systems will facilitate studies benefitting from expression of genotype-specific NS4A in a constant backbone in the context of the complete viral replication cycle, including functional studies and evaluations of the efficacy of antivirals.
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http://dx.doi.org/10.1128/AAC.01176-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837860PMC
December 2013

Clinical simulation as a boundary object in design of health IT-systems.

Stud Health Technol Inform 2013 ;194:173-8

IT, Medico and Telecommunications - IMT, the Capital Region of Denmark, Denmark.

Healthcare organizations are very complex, holding numerous stakeholders with various approaches and goals towards the design of health IT-systems. Some of these differences may be approached by applying the concept of boundary objects in a participatory IT-design process. Traditionally clinical simulation provides the opportunity to evaluate the design and the usage of clinical IT-systems without endangering the patients and interrupting clinical work. In this paper we present how clinical simulation additionally holds the potential to function as a boundary object in the design process. The case points out that clinical simulation provides an opportunity for discussions and mutual learning among the various stakeholders involved in design of standardized electronic clinical documentation templates. The paper presents and discusses the use of clinical simulation in the translation, transfer and transformation of knowledge between various stakeholders in a large healthcare organization.
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May 2014

Fidelity in clinical simulation: how low can you go?

Stud Health Technol Inform 2013 ;194:147-53

Department of Development and Planning, Aalborg University, Denmark.

Clinical simulation may be used to identify user needs for context sensitive functionalities in e-Health. The objective with this paper is to describe how user requirements and use cases in a large EHR-platform procurement may be validated by clinical simulation using a very low-fidelity prototype without any existing test data. Instead of using test scenarios and use cases, the healthcare professionals who are participating in the clinical simulation are generating both scenario and patient data themselves. We found that this approach allows for an imaginative discussion, not restricted by known functionalities and limitations, of the ideal EHR-platform. Subsequently, we discuss benefits and challenges of using an extremely low fidelity environment and discuss the degree of fidelity necessary for conducting clinical simulation.
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May 2014

Use of clinical simulation for assessment in EHR-procurement: design of method.

Stud Health Technol Inform 2013 ;192:576-80

Department of Development and Planning, Aalborg University, Denmark.

In Denmark, two large regions cooperate in a public intervention process of acquiring a new eHealth-platform to support the daily clinical work of approximately 40,000 users in 14 hospitals. It is essential that the new platform, besides fulfilling comprehensive detailed specifications, supports the daily work practice consisting of numerous mixed tasks executed by many different clinical actors in various settings. Within health informatics it has proven beneficial to use human factors approaches in the design process to secure systems that are responsive to the actual field of application. While design methods are widely described, there are very limited descriptions of how to assess and compare different EHR-platforms and their support in work processes upon its procurement. This paper describes the method we have developed to undertake this task. It is discussed how the method differs and how it has been adjusted from existing assessment methods. Finally, future considerations are discussed.
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April 2015