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Institute
- Medizin (500) (remove)
Patient therapy is based mainly on a combination of diagnosis, suitable monitoring or support devices and drug treatment and is usually employed for a pre-existing disease condition. Therapy remains predominantly symptom-based, although it is increasingly clear that individual treatment is possible and beneficial. However, reasonable precision medicine can only be realized with the coordinated use of diagnostics, devices and drugs in combination with extensive databases (4Ds), an approach that has not yet found sufficient implementation. The practical combination of 4Ds in health care is progressing, but several obstacles still hamper their extended use in precision medicine.
Background: Until now, a few studies have addressed the accuracy of intraoral scanners (IOSs) in implantology. Hence, the aim of this in vitro study was to assess the accuracy of 5 different IOSs in the impressions of single and multiple implants, and to compare them.
Methods: Plaster models were prepared, representative of a partially edentulous maxilla (PEM) to be restored with a single crown (SC) and a partial prosthesis (PP), and a totally edentulous maxilla (TEM) to be restored with a full-arch (FA). These models were scanned with a desktop scanner, to capture reference models (RMs), and with 5 IOSs (CS 3600®, Trios3®, Omnicam®, DWIO®, Emerald®); 10 scans were taken for each model, using each IOS. All IOS datasets were loaded into a reverse-engineering software where they were superimposed on the corresponding RMs, to evaluate trueness, and superimposed on each other within groups, to determine precision. A statistical analysis was performed.
Results: In the SC, CS 3600® had the best trueness (15.2 ± 0.8 μm), followed by Trios3® (22.3 ± 0.5 μm), DWIO® (27.8 ± 3.2 μm), Omnicam® (28.4 ± 4.5 μm), Emerald® (43.1 ± 11.5 μm). In the PP, CS 3600® had the best trueness (23 ± 1.1 μm), followed by Trios3® (28.5 ± 0.5 μm), Omnicam® (38.1 ± 8.8 μm), Emerald® (49.3 ± 5.5 μm), DWIO® (49.8 ± 5 μm). In the FA, CS 3600® had the best trueness (44.9 ± 8.9 μm), followed by Trios3® (46.3 ± 4.9 μm), Emerald® (66.3 ± 5.6 μm), Omnicam® (70.4 ± 11.9 μm), DWIO® (92.1 ± 24.1 μm). Significant differences were found between the IOSs; a significant difference in trueness was found between the contexts (SC vs. PP vs. FA). In the SC, CS 3600® had the best precision (11.3 ± 1.1 μm), followed by Trios3® (15.2 ± 0.8 μm), DWIO® (27.1 ± 10.7 μm), Omnicam® (30.6 ± 3.3 μm), Emerald® (32.8 ± 10.7 μm). In the PP, CS 3600® had the best precision (17 ± 2.3 μm), followed by Trios3® (21 ± 1.9 μm), Emerald® (29.9 ± 8.9 μm), DWIO® (34.8 ± 10.8 μm), Omnicam® (43.2 ± 9.4 μm). In the FA, Trios3® had the best precision (35.6 ± 3.4 μm), followed by CS 3600® (35.7 ± 4.3 μm), Emerald® (61.5 ± 18.1 μm), Omnicam® (89.3 ± 14 μm), DWIO® (111 ± 24.8 μm). Significant differences were found between the IOSs; a significant difference in precision was found between the contexts (SC vs. PP vs. FA).
Conclusions: The IOSs showed significant differences between them, both in trueness and in precision. The mathematical error increased in the transition from SC to PP up to FA, both in trueness than in precision.
Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.
Leigh syndrome is one of the most common neurological phenotypes observed in pediatric mitochondrial disease presentations. It is characterized by symmetrical lesions found on neuroimaging in the basal ganglia, thalamus, and brainstem and by a loss of motor skills and delayed developmental milestones. Genetic diagnosis of Leigh syndrome is complicated on account of the vast genetic heterogeneity with >75 candidate disease-associated genes having been reported to date. Candidate genes are still emerging, being identified when “omics” tools (genomics, proteomics, and transcriptomics) are applied to manipulated cell lines and cohorts of clinically characterized individuals who lack a genetic diagnosis. NDUFAF8 is one such protein; it has been found to interact with the well-characterized complex I (CI) assembly factor NDUFAF5 in a large-scale protein-protein interaction screen. Diagnostic next-generation sequencing has identified three unrelated pediatric subjects, each with a clinical diagnosis of Leigh syndrome, who harbor bi-allelic pathogenic variants in NDUFAF8. These variants include a recurrent splicing variant that was initially overlooked due to its deep-intronic location. Subject fibroblasts were found to express a complex I deficiency, and lentiviral transduction with wild-type NDUFAF8-cDNA ameliorated both the assembly defect and the biochemical deficiency. Complexome profiling of subject fibroblasts demonstrated a complex I assembly defect, and the stalled assembly intermediates corroborate the role of NDUFAF8 in early complex I assembly. This report serves to expand the genetic heterogeneity associated with Leigh syndrome and to validate the clinical utility of orphan protein characterization. We also highlight the importance of evaluating intronic sequence when a single, definitively pathogenic variant is identified during diagnostic testing.
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide–sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.As one of the first Direct Acting Antivirals (DAA), the protease inhibitor Telaprevir (TVR) was available in the European Union from 9/2011 until 9/2016 as a new treatment option for chronic Hepatitis C.Aim. To assess the implementation of therapy stopping rules or shortening of the treatment and their impact on sustained virological response (SVR), as well as the safety and efficacy of the TVR-based therapy during routine daily treatment of patients in Germany.Materials and Methods. 802 patients were assessed (272 treatment naïve, 520 pre-treated) in the noninterventional, multi-center study.Results. 56.6 % of the patients achieved SVR. SVR rate was higher in patients with relapse after previous treatment (68.0 %) than in patients with a previous null-response (31.1 %) and in previously untreated patients (58.1 %). Stopping rule conditions were fulfilled by 3.2 % of patients and it was implemented in 65.4 % of these. 34.3 % of the patients fulfilled the conditions for a therapy shortening. This rule was adhered to in 48.4 % of these, in 34.5 % it was not adhered to. Thus recommendations were not always being followed. Therapy shortening was considered more frequently in previously untreated (54.8 %) than for previously treated patients (24.2 %). Stopping rule application but not shortened treatment reduced therapy costs.Conclusion. The TVR-based therapy represented a breakthrough at that time. Further DAAs have been added as therapeutic options since, increasing the complexity of treatment choice and correct implementation. They represent both an opportunity and a challenge for all those involved.
Changes of left ventricular systolic function in patients undergoing coronary artery bypass grafting
(2019)
AIM: This prospective study was designed to evaluate the changes in left ventricular (LV) systolic function after coronary artery bypass grafting (CABG) in patients with both normal and abnormal pre-operative systolic function. METHODS: During the period from October 2017 to October 2018, forty-seven consecutive patients undergoing CABG were enrolled in this prospective study. Transthoracic echocardiography was performed within 1 week before CABG as well as 4 to 6 months after surgery. All measurements were made by a single experienced investigator. RESULTS: While the mean LV ejection fraction (LVEF) showed neither improvement nor significant reduction in the whole group of patients following CABG (from 54.21 ± 15.36 to 53.66 ± 11.56%, p = 0.677), significant improvement in LVEF was detected in the subgroup of patients with pre-operative LV dysfunction (from 40.05 ± 8.65 to 45.85 ± 9.04%, p = 0.008). On the other hand, there was a significant decline in LEFT in the subgroup of patients with normal pre-operative LEFT (from 64.70 ± 9.72 to 59.44 ± 9.75%, p = 0.008). As for the other parameters of systolic function, significant decrease in LV end-diastolic volume index (LVEDVI) (p = 0.001), LV end-systolic volume index (LVESVI) (p = 0.0001), wall motion score index (WMSI) (p = 0.013) and LVmass index in male patients (p = 0.011) was shown only in patients with decreased LVEF after CABG. Patients with improved postoperative LVEF (53.2% of all patients) had significantly lower baseline LVEF (p = 0.0001), higher LVESVI (0.009) and higher WMSI (p = 0.006) vs patients with worsened postoperative LVEF (38.3% of all patients). Postoperative improvement of LVEF was correlated with stabile angina, lack of preoperative myocardial infarction and smoking, higher baseline WMSI, higher LV internal diameters and indexed volumes in diastole and systole and lower baseline LVEF. In stepwise linear regression analysis the value of baseline LVEF appeared as independent predictor of improved LVEF after CABG (B = 0,836%; 95% CI 0.655-1.017; p = 0.0001). CONCLUSION: Our study showed that LVEF, internal baseline diameters and indexed volumes of LV in diastole and systole are important determinants of postoperative change in LVEF. In patients with preoperative depressed myocardial function, there is an improvement in systolic function, whereas in patients with preserved preoperative myocardial function, the decline in postoperative LVEF was detected.
Immunotherapy with oncolytic herpes simplex virus-1 therapy offers an innovative, targeted, less-toxic approach for treating brain tumors. However, a major obstacle in maximizing oncolytic virotherapy is a lack of comprehensive understanding of the underlying mechanisms that unfold in CNS tumors/associated microenvironments after infusion of virus. We demonstrate that our multiplex biomarker screening platform comprehensively informs changes in both topographical location and functional states of resident/infiltrating immune cells that play a role in neuropathology after treatment with HSV G207 in a pediatric Phase 1 patient. Using this approach, we identified robust infiltration of CD8+ T cells suggesting activation of the immune response following virotherapy; however there was a corresponding upregulation of checkpoint proteins PD-1, PD-L1, CTLA-4, and IDO revealing a potential role for checkpoint inhibitors. Such work may ultimately lead to an understanding of the governing pathobiology of tumors, thereby fostering development of novel therapeutics tailored to produce optimal responses.
The aim of this study was to determine association between constitutional, medical history and axiographic parameters with postural control parameters. Overall, 106 healthy female subjects aged between 21 and 30 years were measured. Data collection was carried out by completing a questionnaire on constitutional parameters, illnesses, accidents and medical/orthodontic therapies, as well as by axio- and posturographic measurements. Data were analyzed using correlations, pair comparisons and group comparisons. The significance level was set at p ≤ 0.05. The statistical evaluation showed significant correlations between sporting exercise and body sway in the sagittal direction (p ≤ 0.03), the BMI and the load on the forefoot/rear foot (p ≤ 0.01), the mouth opening and the load on the forefoot/rearfoot (p ≤ 0.01) and the presence of a deviation with the load on the left/right foot (p ≤ 0.01). The physical condition as well as the temporo-mandibular system are associated with the postural control in young women. Therefore, a holistic diagnosis and therapy will be supported by the present outcomes.
Purpose: The purpose of this paper was to review the available approaches for bone strength assessment, osteoporosis diagnosis and fracture risk prediction, and to provide insights into radiofrequency echographic multi spectrometry (REMS), a non-ionizing axial skeleton technique.
Methods: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review the current image-based methods for bone strength assessment and fracture risk estimation, and to discuss the clinical perspectives of REMS.
Results: Areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the consolidated indicator for osteoporosis diagnosis and fracture risk assessment. A more reliable fracture risk estimation would actually require an improved assessment of bone strength, integrating also bone quality information. Several different approaches have been proposed, including additional DXA-based parameters, quantitative computed tomography, and quantitative ultrasound. Although each of them showed a somewhat improved clinical performance, none satisfied all the requirements for a widespread routine employment, which was typically hindered by unclear clinical usefulness, radiation doses, limited accessibility, or inapplicability to spine and hip, therefore leaving several clinical needs still unmet. REMS is a clinically available technology for osteoporosis diagnosis and fracture risk assessment through the estimation of BMD on the axial skeleton reference sites. Its automatic processing of unfiltered ultrasound signals provides accurate BMD values in view of fracture risk assessment.
Conclusions: New approaches for improved bone strength and fracture risk estimations are needed for a better management of osteoporotic patients. In this context, REMS represents a valuable approach for osteoporosis diagnosis and fracture risk prediction.