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Institute
Ferstl, Philip ; Queck, Alexander David Roger ; Bremer, Katharina ; Filmann, Sonja Natalie ; Weiler, Nina ; Welker, Martin-Walter ; Waidmann, Oliver ; Knabe, Mate ; Bechstein, Wolf Otto ; Hogardt, Michael ; Kempf, Volkhard A. J. ; Zeuzem, Stefan ; Trebicka, Jonel ; Friedrich-Rust, Mireen ; Walter, Dirk
Objectives: Stenosis of the biliary anastomosis predisposes liver graft recipients to bacterial cholangitis. Antibiotic therapy (AT) is performed according to individual clinical judgment, but duration of AT remains unclear.
Methods: All liver graft recipients with acute cholangitis according to the Tokyo criteria grade 1 and 2 after endoscopic retrograde cholangiography (ERC) were included. Outcome of patients treated with short AT (<7 days) was compared to long AT (>6 days). Recurrent cholangitis (RC) within 28 days was the primary end point.
Results: In total, 30 patients were included with a median of 313 (range 34–9849) days after liver transplantation until first proven cholangitis. Among 62 cases in total, 51/62 (82%) were graded as Tokyo-1 and 11/62 (18%) as Tokyo-2. Overall median duration of AT was 6 days (1–14) with 36 cases (58%) receiving short AT and 26 (42%) receiving long AT. RC was observed in 10 (16%) cases, without significant difference in occurrence of RC in short versus long AT cases. CRP and bilirubin were significantly higher in patients with long AT, while low serum albumin and low platelets were associated with risk of RC.
Conclusion: A shorter antibiotic course than 7 days shows good results in selected, ERC-treated patients for post-transplantation biliary strictures.
Kessel, Johanna ; Göymen, Elif ; Wolf, Timo ; Wetzstein, Nils ; Küpper-Tetzel, Claus Philippe ; Behrens, Pia ; Borgans, Frauke ; Balaban, Ümniye ; Hogardt, Michael ; Wichelhaus, Thomas A. ; Stephan, Christoph
Highlights
• Open pulmonary tuberculosis patient discharge policy was not reviewed for decades.
• After smear-negativity conversion, substantial cultural positivity may remain.
• It remains unclear, whether smear-negative patients still may be infective.
• The clinical relevance of this finding warrants further investigation.
Abstract
Objectives: Patients with open pulmonary tuberculosis (opTB) are subject to strict isolation rules. Sputum smear microscopy is used to determine infectivity, but sensitivity is lower than for culture. This study aimed to investigate the clinical relevance of this mismatch in contemporary settings.
Methods: Differential results between microscopy and culture were determined at the time of microscopic sputum conversion, from all patients with opTB between 01/2013 and 12/2017. In addition, data on HIV, multi/extensive drug-resistant TB status, time to smear- and cultural-negativity conversion were analyzed; and a Kaplan-Meier curve was developed.
Results: Of 118 patients with opTB, 58 had demographic data available for microbiological and clinical follow-up analysis; among these, 26 (44.8%) had still at least one positive culture result. Median time from opTB-treatment initiation to full microscopic sputum- or culture conversion, was 16.5 days (range 2-105), and 20 days (1-105), respectively (median difference: +3.5 days). Sixteen days after de-isolation, >90% had converted culturally. HIV- or multi/extensive drug-resistant TB status did not impact conversion time.
Conclusion: When patients with opTB were de-isolated after 3 negative sputum smear microscopy tests, a substantial part still revealed cultural growth of Mycobacterium tuberculosis complex, but it remains unclear, whether smear-negative and culturally-positive individuals on therapy are really infective. Thus, the clinical relevance of this finding warrants further investigation.
Dultz, Georg ; Seelhof, Martin ; Herrmann, Eva ; Welker, Martin-Walter ; Friedrich-Rust, Mireen ; Teuber, Gerlinde ; Kronenberger, Bernd ; Wagner, Michael von ; Vermehren, Johannes ; Sarrazin, Christoph ; Zeuzem, Stefan ; Hofmann, Wolf-Peter
Background and Aims: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined.
Methods: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18±2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240weeks, ±SD 136weeks).
Results: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p = 0.015), mean platelets (102.64 vs. 138.95/nl, p = 0.014) and mean leukocytes (4.02 vs. 5.68/nl, p = 0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18–2.07; p = 0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6–9, 10–13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001).
Conclusions: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.
Grent-'t-Jong, Tineke ; Groß, Joachim ; Goense, Jozien ; Wibral, Michael ; Gajwani, Ruchika ; Gumley, Andrew I. ; Lawrie, Stephen M. ; Schwannauer, Matthias ; Schultze-Lutter, Frauke ; Schröder, Tobias Navarro ; Köthe, Dagmar ; Leweke, F. Markus ; Singer, Wolf ; Uhlhaas, Peter J.
We examined alterations in E/I-balance in schizophrenia (ScZ) through measurements of resting-state gamma-band activity in participants meeting clinical high-risk (CHR) criteria (n = 88), 21 first episode (FEP) patients and 34 chronic ScZ-patients. Furthermore, MRS-data were obtained in CHR-participants and matched controls. Magnetoencephalographic (MEG) resting-state activity was examined at source level and MEG-data were correlated with neuropsychological scores and clinical symptoms. CHR-participants were characterized by increased 64–90 Hz power. In contrast, FEP- and ScZ-patients showed aberrant spectral power at both low- and high gamma-band frequencies. MRS-data showed a shift in E/I-balance toward increased excitation in CHR-participants, which correlated with increased occipital gamma-band power. Finally, neuropsychological deficits and clinical symptoms in FEP and ScZ-patients were correlated with reduced gamma band-activity, while elevated psychotic symptoms in the CHR group showed the opposite relationship. The current study suggests that resting-state gamma-band power and altered Glx/GABA ratio indicate changes in E/I-balance parameters across illness stages in ScZ.
Grent-'t-Jong, Tineke ; Rivolta, Davide ; Groß, Joachim ; Gajwani, Ruchika ; Lawrie, Stephen M. ; Schwannauer, Matthias ; Heidegger, Tonio ; Wibral, Michael ; Singer, Wolf ; Sauer, Andreas ; Scheller, Bertram ; Uhlhaas, Peter J.
Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1–90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63–80 Hz) in occipital regions and upregulated low frequency (5–28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.
Nguyen, Lien Thi Kim ; Aydemir, Umut ; Baitinger, Michael ; Custers, Jeroen ; Haghighirad, Amir-Abbas ; Höfler, Rudolf ; Luther, Klaus-Dieter ; Ritter, Franz ; Grin, Yuri ; Aßmus, Wolf ; Paschen, Silke
Clathrates are candidate materials for thermoelectric applications because of a number of unique properties. The clathrate I phases in the Ba-Ni-Ge ternary system allow controlled variation of the charge carrier concentration by adjusting the Ni content. Depending on the Ni content, the physical properties vary from metal-like to insulator-like and show a transition from p-type to n-type conduction. Here we present first results on the characterization of millimeter-sized single crystals grown by the Bridgman technique. Single crystals with a composition of Ba8Ni3.5Ge42.1h0.4 show metallic behavior (dp/dT > 0) albeit with high resistivity at room temperature [p (300 K) = 1 mOhm cm]. The charge carrier concentration at 300 K, as determined from Hall-effect measurements, is 2.3 e-/unit cell. The dimensionless thermoelectric figure of merit estimated at 680 K is ZT ~ 0.2. Keywords Clathrates - thermoelectric material - intermetallic compound - nickel
Hofmann, Wolf-Peter ; Mauß, Stefan ; Lutz, Thomas ; Schober, Andreas ; Böker, Klaus ; Moog, Gero ; Baumgarten, Axel ; Pfeiffer-Vornkahl, Heike ; Alshuth, Ulrich ; Hüppe, Dietrich ; Wedemeyer, Heiner ; Manns, Michael P. ; Schott, Eckart
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Farnik, Harald ; Driller, Marlene ; Kratt, Thomas ; Schmidt, Carsten ; Fähndrich, Martin ; Filmann, Natalie ; Königsrainer, Alfred ; Stallmach, Andreas ; Heike, Michael ; Bechstein, Wolf Otto ; Zeuzem, Stefan ; Albert, Jörg Gerhard
Background: Intestinal perforation or leakage increases morbidity and mortality of surgical and endoscopic interventions. We identified criteria for use of full-covered, extractable self-expanding metal stents (cSEMS) vs. "Over the scope"-clips (OTSC) for leak closure.
Methods: Patients who underwent endoscopic treatment for postoperative leakage, endoscopic perforation, or spontaneous rupture of the upper gastrointestinal tract between 2006 and 2013 were identified at four tertiary endoscopic centers. Technical success, outcome (e.g. duration of hospitalization, in-hospital mortality), and complications were assessed and analyzed with respect to etiology, size and location of leakage.
Results: Of 106 patients (male: 75 (71%), female: 31 (29%); age (mean ± SD): 62.5 ± 1.3 years, 72 (69%) were treated by cSEMS and 34 (31%) by OTSC. For cSEMS vs. OTSC, mean treatment duration was 41.1 vs. 25 days, p<0.001, leakage size 10 (1-50) vs. 5 (1-30) mm (median (range)), and complications were observed in 68% vs. 8.8%, p<0.001, respectively. Clinical success for primary interventional treatment was observed in 29/72 (40%) vs. 24/34 (70%, p = 0.006), and clinical success at the end of follow-up was 46/72 (64%) vs. 29/34 (85%) for patients treated by cSEMS vs. OTSC; p = 0.04.
Conclusion: OTSC is preferred in small-sized lesions and in perforation caused by endoscopic interventions, cSEMS in patients with concomitant local infection or abscess. cSEMS is associated with a higher frequency of complications. Therefore, OTSC might be preferred if technically feasible. Indication criteria for cSEMS vs. OTSC vary and might impede design of randomized studies.
Faqar-Uz-Zaman, Sara Fatima ; Filmann, Natalie ; Mahkovic, Dora ; Wagner, Michael von ; Detemble, Charlotte ; Kippke, Ulf ; Marschall, Ursula ; Anantharajah, Luxia ; Baumartz, Philipp ; Sobotta, Paula ; Bechstein, Wolf Otto ; Schnitzbauer, Andreas
Introduction Occurrence of inaccurate or delayed diagnoses is a significant concern in patient care, particularly in emergency medicine, where decision making is often constrained by high throughput and inaccurate admission diagnoses. Artificial intelligence-based diagnostic decision support system have been developed to enhance clinical performance by suggesting differential diagnoses to a given case, based on an integrated medical knowledge base and machine learning techniques. The purpose of the study is to evaluate the diagnostic accuracy of Ada, an app-based diagnostic tool and the impact on patient outcome.
Methods and analysis The eRadaR trial is a prospective, double-blinded study with patients presenting to the emergency room (ER) with abdominal pain. At initial contact in the ER, a structured interview will be performed using the Ada-App and both, patients and attending physicians, will be blinded to the proposed diagnosis lists until trial completion. Throughout the study, clinical data relating to diagnostic findings and types of therapy will be obtained and the follow-up until day 90 will comprise occurrence of complications and overall survival of patients. The primary efficacy of the trial is defined by the percentage of correct diagnoses suggested by Ada compared with the final discharge diagnosis. Further, accuracy and timing of diagnosis will be compared with decision making of classical doctor–patient interaction. Secondary objectives are complications, length of hospital stay and overall survival.
Ethics and dissemination Ethical approval was received by the independent ethics committee (IEC) of the Goethe-University Frankfurt on 9 April 2020 including the patient information material and informed consent form. All protocol amendments must be reported to and adapted by the IEC. The results from this study will be submitted to peer-reviewed journals and reported at suitable national and international meetings.
Trial registration number DRKS00019098.
Effenberger, Pauline S. ; Send, Tabea ; Gilles, Maria ; Wolf, Isabell Ann-Cathrin ; Frank, Josef ; Bongard, Stephan ; Kumsta, Robert ; Witt, Stephanie ; Rietschel, Marcella ; Rietschel, Marcella ; Deuschle, Michael ; Streit, Fabian
Growing up in cities is associated with increased risk for developing mental health problems. Stress exposure and altered stress regulation have been proposed as mechanisms linking urbanicity and psychopathology, with most research conducted in adult populations. Here, we focus on early childhood, and investigate urbanicity, behavior problems and the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, a central circuit of the stress system, in a sample of N = 399 preschoolers aged 45 months. Urbanicity was coded dichotomously distinguishing between residences with more or less than 100,000 inhabitants. Behavior problems were measured using the Child Behavior Checklist (CBCL) 1½ - 5. Cortisol stress reactivity was assessed using an age-appropriated game-like stress task, and cortisol in the first morning urine was measured to assess nocturnal HPA axis activity. Urbanicity was not associated with behavior problems, urinary cortisol or the cortisol stress response. Neither urinary cortisol nor salivary cortisol response after stress exposure were identified as mediators of the relationship between urbanicity and behavior problems. The findings suggest no strong association of urbanicity with behavior problems and HPA axis regulation in preschool age. To our knowledge, this is the youngest sample to date studying the relationship between urbanicity and behavior problems as well as HPA axis regulation. Future research should examine at which age associations can first be identified and which mechanisms contribute to these relationships.
Malkomes, Patrizia ; Lunger, Ilaria ; Lütticke, Alexander ; Oppermann, Elsie ; Hätscher, Nadine ; Serve, Hubert ; Holzer, Katharina ; Bechstein, Wolf Otto ; Rieger, Michael A.
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.