Severe CSF immune cell alterations in cryptococcal meningitis gradually resolve during antifungal therapy.

Cryptococcal meningitis (CM) is a severe fungal disease in immunocompromised patients affecting the central nervous system (CNS). Host response and immunological alterations in the cerebrospinal fluid (CSF) after invasion of Cryptococcus neoformans to the central nervous system have been investigated before but rigorous and comprehensive studies examining cellular changes in the CSF of patients with cryptococccal meningitis are still rare. We retrospectively collected CSF analysis and flow cytometry data of CSF and blood in patients with CM (n = 7) and compared them to HIV positive patients without meningitis (n = 13) and HIV negative healthy controls (n = 7). Within the group of patients with CM we compared those with HIV infection (n = 3) or other immunocompromised conditions (n = 4). Flow cytometry analysis revealed an elevation of natural killer cells and natural killer T cells in the CSF and blood of HIV negative patients with CM, pointing to innate immune activation in early stages after fungal invasion. HIV positive patients with CM exhibited stronger blood-CSF-barrier disruption. Follow-up CSF analysis over up to 150 days showed heterogeneous cellular courses in CM patients with slow normalization of CSF after induction of antifungal therapy.

Unused potential of lipid-lowering therapy in very high-risk patients with atherosclerotic cardiovascular disease. A retrospective data analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the most common cause of death in Europe. Although the 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias claim a target low-density lipoprotein cholesterol (LDL-C) value of <55 mg/dL for very high-risk patients by use of lipid-lowering therapy (LLT) and lifestyle adaptations, the target level achievement is not satisfactory. We examined LLT use in ASCVD patients exceeding LDL-C target levels at admission and its adaptations at discharge. METHODS AND RESULTS: Between January 2017 and February 2020, 1091 patients with LDL-C >100 mg/dL and ASCVD defined as diagnosis of angina pectoris (AP, n = 179), acute myocardial infarction (AMI, n = 317), chronic ischemic heart disease (CHD, n = 195), or peripheral artery disease (PAD, n = 400) were extracted from hospital records. LLT use on admission and discharge as well as recommendations on lifestyle and nutrition were analysed. On admission, 51% of the patients were not taking LLT. At discharge, 91% were prescribed statins and 87% were advised on lifestyle adaptation and/or pharmacological treatment. High-intensity statin use at discharge was present in 63% of the AP-group, 92% of the AMI-group, 62% of the CHD-group and 71% of the PAD-group. Ezetimibe was present in 16% and proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) in 1%. However, of those on high-intensity statin, 25% remained on insufficient statin dosage. CONCLUSION: Switch to high-intensity statins and use of ezetimibe and PCSK9i was low in chronic ASCVD patients. Even though statin intake was high in high-risk patients, target levels were still not reached.

Role and relevance of dentists in a multiprofessional palliative care team: results of a cross-sectional survey study.

PURPOSE: Despite the multiprofessional concept surrounding palliative care patients (PCPs) and their high prevalence of oral issues, licensed dentists (LDs) are often not included in their treatment team. This study aimed to examine the current state of cooperation and to determine whether and how LDs should be included in the care for PCPs. METHODS: This single-centre cross-sectional study was conducted at the University Hospital Muenster, Germany. We surveyed three participant groups: PCPs, LDs, and healthcare professionals (HCPs). Questionnaires were tailored for each group, with some questions common for comparison. RESULTS: The study encompassed the results of 48 questionnaires from LDs, 50 from PCPs along with 50 from HCPs. Consensus was reached among all parties (LDs: 73% (n = 35/48); HCPs: 94%, n = 47/50; PCPs: 60%, n = 30/50) that involving LDs in the treatment concept is favourable. On the other hand, a significant discrepancy emerged in the perception of the dental treatment effort required by PCPs. While LDs (81%; n = 39/48) and HCPs (64%; n = 32/50) were convinced of increased effort, PCPs (34%; n = 17/50) largely did not share this perspective. To enhance patient care and formulate appropriate treatment plans, LDs consider both training (58%; n = 28/48) and guidebooks (71%; n = 34/48) to be valuable and would attend or use such resources. CONCLUSION: This study sheds light on the current gaps in including LDs in palliative care teams and emphasizes the importance of multidisciplinary collaboration to address oral health needs effectively. Development of continuing education options and collaborative models between LDs and HCPs needs to be further expanded in future.

Telemedicine Plus Standard Care Versus Standard Care Only in Specialized Outpatient Palliative Care: A Randomized Controlled Noninferiority Trial.

Background: Patients suffering from incurable diseases are more likely to die in the hospital than at home. Specialized outpatient palliative care (PC) may be able to counteract this tendency. Similarly, potential benefits of telemedicine in health care were scientifically reported. The aim of this research was to compare patients receiving specialized outpatient PC plus telemedicine with those receiving standard specialized outpatient PC only. In this study, telemedicine is assumed to decrease the number of home visits and therefore should not be considered a mere add-on. Methods: This is a randomized controlled noninferiority trial. Recruitment lasted between January 2020 and October 2021. Quality of care was evaluated using the Integrated Palliative Care Outcome Scale (IPOS) at day 0, 7, and 14 after randomization. Change from day 0 to 7 was defined as the primary outcome (noninferiority margin = 4 points). This study was conducted in an urban setting in collaboration with a university hospital and a local specialized outpatient PC service. Results: A total of 196 patients were screened with 34 patients included (18 telemedicine/16 standard care). The mean change in the total score of the IPOS from day 0 to 7 amounted to -1.8 ± 3.9 (telemedicine) versus 1.2 ± 5.7 (standard care). The telemedicine group was statistically not relevantly inferior to the standard care group (t-test for noninferiority, p = 0.005). Conclusions: Although, due to COVID-19, the sample size remained rather small, our findings indicate that telemedical approaches offer a promising and equally effective option to provide specialized outpatient PC. Clinical Trial Registration Number: NCT06054048.

Comparison of German Translations of the System Usability Scale - Which to Take?

The System Usability Scale (SUS) is a reliable tool for usability measurement and evaluation. Since its original language is English, a translation is required before a target group can answer it in their native language. The challenge of translating questionnaires lies in the preservation of its original properties. Different versions of a German SUS have been proposed and are currently in use. Objective of this work is to find and compare available German translations. Four versions were found and compared in terms of the translation process and the exact wording of the translation. Only the version of Gao et al. has been systematically validated, but has an unnatural wording. Although not validated yet, the proposed version of Rummel et al. is a good compromise between wording and methodically clean development. The version of Lohmann and Schäffer is the close runner up, as it may improve the wording at the expense of methodological accuracy. Since the version of Rauer gives no information about its translation process, it is considered least preferred of the four compared translations.

Development of a Command Line Interface for the Analysis of Result Sets from Automated Queries to Literature Databases.

The first step of a systematic review is the identification of publications related to a research question in different literature databases. The quality of the final review is mainly influenced by finding the best search query resulting in high precision and recall. Usually, this process is iterative and requires refining the initial query and comparing the different result sets. Furthermore, result sets of different literature databases must be compared as well. Objective of this work is to develop a command line interface, which supports the automated comparison of result sets of publications from literature databases. The tool should incorporate existing application programming interfaces of literature database and should be integrable into more complex analysis scripts. We present a command line interface written in Python and available as open-source application at https://imigitlab.uni-muenster.de/published/literature-cli under MIT license. The tool calculates the intersection and differences of the result sets of multiple queries on a single literature database or of the same query on different databases. These results and their configurable metadata can be exported as CSV-files or in Research Information System format for post-processing or as starting point for a systematic review. Due to the support of inline parameters, the tool can be integrated into existing analysis scripts. Currently, the literature databases PubMed and DBLP are supported, but the tool can easily be extended to support any literature database providing a web-based application programming interface.

Supporting the differential diagnosis of connective tissue diseases with neurological involvement by blood and cerebrospinal fluid flow cytometry.

OBJECTIVE: Neurological manifestations of autoimmune connective tissue diseases (CTD) are poorly understood and difficult to diagnose. We here aimed to address this shortcoming by studying immune cell compositions in CTD patients with and without neurological manifestation. METHODS: Using flow cytometry, we retrospectively investigated paired cerebrospinal fluid (CSF) and blood samples of 28 CTD patients without neurological manifestation, 38 CTD patients with neurological manifestation (N-CTD), 38 non-inflammatory controls, and 38 multiple sclerosis (MS) patients, a paradigmatic primary neuroinflammatory disease. RESULTS: We detected an expansion of plasma cells in the blood of both N-CTD and CTD compared to non-inflammatory controls and MS. Blood plasma cells alone distinguished the clinically similar entities N-CTD and MS with high discriminatory performance (AUC: 0.81). Classical blood monocytes indicated higher disease activity in systemic lupus erythematosus (SLE) patients. Surprisingly, immune cells in the CSF did not differ significantly between N-CTD and CTD, while CD4+ T cells and the CD4+/CD8+ ratio were elevated in the blood of N-CTD compared to CTD. Several B cell-associated parameters partially overlapped in the CSF in MS and N-CTD. We built a machine learning model that distinguished N-CTD from MS with high discriminatory power using either blood or CSF. CONCLUSION: We here find that blood flow cytometry alone surprisingly suffices to distinguish CTD with neurological manifestations from clinically similar entities, suggesting that a rapid blood test could support clinicians in the differential diagnosis of N-CTD.

Secondary Prevention in Lower Extremity Artery Disease Patients: Lipid-Lowering Therapy and Long-Term Guideline Adherence.

Lower extremity artery disease (LEAD) affects millions of elderly patients and is associated with elevated cardiovascular morbidity and mortality. Risk factor modification, including the therapy of dyslipidaemia, is mandatory to reduce cardiovascular event rates and to improve survival rates. However, only a minority achieve the recommended low-density lipoprotein cholesterol (LDL-C) target level < 55 mg/dL, according to the current ESC/EAS guidelines on the treatment of dyslipidaemia. This study elucidated the implementation of the lipid-lowering guideline recommendations of 400 LEAD patients with LDL-C > 100 mg/dL and their adherence to treatment adjustment during follow-up. Despite a sustained statin prescription in 93% of the patients, including 77% with high-intensity statins at follow-up, only 18% achieved the target level. Ezetimibe appeared in 21% and LDL-C goals were reached significantly more often with combination therapy. Recurrent revascularization appeared more often (28%) than coronary artery or cerebrovascular disease progression (14%) and 7% died. Despite the frequent use of high-intensity statins and expandable rates of ezetimibe, the progression of cardiovascular events remained inevitable. Only 18% of the patients had received recommendations on lifestyle modification, including dietary adaptations, which is key for a holistic approach to risk factor control. Thus, efforts for both pharmacological and behavioral strategies are needed to improve clinical outcomes and survival rates.

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma.

Introduction: A variety of biomarkers are considered for diagnosis (e.g., ß2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence in situ hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution. Methods: We performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical information analyzing blood samples collected at several time points during follow-up (median follow-up: 3.26 years since first diagnosis). We split our cohort into two subgroups: with and without new FISH clones developing in the course of disease. Results: Each subgroup showed a characteristic chromosomal profile. Forty-three percent of patients had evidence of appearing new clones. The patients with new clones showed an increased number of translocations affecting chromosomes 14 (78% vs. 33%; p = 0.0805) and 11, and alterations in chromosome 4 (amplifications and translocations). New clones, on the contrary, were characterized by alterations affecting chromosome 17. Subsequent to the development of the new clone, 6 out of 9 patients experienced disease progression compared to 3 out of 12 for patients without new clones. Duration of the therapy applied for the longest time was significantly shorter within the group of patients developing new clones (median: 273 vs. 406.5 days; p = 0.0465). Discussion: We demonstrated that the development of new clones, carrying large-scale alterations, was associated with inferior disease course and shorter response to therapy, possibly affecting progression-free survival and overall survival as well. Further studies evaluating larger cohorts are necessary for the validation of our results.

Linking EMR Data to REDCap: Implementation in the SOLKID Register.

Secondary use, the reuse of medical patient data stored during routine care in the hospital's electronic medical records (EMR) for research purpose is common, especially for registers and pragmatic trials. Often the medical data items are copied manually from the EMR into the used research database. This process is time consuming and error prone. In the "Safety of the Living Kidney Donor - The German National Register" (SOLKID-GNR), laboratory results gathered during control check-ups of the living donors before and after the transplantation are to be transferred from the EMR into the electronic data capture system REDCap of the register. In this work, we present our approach of realizing an automated transfer of time-dependent laboratory results from the EMR of the University Hospital of Münster to REDCap. A challenge lies in the multi-center structure of SOLKID-GNR. The participating transplant centers are using different EMR systems, which requires a flexible architecture design. In addition, we aimed to support reuse of the implementation for other research settings with other medical data items of interest.

MainzelHandler: A Library for a Simple Integration and Usage of the Mainzelliste.

Pseudonymization plays a vital role in medical research. In Germany, the Technologie- und Methodenplattform für die vernetzte medizinische Forschung e.V. (TMF) has developed guidelines on how to create pseudonyms and how to handle personally identifiable information (PII) during this process. An open-source implementation of a pseudonymization service following these guidelines and therefore recommended by the TMF is the so-called "Mainzelliste". This web application supports a REST-API for (de-) pseudonymization. For security reasons, a complex session and tokening mechanism for each (de-) pseudonymization is required and a careful interaction between front- and backend to ensure a correct handling of PII. The objective of this work is the development of a library to simplify the integration and usage of the Mainzelliste's API in a TMF conform way. The frontend library uses JavaScript while the backend component is based on Java with an optional Spring Boot extension. The library is available under MIT open-source license from https://github.com/DanielPreciado-Marquez/MainzelHandler.

A Seamless Pseudonymization and Randomization Workflow for REDCap.

The interaction of multiple computer systems during multi-center randomized controlled trials (RCTs) is a hurdle for IT-specialists as well as medical staff. A common workflow for the initial registration of a patient requires the generation of a pseudonym by a pseudonymization service, a manual transmission of the pseudonym to a randomization service, and a manual transfer of the pseudonym and assigned study arm into an electronic data capture (EDC) system. This interaction is often time consuming and error prone due to multiple system changes. Objective of this work is to enhance a commonly used EDC system, Research Electronic Data Capture (REDCap), as a single source of interaction for multi-center RCTs. This is achieved by providing two modules for a seamless integration of a pseudonymization service, i.e., Mainzelliste, and a randomization service, i.e., RandIMI. Thus, no site-specific system changes are required, which increases time efficiency and reduces errors. From a technical perspective, only authentication credentials and firewall exposure for a single system must be managed. To evaluate the usability of our implementation, the system usability scale was employed. The increase of time efficiency was measured in laboratory conditions by a comparison of the time for patient registrations with and without our modules. An "excellent" usability was shown and an average time reduction by nearly 64 %. Both open-source modules are available from the REDCap Repository of External Modules.

FhirExtinguisher: A FHIR Resource Flattening Tool Using FHIRPath.

Data analysis with popular statistical toolchains like R usually needs to be performed on "flat tables" (so-called dataframes). However, data exchange is often done with FHIR, a format that is based on a hierarchical data model. In this paper, we want to present our tool FhirExtinguisher, which tackles the problems of loading FHIR data into statistical tools by extending the FHIRSearch API with an additional projection layer using FHIRPath. This projection layer can be used to select the data elements of interest and create a CSV file, which can be easily read as dataframe by almost any statistical toolchain.

Patient Empowerment Through Digital Voice Pens: A Feasibility Study.

Reading is an important ability, especially for patients during their medical treatment. It is needed, for instance, to complete administrative forms and patient-reported outcome questionnaires in clinical routine. Unfortunately, not every patient is able to read caused by illiteracy, low vision or simply speaking another language. Thus, a minder is required to support the mentioned reading tasks. Providing patients with the possibility to read and understand texts without additional help is an important factor to improve their self-empowerment. Digital voice pens can be programmed to play prerecorded audio files if tipped onto predefined areas of interactive paper. They can be a tool for impaired patients to read texts aloud in multiple languages. In this work, we wanted to evaluate the possibilities of these digital voice pens. A feasibility study was conducted by using the commercially available tiptoi digital voice pen by Ravensburger AG and the tttool application by Joachim Breitner for the programming of the pen. Focusing on the use case of questionnaires, a schematic questionnaire was implemented which enforced the usage of a digital voice pen. To simulate foreign languages or illiteracy, questions and answers of the document were represented by placeholders and the digital voice pen was required to read aloud the question texts. The correctness of the given answers was documented and the usability of the digital voice pen was measured by the System Usability Scale. The evaluation was performed by 15 volunteers (8 male/7 female) between 24 and 35 years old. The usability and acceptance of digital voice pens were rated as "Good" in our constructed setting.

ODM Clinical Data Generator: Syntactically Correct Clinical Data Based on Metadata Definition.

The Operational Data Model (ODM) is a data standard for interchanging clinical trial data. ODM contains the metadata definition of a study, i.e., case report forms, as well as the clinical data, i.e., the answers of the participants. The portal of medical data models is an infrastructure for creation, exchange, and analysis of medical metadata models. There, over 23000 metadata definitions can be downloaded in ODM format. Due to data protection law and privacy issues, clinical data is not contained in these files. Access to exemplary clinical test data in the desired metadata definition is necessary in order to evaluate systems claiming to support ODM or to evaluate if a planned statistical analysis can be performed with the defined data types. In this work, we present a web application, which generates syntactically correct clinical data in ODM format based on an uploaded ODM metadata definition. Data types and range constraints are taken into account. Data for up to one million participants can be generated in a reasonable amount of time. Thus, in combination with the portal of medical data models, a large number of ODM files including metadata definition and clinical data can be provided for testing of any ODM supporting system. The current version of the application can be tested at https://cdgen.uni-muenster.de and source code is available, under MIT license, at https://imigitlab.uni-muenster.de/published/odm-clinical-data-generator.

Evaluation of openEHR Repositories Regarding Standard Compliance.

We evaluated three repositories implementing the emerging healthcare data standard openEHR for their standard compliance, completeness and vendor lock-in. We found the basic functionality to work consistently across all tested repositories. At the same time, no vendor supports the entire API yet. Some functions like template listing differ slightly in their behavior. Some vendors offer additional custom APIs that are easier to use but lead to vendor lock-in. The openEHR standard itself is designed inconsistently regarding data formats and is missing some basic functionality, for example deletion of templates. With openEHR being a young standard, these issues may be resolved in future releases.

EMR-integrated minimal core dataset for routine health care and multiple research settings: A case study for neuroinflammatory demyelinating diseases.

Although routine health care and clinical trials usually require the documentation of similar information, data collection is performed independently from each other, resulting in redundant documentation efforts. Standardizing routine documentation can enable secondary use for medical research. Neuroinflammatory demyelinating diseases (NIDs) represent a heterogeneous group of diseases requiring further research to improve patient management. The aim of this work is to develop, implement and evaluate a minimal core dataset in routine health care with a focus on secondary use as case study for NIDs. Therefore, a draft minimal core dataset for NIDs was created by analyzing routine, clinical trial, registry, biobank documentation and existing data standards for NIDs. Data elements (DEs) were converted into the standard format Operational Data Model, semantically annotated and analyzed via frequency analysis. The analysis produced 1958 DEs based on 864 distinct medical concepts. After review and finalization by an interdisciplinary team of neurologists, epidemiologists and medical computer scientists, the minimal core dataset (NID CDEs) consists of 46 common DEs capturing disease-specific information for reuse in the discharge letter and other research settings. It covers the areas of diagnosis, laboratory results, disease progress, expanded disability status scale, therapy and magnetic resonance imaging findings. NID CDEs was implemented in two German university hospitals and a usability study in clinical routine was conducted (participants n = 16) showing a good usability (Mean SUS = 75). From May 2017 to February 2018, 755 patients were documented with the NID CDEs, which indicates the feasibility of developing a minimal core dataset for structured documentation based on previously used documentation standards and integrating the dataset into clinical routine. By sharing, translating and reusing the minimal dataset, a transnational harmonized documentation of patients with NIDs might be realized, supporting interoperability in medical research.