Recent Submissions

  • Journal Article

    German guidelines on the diagnosis and treatment of neurosyphilis 

    Klein, Matthias; Angstwurm, Klemens; Esser, Stefan; Hahn, Kathrin; Maschke, Matthias; Scheithauer, Simone; Schoefer, Helmut; Sturzenegger, Matthias; Wildemann, Brigitte; Weber, Jörg
    Neurological Research and Practice 2020; 2(1) p.1-9: Art. 33
    Introduction In view of the importance of neurosyphilis and the difficulties encountered in diagnosing it, the S1 guideline “Neurosyphilis” has been published by the German Society for Neurology (DGN) in accordance with the stipulations of the Association of the Scientific Medical Societies in Germany (AWMF). The present article is an abridged translation of that German guideline. Main recommendations (a) Neurosyphilis can manifest as early neurosyphilis (meningitis, meningovascular neurosyphilis or syphilitic gummas) or late neurosyphilis (tabes dorsalis, general paresis). (b) The following diagnostic criteria help to establish the presence of probable neurosyphilis (always point iv, accompanied by any two of points i to iii): (i) subacute or chronic neuro-psychiatric symptoms; (ii) increased cerebrospinal fluid (CSF) cell count or signs of blood–CSF barrier disruption; (iii) positive effect of anti-neurosyphilis antibiotic therapy on clinical course and CSF findings; (iv) positive TPHA/TPPA or FTA test in serum. (c) The diagnosis of neurosyphilis is confirmed by the subsequent detection of intrathecal production of antibodies against Treponema pallidum. (d) In neurosyphilis, treatment with intravenous penicillin or ceftriaxone for 14 days is recommended. (e) The following parameters can be used to assess a therapeutic effect: clinical findings, serum VDRL, and CSF cell count. Conclusion The German guideline on the diagnosis and treatment of neurosyphilis is a practical tool to support clinicians in diagnosing and treating patients with neurosyphilis. This article is an abridged translation of this guideline (Klein MW, J.; Angstwurm, K.; Esser, S.; Hahn, K.; Matschke, M.; Scheithauer, S.; Schoefer, H.; Sturzenegger, M.; Wildemann, B. Neurosyphilis, S1-Leitlinie. Deutsche Gesellschaft für Neurologie, Leitlinien für Diagnostik und Thearpie in der Neurologie 2020).
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  • Journal Article

    Repeating noninvasive risk stratification improves prediction of outcome in ICD patients. 

    Vandenberk, Bert; Floré, Vincent; Röver, Christian; Vos, Mark A; Dunnink, Albert; Leftheriotis, Dionyssios; Friede, Tim; Flevari, Panagiota; Zabel, Markus; Willems, Rik
    Annals of Noninvasive Electrocardiology 2020-08-17; 25(6): Art. e12794
    BACKGROUND: Noninvasive risk stratification aims to detect abnormalities in the pathophysiological mechanisms underlying ventricular arrhythmias. We studied the predictive value of repeating risk stratification in patients with an implantable cardioverter-defibrillator (ICD). METHODS: The EUTrigTreat clinical study was a prospective multicenter trial including ischemic and nonischemic cardiomyopathies and arrhythmogenic heart disease. Left ventricular ejection fraction ≤40% (LVEF), premature ventricular complexes >400/24 hr (PVC), non-negative microvolt T-wave alternans (MTWA), and abnormal heart rate turbulence (HRT) were considered high risk. Tests were repeated within 12 months after inclusion. Adjusted Cox regression analysis was performed for mortality and appropriate ICD shocks. RESULTS: In total, 635 patients had analyzable baseline data with a median follow-up of 4.4 years. Worsening of LVEF was associated with increased mortality (HR 3.59, 95% CI 1.17-11.04), as was consistent abnormal HRT (HR 8.34, 95%CI 1.06-65.54). HRT improvement was associated with improved survival when compared to consistent abnormal HRT (HR 0.10, 95%CI 0.01-0.82). For appropriate ICD shocks, a non-negative MTWA test or high PVC count at any moment was associated with increased arrhythmic risk independent of the evolution of test results (worsening: HR 3.76 (95%CI 1.43-9.88) and HR 2.50 (95%CI 1.15-5.46); improvement: HR 2.80 (95%CI 1.03-7.61) and HR 2.45 (95%CI 1.07-5.62); consistent: HR 2.47 (95%CI 0.95-6.45) and HR 2.40 (95%CI 1.33-4.33), respectively). LVEF improvement was associated with a lower arrhythmic risk (HR 0.34, 95%CI 0.12-0.94). CONCLUSIONS: Repeating LVEF and HRT improved the prediction of mortality, whereas stratification of ventricular arrhythmias may be improved by repeating LVEF measurements, MTWA and ECG Holter monitoring.
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  • Journal Article

    KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer 

    Jo, Peter; Bernhardt, Markus; Nietert, Manuel; König, Alexander; Azizian, Azadeh; Schirmer, Markus A.; Grade, Marian; Kitz, Julia; Reuter-Jessen, Kirsten; Ghadimi, Michael; et al.
    Ströbel, PhilippSchildhaus, Hans-UlrichGaedcke, Jochen
    PLOS ONE 2020; 15(10) p.1-13: Art. e0239806
    Introduction: Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. Materials and methods: KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. Results: The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis. Conclusions: We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.
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  • Journal Article

    TIM-3 Genetic Variants Are Associated with Altered Clinical Outcome and Susceptibility to Gram-Positive Infections in Patients with Sepsis 

    Mewes, Caspar; Alexander, Tessa; Büttner, Benedikt; Hinz, José; Alpert, Ayelet; Popov, Aron-F.; Ghadimi, Michael; Beißbarth, Tim; Tzvetkov, Mladen; Grade, Marian; et al.
    Quintel, MichaelBergmann, IngoMansur, Ashham
    International Journal of Molecular Sciences 2020; 21(21) p.1-16: Art. 8318
    Background: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. Methods: Patients with sepsis (n = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. Results: Kaplan–Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, p = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and Staphylococcus epidermidis infections, and rs10515746 CC homozygotes presented more Staphylococcus epidermidis infections. Conclusion: The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.
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  • Journal Article

    Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models 

    Wirths, Oliver; Zampar, Silvia
    International Journal of Molecular Sciences 2020; 21(21) p.1-19: Art. 8144
    Transgenic mouse models represent an essential tool for the exploration of Alzheimer’sdisease (AD) pathological mechanisms and the development of novel treatments, which at presentprovide only symptomatic and transient effects. While a variety of mouse models successfullyreflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β(Aβ) deposits,intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well asbehavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficultto achieve. In this review, we summarize information on classic and more recent transgenic mousemodels for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Althoughthe cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronalAβaccumulation in several transgenic mouse models, especially in pyramidal neurons.
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  • Journal Article

    Effects of strategies to improve general practitioner-nurse collaboration and communication in regard to hospital admissions of nursing home residents (interprof ACT): study protocol for a cluster randomised controlled trial 

    Müller, Christiane; Hesjedal-Streller, Berit; Fleischmann, Nina; Tetzlaff, Britta; Mallon, Tina; Scherer, Martin; Köpke, Sascha; Balzer, Katrin; Gärtner, Linda; Maurer, Indre; et al.
    Friede, TimKönig, Hans-HelmutHummers, Eva
    Trials 2020; 21(1) p.1-14: Art. 913
    Abstract Background In Germany, up to 50% of nursing home residents are admitted to a hospital at least once a year. It is often unclear whether this is beneficial or even harmful. Successful interprofessional collaboration and communication involving general practitioners (GPs) and nurses may improve medical care of nursing home residents. In the previous interprof study, the six-component intervention package interprof ACT was developed to facilitate collaboration of GPs and nurses in nursing homes. The aim of this study is to evaluate the effectiveness of the interprof ACT intervention. Methods This multicentre, cluster randomised controlled trial compares nursing homes receiving the interprof ACT intervention package for a duration of 12 months (e.g. comprising appointment of mutual contact persons, shared goal setting, standardised GPs’ home visits) with a control group (care as usual). A total of 34 nursing homes are randomised, and overall 680 residents recruited. The intervention package is presented in a kick-off meeting to GPs, nurses, residents/relatives or their representatives. Nursing home nurses act as change agents to support local adaption and implementation of the intervention measures. Primary outcome is the cumulative incidence of hospitalisation within 12 months. Secondary outcomes include admissions to hospital, days admitted to hospital, use of other medical services, prevalence of potentially inappropriate medication and quality of life. Additionally, health economic and a mixed methods process evaluation will be performed. Discussion This study investigates a complex intervention tailored to local needs of nursing homes. Outcomes reflect the healthcare and health of nursing home residents, as well as the feasibility of the intervention package and its impact on interprofessional communication and collaboration. Because of its systematic development and its flexible nature, interprof ACT is expected to be viable for large-scale implementation in routine care services regardless of local organisational conditions and resources available for medical care for nursing home residents on a regular basis. Recommendations will be made for an improved organisation of primary care for nursing home residents. In addition, the results may provide important knowledge and data for the development and evaluation of further strategies to improve outpatient care for elderly care-receivers. Trial registration ClinicalTrials.gov NCT03426475 . Initially registered on 7 February 2018.
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  • Journal Article

    Associated factors to caries experience of children undergoing general anaesthesia and treatment needs characteristics over a 10 year period 

    Bekes, Katrin; Steuber, Antonia; Challakh, Nadia; Schmidt, Jana; Haak, Rainer; Hraský, Valentina; Ziebolz, Dirk
    BMC Oral Health 2020; 20(1) p.1-7: Art. 307
    Abstract Background Aim of this study was to describe the characteristics of 1- to 6-year-old children who underwent general anesthesia (GA) in a German specialized pediatric dental institution between 2002 and 2011, and to evaluate the risk factors (age, migration background, nutritional status) for caries experience (dmf-s) in these children. Methods A cross-sectional study with retrospective data collection was designed. Children who underwent comprehensive dental treatment under GA were enrolled in the study. The data were collected from patient records and included personal background: age, sex, dmf-s, nutritional status, reasons for GA and treatments provided. Mann–Whitney-U test, Chi-square tests, and linear regression modelling were applied for statistical analyses. Results 652 children (median age: 3 years [IQR: 2–4], 41.6% female) were treated under GA between 2002 and 2011. Of these, 30.8% had migration background, 17.3% were underweight and 14.8% overweight. The median dmf-s was 28 (IQR: 19–43.5). Univariate, only age and migration showed a significant association with dmf-s (p < 0.01) up to the age of 5 years. In the linear regression analysis, this association of dmf-s with age (OR: 4.04/CI: 2.81–5.27; p < 0.01) and migration (OR: 4.26/CI: 0.89–7.62; p = 0.013) was confirmed. At the patient level, tooth extraction was the most chosen option in both time periods, however, more restorative approaches were taken between 2007 and 2011 including pulp therapy and the use of strip and stainless steel crowns compared to 2002–2006. Conclusions Children aged 1–6 years treated under GA showed a high caries experience (dmf-s), whereby age as well as migration, but not BMI, were relevant risk factors. Although tooth extraction is the first choice in most cases in the first time period, more conservative procedures were performed in the second half of the follow-up period.
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  • Journal Article

    Strategies to reduce antibiotic use in women with uncomplicated urinary tract infection in primary care: protocol of a systematic review and meta-analysis including individual patient data. 

    Heinz, Judith; Röver, Christian; Furaijat, Ghefar; Kaußner, Yvonne; Hummers, Eva; Debray, Thomas; Hay, Alastair D; Heytens, Stefan; Vik, Ingvild; Little, Paul; et al.
    Moore, MichaelStuart, BethWagenlehner, FlorianKronenberg, AndreasFerry, SvenMonsen, TorLindbaek, MortenFriede, TimGagyor, Ildiko
    BMJ open 2020-10-01; 10: Art. e035883
    INTRODUCTION: Uncomplicated urinary tract infection (UTI) in women is a common reason to present in general practice and is usually treated with antibiotics to reduce symptom severity and duration. Results of recent clinical trials indicate that non-antibiotic treatment approaches can also be effective. However, it remains unclear which patients would benefit from antibiotic treatment and which can effectively and safely be treated without antibiotics. This systematic review and meta-analysis aims to estimate the effect of treatment strategies to reduce antibiotic use in comparison with immediate antibiotic treatment and to identify prognostic factors and moderators of treatment effects. A further aim is to identify subgroups of patients benefiting from a specific therapy. METHODS AND ANALYSIS: A systematic literature search will be performed to identify randomised controlled trials which investigated the effect of treatment strategies to reduce antibiotic use in female adults with uncomplicated UTI compared with immediate antibiotic treatment. Therefore, the primary outcome of the meta-analysis is incomplete recovery. Anonymised individual patient data (IPD) will be collected. Aggregate data will be used for pairwise comparisons of treatment strategies using meta-analysis models with random effects accounting for potential between-study heterogeneity. Potential effect moderators will be explored in meta-regressions. For IPD, generalised linear mixed models will be used, which may be adjusted for baseline characteristics. Interactions of baseline variables with treatment effects will be explored. These models will be used to assess direct comparisons of treatment, but might be extended to networks. ETHICS AND DISSEMINATION: The local institutional review and ethics board judged the project a secondary analysis of existing anonymous data which meet the criteria for waiver of ethics review. Dissemination of the results will be via published scientific papers and presentations. Key messages will be promoted for example, via social media or press releases. PROSPERO REGISTRATION NUMBER: CRD42019125804.
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  • Journal Article

    Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development. 

    Ambati, Jayakrishna; Magagnoli, Joseph; Leung, Hannah; Wang, Shao-Bin; Andrews, Chris A; Fu, Dongxu; Pandey, Akshat; Sahu, Srabani; Narendran, Siddharth; Hirahara, Shuichiro; et al.
    Fukuda, ShinichiSun, JianPandya, LekhaAmbati, MeenakshiPereira, FelipeVarshney, AkhilCummings, TammyHardin, James WEdun, BabatundeBennett, Charles LAmbati, KameshwariFowler, Benjamin JKerur, NagarajRöver, ChristianLeitinger, NorbertWerner, Brian CStein, Joshua DSutton, S ScottGelfand, Bradley D
    Nature communications 2020-09-23; 11(1): Art. 4737
    Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.
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  • Journal Article

    Visual attention outperforms visual-perceptual parameters required by law as an indicator of on-road driving performance 

    Grundler, Wolfgang; Strasburger, Hans
    PLOS ONE 2020; 15(8) p.1-24: Art. e0236147
    Purpose A variety of visual and psychometric tests have been developed for assessing on-road driving performance and fitness to drive. The diagnostic power of a state of the art psychometric test battery (Vienna Test System) combined with a set of standard visual parameters recommended for assessing fitness to drive is investigated using an on-road driving test. The study aimed to determine whether a psychometric test battery could predict older adults’ on-road driving performance. The relevance of visual standards required by law is discussed. Methods Vision impairment is more prevalent in later adulthood and many studies on visual and cognitive impact on driving safety and performance therefore focus on adults above 60 years of age. We therefore acquired an extensive set of driving-related visual and psychometric performance parameters in a group of elderly drivers (N = 84, median age 69, SD 6.6 years). Visual assessment included foveal acuity, perimetric field size, and dynamic aspects of peripheral vision (termed “PP”) in the computer-based Vienna Test System (VTS; Schuhfried), as well as letter contrast thresholds in foveal and parafoveal vision in a separate setup. A selection of psychometric driving-aptitude tests that demonstrated the battery’s capacity to predict aspects of driving performance and safety were further conducted on the VTS. Driving performance was assessed in a standardized on-road driving test. Two independent observers rated driving performance using a fixed scoring system assessing the number of driving errors in pre-defined traffic situations. In addition, globalized driving competence scores were assigned on a 6-point scale. Results The test battery performed excellent in identification of good drivers but failed in the prediction of bad driving performance. Visual performance indicators required by German law were less indicative of driving ability than psychometric assessment. Selective and divided attention turned out to be much more important for predicting fitness to drive than either visual acuity, size of the visual field, or contrast sensitivity. Conclusion Predicting fitness to drive by means of visual and psychometric tests is an ambitious challenge. On the one hand sensitivity of a multi-disciplinary test-battery is too low to predict reliable driving ability in diagnostic settings which require an unambiguous interpretation of test results for individual drivers. Low sensitivity and low predictive values are incompatible with that objective. On the other hand, the results are valuable for a routine screening of fitness to drive. For that case, the assessment of attentional abilities in particular appears to be promising. Performance measures of divided and selective attention showed themselves to be the most predictive for fitness to drive in a sample pre-screened for clear visual deficits. Visual performance parameters required by law, in contrast, had no meaningful impact on driving performance, indicating a gap between mandatory regulations of state authorities and research results. Our results suggest that visual acuity tests designed for clinical diagnosis and monitoring of eye diseases should not at all be the choice for a screening of fitness to drive.
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  • Journal Article

    Association of serum interleukin-6 and soluble interleukin-2-receptor levels with disease activity status in patients with inflammatory bowel disease: A prospective observational study 

    Mavropoulou, Eirini; Mechie, Nicolae-Catalin; Knoop, Richard; Petzold, Golo; Ellenrieder, Volker; Kunsch, Steffen; Pilavakis, Yiannis; Amanzada, Ahmad
    PLOS ONE 2020; 15(5) p.1-15: Art. e0233811
    Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by overexpression of proinflammatory cytokines. We determined the association of serum levels of interleukin (IL)-6, soluble-IL-2-receptor (sIL-2R) and CRP as well as of faecal calprotectin (FC) values with disease activity in CD and UC patients. This prospective study included 145 CD and 84 UC patients. Serum proinflammatory biomarkers and FC levels were measured and demographic, clinical and endoscopic characteristics were collected. Uni- and multivariate statistical analyses were performed. Serum IL-6 and CRP levels as well as FC values of CD patients were associated with clinical and endoscopic remission. In multivariate analysis serum IL-6 levels remained significantly associated with clinical and endoscopic remission. FC levels were also associated with endoscopic remission in CD patients. CD patients under the threshold levels of 8.5 pg/mL and 5.5 pg/mL for serum IL-6 were in 70% and 66% in clinical and endoscopic remission, respectively. Serum sIL-2R, CRP levels and FC values of UC patients were associated in univariate analysis with clinical and endoscopic remission. In multivariate analysis CRP and FC values were associated with clinical remission and serum sIL-2R as well as FC levels with endoscopic remission. UC patients under the threshold levels of 759 IU/mL and 646 IU/mL for serum sIL-2R were in 76% and 76% in clinical and endoscopic remission, respectively. Beside CRP and FC, serum IL-6 levels in CD patients and sIL-2R levels in UC patients can be a further useful non-invasive biomarker to identify the disease activity status.
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  • Journal Article

    Designing and piloting a generic research architecture and workflows to unlock German primary care data for secondary use 

    Bahls, Thomas; Pung, Johannes; Heinemann, Stephanie; Hauswaldt, Johannes; Demmer, Iris; Blumentritt, Arne; Rau, Henriette; Drepper, Johannes; Wieder, Philipp; Groh, Roland; et al.
    Hummers, EvaSchlegelmilch, Falk
    Journal of Translational Medicine. 2020 Oct 19;18(1):394
    Background Medical data from family doctors are of great importance to health care researchers but seem to be locked in German practices and, thus, are underused in research. The RADAR project (Routine Anonymized Data for Advanced Health Services Research) aims at designing, implementing and piloting a generic research architecture, technical software solutions as well as procedures and workflows to unlock data from family doctor’s practices. A long-term medical data repository for research taking legal requirements into account is established. Thereby, RADAR helps closing the gap between the European countries and to contribute data from primary care in Germany. Methods The RADAR project comprises three phases: (1) analysis phase, (2) design phase, and (3) pilot. First, interdisciplinary workshops were held to list prerequisites and requirements. Second, an architecture diagram with building blocks and functions, and an ordered list of process steps (workflow) for data capture and storage were designed. Third, technical components and workflows were piloted. The pilot was extended by a data integration workflow using patient-reported outcomes (paper-based questionnaires). Results The analysis phase resulted in listing 17 essential prerequisites and guiding requirements for data management compliant with the General Data Protection Regulation (GDPR). Based on this list existing approaches to fulfil the RADAR tasks were evaluated—for example, re-using BDT interface for data exchange and Trusted Third Party-approach for consent management and record linkage. Consented data sets of 100 patients were successfully exported, separated into person-identifying and medical data, pseudonymised and saved. Record linkage and data integration workflows for patient-reported outcomes in the RADAR research database were successfully piloted for 63 responders. Conclusion The RADAR project successfully developed a generic architecture together with a technical framework of tools, interfaces, and workflows for a complete infrastructure for practicable and secure processing of patient data from family doctors. All technical components and workflows can be reused for further research projects. Additionally, a Trusted Third Party-approach can be used as core element to implement data privacy protection in such heterogeneous family doctor’s settings. Optimisations identified comprise a fully-electronic consent recording using tablet computers, which is part of the project’s extension phase.
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  • Journal Article

    Analysis of low-dose estrogen on callus BMD as measured by pQCT in postmenopausal women 

    Jäckle, K.; Kolb, J. P; Schilling, A. F; Schlickewei, C.; Amling, M.; Rueger, J. M; Lehmann, W.
    BMC Musculoskeletal Disorders. 2020 Oct 19;21(1):693
    Background Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture. Methods To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ±11.99) were treated with estrogen and 45 patients (75.62 years ±10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and 6 weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm. Results We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients. Conclusions Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models. Trial registration Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858. Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858.
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  • Journal Article

    Radiomic Features and Machine Learning for the Discrimination of Renal Tumor Histological Subtypes: A Pragmatic Study Using Clinical-Routine Computed Tomography 

    Uhlig, Johannes; Leha, Andreas; Delonge, Laura M.; Haack, Anna-Maria; Shuch, Brian; Kim, Hyun S.; Bremmer, Felix; Trojan, Lutz; Lotz, Joachim; Uhlig, Annemarie
    Cancers 2020; 12(10) p.1-13: Art. 3010
    This study evaluates the diagnostic performance of radiomic features and machine learning algorithms for renal tumor subtype assessment in venous computed tomography (CT) studies from clinical routine. Patients undergoing surgical resection and histopathological assessment of renal tumors at a tertiary referral center between 2012 and 2019 were included. Preoperative venous-phase CTs from multiple referring imaging centers were segmented, and standardized radiomic features extracted. After preprocessing, class imbalance handling, and feature selection, machine learning algorithms were used to predict renal tumor subtypes using 10-fold cross validation, assessed as multiclass area under the curve (AUC). In total, n = 201 patients were included (73.7% male; mean age 66 ± 11 years), with n = 131 clear cell renal cell carcinomas (ccRCC), n = 29 papillary RCC, n = 11 chromophobe RCC, n = 16 oncocytomas, and n = 14 angiomyolipomas (AML). An extreme gradient boosting algorithm demonstrated the highest accuracy (multiclass area under the curve (AUC) = 0.72). The worst discrimination was evident for oncocytomas vs. AML and oncocytomas vs. chromophobe RCC (AUC = 0.55 and AUC = 0.45, respectively). In sensitivity analyses excluding oncocytomas, a random forest algorithm showed the highest accuracy, with multiclass AUC = 0.78. Radiomic feature analyses from venous-phase CT acquired in clinical practice with subsequent machine learning can discriminate renal tumor subtypes with moderate accuracy. The classification of oncocytomas seems to be the most complex with the lowest accuracy.
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  • Journal Article

    3D virtual pathohistology of lung tissue from Covid-19 patients based on phase contrast X-ray tomography 

    Eckermann, Marina; Frohn, Jasper; Reichardt, Marius; Osterhoff, Markus; Sprung, Michael; Westermeier, Fabian; Tzankov, Alexandar; Werlein, Christopher; Kühnel, Mark; Jonigk, Danny; et al.
    Salditt, Tim
    eLife 2020; 9 p.1-25: Art. e60408
    We present a three-dimensional (3D) approach for virtual histology and histopathology based on multi-scale phase contrast x-ray tomography, and use this to investigate the parenchymal architecture of unstained lung tissue from patients who succumbed to Covid-19. Based on this first proof-of-concept study, we propose multi-scale phase contrast x-ray tomography as a tool to unravel the pathophysiology of Covid-19, extending conventional histology by a third dimension and allowing for full quantification of tissue remodeling. By combining parallel and cone beam geometry, autopsy samples with a maximum cross section of 8 mm are scanned and reconstructed at a resolution and image quality, which allows for the segmentation of individual cells. Using the zoom capability of the cone beam geometry, regions-of-interest are reconstructed with a minimum voxel size of 167 nm. We exemplify the capability of this approach by 3D visualization of diffuse alveolar damage (DAD) with its prominent hyaline membrane formation, by mapping the 3D distribution and density of lymphocytes infiltrating the tissue, and by providing histograms of characteristic distances from tissue interior to the closest air compartment.
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  • Journal Article

    Generation of homozygous CRISPRa human induced pluripotent stem cell (hiPSC) lines for sustained endogenous gene activation 

    Schoger, Eric; Argyriou, Loukas; Cyganek, Lukas; Zelarayán, Laura Cecilia
    Stem Cell Research 2020; 48 p.1-6: Art. 101944
    CRISPR/Cas9 technology is a powerful tool, owing to its robust on-target activity and high fidelity. Mutated Cas9 without nuclease activity (dCas9) fused to transcriptional modulators, can function as transcriptional inhibitors or activators (CRISPRa). We generated homozygous human induced pluripotent stem cell (hiPSC) lines with an inserted CRISPRa cassette into the AAVS1 locus whilst maintaining pluripotency and genomic integrity, the ability to differentiate into all three germ layers, generate functional cardiomyocytes, and validated Cas9-mediated induction of endogenous gene expression. Our generated hiPSC-CRISPRa offers a valuable tool for studying endogenous transcriptional modulation with single and multiplexed possibilities in all human cell types.
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  • Journal Article

    Key components and IT assistance of participant management in clinical research: a scoping review 

    Pung, Johannes; Rienhoff, Otto
    JAMIA Open 2020; 00(0) p.1-10
    Objectives Managing participants and their data are fundamental for the success of a clinical trial. Our review identifies and describes processes that deal with management of trial participants and highlights information technology (IT) assistance for clinical research in the context of participant management. Methods A scoping literature review design, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, was used to identify literature on trial participant-related proceedings, work procedures, or workflows, and assisting electronic systems. Results The literature search identified 1329 articles of which 111 were included for analysis. Participant-related procedures were categorized into 4 major trial processes: recruitment, obtaining informed consent, managing identities, and managing administrative data. Our results demonstrated that management of trial participants is considered in nearly every step of clinical trials, and that IT was successfully introduced to all participant-related areas of a clinical trial to facilitate processes. Discussion There is no precise definition of participant management, so a broad search strategy was necessary, resulting in a high number of articles that had to be excluded. Nevertheless, this review provides a comprehensive overview of participant management-related components, which was lacking so far. The review contributes to a better understanding of how computer-assisted management of participants in clinical trials is possible.
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  • Journal Article

    SARS-CoV-2, immunosenescence and inflammaging: partners in the COVID-19 crime 

    Domingues, Renato; Lippi, Alice; Setz, Cristian; Outeiro, Tiago F.; Krisko, Anita
    Aging 2020; 12(18) p.18778-18789
    Pneumonia outbreak in the city of Wuhan, China, prompted the finding of a novel strain of severe acute respiratory syndrome virus (SARS-CoV-2). Here, we discuss potential long-term consequences of SARS-CoV-2 infection, and its possibility to cause permanent damage to the immune system and the central nervous system. Advanced chronological age is one of the main risk factors for the adverse outcomes of COVID-19, presumably due to immunosenescence and chronic low-grade inflammation, both characteristic of the elderly. The combination of viral infection and chronic inflammation in advanced chronological age might cause multiple detrimental unforeseen consequences for the predisposition and severity of neurodegenerative diseases and needs to be considered so that we can be prepared to deal with future outcomes of the ongoing pandemic.
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  • Journal Article

    COVID-19: scientific reasoning, pragmatism and emotional bias 

    Gattinoni, Luciano; Marini, John J.; Chiumello, Davide; Busana, Mattia; Camporota, Luigi
    Annals of Intensive Care. 2020 Oct 12;10(1):134
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  • Journal Article

    Correction to: Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle 

    Dammann, Insa; Wemheuer, Wiebke M.; Wrede, Arne; Wemheuer, Wilhelm E.; Campe, Amely; Petschenka, Jutta; Schulze-Sturm, Ulf; Hahmann, Uwe; Czerny, Claus P.; Münster, Pia; et al.
    Brenig, BertramKreienbrock, LotharHerden, ChristianeSchulz-Schaeffer, Walter J.
    Veterinary Research. 2020 Oct 15;51(1):130
    An amendment to this paper has been published and can be accessed via the original article.
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