Institutes
Refine
Year of publication
- 2020 (245) (remove)
Document Type
- Article (196)
- Preprint (39)
- Doctoral Thesis (10)
Language
- English (245) (remove)
Has Fulltext
- yes (245)
Is part of the Bibliography
- no (245)
Keywords
- COVID-19 (9)
- SARS-CoV-2 (5)
- bladder cancer (4)
- Aortic stenosis (3)
- Hypoxia (3)
- Inflammation (3)
- Macrophages (3)
- Mortality (3)
- Peri-implantitis (3)
- Postural control (3)
Institute
- Medizin (245)
- Biowissenschaften (3)
- Ernst Strüngmann Institut (3)
- Frankfurt Institute for Advanced Studies (FIAS) (3)
- MPI für Hirnforschung (3)
- Psychologie (2)
- Biochemie und Chemie (1)
- Biochemie, Chemie und Pharmazie (1)
- Buchmann Institut für Molekulare Lebenswissenschaften (BMLS) (1)
- Informatik und Mathematik (1)
Oral swabs, sputum and blood samples from 18 patients with SARS-CoV-2 infection were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) testing. Whereas oral swabs or sputum from the lower respiratory tract were tested RT-PCR positive in all patients, RNAemia was neither detected in 3 patients without symptoms nor in 14 patients with flu-like symptoms, fever or pneumonia. The only patient with RNAemia suffered from acute respiratory distress syndrome (ARDS) and was artificially ventilated in an intensive care unit. Risk for SARS-CoV-2 transmission through blood components in asymptomatic SARS-CoV-2 infected individuals therefore seems negligible but further studies are needed.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.
SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P2). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.
Objective: To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring.
Methods: We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form.
Results: A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3–74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2–3.4%) and 3.2% per patient (95% CI 1.8–5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5–2.2%) and 1.7% per patient (95% CI 0.8–3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section.
Conclusions: GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.
There is limited knowledge on the prevalence and risk factors of diabetic retinopathy (DR) in dialysis patients. We have investigated the association between diabetes mellitus and lipid-related biomarkers and retinopathy in hemodialysis patients. We reviewed 1,255 hemodialysis patients with type 2 diabetes mellitus (T2DM) who participated in the German Diabetes and Dialysis Study (4D Study). Associations between categorical clinical, biochemical variables and diabetic retinopathy were examined by logistic regression. On average, patients were 66 ± 8 years of age, 54% were male and the HbA1c was 6.7% ± 1.3%. DR, found in 71% of the patients, was significantly and positively associated with fasting glucose, HbA1c, time on dialysis, age, systolic blood pressure, body mass index and the prevalence of other microvascular diseases (e.g. neuropathy). Unexpectedly, DR was associated with high HDL cholesterol and high apolipoproteins AI and AII. Patients with coronary artery disease were less likely to have DR. DR was not associated with gender, smoking, diastolic blood pressure, VLDL cholesterol, triglycerides, and LDL cholesterol. In summary, the prevalence of DR in patients with type 2 diabetes mellitus requiring hemodialysis is higher than in patients suffering from T2DM, who do not receive hemodialysis. DR was positively related to systolic blood pressure (BP), glucometabolic control, and, paradoxically, HDL cholesterol. This data suggests that glucose and blood pressure control may delay the development of DR in patients with diabetes mellitus on dialysis.
Background: The high-oblique sagittal osteotomy (HOSO) is an alternative to a bilateral sagittal split osteotomy (BSSO). Due to its novelty, there are no long-term studies which have focused on describing the incidence and type of complications encountered in the post-operative follow-up. The aim of this retrospective study is to analyze patients operated on with this surgical technique and the post-operative complications encountered. Patient and methods: The electronic medical records of all patients treated with orthognathic surgery at the Department of Oral, Maxillofacial and Facial Plastic Surgery, University Hospital Frankfurt, Goethe University, Frankfurt, Germany, between the years 2009 and 2016 were retrospectively reviewed. Results: A total of 116 patients fulfilled the inclusion criteria. The cases operated on with the standard osteosynthesis (X, Y, and straight) showed a complication rate of 36.37% (n = 4/11). The cases operated on with the HOSO-dedicated plates (HOSO-DP) showed, in total, a complication rate of 6.67% (n = 7/105). The most common post-operative complication resulting from both fixation methods was a reduction in mouth opening and TMJ pain for 4.3%. During the first years of performing the surgery (2009–211), a variety of standard plates had material failure causing non-union or pseudarthrosis. No cases of material failure were observed in the cases operated on with the HOSO-DP. The statistical results showed a highly significant dependence of a reduction in OP-time over the years, when the HOSO was performed without additional procedures (R2 > 0.83, P < 0.0015). Conclusion: The rate of complications in the HOSO were shown to be comparable to the rate of complications from the BSSO reported in the literature. Moreover, the use of the ramus dedicated plate appears to provide enough stability to the bone segments, making the surgery safer. Clinical relevance: The HOSO needs to be considered by surgeons as an alternative to BSSO. Once the use of the HOSO-DP was established, the rate of complications and the operation time reduced considerably.
Background and Objective: Long-term tooth retention is the ultimate goal of periodontal therapy. Aim of this study was to evaluate tooth loss (TL) during 10 years of supportive periodontal therapy (SPT) in periodontal compromised patients and to identify factors influencing TL on patient level. Material and Methods: Patients were re-examined 120 ± 12 months after active periodontal therapy. TL and risk factors [smoking, initial diagnosis, SPT adherence, interleukin-1 polymorphism, cardiovascular diseases, age at baseline, bleeding on probing (BOP), change of practitioner, insurance status, number of SPT, marital and educational status] influencing TL on patient level were assessed. Results: One-hundred patients (52 female, mean age 65.6 ± 11 years) lost 121 of 2428 teeth (1.21 teeth/patient; 0.12 teeth/patient/y) during 10 years of SPT. Forty-two of these were lost for periodontal reasons (0.42 teeth/patient; 0.04 teeth/patient/y). Significantly more teeth were lost due to other reasons (P < .001). Smoking, baseline severity of periodontitis, non-adherent SPT, positive interleukin-1 polymorphism, marital and educational status, private insurance, older age at baseline and BOP, small number of SPT were identified as patient-related risk factors for TL (P < .05). Conclusion: During 120 ± 12 months of SPT, only a small number of teeth was lost in periodontally compromised patients showing the positive effect of a well-established periodontal treatment concept. The remaining risk for TL should be considered using risk-adopted SPT allocation.
Reliable and efficient recording of the error-related negativity with a speeded Eriksen Flanker task
(2020)
There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are standardized and reliable measurements. Additional psychiatry specific requirements are time efficiency and patient-friendliness.
The aim of the present study is to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.
Healthy subjects (N=27) performed a modified Eriksen Flanker Task with adaptive reaction time window and only incongruent stimuli that maximizes the number of errors. All participants were tested for mental health by the Mini International Neuropsychiatric Interview (M.I.N.I.). The first N=12 subjects were part of a pilot study and further N=14 subjects were included for analysis (one subject was excluded due to technical problems). In a test-retest design with two sessions separated by 28 days the reliability of the ERN has been assessed. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (1) number of errors and (2) negative affect. State affect of each subject was measured by the Positive and Negative Affect Schedule. In order to optimize the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.
We found excellent reliability of the ERN (intraclass correlation coefficient =0.806-0.947) and replicated specific correlation patterns (ERN amplitude with relative number of errors: r=0.394; p=0.082; ERN amplitude with negative affect: r=-0.583, p=0.014). The task can be shortened to a patient-friendly and clinically feasible length of only 8 minutes keeping reliability >0.80.
To conclude, the present modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
White matter hyperintensities (WMHs) in the cerebral white matter and attenuation of alpha oscillations (AO; 7–13 Hz) occur with the advancing age. However, a crucial question remains, whether changes in AO relate to aging per se or they rather reflect the impact of age-related neuropathology like WMHs. In this study, using a large cohort (N=907) of elderly participants (60-80 years), we assessed relative alpha power (AP), individual alpha peak frequency (IAPF) and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. In contrast, we observed no significant relation of probability of WMH occurrence with IAPF and LRTC. We argue that the WMH-associated increase of AP reflects generalized and likely compensatory changes of AO leading to a larger number of synchronously recruited neurons.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2020)
Objective: To investigate whether regional white matter hyperintensities (WMHs) relate to alpha oscillations (AO) in a large population-based sample of elderly individuals.
Methods: We associated voxel-wise WMHs from high-resolution 3-Tesla MRI with neuronal alpha oscillations (AO) from resting-state multichannel EEG at sensor (N=907) and source space (N=855) in older participants of the LIFE-Adult study (60–80 years). In EEG, we computed relative alpha power (AP), individual alpha peak frequency (IAPF), as well as long-range temporal correlations (LRTC) that represent dynamic properties of the signal. We implemented whole-brain voxel-wise regression models to identify regions where parameters of AO were linked to probability of WMH occurrence. We further used mediation analyses to examine whether WMH volume mediated the relationship between age and AO.
Results: Higher prevalence of WMHs in the superior and posterior corona radiata was related to elevated relative AP, with strongest correlations in the bilateral occipital cortex, even after controlling for potential confounding factors. The age-related increase of relative AP in the right temporal brain region was shown to be mediated by total WMH volume.
Conclusion: A high relative AP corresponding to increased regional WMHs was not associated with age per se, in fact, this relationship was mediated by WMHs. We argue that the WMH-associated increase of AP reflects a generalized and likely compensatory spread of AO leading to a larger number of synchronously recruited neurons. Our findings thus suggest that longitudinal EEG recordings might be sensitive to detect functional changes due to WMHs.
Background: Experienced and anticipated regret influence physicians’ decision-making. In medicine, diagnostic decisions and diagnostic errors can have a severe impact on both patients and physicians. Little empirical research exists on regret experienced by physicians when they make diagnostic decisions in primary care that later prove inappropriate or incorrect. The aim of this study was to explore the experience of regret following diagnostic decisions in primary care.
Methods: In this qualitative study, we used an online questionnaire on a sample of German primary care physicians. We asked participants to report on cases in which the final diagnosis differed from their original opinion, and in which treatment was at the very least delayed, possibly resulting in harm to the patient. We asked about original and final diagnoses, illness trajectories, and the reactions of other physicians, patients and relatives. We used thematic analysis to assess the data, supported by MAXQDA 11 and Microsoft Excel 2016.
Results: 29 GPs described one case each (14 female/15 male patients, aged 1.5–80 years, response rate < 1%). In 26 of 29 cases, the final diagnosis was more serious than the original diagnosis. In two cases, the diagnoses were equally serious, and in one case less serious. Clinical trajectories and the reactions of patients and relatives differed widely. Although only one third of cases involved preventable harm to patients, the vast majority (27 of 29) of physicians expressed deep feelings of regret.
Conclusion: Even if harm to patients is unavoidable, regret following diagnostic decisions can be devastating for clinicians, making them ‘second victims’. Procedures and tools are needed to analyse cases involving undesirable diagnostic events, so that ‘true’ diagnostic errors, in which harm could have been prevented, can be distinguished from others. Further studies should also explore how physicians can be supported in dealing with such events in order to prevent them from practicing defensive medicine.
Background: The treatment of severely injured patients, especially in older age, is complex, and based on strict guidelines. Methods: We conducted a retrospective study by analyzing our internal registry for mortality risk factors in deceased trauma patients. All patients that were admitted to the trauma bay of our level-1-trauma center from 2014 to 2018, and that died during the in-hospital treatment, were included. The aim of this study was to carry out a quality assurance concerning the initial care of severely injured patients. Results: In the 5-year period, 135 trauma patients died. The median (IQR) age was 69 (38–83) years, 71% were male, and the median (IQR) Injury Severity Score (ISS) was 25 (17–34) points. Overall, 41% of the patients suffered from severe traumatic brain injuries (TBI) (AIShead ≥ 4 points). For 12.7%, therapy was finally limited owing to an existing patient’s decree; in 64.9% with an uncertain prognosis, a ‘therapia minima’ was established in consensus with the relatives. Conclusion: Although the mortality rate was primarily related to the severity of the injury, a significant number of deaths were not exclusively due to medical reasons, but also to a self-determined limitation of therapy for severely injured geriatric patients. The conscientious documentation concerning the will of the patient is increasingly important in supporting medical decisions.
Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
Two-person neuroscience (2 PN) is a recently introduced conceptual and methodological framework used to investigate the neural basis of human social interaction from simultaneous neuroimaging of two or more subjects (hyperscanning). In this study, we adopted a 2 PN approach and a multiple-brain connectivity model to investigate the neural basis of a form of cooperation called joint action. We hypothesized different intra-brain and inter-brain connectivity patterns when comparing the interpersonal properties of joint action with non-interpersonal conditions, with a focus on co-representation, a core ability at the basis of cooperation. 32 subjects were enrolled in dual-EEG recordings during a computerized joint action task including three conditions: one in which the dyad jointly acted to pursue a common goal (joint), one in which each subject interacted with the PC (PC), and one in which each subject performed the task individually (Solo).
A combination of multiple-brain connectivity estimation and specific indices derived from graph theory allowed to compare interpersonal with non-interpersonal conditions in four different frequency bands. Our results indicate that all the indices were modulated by the interaction, and returned a significantly stronger integration of multiple-subject networks in the joint vs. PC and Solo conditions. A subsequent classification analysis showed that features based on multiple-brain indices led to a better discrimination between social and non-social conditions with respect to single-subject indices. Taken together, our results suggest that multiple-brain connectivity can provide a deeper insight into the understanding of the neural basis of cooperation in humans.
The aim of this study is to provide a systematic assessment of the influence of the position on the arterial input function (AIF) for perfusion quantification. In 39 patients with a wide range of left ventricular function the AIF was determined using a diluted contrast bolus of a cardiac magnetic resonance imaging in three left ventricular levels (basal, mid, apex) as well as aortic sinus (AoS). Time to peak signal intensities, baseline corrected peak signal intensity and upslopes were determined and compared to those obtained in the AoS. The error induced by sampling the AIF in a position different to the AoS was determined by Fermi deconvolution. The time to peak signal intensity was strongly correlated (r2 > 0.9) for all positions with a systematic earlier arrival in the basal (− 2153 ± 818 ms), the mid (− 1429 ± 928 ms) and the apical slice (− 450 ± 739 ms) relative to the AoS (all p < 0.001). Peak signal intensity as well as upslopes were strongly correlated (r2 > 0.9 for both) for all positions with a systematic overestimation in all positions relative to the AoS (all p < 0.001 and all p < 0.05). Differences between the positions were more pronounced for patients with reduced ejection fraction. The error of averaged MBF quantification was 8%, 13% and 27% for the base, mid and apex. The location of the AIF significantly influences core parameters for perfusion quantification with a systematic and ejection fraction dependent error. Full quantification should be based on obtaining the AIF as close as possible to the myocardium to minimize these errors.
Autism spectrum disorders (ASD) are highly heritable and are characterized by deficits in social communication and restricted and repetitive behaviors. Twin studies on phenotypic subdomains suggest a differing underlying genetic etiology. Studying genetic variation explaining phenotypic variance will help to identify specific underlying pathomechanisms. We investigated the effect of common variation on ASD subdomains in two cohorts including >2500 individuals. Based on the Autism Diagnostic Interview-Revised (ADI-R), we identified and confirmed six subdomains with a SNP-based genetic heritability h2SNP = 0.2–0.4. The subdomains nonverbal communication (NVC), social interaction (SI), and peer interaction (PI) shared genetic risk factors, while the subdomains of repetitive sensory-motor behavior (RB) and restricted interests (RI) were genetically independent of each other. The polygenic risk score (PRS) for ASD as categorical diagnosis explained 2.3–3.3% of the variance of SI, joint attention (JA), and PI, 4.5% for RI, 1.2% of RB, but only 0.7% of NVC. We report eight genome-wide significant hits—partially replicating previous findings—and 292 known and novel candidate genes. The underlying biological mechanisms were related to neuronal transmission and development. At the SNP and gene level, all subdomains showed overlap, with the exception of RB. However, no overlap was observed at the functional level. In summary, the ADI-R algorithm-derived subdomains related to social communication show a shared genetic etiology in contrast to restricted and repetitive behaviors. The ASD-specific PRS overlapped only partially, suggesting an additional role of specific common variation in shaping the phenotypic expression of ASD subdomains.
Aims: The study aimed to evaluate the prevalence of mental distress in patients with newly diagnosed bladder cancer, the cancer-information search behavior, and the influence of information seeking on distress. Methods: One hundred and one bladder cancer patients answered 2 established questionnaires (“Hospital Anxiety and Depression Scale” [HADS] and the “Fragebogen zur Belastung von Krebskranken” [FBK-R23]) for evaluation of mental distress and a self-developed questionnaire with questions concerning information seeking and socioeconomic facts. Results: Regarding risk group stratification, 57.4% were classified as high-risk and 42.6% as low-risk tumor-bearing patients. Analysis of mental distress showed that 23.2% had a score above the HADS-A cutoff, 25.3% above the HADS-D cutoff, and 21.4% showed a pathologic FBK-R23 score. Overall, 75% felt well informed about their illness. Risk group stratification did not correlate with HADS-A, HADS-D, or FBK-R23 score. Furthermore, active search for information or the use of the Internet did not correlate with the HADS-A, HADS-D, or FBK-R23 score. However, the quality of the urologist’s information and the feeling of being informed correlated with the grade of mental distress. Conclusion: Besides the treatment of bladder cancer, informing the patient about the disease in a psychologically wholesome manner and working together with psycho-oncologically trained psychologists are essential tasks for the treating urologist.
Manufacturing processes of custom implant abutments may contaminate their surfaces with micro wear deposits and generic pollutants. Such particulate debris, if not removed, might be detrimental and provoke inflammatory reactions in peri-implant tissues. Although regulatory guidelines for adequate cleaning, disinfection, or sterilization exist, there does not appear to be a consistent application and data on the amount and extent of such contaminants is lacking. The aim of the present in vitro study was to evaluate the quality and quantity of processing-related surface contamination of computer-aided design/computer-aided manufacturing (CAD/CAM) abutments in the state of delivery and after ultrasonic cleaning. A total of 28 CAD/CAM monotype and hybrid abutments were cleaned and disinfected applying a three-stage ultrasonic protocol (Finevo protocol). Before and after cleaning, the chemical composition and the contamination of the abutments were assessed using scanning electron microscopy (SEM), dispersive X-ray spectroscopy(EDX),andcomputer-aidedplanimetricmeasurement(CAPM).Inthedeliverycondition, monotype abutments showed a significantly higher amount of debris compared to hybrid abutments (4.86±6.10% vs. 0.03 ± 0.03%, p < 0.001). The polishing process applied in the laboratory after bonding the hybrid abutment components reduces the surface roughness and thus contributes substantially to their purity. The extent of contamination caused by computer-aided manufacturing of custom abutments can be substantially minimized using a three-stage ultrasonic protocol.
Correct cellular function is ensured by a complex network of proteins and enzymes, regulating protein synthesis and degradation. This protein network, maintaining the so-called protein homeostasis, regulates those processes on multiple levels, producing new or degrading old proteins to cope with changing intra- and extracellular environments. Disturbance of this tightly regulated machinery can have severe effects on the cell and can lead to a variety of pathologies on organism level. Diseases including cancer, neurodegeneration and infections are associated with causative or consequent alterations in protein homeostasis. To understand the pathologies of these diseases, it is therefore critical to examine how perturbations of protein homeostasis affect cellular pathways and physiology. In the recent years, analysis of protein homeostasis networks has resulted in the development of novel therapeutic approaches. However, for many factors it remains unclear how the cell is affected, if they are disturbed. Protein synthesis and degradation represent immediate responses of the cell to changes and need to be studied in the right timeframe, making them difficult to access by common methodology. In this work we developed a new mass spectrometry (MS) based method to study protein synthesis and degradation on a system-wide scale. Multiplexed enhanced protein dynamic (mePROD) MS was developed, overcoming these limitations by special sample mixing and novel data analysis protocols. MePROD thereby enables the measurement of rapid and transient (e.g. minutes) changes in protein synthesis of thousands of proteins. During responses of the cell to stressors (e.g. protein misfolding, oxidation or infection), two major pathways regulate the protein synthesis: the Integrated Stress Response (ISR) and mammalian target of rapamycin (mTOR). Both pathways have been connected with various diseases in the past and are common therapy targets. Although both pathways target protein synthesis in stress responses, the set of targets regulated by these pathways was believed to differ. Through the new mePROD MS method we could measure a comprehensive comparison of both pathways for the first time, revealing comparable system-wide patterns of regulation between the two pathways. This changed the current view on the regulation elicited by these pathways and furthermore represents a useful resource for the whole field of research. We could further develop the mePROD method and decrease MS measurement time needed to obtain an in-depth dataset. Through implementation of logic based instrument methods, it was possible to enhance the number of measured proteins by approximately three-fold within the same measurement time.
The dynamics of protein synthesis and degradation are frequently modulated by pathogens infecting the cell to promote pathogen replication. At the same time, the cell counteracts the infection by modulating protein dynamics as well. To develop useful therapy approaches to fight infections, it therefore is necessary to understand the complex changes within the host cell during infections on a system-wide scale. In 2019, a novel coronavirus spread around the world, causing a world-wide health-crisis. To better understand this novel virus and its infection of the host cell we conducted a study applying the mePROD methodology and classical proteomics to characterize the dynamic changes during the infection course in vitro. We discovered that the infection remodeled a diverse set of host cell pathways (e.g. mRNA splicing, glycolysis, DNA synthesis and protein homeostasis) and thereby showed possible targets for antiviral therapy. By targeted inhibition of these pathways, we could observe that these pathways indeed are necessary for SARS-CoV-2 replication and their inhibition could reduce viral load in the cells. Another experimental approach focused on the dynamic changes of protein modification, namely phosphorylation, after infection with SARS-CoV-2. Here, we could show the very important participation of growth factor signaling pathways in viral proliferation. Both studies together revealed critical pathways that are needed for the viral proliferation and hence are promising candidates for further therapies. Subsequent targeting of these pathways by either already approved drugs (Ribavirin and Sorafenib) or drugs in clinical trials (2-deoxyglucose, Pladienolide-B, NMS-873, Pictilisib, Omipalisib, RO5126766 and Lonafarnib) could block viral replication in vitro and suggests important clinical approaches targeting SARS-COV-2 infection.
Background Stigma has been considered a significant barrier both in treatment, rehabilitation and help-seeking behaviours of people diagnosed with depression. This study aimed to assess the influence of the type of previous experience with depression on depression stigma, identify the effects of previous experience with depression on stigma and to analyse the effects of stigma on help-seeking attitudes.
Methods A total of 1693 participants with a mean age of 47.2 (SD=18.17) completed the Depression Stigma Scale (DSS), the Attitude Toward Seeking Professional Psychological Help (ATSPPH), and a sociodemographic questionnaire. We categorised participants into four comparison groups: no previous experience with depression (n=479), indirect experience with depression (n=661), direct experience with depression (n=137), and both direct and indirect experience with depression (n=416). Data were analysed using SPSS 24.0.
Results Levels of personal stigma were lower in people who had family and friends experiencing depression in comparison with individuals with no history of depression experience. Better attitudes towards help-seeking were evident in those with lower personal stigma, and worse help-seeking attitudes were associated with higher perceived stigma in the indirect previous experience group.
Limitations Duration of participant exposure to depression was not collected.
Conclusions The individual’s experience with depression influences the development of personal stigmatisation towards depression and plays a role in help-seeking behaviours. Addressing people’s experience of depression might be a practical way of reducing depression stigma and improve help-seeking behaviours.
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2−/− mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2−/− mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2−/− mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2−/− mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2−/− were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2−/− phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
Background: The adequate allocation of inpatient care resources requires assumptions about the need for health care and how this need will be met. However, in current practice, these assumptions are often based on outdated methods (e.g. Hill-Burton Formula). This study evaluated floating catchment area (FCA) methods, which have been applied as measures of spatial accessibility, focusing on their ability to predict the need for health care in the inpatient sector in Germany.
Methods: We tested three FCA methods (enhanced (E2SFCA), modified (M2SFCA) and integrated (iFCA)) for their accuracy in predicting hospital visits regarding six medical diagnoses (atrial flutter/fibrillation, heart failure, femoral fracture, gonarthrosis, stroke, and epilepsy) on national level in Germany. We further used the closest provider approach for benchmark purposes. The predicted visits were compared with the actual visits for all six diagnoses using a correlation analysis and a maximum error from the actual visits of ± 5%, ± 10% and ± 15%.
Results: The analysis of 229 million distances between hospitals and population locations revealed a high and significant correlation of predicted with actual visits for all three FCA methods across all six diagnoses up to ρ = 0.79 (p < 0.001). Overall, all FCA methods showed a substantially higher correlation with actual hospital visits compared to the closest provider approach (up to ρ = 0.51; p < 0.001). Allowing a 5% error of the absolute values, the analysis revealed up to 13.4% correctly predicted hospital visits using the FCA methods (15% error: up to 32.5% correctly predicted hospital). Finally, the potential of the FCA methods could be revealed by using the actual hospital visits as the measure of hospital attractiveness, which returned very strong correlations with the actual hospital visits up to ρ = 0.99 (p < 0.001).
Conclusion: We were able to demonstrate the impact of FCA measures regarding the prediction of hospital visits in non-emergency settings, and their superiority over commonly used methods (i.e. closest provider). However, hospital beds were inadequate as the measure of hospital attractiveness resulting in low accuracy of predicted hospital visits. More reliable measures must be integrated within the proposed methods. Still, this study strengthens the possibilities of FCA methods in health care planning beyond their original application in measuring spatial accessibility.
Background: While swallowing disorders are frequent sequela following posterior fossa tumor (PFT) surgery in children, data on dysphagia frequency, severity, and outcome in adults are lacking. The aim of this study was to investigate dysphagia before and after surgical removal of PFT. Additionally, we tried to identify clinical predictors for postsurgical swallowing disorders. Furthermore, this study explored the three-month outcome of dysphagic patients.
Methods: In a cohort of patients undergoing PFT surgery, dysphagia was prospectively assessed pre- and postoperatively using fiberoptic endoscopic evaluation of swallowing. Patients with severe dysphagia at discharge were re-evaluated after three months. Additionally, clinical and imaging data were collected to identify predictors for post-surgical dysphagia. Results: We included 26 patients of whom 15 had pre-operative swallowing disorders. After surgery, worsening of pre-existing dysphagia could be noticed in 7 patients whereas improvement was observed in 2 and full recovery in 3 subjects. New-onset dysphagia after surgery occurred in a minority of 3 cases. Postoperatively, 47% of dysphagic patients required nasogastric tube feeding. Re-evaluation after three months of follow-up revealed that all dysphagic patients had returned to full oral intake.
Conclusion: Dysphagia is a frequent finding in patients with PFT already before surgery. Surgical intervention can infer a deterioration of impaired swallowing function placing affected patients at temporary risk for aspiration. In contrast, surgery can also accomplish beneficial results resulting in both improvement and full recovery. Overall, our findings show the need of early dysphagia assessment to define the safest feeding route for the patient.
The sudden infant death syndrome (SIDS) is one of the leading causes of postneonatal infant death. It has been shown that there exists a complex relationship between SIDS and inherited cardiac disease. Next-generation sequencing and surveillance of cardiac channelopathy and cardiomyopathy genes represent an important tool for investigating the cause of death in SIDS cases. In the present study, targeted sequencing of 80 genes associated with genetic heart diseases in a cohort of 31 SIDS cases was performed. To determine the spectrum and prevalence of genetic heart disease associated mutations as a potential monogenic basis for SIDS, a stringent variant classification was applied and the percentage of rare (minor allele frequency ≤ 0.2%) and ultra-rare variants (minor allele frequency ≤ 0.005%) in these genes was assessed. With a minor allele frequency of ≤ 0.005%, about 20% of the SIDS cases exhibited a variant of uncertain significance (VUS), but in only 6% of these cases, gene variants proved to be “potentially informative.” The present study shows the importance of careful variant interpretation. Applying stringent criteria misinterpretations are avoided, as the results of genetic analyses may have an important impact of the family members involved.
Diabetes mellitus is a major risk factor for cardiovascular disease. Platelets from diabetic patients are hyperreactive and release microparticles that carry activated cysteine proteases or calpains. Whether platelet-derived calpains contribute to the development of vascular complications in diabetes is unknown. Here we report that platelet-derived calpain1 (CAPN1) cleaves the protease-activated receptor 1 (PAR-1) on the surface of endothelial cells, which then initiates a signaling cascade that includes the activation of the tumor necrosis factor (TNF)-α converting enzyme (TACE). The latter elicits the shedding of the endothelial protein C receptor and the generation of TNF-α, which in turn, induces intracellular adhesion molecule (ICAM)-1 expression to promote monocyte adhesion. All of the effects of CAPN1 were mimicked by platelet-derived microparticles from diabetic patients or from wild-type mice but not from CAPN1−/− mice, and were not observed in PAR-1-deficient endothelial cells. Importantly, aortae from diabetic mice expressed less PAR-1 but more ICAM-1 than non-diabetic mice, effects that were prevented by treating diabetic mice with a calpain inhibitor as well as by the platelet specific deletion of CAPN1. Thus, platelet-derived CAPN1 contributes to the initiation of the sterile vascular inflammation associated with diabetes via the cleavage of PAR-1 and the release of TNF-α from the endothelial cell surface.
Aims: This post hoc analysis of ELIMINATE-AF evaluated requirements of unfractionated heparin (UFH) and procedure-related bleeding in atrial fibrillation (AF) patients undergoing ablation with uninterrupted edoxaban or vitamin K antagonist (VKA) therapy.
Methods and results: Patients were randomized 2:1 to once-daily edoxaban 60 mg (or dose-reduced 30 mg) or dose-adjusted VKA (target international normalized ratio: 2.0–3.0). Uninterrupted anticoagulation was mandated for 21–28 days’ pre-ablation and 90 days’ post-ablation. During ablation, UFH administration targeted an activated clotting time (ACT) of 300–400 s. Periprocedural bleeding was differentiated between procedure-related (bleeding at puncture side, cardiac tamponade) and unrelated events. Of 614 randomized patients, 553 received study drug and underwent catheter ablation (edoxaban n = 375; VKA n = 178). The median (Q1–Q3) time from last dose to ablation procedure was 14.8 (13.3–16.5) vs. 16.5 (14.8–19.5) h (edoxaban vs. VKA group, respectively). Mean ACT (SD) ≥300 s was observed in 52% edoxaban- vs. 76% VKA-treated patients, despite a higher mean (SD) UFH dose in the edoxaban vs. VKA group [14 261 (6397) IU vs. 11 473 (4300) IU; exploratory P-value < 0.0001]. In the edoxaban group, 13 patients (3.5%) had procedure-related bleeds of whom 9 had received an UFH dose above the median (13 000 IU). In the VKA arm, 7 patients (3.9%) had procedure-related bleeds of whom 3 had received an UFH dose above the median (10 225 IU).
Conclusion: The rate of procedure-related major/clinically relevant non-major bleeding did not differ between the treatment arms despite higher doses of UFH used with edoxaban vs. VKA to achieve a target ACT during AF ablation.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors – introduced during the hysteresis experiment – lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors—introduced during the hysteresis experiment—lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Fasting Ramadan is known to influence patients’ medication adherence. Data on patients’ behavior to oral anticoagulant (OAC) drug intake during Ramadan is missing. We aimed to determine patient-guided modifications of OAC medication regimen during Ramadan and to evaluate its consequences. A multicenter cross-sectional study conducted in Saudi Arabia. Data were collected shortly after Ramadan 2019. Participants were patients who fasted Ramadan and who were on long-term anticoagulation. Patient-guided medication changes during Ramadan in comparison to the regular intake schedule before Ramadan were recorded. Modification behavior was compared between twice daily (BID) and once daily (QD) treatment regimens. Rates of hospital admission during Ramadan were determined. We included 808 patients. During Ramadan, 53.1% modified their intake schedule (31.1% adjusted intake time, 13.2% skipped intakes, 2.2% took double dosing). A higher frequency of patient-guided modification was observed in patients on BID regimen compared to QD regimen. During Ramadan, 11.3% of patients were admitted to hospital. Patient-guided modification was a strong predictor for hospital admission. Patient-guided modification of OAC intake during Ramadan is common, particularly in patients on BID regimen. It increases the risk of hospital admission during Ramadan. Planning of OAC intake during Ramadan and patient education on the risk of low adherence are advisable.
Deubiquitinases (DUBs) are vital for the regulation of ubiquitin signals, and both catalytic activity of and target recruitment by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (also known as OTU domain–containing protein 7B (OTUD7B)), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for factor inhibiting HIF1 (FIH1)- and oxygen-dependent asparagine hydroxylation. We found that FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show that UBACez binds Lys11-, Lys48-, Lys63-, and Met1-linked ubiquitin chains in vitro, establishing UBACez as a functional ubiquitin-binding domain. Our findings also reveal that the interaction of UBACez with ubiquitin is mediated via a noncanonical surface and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that Cezanne recruitment to specific target proteins depends on UBACez. Our results indicate that UBACez can indeed fulfill this role as regulatory domain by binding various ubiquitin chain types. They also uncover that this interaction with ubiquitin, and thus with modified substrates, can be modulated by oxygen-dependent asparagine hydroxylation, suggesting that Cezanne is regulated by oxygen levels.
We studied oscillatory mechanisms of memory formation in 48 younger and 51 older adults in an intentional associative memory task with cued recall. While older adults showed lower memory performance than young adults, we found subsequent memory effects (SME) in alpha/beta and theta frequency bands in both age groups. Using logistic mixed effects models, we investigated whether interindividual differences in structural integrity of key memory regions could account for interindividual differences in the strength of the SME. Structural integrity of inferior frontal gyrus (IFG) and hippocampus was reduced in older adults. SME in the alpha/beta band were modulated by the cortical thickness of IFG, in line with its hypothesized role for deep semantic elaboration. Importantly, this structure–function relationship did not differ by age group. However, older adults were more frequently represented among the participants with low cortical thickness and consequently weaker SME in the alpha band. Thus, our results suggest that differences in the structural integrity of the IFG contribute not only to interindividual, but also to age differences in memory formation.
Background: Many patients suffering from exercise-induced asthma (EIA) have normal lung function at rest and show symptoms and a decline in FEV1 when they do sports or during exercise-challenge. It has been described that long-chain polyunsaturated fatty acids (LCPUFA) could exert a protective effect on EIA.
Methods: In this study the protective effect of supplementation with a special combination of n-3 and n-6 LCPUFA (sc-LCPUFA) (total 1.19 g/ day) were investigated in an EIA cold air provocation model. Primary outcome measure: Decrease in FEV1 after exercise challenge and secondary outcome measure: anti-inflammatory effects monitored by exhaled NO (eNO) before and after sc-LCPUFA supplementation versus placebo.
Results: Ninety-nine patients with exercise-induced symptoms aged 10 to 45 were screened by a standardized exercise challenge in a cold air chamber at 4 °C. Seventy-three patients fulfilled the inclusion criteria of a FEV1 decrease > 15% and were treated double-blind placebo-controlled for 4 weeks either with sc-LCPUFA or placebo. Thirty-two patients in each group completed the study. Mean FEV1 decrease after cold air exercise challenge and eNO were unchanged after 4 weeks sc-LCPUFA supplementation.
Conclusion: Supplementation with sc-LCPUFA at a dose of 1.19 g/d did not have any broncho-protective and anti-inflammatory effects on EIA.
Trial registration: Clinical trial registration number: NCT02410096. Registered 7 February 2015 at Clinicaltrial.gov
Attention selects relevant information regardless of whether it is physically present or internally stored in working memory. Perceptual research has shown that attentional selection of external information is better conceived as rhythmic prioritization than as stable allocation. Here we tested this principle using information processing of internal representations held in working memory. Participants memorized four spatial positions that formed the endpoints of two objects. One of the positions was cued for a delayed match-non-match test. When uncued positions were probed, participants responded faster to uncued positions located on the same object as the cued position than to those located on the other object, revealing object-based attention in working memory. Manipulating the interval between cue and probe at a high temporal resolution revealed that reaction times oscillated at a theta rhythm of 6 Hz. Moreover, oscillations showed an anti-phase relationship between memorized but uncued positions on the same versus other object as the cued position, suggesting that attentional prioritization fluctuated rhythmically in an object-based manner. Our results demonstrate the highly rhythmic nature of attentional selection in working memory. Moreover, the striking similarity between rhythmic attentional selection of mental representations and perceptual information suggests that attentional oscillations are a general mechanism of information processing in human cognition. These findings have important implications for current, attention-based models of working memory.
The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.
Background: In the pandemic, testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by real-time polymerase chain reaction is one of the pillars on which countermeasures are based. Factors limiting the output of laboratories interfere with the effectiveness of public health measures. Conserving reagents by pooling samples in low-probability settings is proposed but may cause dilution and loss of sensitivity. Blood transfusion services had experience in performance of high throughput nucleic acid testing (NAT) analysis and can support the national health system by screening of the inhabitants for SARS-COV-2.
Methods: We evaluated a new approach of a multiple-swab method by simultaneously incubating multiple respiratory swabs in a single tube. Analytical sensitivity was constant up to a total number of 50 swabs. It was consequently applied in the testing of 50 symptomatic patients (5-sample pools) as well as 100 asymptomatic residents of a nursing home (10-sample pools).
Results: The novel method did not cause false-negative results with nonsignificantly differing cycle threshold values between single-swab and multiple-swab NAT. In two routine applications, all minipools containing positive patient samples were correctly identified.
Conclusions: The new method enables countries to increase the total number of testing significantly. The multiple-swab method is able to screen system relevant groups of employees frequently. The example in Germany shows that blood transfusion services can support general health systems with their experience in NAT and their high-throughput instruments. Screening of a huge number of inhabitants is currently the only option to prevent a second infection wave and enable exit strategies in many countries.
Rationale: Dysregulation of dopaminergic neurotransmission, specifically altered reward processing assessed via the reward anticipation in the MID task, plays a central role in the etiopathogenesis of neuropsychiatric disorders. Objectives: We hypothesized to find a difference in the activity level of the reward system (measured by the proxy reward anticipation) under drug administration versus placebo, in that amisulpride reduces, and L-DOPA enhances, its activity. Methods: We studied the influence of dopamine agonist L-DOPA and the antagonist amisulpride on the reward system using functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task in n = 45 healthy volunteers in a randomized, blinded, cross-over study. Results: The MID paradigm elicits strong activation in reward-dependent structures (such as ventral striatum, putamen, caudate, anterior insula) during reward anticipation. The placebo effect demonstrated the expected significant blood oxygen level–dependent activity in reward-dependent brain regions. Neither amisulpride nor L-DOPA led to significant changes in comparison with the placebo condition. This was true for whole-brain analysis as well as analysis of a pre-defined nucleus accumbens region-of-interest mask. Conclusion: The present results cast doubt on the sensitivity of reward anticipation contrast in the MID task for assessing dopamine-specific changes in healthy volunteers by pharmaco-fMRI. While our task was not well-suited for detailed analysis of the outcome phase, we provide reasonable arguments that the lack of effect in the anticipation phase is not due to an inefficient task but points to unexpected behavior of the reward system during pharmacological challenge. Group differences of reward anticipation should therefore not be seen as simple representatives of dopaminergic states.
Needlestick injuries: a density-equalizing mapping and socioeconomic analysis of the global research
(2020)
Background: Needlestick injuries have caused a deleterious effect on the physical and mental health of millions of health-care workers over the past decades, being responsible for occupational infections with viruses such as HIV or hepatis C. Despite this heavy burden of disease, no concise studies have been published on the global research landscape so far.
Methods: We used the New Quality and Quantity Indices in Science platform to analyze global NSI research (n = 2987 articles) over the past 115 years using the Web of Science and parameters such as global versus country-specific research activities, semi-qualitative issues, and socioeconomic figures.
Results: Density-equalizing mapping showed that although a total of n = 106 countries participated in NSI research, large parts of Africa and South America were almost invisible regarding global participation in NSI research. Average citation rate (cr) analysis indicated a high rate for Switzerland (cr = 25.1), Italy (cr = 23.5), and Japan (cr = 19.2). Socioeconomic analysis revealed that the UK had the highest quotient QGDP of 0.13 NSI-specific publications per bill. US-$ gross domestic product (GDP), followed by South Africa (QGDP = 0.12). Temporal analysis of HIV versus hepatitis research indicated that NSI-HIV research culminated in the early 1990s, whereas NSI-hepatitis research increased over the observed period from the 1980s until the last decade.
Conclusion: Albeit NSI research activity is generally increasing, the growth is asymmetrical from a global viewpoint. International strategies should be followed that put a focus on NSI in non-industrialized areas of the world.
Objectives: The aim of the present study was to characterize the cellular reaction to a xenogeneic resorbable collagen membrane of porcine origin using a subcutaneous implantation model in Wistar rats over 30 days.
Materials and methods: Ex vivo, liquid platelet-rich fibrin (PRF), a leukocyte and platelet-rich cell suspension, was used to evaluate the blood cell membrane interaction. The material was implanted subcutaneously in rats. Sham-operated rats without biomaterial displayed physiological wound healing (control group). Histological, immunohistological, and histomorphometric analyses were focused on the inflammatory pattern, vascularization rate, and degradation pattern.
Results: The membrane induced a large number of mononuclear cells over the observation period, including lymphocytes, macrophages, and fibroblasts. After 15 days, multinucleated giant cells (MNGCs) were observed on the biomaterial surface. Their number increased significantly, and they proceeded to the center of the biomaterial on day 30. These cells highly expressed CD-68, calcitonin receptor, and MMP-9, but not TRAP or integrin-ß3. Thus, the membrane lost its integrity and underwent disintegration as a consequence of the induction of MNGCs. The significant increase in MNGC number correlated with a high rate of vascularization, which was significantly higher than the control group. Physiological wound healing in the control group did not induce any MNGCs at any time point. Ex vivo blood cells from liquid-PRF did not penetrate the membrane.
Conclusion: The present study suggests a potential role for MNGCs in biomaterial degradation and questions whether it is beneficial to accept them in clinically approved biomaterials or focus on biomaterials that induce only mononuclear cells. Thus, further studies are necessary to identify the function of biomaterial-induced MNGCs.
Clinical relevance: Understanding the cellular reaction to biomaterials is essential to assess their suitability for specific clinical indications and outline the potential benefit of specific group of biomaterials in the respective clinical indications.
Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
Introduction: Cancer patients tend to prefer oral instead of parenteral chemotherapy. To date, there is little evidence on the medication adherence in cancer patients. We investigated medication adherence to tyrosine kinase inhibitors in patients suffering from non-small cell lung cancer. Methods: Tyrosine kinase inhibitor adherence was measured electronically by MEMS® (medication event monitoring system) over at least six months. Adherence rates were calculated in terms of Dosing Compliance, Timing Compliance, Taking Compliance, and Drug Holidays. Patients were dichotomized as adherent when Dosing Compliance and Timing Compliance were ≥80%, Taking Compliance ranged between 90 and 110%, and <1 Drug Holiday was registered. Quality of life was assessed by two questionnaires (EORTC QLQ-C30 version 3.0, EORTC QLQ-LC13) at three time points. Adverse drug events were reported via patient diaries. Results: Out of 32 patients enrolled, data from 23 patients were evaluable. Median Dosing Compliance, Taking Compliance, and Timing Compliance adherence rates of tyrosine kinase inhibitor intake amounted to 100%, 98%, and 99%, respectively; Drug Holidays were observed in three patients. Four patients were dichotomized as non-adherent. Three of them had a twice-daily tyrosine kinase inhibitor regimen. Median quality of life scores amounted to 67 (max. 100) and remained unchanged over the study period. Fatigue and rash were the most frequently reported adverse drug events. Conclusion: Medication adherence of non-small cell lung cancer patients treated with tyrosine kinase inhibitors was extraordinarily high and is likely to support the effectiveness of tyrosine kinase inhibitor treatment and a good quality of life over a long period of time. Adherence facilitating information and education is especially relevant for patients taking tyrosine kinase inhibitors in a twice-daily regimen.
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine expansion in Ataxin-2 (ATXN2). This factor binds RNA/proteins to modify metabolism after stress, and to control calcium (Ca2+) homeostasis after stimuli. Cerebellar ataxias and corticospinal motor neuron degeneration are determined by gain/loss in ATXN2 function, so we aimed to identify key molecules in this atrophic process, as potential disease progression markers. Our Atxn2-CAG100-Knock-In mouse faithfully models features observed in patients at pre-onset, early and terminal stages. Here, its cerebellar global RNA profiling revealed downregulation of signaling cascades to precede motor deficits. Validation work at mRNA/protein level defined alterations that were independent of constant physiological ATXN2 functions, but specific for RNA/aggregation toxicity, and progressive across the short lifespan. The earliest changes were detected at three months among Ca2+ channels/transporters (Itpr1, Ryr3, Atp2a2, Atp2a3, Trpc3), IP3 metabolism (Plcg1, Inpp5a, Itpka), and Ca2+-Calmodulin dependent kinases (Camk2a, Camk4). CaMKIV–Sam68 control over alternative splicing of Nrxn1, an adhesion component of glutamatergic synapses between granule and Purkinje neurons, was found to be affected. Systematic screening of pre/post-synapse components, with dendrite morphology assessment, suggested early impairment of CamKIIα abundance together with the weakening of parallel fiber connectivity. These data reveal molecular changes due to ATXN2 pathology, primarily impacting excitability and communication.
Mongolian spots (MS) are congenital dermal conditions resulting from neural crest-derived melanocytes migration to the skin during embryogenesis. MS incidences are highly variable in different populations. Morphologically, MS present as hyperpigmented maculae of varying size and form, ranging from round spots of 1 cm in diameter to extensive discolorations covering predominantly the lower back and buttocks. Due to their coloring, which is also dependent on the skin type, MS may mimic hematoma thus posing a challenge on the physician conducting examinations of children in cases of suspected child abuse. In the present study, MS incidences and distribution, as well as skin types, were documented in a collective of 253 children examined on the basis of suspected child abuse. From these data, a classification scheme was derived to document MS and to help identify cases with a need for recurrent examination for unambiguous interpretation of initial findings alongside the main decisive factors for re-examination such as general circumstances of the initial examination (e. g., experience of the examiner, lighting conditions) and given dermatological conditions of the patient (e. g., diaper rash).
While the liver, specifically hepatocytes, are widely accepted as the main source for hepatitis C virus (HCV) production, the role of the liver/hepatocytes in the clearance of circulating HCV remains largely unknown. Here we evaluated the function of the liver/hepatocytes in clearing virus from the circulation by investigating viral clearance during liver transplantation and from culture medium in vitro. Frequent HCV kinetic data during liver transplantation were recorded from 5 individuals throughout the anhepatic (AH) phase and for 4 hours after reperfusion (RP), along with recordings of fluid balances. Using mathematical modeling, the serum viral clearance rate, c, was estimated. Analogously, we monitored the clearance rate of HCV at 37°C from culture medium in vitro in the absence and presence of chronically infected Huh7 human hepatoma cells. During the AH phase, in 3 transplant cases viral levels remained at pre-AH levels, while in the other 2 cases HCV declined (half-life, t1/2~1h). Immediately post-RP, virus declined in a biphasic manner in Cases 1-4 consisting of an extremely rapid (median t1/2=5min) decline followed by a slower decline (HCV t1/2=67min). In Case 5, HCV remained at the same level post-RP as at the end of AH. Declines in virus level were not explained by adjusting for dilution from IV fluid and blood products. Consistent with what was observed in the majority of patients in the anhepatic phase, the t1/2 of HCV in cell culture was much longer in the absence of chronically HCV-infected Huh7 cells. Therefore, kinetic and modeling results from both in vivo liver transplantation cases and in vitro cell culture studies suggest that the liver plays a major role in clearing HCV from the circulation.
Mitochondria have a central role in regulating a range of cellular activities and host responses upon bacterial infection. Multiple pathogens affect mitochondria dynamics and functions to influence their intracellular survival or evade host immunity. On the other side, major host responses elicited against infections are directly dependent on mitochondrial functions, thus placing mitochondria centrally in maintaining homeostasis upon infection. In this review, we summarize how different bacteria and viruses impact morphological and functional changes in host mitochondria and how this manipulation can influence microbial pathogenesis as well as the host cell metabolism and immune responses.
miR-142-3p expression is predictive for severe traumatic brain injury (TBI) in trauma patients
(2020)
Background: Predictive biomarkers in biofluids are the most commonly used diagnostic method, but established markers in trauma diagnostics lack accuracy. This study investigates promisingmicroRNAs(miRNA)releasedfromaffectedtissueafterseveretraumathathavepredictive values for the effects of the injury.
Methods: A retrospective analysis of prospectively collected data and blood samples of n = 33 trauma patients (ISS≥16) is provided. Levels of miR-9-5p, -124-3p, -142-3p, -219a-5p, -338-3pand-423-3p inseverelyinjuredpatients (PT)withouttraumatic braininjury (TBI) or with severe TBI (PT + TBI) and patients with isolated TBI (isTBI) were measured within 6 h after trauma.
Results: The highest miR-423-3p expression was detected in patients with severe isTBI, followed by patients with PT + TBI, and lowest levels were found in PT patients without TBI (2−∆∆Ct,p = 0.009). ApositivecorrelationbetweenmiR-423-3plevelandincreasingAIShead (p = 0.001) and risk of mortality (RISC II, p = 0.062) in trauma patients (n = 33) was found. ROC analysis of miR-423-3p levels revealed them as statistically significant to predict the severity of brain injury in trauma patients (p = 0.006). miR-124-3p was only found in patients with severe TBI, miR-338-3p was shown in all trauma groups. miR-9-5p, miR-142-3p and miR-219a-5p could not be detected in any of the four groups. Conclusion: miR-423-3p expression is significantly elevated after isolated traumatic braininjuryandpredictableforsevereTBIinthefirsthoursaftertrauma. miR-423-3pcouldrepresent a promising new biomarker to identify severe isolated TBI.
Depletion of yeast/fly Ataxin-2 rescues TDP-43 overexpression toxicity. In mouse models of Amyotrophic Lateral Sclerosis via TDP-43 overexpression, depletion of its ortholog ATXN2 mitigated motor neuron degeneration and extended lifespan from 25 days to >300 days. There is another ortholog in mammals, named ATXN2L (Ataxin-2-like), which is almost uncharacterized but also functions in RNA surveillance at stress granules. We generated mice with Crispr/Cas9-mediated deletion of Atxn2l exons 5-8, studying homozygotes prenatally and heterozygotes during aging. Our novel findings indicate that ATXN2L absence triggers mid-gestational embryonic lethality, affecting female animals more strongly. Weight and development stages of homozygous mutants were reduced. Placenta phenotypes were not apparent, but brain histology showed lamination defects and apoptosis. Aged heterozygotes showed no locomotor deficits or weight loss over 12 months. Null mutants in vivo displayed compensatory efforts to maximize Atxn2l expression, which were prevented upon nutrient abundance in vitro. Mouse embryonal fibroblast cells revealed more multinucleated giant cells upon ATXN2L deficiency. In addition, in human neural cells, transcript levels of ATXN2L were induced upon starvation and glucose and amino acids exposure, but this induction was partially prevented by serum or low cholesterol administration. Neither ATXN2L depletion triggered dysregulation of ATXN2, nor a converse effect was observed. Overall, this essential role of ATXN2L for embryogenesis raises questions about its role in neurodegenerative diseases and neuroprotective therapies.