Recent Submissions

• Journal Article

The Specific Bile Acid Profile of Shock: A Hypothesis Generating Appraisal of the Literature ﻿

Journal of Clinical Medicine 2020; 9(12) p.1-9: Art. 3844
Background: Bile acid synthesis and regulation of metabolism are tightly regulated. In critical illness, these regulations are impaired. Consequently, the physiologic bile acid pattern in serum becomes disturbed and a disease-specific bile acid profile seems to become evident. Methods: A literature review was performed and trials reporting the broken-down bile acid pattern were condensed with regard to percent differences in bile acid profiles of defined diseases compared to a human control. Results: Ten articles were identified. Most of the studied bile acid profiles differ statistically significant between disease states, furthermore, neither of the reported disease entities show the same broken-down pattern of individual bile acids. Deoxycholic acid (DCA) was found to be decreased in almost all diseases, except for the two shock-states investigated (cardiogenic shock, septic shock) where it was elevated by about 100% compared to the control. Moreover, the pattern of both examined shock-states are very similar, rendering a specific shock-pattern possible, that we argue could eventually maintain or even worsen the pathological state. Conclusion: The specific broken-down bile acid profile of defined diseases might aid in gaining insight into the body’s adaptive reaction and the differential diagnosis, as well as in the therapy of disease states in the early course of the disease
• Journal Article

Occurrence, Pathogenicity, and Mycotoxin Production of Fusarium temperatum in Relation to Other Fusarium Species on Maize in Germany ﻿

Pathogens 2020; 9(11) p.1-20: Art. 864
Fusarium subglutinans is a plant pathogenic fungus infecting cereal grain crops. In 2011, the species was divided in Fusarium temperatumsp. nov. and F. subglutinans sensu stricto. In order to determine the occurrence and significance of F. temperatum and F. subglutinans on maize, a monitoring of maize ears and stalks was carried out in Germany in 2017 and 2018. Species identification was conducted by analysis of the translation elongation factor 1α (TEF-1α) gene. Ninety-four isolates of F. temperatum and eight isolates of F. subglutinans were obtained during two years of monitoring from 60 sampling sites in nine federal states of Germany. Inoculation of maize ears revealed a superior aggressiveness for F. temperatum, followed by Fusarium graminearum, Fusarium verticillioides, and F. subglutinans. On maize stalks, F. graminearum was the most aggressive species while F. temperatum and F. subglutinans caused only small lesions. The optimal temperature for infection of maize ears with F. temperatum was 24 °C and 21 °C for F. subglutinans. All strains of F. temperatum and F. subglutinans were pathogenic on wheat and capable to cause moderate to severe head blight symptoms. The assessment of mycotoxin production of 60 strains of F. temperatum cultivated on rice revealed that all strains produced beauvericin, moniliformin, fusaric acid, and fusaproliferin. The results demonstrate a higher prevalence and aggressiveness of F. temperatum compared to F. subglutinans in German maize cultivation areas.
• Journal Article

Overshooting Subcellular Redox-Responses in Rett-Mouse Hippocampus during Neurotransmitter Stimulation ﻿

Cells 2020; 9(12) p.1-23: Art. 2539
Rett syndrome (RTT) is a neurodevelopmental disorder associated with disturbed neuronal responsiveness and impaired neuronal network function. Furthermore, mitochondrial alterations and a weakened cellular redox-homeostasis are considered part of the complex pathogenesis. So far, overshooting redox-responses of MeCP2-deficient neurons were observed during oxidant-mediated stress, hypoxia and mitochondrial inhibition. To further clarify the relevance of the fragile redox-balance for the neuronal (dys)function in RTT, we addressed more physiological stimuli and quantified the subcellular redox responses to neurotransmitter-stimulation. The roGFP redox sensor was expressed in either the cytosol or the mitochondrial matrix of cultured mouse hippocampal neurons, and the responses to transient stimulation by glutamate, serotonin, dopamine and norepinephrine were characterized. Each neurotransmitter evoked more intense oxidizing responses in the cytosol of MeCP2-deficient than in wildtype neurons. In the mitochondrial matrix the neurotransmitter-evoked oxidizing changes were more moderate and more uniform among genotypes. This identifies the cytosol as an important reactive oxygen species (ROS) source and as less stably redox buffered. Fura-2 imaging and extracellular Ca$^{2+}$ withdrawal confirmed cytosolic Ca$^{2+}$ transients as a contributing factor of neurotransmitter-induced redox responses and their potentiation in the cytosol of MeCP2-deficient neurons. Chemical uncoupling demonstrated the involvement of mitochondria. Nevertheless, cytosolic NADPH- and xanthine oxidases interact to play the leading role in the neurotransmitter-mediated oxidizing responses. As exaggerated redox-responses were already evident in neonatal MeCP2-deficient neurons, they may contribute remarkably to the altered neuronal network performance and the disturbed neuronal signaling, which are among the hallmarks of RTT.
• Journal Article

Low Intensity, Transcranial, Alternating Current Stimulation Reduces Migraine Attack Burden in a Home Application Set-Up: A Double-Blinded, Randomized Feasibility Study ﻿

Brain Sciences 2020; 10(11) p.1-10: Art. 888
Background: Low intensity, high-frequency transcranial alternating current stimulation (tACS) applied over the motor cortex decreases the amplitude of motor evoked potentials. This double-blind, placebo-controlled parallel group study aimed to test the efficacy of this method for acute management of migraines. Methods: The patients received either active (0.4 mA, 140 Hz) or sham stimulation for 15 min over the visual cortex with the number of terminated attacks two hours post-stimulation as the primary endpoint, as a home therapy option. They were advised to treat a maximum of five migraine attacks over the course of six weeks. Results: From forty patients, twenty-five completed the study, sixteen in the active and nine in the sham group with a total of 102 treated migraine attacks. The percentage of terminated migraine attacks not requiring acute rescue medication was significantly higher in the active (21.5%) than in the sham group (0%), and the perceived pain after active stimulation was significantly less for 2–4 h post-stimulation than after sham stimulation. Conclusion: tACS over the visual cortex has the potential to terminate migraine attacks. Nevertheless, the high drop-out rate due to compliance problems suggests that this method is impeded by its complexity and time-consuming setup.
• Journal Article

Tumefactive inflammatory lesions in juvenile metachromatic leukodystrophy ﻿

Neurology - Neuroimmunology Neuroinflammation 2020; 8(1) p.1-4: Art. e922
Juvenile metachromatic leukodystrophy (MLD) is caused by autosomal recessive defects in the ARSA gene coding for arylsulfatase A. Clinically, it is characterized by slowly progressive ataxia, spasticity, cognitive decline, and behavioral disturbances starting at age 4–10 years. White matter abnormalities are often first seen in the corpus callosum subsequently extending into the periventricular regions with a diffuse symmetrical pattern.
• Journal Article

Camostat Mesylate May Reduce Severity of Coronavirus Disease 2019 Sepsis: A First Observation ﻿

Critical Care Explorations 2020; 2(11) p.1-5: Art. e0284
Objectives: Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown. Design: Retrospective observational case series. Setting: Patient treated in ICU of University hospital Göttingen, Germany. Patients: Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU. Interventions: Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group). Measurements and Main Results: Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation. Conclusions: The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.
• Journal Article

Optimization of the Real-Time Quaking-Induced Conversion Assay for Prion Disease Diagnosis ﻿

Frontiers in Bioengineering and Biotechnology 2020; 8 p.1-8: Art. 586890
The real-time quaking-induced conversion (RT-QuIC) assay is a highly reproducible and robust methodology exhibiting an excellent pre-mortem diagnostic accuracy for prion diseases. However, the protocols might be time-consuming and improvement of the detection technology is needed. In the present study, we investigated the influence of a pre-analytical cerebrospinal fluid (CSF) treatment with proteinase K (PK) on the kinetic of the RT-QuIC signal response. For this purpose, we added PK at different concentrations in RT-QuIC reactions seeded with Creutzfeldt–Jakob disease (sCJD) CSF. We observed that a mild pre-analytical PK treatment of CSF samples resulted in an increased seeding efficiency of the RT-QuIC reaction. Quantitative seeding parameters, such as a higher area under the curve (AUC) value or a shorter lag phase indicated a higher conversion efficiency after treatment. The diagnostic accuracy resulting from 2 μg/ml PK treatment was analyzed in a retrospective study, where we obtained a sensitivity of 89%. Additionally, we analyzed the agreement with the previously established standard RT-QuIC protocol without PK treatment in a prospective study. Here, we found an overall agreement of 94% to 96%. A Cohen’s kappa of 0.9036 (95% CI: 0.8114–0.9958) indicates an almost perfect agreement between both protocols. In conclusion, the outcome of our study can be used for a further optimization of the RT-QuIC assay in particular for a reduction of the testing time.
• Journal Article

German guidelines on the diagnosis and treatment of neurosyphilis ﻿

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).
• Journal Article

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

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.
• Journal Article

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

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.
• Journal Article

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

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.
• Journal Article

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

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.
• 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 ﻿

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.
• Journal Article

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

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.
• 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. ﻿

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.
• Journal Article

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

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.
• Journal Article

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

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.
• 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 ﻿

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.
• Journal Article

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

Journal of Translational Medicine. 2020 Oct 19;18(1):394