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Augmenting LTP-like plasticity in human motor cortex by spaced paired associative stimulation
(2015)
Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60min and 180min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60min and 180min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.
Influence of antibiotic-regimens on intensive-care unit-mortality and liver-cirrhosis as risk factor
(2016)
AIM: To assess the rate of infection, appropriateness of antimicrobial-therapy and mortality on intensive care unit (ICU). Special focus was drawn on patients with liver cirrhosis.
METHODS: The study was approved by the local ethical committee. All patients admitted to the Internal Medicine-ICU between April 1, 2007 and December 31, 2009 were included. Data were extracted retrospectively from all patients using patient charts and electronic documentations on infection, microbiological laboratory reports, diagnosis and therapy. Due to the large hepatology department and liver transplantation center, special interest was on the subgroup of patients with liver cirrhosis. The primary statistical-endpoint was the evaluation of the influence of appropriate versus inappropriate antimicrobial-therapy on in-hospital-mortality.
RESULTS: Charts of 1979 patients were available. The overall infection-rate was 53%. Multiresistant-bacteria were present in 23% of patients with infection and were associated with increased mortality (P < 0.000001). Patients with infection had significantly increased in-hospital-mortality (34% vs 17%, P < 0.000001). Only 9% of patients with infection received inappropriate initial antimicrobial-therapy, no influence on mortality was observed. Independent risk-factors for in-hospital-mortality were the presence of septic-shock, prior chemotherapy for malignoma and infection with Pseudomonas spp. Infection and mortality-rate among 175 patients with liver-cirrhosis was significantly higher than in patients without liver-cirrhosis. Infection increased mortality 2.24-fold in patients with cirrhosis. Patients with liver cirrhosis were at an increased risk to receive inappropriate initial antimicrobial therapy.
CONCLUSION: The results of the present study report the successful implementation of early-goal-directed therapy. Liver cirrhosis patients are at increased risk of infection, mortality and to receive inappropriate therapy. Increasing burden are multiresistant-bacteria.
Background: Sphingolipids constitute bioactive molecules with functional implications in liver homeostasis. Particularly, ablation of very long chain ceramides in a knockout mouse model has been shown to cause a severe hepatopathy.
Methods: We aimed to evaluate the serum sphingolipid profile of 244 patients with cirrhosis prospectively followed for a median period of 228±217 days via mass spectrometry.
Results: We thereby observed a significant decrease of long and very long chain ceramides, particularly of C24ceramide, in patients with increasing severity of cirrhosis (p<0.001). Additionally, hydropic decompensation, defined by clinical presentation of ascites formation, was significantly correlated to low C24ceramide levels (p<0.001) while a significant association to hepatic decompensation and poor overall survival was observed for low serum concentrations of C24ceramide (p<0.001) as well. Multivariate analysis further identified low serum C24ceramide to be independently associated to overall survival (standard beta = -0.001, p = 0.022).
Conclusions: In our current analysis serum levels of very long chain ceramides show a significant reciprocal correlation to disease severity and hepatic decompensation and are independently associated with overall survival in patients with cirrhosis. Serum sphingolipid metabolites and particularly C24ceramide may constitute novel molecular targets of disease severity, hepatic decompensation and overall prognosis in cirrhosis and should be further evaluated in basic research studies.
Background and aims: Liver steatosis has shown to be associated with coronary artery disease (CAD). The aim of our study was to evaluate the association between the presence and severity of CAD and Non-alcoholic fatty liver disease (NAFLD) assessed by transient elastography (TE) and controlled attenuation parameter (CAP).
Methods: 576 Patients undergoing coronary angiography were enrolled in this prospective study, receiving at least 10 TE and CAP measurements using the FibroScan® M-probe. Clinically relevant CAD (CAD 3) was defined as stenosis with ≥75% reduction of the luminal diameter. NAFLD was determined by CAP ≥234 dB/m. NAFLD with advanced fibrosiswas determined by TE-values ≥7.9kPa in the presence of NAFLD and absence of congestive or right-sided heart failure. Rates and 95% confidence intervals are shown.
Results: 505 patients were available for analysis of NAFLD. However, only 392 patients were available for analysis of NAFLD with advanced fibrosis, since 24 patients had to be excluded due to non valid TE-measurements and 89 patients due to congestive or right-sided heart failure or suspected concomitant liver disease, respectively. 70.5% (66.3%-74.4%) of patients had CAD 3, 71.5% (67.3%-75.4%) were diagnosed with NAFLD, and 11.2% (8.3%-14.8%) with NAFLD with advanced fibrosis. Patients with CAD 3 had higher median CAP-values (273±61 vs. 260±66 dB/m; p = 0.038) and higher degrees of steatosis as compared to patients without CAD 3. While NAFLD was significantly more often diagnosed in patients with CAD 3 (75.0% vs. 63.1%, p = 0.0068), no significant difference was found for NAFLD with advanced fibrosis (10.7% vs. 12.5%, p = 0.60).
Conclusions: Clinically relevant CAD is frequently associated with the presence of NAFLD, but not NAFLD with advanced fibrosis.
Background: Cell salvage is commonly used as part of a blood conservation strategy. However concerns among clinicians exist about the efficacy of transfusion of washed cell salvage.
Methods: We performed a meta-analysis of randomized controlled trials in which patients, scheduled for all types of surgery, were randomized to washed cell salvage or to a control group with no cell salvage. Data were independently extracted, risk ratio (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary endpoint was the number of patients exposed to allogeneic red blood cell (RBC) transfusion.
Results: Out of 1140 search results, a total of 47 trials were included. Overall, the use of washed cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (RR = 0.61; 95% CI 0.57 to 0.65; P < 0.001), resulting in an average saving of 0.20 units of allogeneic RBC per patient (weighted mean differences [WMD] = -0.20; 95% CI -0.22 to -0.18; P < 0.001), reduced risk of infection by 28% (RR = 0.72; 95% CI 0.54 to 0.97; P = 0.03), reduced length of hospital stay by 2.31 days (WMD = -2.31; 95% CI -2.50 to -2.11; P < 0.001), but did not significantly affect risk of mortality (RR = 0.92; 95% CI 0.63 to 1.34; P = 0.66). No statistical difference could be observed in the number of patients exposed to re-operation, plasma, platelets, or rate of myocardial infarction and stroke.
Conclusions: Washed cell salvage is efficacious in reducing the need for allogeneic RBC transfusion and risk of infection in surgery.
Ongoing liver inflammation in patients with chronic hepatitis C and sustained virological response
(2017)
Background: Novel direct-acting antiviral DAA combination therapies tremendously improved sustained virologic response (SVR) rates in patients with chronic HCV infection. SVR is typically accompanied by normalization of liver enzymes, however, hepatic inflammation, i.e. persistently elevated aminotransferase levels may persist despite HCV eradication. Aim: To investigate prevalence and risk factors for ongoing hepatic inflammation after SVR in two large patient cohorts.
Methods: This post-hoc analysis was based on prospectively collected demographic and clinical data from 834 patients with SVR after HCV treatment with either PegIFN- or DAA-based treatment regimens from the PRAMA trial (n = 341) or patients treated at our outpatient clinic (n = 493).
Results: We observed an unexpected high prevalence of post-SVR inflammation, including patients who received novel IFN-free DAA-based therapies. Up to 10% of patients had ongoing elevation of aminotransferase levels and another 25% showed aminotransferase activity above the so-called healthy range. Several baseline factors were independently associated with post-SVR aminotransferase elevation. Among those, particularly male gender, advanced liver disease and markers for liver steatosis were strongly predictive for persistent ALT elevation. The use of IFN-based antiviral treatment was independently correlated with post-SVR inflammation, further supporting the overall benefit of IFN-free combination regimens.
Conclusion: This is the first comprehensive study on a large patient cohort investigating the prevalence and risk factors for ongoing liver inflammation after eradication of HCV. Our data show a high proportion of patients with ongoing hepatic inflammation despite HCV eradication with potential implications for the management of approximately one third of all patients upon SVR.
Aim: Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity.
Patients and Methods: Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry.
Results: Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027).
Conclusion: CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis.
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study.
Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles.
Purpose: The aim of the study was to compare three different elastography methods, namely Strain Elastography (SE), Point Shear-Wave Elastography (pSWE) using Acoustic Radiation Force Impulse (ARFI)-Imaging and 2D-Shear Wave Elastography (2D-SWE), in the same study population for the differentiation of thyroid nodules.
Materials and methods: All patients received a conventional ultrasound scan, SE and 2D-SWE, and all patients except for two received ARFI-Imaging. Cytology/histology of thyroid nodules was used as a reference method. SE measures the relative stiffness within the region of interest (ROI) using the surrounding tissue as reference tissue. ARFI mechanically excites the tissue at the ROI using acoustic pulses to generate localized tissue displacements. 2D-SWE measures tissue elasticity using the velocity of many shear waves as they propagate through the tissue.
Results: 84 nodules (73 benign and 11 malignant) in 62 patients were analyzed. Sensitivity, specificity and NPV of SE were 73%, 70% and 94%, respectively. Sensitivity, specificity and NPV of ARFI and 2D-SWE were 90%, 79%, 98% and 73%, 67%, 94% respectively, using a cut-off value of 1.98m/s for ARFI and 2.65m/s (21.07kPa) for 2D-SWE. The AUROC (Area under the Receiver Operating Characteristic) of SE, ARFI and 2D-SWE for the diagnosis of malignant thyroid nodules were 52%, 86% and 71%, respectively. A significant difference in AUROC was found between SE and ARFI (p = 0.008), while no significant difference was found between ARFI and SWE (86% vs. 71%, p = 0.31), or SWE and SE (71% vs. 52%, p = 0.26).
Conclusion: pSWE using ARFI and 2D-SWE showed comparable results for the differentiation of thyroid nodules. ARFI was superior to elastography using SE.
Acute cholecystitis – a cohort study in a real-world clinical setting (REWO study, NCT02796443)
(2018)
Background: For decades, the optimal timing of surgery for acute cholecystitis has been controversial. Recent meta-analyses and population-based studies favor early surgery. One recent large randomized trial has demonstrated that a delayed approach increases morbidity and cost compared to early surgery within 24 hours of hospital admission. Since cases of severe cholecystitis were excluded from this trial, we argue that these results do not reflect real-world clinical situations. From our point of view, these results were in contrast to the clinical experience with our patients; so, we decided to analyze critically all our patients with the null hypothesis that the patients treated with a delayed cholecystectomy after an acute cholecystitis have a similar or even better outcome than those treated with an early operative approach.
Patients and methods: We retrospectively analyzed clinical data from all patients with cholecystectomies in the period between January 2006 and September 2015. A total of 1,723 patients were categorized into four groups: early (n=138): urgent surgery of patients with acute cholecystitis within the first 72 hours of the onset of symptoms; intermediate (n=297): surgery of patients with acute cholecystitis within an average of 10 days after the onset of symptoms; delayed (n=427): initial non-surgical treatment of acute cholecystitis with surgery performed within 6–12 weeks of the onset of symptoms; and elective (n=868): cholecystectomy within a symptom-free interval of choice in patients with symptomatic cholecystolithiasis without signs of acute cholecystitis.
Results: In a real-world scenario, early/intermediate cholecystectomy in acute cholecystitis was associated with a significant increase in morbidity and mortality (Clavien–Dindo score) compared to a delayed approach with surgery performed 6–12 weeks after the onset of symptoms. The adjusted linear rank statistics showed a decrease in the complication score with values of 2.29 in the early group, 0.48 in the intermediate group, –0.26 in the delayed group and –2.12 in the elective group. The results translate into a continuous decrease of the complication score from early over intermediate and delayed to the elective group.
Conclusion: These results demonstrate that delayed cholecystectomy can be performed safely. In cases with severe cholecystitis, early and/or intermediate approaches still have a relatively high risk of morbidity and mortality.
Background: Subdural hematoma (SDH) is a common disease associated with high morbidity, which is becoming more prominent due to the increasing incidence. Decision for a surgical evacuation is made depending on the clinical appearance and the volume of SDH, wherefore it is important to have a simple ‘bedside’ method to measure and compare the volume of SDH.
Objective: The aim of the study was to verify the accuracy of the simplified ABC/2 volumetric formula to determine a valuable tool for the clinical practice.
Methods: Preoperative CT-scans of 83 patients with SDHs were used for the computer-assisted volumetric measurement via BrainLab® as well as the ABC/2 volumetric measurement. A = largest length (anterior to posterior) of the SDH; B = maximum width (lateral to midline) 90° to A; C = maximum height (coronal plane or multiplication of slices) of the hematoma. These measurements were performed by two independent clinicians in a blinded fashion. Both volumes were compared by linear regression analysis of Pearson and Bland-Altman regression analysis.
Results: Among 100 SDHs, 53% were under an 47% were over 100cm3 showing a well distribution of the hematoma sizes. There was an excellent correlation between computer-assisted volumetric measurement and ABC/2 (R2 = 0.947, p<0.0001) and no undesirable deviation and trend were detected (p = 0.101; p = 0.777). A 95% tolerance region of the ratios of both methods was [0.805–1.201].
Conclusion: The ABC/2 method is a simple and fast bedside formula for the measurement of SDH volume in a timely manner without limited access through simple adaption, which may replace the computer-assisted volumetric measurement in the clinical and research area. Reason for the good accuracy seems to be the spherical form of SDH, which has a similarity to a half ellipsoid.
The free radical theory of aging suggests reactive oxygen species as a main reason for accumulation of damage events eventually leading to aging. Nox4, a member of the family of NADPH oxidases constitutively produces ROS and therefore has the potential to be a main driver of aging. Herein we analyzed the life span of Nox4 deficient mice and found no difference when compared to their wildtype littermates. Accordingly neither Tert expression nor telomere length was different in cells isolated from those animals. In fact, Nox4 mRNA expression in lungs of wildtype mice dropped with age. We conclude that Nox4 has no influence on lifespan of healthy mice.
The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.
Background: Physical activity is an important part of life, and hence exercise-induced bronchoconstriction (EIB) can reduce the quality of life. A standardized test is needed to diagnose EIB. The American Thoracic Society (ATS) guidelines recommend an exercise challenge in combination with dry air. We investigated the feasibility of a new, ATS guidelines conform exercise challenge in a cold chamber (ECC) to detect EIB. The aim of this study was to investigate the surrogate marker reaction to methacholine, ECC and exercise challenge in ambient temperature for the prediction of a positive reaction and to re-evaluate the reproducibility of the response to an ECC.
Methods: Seventy-eight subjects aged 6 to 40 years with suspected EIB were recruited for the study. The subjects performed one methacholine challenge, two ECCs, and one exercise challenge at an ambient temperature. To define the sensitivity and specificity of the predictor, a receiver-operating characteristic curve was plotted. The repeatability was evaluated using the method described by Bland and Altman (95% Limits of agreement).
Results: The following cut-off values showed the best combination of sensitivity and specificity: the provocation dose causing a 20% decrease in the forced expiratory volume in 1 s (PD20FEV1) of methacholine: 1.36 mg (AUC 0.69, p < 0.05), the maximal decrease in FEV1 during the ECC: 8.5% (AUC 0.78, p < 0.001) and exercise challenges at ambient temperatures: FEV1 5.2% (AUC 0.64, p = 0.13). The median decline in FEV1 was 14.5% (0.0–64.2) during the first ECC and 10.7% (0.0–52.5) during the second ECC. In the comparison of both ECCs, the Spearman rank correlation of the FEV1 decrease was r = 0.58 (p < 0.001). The 95% limits of agreement (95% LOAs) for the FEV1 decrease were − 17.7 to 26.4%.
Conclusions: The surrogate markers PD20FEV1 of methacholine and maximal decrease in FEV1 during ECC can predict a positive reaction in another ECC, whereas the maximal FEV1 decrease in an exercise challenge at an ambient temperature was not predictive. Compared with previous studies, we can achieve a similar reproducibility with an ECC.
Clinical trial registration: NCT02026492 (retrospectively registered 03/Jan/2014).
Hintergrund: Das genaue Wissen um die Umstände eines jeden tödlichen Arbeitsunfalls ist Voraussetzung für die Identifizierung von Unfallschwerpunkten und ermöglicht eine effektive Präventionsarbeit. Mit dieser rechtsmedizinischen Studie zum Arbeitsunfallgeschehen soll ein Beitrag dazu geleistet werden, die Zahl tödlicher Arbeitsunfälle in Deutschland zu senken.
Material und Methode: Zur Untersuchung kamen die tödlichen Arbeitsunfälle, die sich im Einzugsbereich des rechtsmedizinischen Instituts Frankfurt am Main in den Jahren von 2005 bis 2016 ereigneten. Ausgewertet wurden Obduktionsprotokolle sowie die dem Institut zur Verfügung gestellten staatsanwaltschaftlichen Ermittlungsakten.
Ergebnisse: Es fanden sich 87 tödliche Arbeitsunfälle in dem genannten Zwölfjahreszeitraum. Die Altersstruktur reichte vom jugendlichen Alter bis in das Rentenalter. Betroffen waren zum größten Teil männliche Arbeiter (96,6 %, p < 0,0001), verhältnismäßig häufig ausländischer Nationalität (34,5 %). Die meisten Unfälle ereigneten sich in der 2. Jahreshälfte (58,6 %), an Montagen (26,4 %), kurz vor und nach der Mittagspause. In 3 Fällen lag die Blutalkoholkonzentration über 0,5‰. Die Baubranche (55,2 %) war der unfallträchtigste Wirtschaftszweig. Der Absturz (28,7 %) war der häufigste Unfallmechanismus und das Polytrauma (39,1 %) gemeinsam mit dem Schädel-Hirn-Trauma (24,1 %) gemäß dem ISS die häufigste Todesursache.
Diskussion: Nach den Ergebnissen dieser Studie sollten Alter der Arbeiter sowie die Tages‑, Wochen- und Jahreszeit bei der Ausführung risikoreicher Arbeiten im Baugewerbe berücksichtigt werden. Besonderes Augenmerk sollten Arbeitgeber auf die Kontrolle von Sicherheitsvorkehrungen bei Arbeiten in der Höhe sowie auf die Durchsetzung der Helmpflicht gerade auch bei ausländischen Arbeitnehmern legen.
Background: Chronic hepatitis C virus (HCV) infections are causally linked with metabolic comorbidities such as insulin resistance, hepatic steatosis, and dyslipidemia. However, the clinical impact of HCV eradication achieved by direct-acting antivirals (DAAs) on glucose and lipid homeostasis is still controversial. The study aimed to prospectively investigate whether antiviral therapy of HCV with DAAs alters glucose and lipid parameters. Methods: 50 patients with chronic HCV who were treated with DAAs were screened, and 49 were enrolled in the study. Biochemical and virological data, as well as noninvasive liver fibrosis parameters, were prospectively collected at baseline, at the end of treatment (EOT) and 12 and 24 weeks post-treatment. Results: 45 of 46 patients achieved sustained virologic response (SVR). The prevalence of insulin resistance (HOMA-IR) after HCV clearance was significantly lower, compared to baseline (5.3 ± 6.1 to 2.5 ± 1.9, p < 0.001), which is primarily attributable to a significant decrease of fasting insulin levels (18.9 ± 17.3 to 11.7 ± 8.7; p = 0.002). In contrast to that, HCV eradication resulted in a significant increase in cholesterol levels (total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL-C) levels) and Controlled Attenuated Score (CAP), although BMI did not significantly change over time (p = 0.95). Moreover, HOMA-IR correlated significantly with noninvasive liver fibrosis measurements at baseline und during follow-up (TE: r = 0.45; p = 0.003, pSWE: r = 0.35; p = 0.02, APRI: r = 0.44; p = 0.003, FIB-4: r = 0.41; p < 0.001). Conclusion: Viral eradication following DAA therapy may have beneficial effects on glucose homeostasis, whereas lipid profile seems to be worsened.
Rationale: The clinical relevance of sensitization to Aspergillus (A) fumigatus in cystic fibrosis (CF) is unclear. Some researchers propose that specific A fumigatus IgE is an innocent bystander, whereas others describe it as the major cause of TH‐2‐driven asthma‐like disease.
Objectives: Lung function parameters in mild CF patients may be different in patients with and without A fumigatus sensitization. We aimed to ascertain whether allergen exposure to A fumigatus by bronchial allergen provocation (BAP) induces TH‐2 inflammation comparable to an asthma‐like disease.
Methods: A total of 35 patients, aged 14.8 ± 8.5 years, and 20 healthy controls were investigated prospectively. The patients were divided into two groups: group 1 (n = 18): specific (s)IgE negative, and group 2 (n = 17): sIgE positive (≥0.7 KU/L) for A fumigatus. Lung function, exhaled NO, and induced sputum were analysed. All sensitized patients with an FEV1 > 75% (n = 13) underwent BAP with A fumigatus, and cell counts, and the expression of IL‐5, IL‐13, INF‐γ, and IL‐8 as well as transcription factors T‐bet, GATA‐3, and FoxP3, were measured.
Results: Lung function parameters decreased significantly compared to controls, but not within the CF patient group. After BAP, 8 of 13 patients (61%) had a significant asthmatic response and increased eNO 24 hours later. In addition, marked TH‐2‐mediated inflammation involving eosinophils, IL‐5, IL‐13, and FoxP3 became apparent in induced sputum cells.
Conclusion: Our study demonstrated the clinical relevance of A fumigatus for the majority of sensitized CF patients. A distinct IgE/TH‐2‐dominated inflammation was found in induced sputum after A fumigatus exposure.
Purpose: The prevalence of "ocal allergic rhinitis" within individuals suffering from perennial rhinitis remains uncertain, and patients usually are diagnosed with non-allergic rhinitis. The aim of this study was to evaluate the prevalence of a potential "local allergic rhinitis" in subjects suffering from non-allergic rhinitis in a non-selected group of young students.
Methods: 131 students (age 25.0 ± 5.1 years) with a possible allergic rhinitis and 25 non-allergic controls without rhinitis symptoms (age 22.0 ± 2.0 years) were recruited by public postings. 97 of 131 students with rhinitis were tested positive (≥3 mm) to prick testing with 17 frequent allergens at visit 1. Twenty-four 24 subjects with a house dust mite allergy, 21 subjects with a non-allergic rhinitis, and 18 non-allergic controls were further investigated at visit 2. Blood samples were taken, and nasal secretion was examined. In addition, all groups performed a nasal provocation test with house dust mite (HDM).
Results: In serum and nasal secretion, total IgE and house dust mite specific IgE significantly differed between HDM positive subjects and controls. However, no differences between non-allergic subjects and control subjects were quantifiable. Neither a nasal provocation test nor a nasal IgE to HDM allergens showed a measurable positive response in any of the non-allergic rhinitis subjects as well as the healthy controls, whilst being positive in 13 subjects with HDM allergy.
Conclusions: Nasal IgE is present in subjects with HDM allergy, but not in non-allergic rhinitis. In the investigated non-selected population, exclusive local production of IgE is absent. By implication, therefore, our findings challenge the emerging concept of local allergic rhinitis.
Study identifier at ClinicalTrials.gov: NCT 02810535.
Introduction: The number of individuals requesting medical treatment for gender dysphoria has increased significantly within the past years. Our purpose was to examine current biographic and socio‐demographic characteristics and aspects of legal gender reassignment.
Design: Medical files from n = 350 individuals of a German Endocrine outpatient clinic were collected from 2009 to 2017 and analysed retrospectively.
Results: Ratio of transwomen to transmen equates to 1:1.89 with a remarkable increase of transmen by the year 2013, showing a reversal of gender distribution compared with previous studies for the first time. Use of illegal substances or self‐initiated hormone therapy was rare (4.6 and 2.1%). Satisfaction with gender‐affirming hormone therapy was significantly higher in transmen than in transwomen (100% vs 96.2%, P = .005). Use of antidepressants declined significantly after onset of hormone treatment in transmen (13% vs 7%; P = .007). The number of individuals with a graduation diploma was only about half as high as in the general population (14.3% vs 27.3%), whereas unemployment rate was more than twice as high (14% vs 6.9%). Median latency between application for legal gender reassignment and definitive court decision was 9 months.
Conclusions: Our data provide possible indications for a decline of psychosocial burden in individuals diagnosed with gender dysphoria over the last years. However, affected individuals are still limited in their occupational and financial opportunities as well as by a complex and expensive procedure of legal gender reassignment in Germany.