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Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Measurements of event-by-event fluctuations of charged-particle multiplicities in Pb–Pb collisions at sNN−−−√ = 2.76 TeV using the ALICE detector at the CERN Large Hadron Collider (LHC) are presented in the pseudorapidity range |η|<0.8 and transverse momentum 0.2<pT<2.0 GeV/c. The amplitude of the fluctuations is expressed in terms of the variance normalized by the mean of the multiplicity distribution. The η and pT dependences of the fluctuations and their evolution with respect to collision centrality are investigated. The multiplicity fluctuations tend to decrease from peripheral to central collisions. The results are compared to those obtained from HIJING and AMPT Monte Carlo event generators as well as to experimental data at lower collision energies. Additionally, the measured multiplicity fluctuations are discussed in the context of the isothermal compressibility of the high-density strongly-interacting system formed in central Pb–Pb collisions.
We present the first measurement of event-by-event fluctuations in the kaon sector in Pb – Pb collisions at √sNN = 2.76 TeV with the ALICE detector at the LHC. The robust fluctuation correlator νdyn is used to evaluate the magnitude of fluctuations of the relative yields of neutral and charged kaons, as well as the relative yields of charged kaons, as a function of collision centrality and selected kinematic ranges. While the correlator νdyn[K+,K−] exhibits a scaling approximately in inverse proportion of the charged particle multiplicity, νdyn[K0 S ,K±] features a significant deviation from such scaling. Within uncertainties, the value of νdyn[K0 S ,K±] is independent of the selected transverse momentum interval, while it exhibits a pseudorapidity dependence. The results are compared with HIJING, AMPT and EPOS–LHC predictions, and are further discussed in the context of the possible production of disoriented chiral condensates in central Pb – Pb collisions.
In particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD)1. These partons subsequently emit further partons in a process that can be described as a parton shower2, which culminates in the formation of detectable hadrons. Studying the pattern of the parton shower is one of the key experimental tools for testing QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass mQ and energy E, within a cone of angular size mQ/E around the emitter3. Previously, a direct observation of the dead-cone effect in QCD had not been possible, owing to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible hadrons. We report the direct observation of the QCD dead cone by using new iterative declustering techniques4,5 to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.
In our Galaxy, light antinuclei composed of antiprotons and antineutrons can be produced through high-energy cosmic-ray collisions with the interstellar medium or could also originate from the annihilation of dark-matter particles that have not yet been discovered. On Earth, the only way to produce and study antinuclei with high precision is to create them at high-energy particle accelerators. Although the properties of elementary antiparticles have been studied in detail, the knowledge of the interaction of light antinuclei with matter is limited. We determine the disappearance probability of 3He¯¯¯¯¯¯ when it encounters matter particles and annihilates or disintegrates within the ALICE detector at the Large Hadron Collider. We extract the inelastic interaction cross section, which is then used as input to calculations of the transparency of our Galaxy to the propagation of 3He¯¯¯¯¯¯ stemming from dark-matter annihilation and cosmic-ray interactions within the interstellar medium. For a specific dark-matter profile, we estimate a transparency of about 50%, whereas it varies with increasing 3He¯¯¯¯¯¯ momentum from 25% to 90% for cosmic-ray sources. The results indicate that 3He¯¯¯¯¯¯ nuclei can travel long distances in the Galaxy, and can be used to study cosmic-ray interactions and dark-matter annihilation.
Antimatter particles such as positrons and antiprotons abound in the cosmos. Much less common are light antinuclei, composed of antiprotons and antineutrons, which can be produced in our galaxy via high-energy cosmic-ray collisions with the interstellar medium or could also originate from the annihilation of the still undiscovered dark-matter particles. On Earth, the only way to produce and study antinuclei with high precision is to create them at high-energy particle accelerators like the Large Hadron Collider (LHC). Though the properties of elementary antiparticles have been studied in detail, knowledge of the interaction of light antinuclei with matter is rather limited. This work focuses on the determination of the disappearance probability of \ahe\ when it encounters matter particles and annihilates or disintegrates. The material of the ALICE detector at the LHC serves as a target to extract the inelastic cross section for \ahe\ in the momentum range of 1.17≤p<10 GeV/c. This inelastic cross section is measured for the first time and is used as an essential input to calculations of the transparency of our galaxy to the propagation of 3He¯¯¯¯¯¯ stemming from dark-matter decays and cosmic-ray interactions within the interstellar medium. A transparency of about 50% is estimated using the GALPROP program for a specific dark-matter profile and a standard set of propagation parameters. For cosmic-ray sources, the obtained transparency with the same propagation scheme varies with increasing 3He¯¯¯¯¯¯ momentum from 25% to 90%. The absolute uncertainties associated to the 3He¯¯¯¯¯¯ inelastic cross section measurements are of the order of 10%−15%. The reported results indicate that 3He¯¯¯¯¯¯ nuclei can travel long distances in the galaxy, and can be used to study cosmic-ray interactions and dark-matter decays.
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection.
Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L).
Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05).
Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Hintergrund: Am Fachbereich Medizin der Universität Frankfurt werden jedes Jahr zwischen 15 und 20 neue Projekte zur Verbesserung der Lehre durch den Studienausschuss gefördert. Portfolios zur Skizzierung der Projekte werden von den Zentren und Instituten eingereicht. Diese Projekte haben u.a. die Neustrukturierung von Kursen und Praktika, die Implementierung und Evaluation von Prüfungen (z. B. objective structured clinical evaluation), die Förderung der didaktischen Aus- und Weiterbildung von Dozenten und Tutoren oder die curriculare Einbindung von elektronischen Medien in die Lehre zum Inhalt.
Um diese Projekte untereinander zu koordinieren, wurde im Juni 2006 das Frankfurter Ideenforum für Lehre und Unterricht – kurz FILU – geschaffen.
Ziele des Frankfurter Ideenforums für Lehre und Unterricht
1. Das Forum FILU bietet eine Informationsplattform für die Projektleiter der Lehrverbesserungsprojekte.
2. Das Forum übernimmt die Funktion eines Kondensators für thematisches und informationelles Vernetzungspotential der Projekte untereinander.
3. Übersteigt der Arbeits- und Koordinationsbedarf die Möglichkeiten des Forums, initiiert das FILU neue interdisziplinäre Arbeitsgruppen.
4. Der "Journal Club" innerhalb der Treffen des FILU läßt alle Teilnehmer an der aktuellen Studienlage in Ausbildungsforschung teilhaben.
5. Das Forum FILU engagiert sich dafür, die Aktivitäten zur Lehre innerhalb des Fachbereiches Medizin und darüber hinaus bekannt zu machen.
Methode: Koordination und Organisation des Forums übernimmt eine ärztliche wissenschaftliche Mitarbeiterin. Die Treffen finden in 4-Wochenrhythmen à 2 Stunden statt. Pflichtmitglieder sind die Initiatoren und Leiter der Lehrverbesserungsprojekte; weitere interessierte Akteure des Fachbereiches nehmen ebenfalls teil.
Pro Termin werden maximal zwei Lehrverbesserungsprojekte vorgestellt und diskutiert. In einem Journal Club wird eine aktuelle und für den Fachbereich relevante Studie aus den einschlägigen Journalen der Ausbildungsforschung und Medizindidaktik vorgestellt. Nach jedem Treffen erfolgt eine freiwillige Befragung der Mitglieder hinsichtlich Zielvorstellungen, Veranstaltungsankündigungen und Vortragswünschen. Halbjährig erfolgt ein Bericht an den Studienausschuss. [Ein Organigramm stellt bildhaft die Strukturen dar.]
Ergebnisse: Insgesamt haben bisher bei 9 Terminen 202 Personen teilgenommen. Aus der Befragung der Mitglieder initiierten sich ein interdisziplinäres Promotions- und Studienkolleg für Ausbildungsforschung und ein Lehrverbesserungsprojekt zur zentrumsübergreifenden Koordination von Simulationspatienten in OSCE.
Innerhalb des Forums entstand die Planung zur Präsentation der Lehre-Aktivitäten auf einer Veranstaltung der Frankfurter Medizinischen Gesellschaft. Der Fachbereich verfügt durch Anregung aus dem Gremium inzwischen über ein eigenes Online-Portal, einen virtuellen "Treffpunkt Lehre".
[Teilnehmerzahlen, Herkunftszentren der Teilnehmer, Themen der LV-Projekte über die letzten zwei Jahre]
Schlussfolgerung: Das "Frankfurter Ideenforum für Lehre und Unterricht", FILU, bietet seit seiner Implementierung eine lebendige Austausch- und Kommunikationsplattform für die Leiter der Lehrverbesserungsprojekte am Fachbereich. Über das Forum wird eine gemeinsame Nutzung der vorhandenen Ressourcen in der Lehre möglich. Die interdisziplinäre Zusammenarbeit der Akteure wird maßgeblich gefördert und bietet die Möglichkeit, sinnvolle thematische und personelle Synergien zu finden.
Die Bewertung der Nitrataustragsgefährdung (NAG) landwirtschaftlich genutzter Flächen in Wasserschutzgebieten (WSG) erfolgte bislang auf Basis bodenkundlicher Kartierungen und wurde seit 1996 nach einem im Staatsanzeiger für das Land Hessen veröffentlichten Merkblatt des ehemaligen Hessischen Landesamtes für Bodenforschung im Rahmen der Muster-Wasserschutzgebietsverordnung geregelt (HLfB 1996, HMUJFG 1996). Infolge der Verfügbarkeit hochauflösender Bodendaten in Form der „Bodenflächendaten 1: 5.000, landwirtschaftliche Nutzfläche“ (BFD5L) wird die Ermittlung der Nitrataustragsgefährdung landwirtschaftlich genutzter Flächen neu geregelt. Die BFD5L liefert Auswertungen der Bodenschätzungsdaten zur Feldkapazität des Wurzelraums sowie weiterer relevanter Parameter, die zur Bewertung der Nitrataustragsgefährdung herangezogen werden können.
Um die Eignung der BFD5L-Daten zur Ermittlung der Nitrataustragsgefährdung zu überprüfen, wurden in den Jahren 2009 bis 2012 bodenkundliche Vergleichskartierungen im Rahmen eines Pilotvorhabens im Wasserschutzgebiet Eschollbrücken/Pfungstadt in Südhessen, im Wassereinzugsgebiet der Quelle Meineringhausen bei Korbach, im Wasserschutzgebiet des Tiefbrunnens Spieß der Gemeinde Bad Emstal sowie im WSG Quelle Ohmes der Stadt Kirtorf durchgeführt. Ziel war es, die Umsetzungsmöglichkeiten bei der Nutzung der BFD5LDaten in organisatorischer und technischer Hinsicht zu erproben und das bisherige Verfahren zu überarbeiten (PETER & MILLER 2009, PETER & MILLER 2010a und 2010b, PETER & MILLER 2012).
Die Ergebnisse der Vergleichskartierungen zeigen, dass sich die Daten der BFD5L grundsätzlich für die Ermittlung der Nitrataustragsgefährdung in Wasserschutzgebieten eignen. Lediglich für Flächen, für die nach den bislang im System BFD5L enthaltenen Methoden keine Kennwerte abgeleitet werden können sowie für Sonderstandorte, muss die Nitrataustragsgefährdung durch bodenkundliche Geländearbeiten ermittelt werden.
Die Fundmeldungen in Band 33 von Botanik und Naturschutz in Hessen stammen von: Dirk Bönsel, Martin de Jong, Wolfgang Ehmke, Peter Emrich, Benjamin Feller, Brunhilde Göbel, Thomas Gregor, Arthur Händler, Sylvain Hodvina, Gerwin Kasperek, Egbert Korte, Ute Lange, Stefan Meyer, Hasko Friedrich Nesemann, Uwe Raabe, Bernd Sauerwein, Marco Schmidt, Christof Nikolaus Schröder, Antje Schwab, Rainer Stoodt und Michael Uebeler.
Background: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]).
Methods: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion.
Results: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20).
Conclusions: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.
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: 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.
The wide range of immunosuppressive therapies and protocols permits tailored planning of the initial regimen according to the immunological risk status of individual patients. Pre-transplant risk assessment can include many factors, but there is no clear consensus on which parameters to take into account, and their relative importance. In general younger patients are known to be at higher risk for acute rejection, compounded by higher rates of non-adherence in adolescents. Donor age and recipient gender do not appear to exert a meaningful effect on risk of rejection per se, but black recipient ethnicity remains a well-established risk factor even under modern immunosuppression regimens. Little difference in risk is now observed between deceased- and living-donor recipients. Immunological risk assessment has developed substantially in recent years. Cross-match testing with cytotoxic analysis has long been supplemented by flow cytometry, but development of solid-phase single-bead antigen testing of solubilized human leukocyte antigens (HLA) to detect donor-specific antibodies (DSA) permits a far more nuanced stratification of immunological risk status, including the different classes and intensities of HLA antibodies Class I and/or II, including HLA-DSA. Immunologic risk evaluation is now often based on a combination of these tests, but other assessments are becoming more widely introduced, such as measurement of non-HLA antibodies against angiotensin type 1 (AT1) receptors or T-cell ELISPOT assay of alloantigen-specific donor. Targeted densensitization protocols can improve immunological risk, notably for DSA-positive patients with negative cytotoxicity and flow cross-match. HLA mismatch remains an important and undisputed risk factor for rejection. Delayed graft function also increases the risk of subsequent acute rejection, and the early regimen can be modified in such cases. Overall, there is a shift towards planning the immunosuppressive regimen based on pre-transplant immunology testing although certain conventional risk factors retain their importance.
TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.