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Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT).We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated.A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H.We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals.There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.

The immune-pathology in Crohn’s disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn’s disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn’s disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

A 46-year old construction worker presented at the emergency department with two orthostatic syncopes. The patient complained of prolonged fever and coughs for 7 days which had not improved after oral treatment with sultamicillin for 5 days, prescribed by the patient's general practitioner. Physical examination showed high blood pressure due to previously known hypertension. Other vital signs without pathological findings. Pulmonary auscultation showed basal soft crackling noises of the left lung. Laboratory examination showed increased values for LDH, pro-BNP and CRP and normal values for leucocytes and procalcitonin. Conventional X-Ray of the chest showed bipulmonal lateral atypical infiltrates. After the first PCR turned in negative another PCR-analysis for SARS-CoV-2 of a deep oral swab-sample was performed since the clinical, laboratory and radiological findings were typical for COVID-19. Again, SARS-CoV-2-RNA was not detected. A CT-scan of the chest showed bipulmonal lateral ground-glass attenuation, again typical for COVID-19 associated pneumonia. After a third attempt for a PCR-analysis of a deep oral swab-sample was negative, analysis of a sputum was performed which finally confirmed the diagnosis of COVID-19 associated pneumonia. The patient was admitted for evaluation of syncopes and suspect of COVID-19 associated pneumonia. The patient was prophylactically isolated while the result of SARS-CoV-2-PCR from a deep oral swab was pending. Suspecting a possible secondary bacterial infection at the beginning, intravenous antibiotic treatment with ampicillin/sulbactam was initiated. While further examinations showed no indication for bacterial infection, antibiotics were discontinued after 3 days. Due to clinical recovery antiviral therapy was not performed after confirming the diagnosis. The patient was discharged 17 days after onset of first symptoms without any requirements for further isolation. This casuistic describes a case of COVID-19 associated pneumonia presenting with typical clinical features, laboratory and radiological findings. Detection of viral RNA was not successful from deep oral swab-samples despite repeated attempts. Finally, PCR-analysis of sputum confirmed the diagnosis. Analysis of deeper airway samples (sputum, bronchoalveolar lavage, tracheal secretions) or stool for SARS-CoV-2 should be performed in cases of evident clinical suspicion of COVID-19 and negative PCR results from deep oral swabs. Ein 46-jähriger Bauarbeiter stellte sich bei seit ca. 7 Tagen bestehender Infektsymptomatik mit Fieber und teilweise produktivem Husten sowie 2-maliger orthotstatischer Synkope in der Notaufnahme vor. Ambulant war bereits eine orale antibiotische Therapie über 5 Tage mit Sultamicillin durch den Hausarzt eingeleitet worden, die zu keiner Beschwerdebesserung führte. In der klinischen Untersuchung zeigten sich hypertone Blutdruckwerte bei bekannter arterieller Hypertonie, ansonsten unauffällige Vitalparameter sowie pulmonal feinblasige Rasselgeräusche links basal. Laborchemisch präsentierten sich erhöhte Werte für LDH sowie pro-BNP und CRP bei normwertigen Leukozyten und normwertigem Procalcitonin. Bei Verdacht auf Pneumonie wurde zunächst ein konventionelles Röntgenbild der Lunge durchgeführt, das laterale Verschattungen in beiden Lungen zeigte, verdächtig auf eine atypische Pneumonie. Bei initial negativem Rachenabstrich trotz typischer klinischer, radiologischer und laborchemischer Konstellation erfolgte ein erneuter tiefer Rachenabstrich auf SARS-CoV-2, welcher ebenfalls negativ ausfiel. In der nachgeschalteten CT-Untersuchung des Thorax zeigten sich für COVID-19 typische bipulmonale laterale milchglasartige Infiltrate, woraufhin ein dritter Rachenabstrich durchgeführt wurde, der erneut negativ blieb. Nach Asservierung und PCR-Analyse von Sputum konnte schließlich der Nachweis von SARS-CoV-2 erbracht und die Diagnose einer COVID-19-assoziierten Pneumonie gesichert werden. Es erfolgte die stationäre Aufnahme zur Infekt- und Synkopen-Abklärung. Bei zunächst noch ausstehendem Ergebnis des Rachenabstrichs auf SARS-CoV-2 wurde der Patient prophylaktisch isoliert. Bei Verdacht auf eine mögliche bakteriell-superinfizierte Pneumonie wurde eine intravenöse antibiotische Therapie mit Ampicillin/Sulbactam eingeleitet, welche nach 3 Tagen bei fehlenden Hinweisen auf bakterielle Erreger beendet wurde. Nach Diagnosesicherung erfolgte bei bereits eingetretener klinischer Rekonvaleszenz keine antivirale Therapie. Der Patient wurde 17 Tage nach initialem Symptombeginn ohne weitere Quarantäne-Auflagen nach Hause entlassen. Die Kasuistik beschreibt einen Fall von COVID-19, bei dem trotz typischer klinischer Symptomatik sowie typischen radiologischen und laborchemischen Befunden ein Virusnachweis in mehrfach korrekt durchgeführten tiefen Rachenabstrichen nicht möglich war. Erst eine Sputum-Analyse erbrachte den Nachweis der viralen RNA und sicherte die Diagnose. Bei begründetem klinischem Verdacht auf COVID-19 sollte daher bei negativen Rachenabstrichen zum sicheren Ausschluss eine Analyse von tiefen Atemwegssekreten (Sputum, bronchoalveoläre Lavage, Trachealsekret) oder Stuhl erfolgen.

Background The immune pathogenesis of ulcerative colitis (UC) has been linked to imbalanced CD4+ T-cell responses while the contribution of CD8+ T cells is less well characterized. Chronically activated CD8+ T cells may become dysfunctional and acquire an exhausted phenotype during chronic viral infection or cancer. Recently, exhausted T cell (Tex) signatures have been proposed as a potential prognostic marker in autoimmune diseases. We therefore set out to characterize features of CD8+ T cell exhaustion in UC patients in more detail. Methods Lymphocytes were isolated from peripheral blood and sigmoid biopsies of UC patients in remission (n = 9) and active disease (n = 20). Cytokine production and expression of exhaustion-associated markers were analyzed ex vivo by flow cytometry. Results were correlated with disease activity (Mayo Score) and mucosal inflammation (assessed endoscopically and histologically [Nancy Score]). To further analyze the role of CD8+ T cells within the intestinal tissue microenvironment, Imaging Mass Cytometry (IMC) was applied on sigma biopsies (n= 21). Results Analysis of CD8+ Tex marker expression and functionality did not reveal major differences between peripheral blood lymphocytes isolated from UC patients with either active disease or remission as well as healthy controls. In contrast, in the sigmoid colon of patients with active UC, CD8+ T cell numbers were strongly increased. Moreover, expression of exhaustion markers was significantly increased in intestinal CD8+ T cells during active disease compared to remission. These cells also displayed dysfunctional cytokine profile patterns, as assessed by an established functional exhaustion score. This phenotype also closely correlated with clinical, endoscopic and histological markers of UC disease activity. The findings were confirmed by IMC, which revealed the presence of several clusters of CD8+ T cells with an exhaustion signature in inflamed colonic tissues. Conclusion Our findings indicate that inflammation in the intestines of UC patients is associated with the induction of CD8+ T-cell responses that phenotypically and functionally resemble Tex. The functional relevance, prognostic value and therapeutic relevance of these exhausted CD8+ T cell signatures in UC need to be analyzed in future studies.

Eine gros angelegte Studie zeigt eindeutig, dass strukturierte Alkohol-Entwohnungsprogramme den klinischen Verlauf der alkoholischen Hepatitis verbessern. Alle Patienten sollten daher auf ihren Abstinenzwunsch hin gescreent werden.

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.

Eine Vollwandresektion im Kolon und Rektum ist einer endoskopischen Submukosadissektion (ESD) im Hinblick auf Kuration, En-bloc-Resektion und R0-Status uberlegen. Das Full-Thickness-Device (FTRD, Ovesco, Germany) ist das erste kommerziell erhaltliche endoskopische System, das eine peritoneale Verschlusstechnik mit nachfolgender Vollwandresektion in einem Schritt realisiert. In dieser Studie wurde das FTRD in Bezug auf die Effektivitat einer histologisch nachgewiesenen Vollwandresektion, den R0-Status und die Sicherheit im Rektum und Kolon uberpruft. Zwischen November 2014 und Juni 2015 wurden in unserer interdisziplinaren Endoskopie 20 Patienten am Rektum und Kolon mit dem FTRD behandelt und retrospektiv ausgewertet. Folgende Indikationen wurden im Rektum (n = 11) und Kolon (n = 9) behandelt: endoskopisch inkomplett abgetragene T1-Karzinome (n = 6) und neuroendokrine Tumoren (n = 2), inkomplett abgetragene tubulovillose, villose und serratierte Adenome mit niedrigen und hochgradigen intraepithelialen Neoplasien (n = 9), primare Adenome (n = 3) ohne Vorbiopsie. Der technische Erfolg lag bei 75 %. Drei technische Versager indizierten in zwei Fallen eine konventionelle und in einem Fall eine operative Nachresektion der duplizierten Darmwand. Eine konventionell beendete Resektion fuhrte zu einer thermischen Spatperforation, die eine Segmentresektion indizierte. In einem Fall konnte die Lasion im Zokum zwar erreicht, aber nicht abgetragen werden. Die histologisch gesicherte Vollwandresektion betrug 60 % (85,7 % im Kolon, 54,6 % im Rektum). R0-Resektionen wurden in 80 % der Patienten erreicht. Zwei Patienten wurden onkologisch reseziert. Die mediane Grose der Resektate betrug 5 cm2 (1,6–12,9 cm2). Das FTRD ermoglicht es dem interventionellen Endoskopiker erstmals, Vollwandresektionen des unteren Gastrointestinaltrakts standardisiert, sicher und effektiv durchzufuhren. Limitierende Faktoren sind die Grose der Ziellasion, Gewebefibrosierung und die Wandstarke des zu behandelnden Darmabschnitts. Aus diesen Grunden empfiehlt es sich, bereits im Rahmen der Screeningkoloskopie mithilfe spezieller Aufsatzkappen, die dem FTRD entsprechend dimensioniert sein sollten, eine Simulation der Resektion durchzufuhren.

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Bei alteren Patienten besteht eine deutlich erhohte Inzidenz von Komorbiditaten. Diese betreffen samtliche Organsysteme (z. B. Herz, Lunge und Niere). Im Rahmen von Tumorerkrankungen bestehen zusatzlich verminderte physiologische Reserven, die bei grosem operativem Stress nicht mehr ausreichend sein konnen. Dies bedingt eine erhohte postoperative Morbiditat und Mortalitat. Aktuell nimmt die Anzahl alter Patienten mit Tumorerkrankungen deutlich zu, somit ist eine Beschaftigung mit dieser Patientengruppe und ihren Eigenheiten von groser klinischer Relevanz. Grose Operationen bei alten Patienten stellen eine Herausforderung fur das gesamte arztliche Team dar. Eine optimale Versorgung wird am besten durch die Betreuung eines interdisziplinaren Teams gewahrleistet.

1-Benzhydryl-4-phenylmethane sulfonyl piperazine was synthesized from 1-benzhydryl piperazine with phenylmethane sulfonyl chloride. The product obtained was characterized by 1H NMR, MS and IR techniques and finally confirmed by X-ray crystallography. The title compound C24H26N2O2S, M r = 406.53, crystallizes in the orthorhombic crystal class in the space group Pbca with unit cell parameters a = 11.1240(10)A, b = 9.4940(15)A, c = 40.239(4)A, Z = 8 and V = 4249.7(9)A3. The structure was solved by direct methods and refined to R 1=0.0561 for 2,445 reflections with [I > 2 σ(I)]. The piperazine ring adopts a chair conformation. The sulfonyl moiety is in a distorted tetrahedral configuration.

The diagnostic validity of a full-thickness resection is higher compared to endoscopic mucosal resection (EMR) or endoscopic mucosal dissection (ESD). Whereas transanal endoscopic microsurgery techniques (TEM, TAMIS) are established therapeutic procedures in the rectum no established and safe minimally invasive or endoscopic procedure exists in the colon.In this study the novel endoscopic full thickness resection device (FTRD, Ovesco, Germany) was investigated concerning success rates with histologically proven full thickness resections, R0 status as well as patient and device safety for the rectum and colon.In the period from November 2014 to June 2015 full thickness resections in the rectum and colon were performed with the FTRD in 20 patients. Data on technical success, R0 resection rate and histologically confirmed full thickness resections were retrospectively analyzed.The following indications were treated in the rectum (n = 11) and colon (n = 9): T1 carcinoma (n = 6) and neuroendocrine tumors (n = 2), untreated and nonlifting adenomas (n = 3) and incomplete resection of adenomas with low and high grade dysplasia (n = 9). The technical success rate was 75 %, 3 technical failures made a conventional polypectomy necessary in 2 patients and in 1 patient an operative resection of the duplicated intestinal wall had to be performed. The median endoscopic follow-up time was 61.5 days (n = 10) and in 7 patients the clip had dislodged at the first follow-up. A thermal perforation in one case of conventional polypectomy gave rise to indications for a partial resection of the colon. In one patient the lesion in the cecum could be reached but not treated for technical reasons. The histological R0 rate was 80 %, whereas the full thickness resection rate was 60 % (85.7 % in the colon and 54.6 % in the rectum). In two patients with carcinoma and incomplete FTRD, surgical treatment was performed. The median size of the resection specimen was 5 cm(2) (range 1.6-12.9 cm(2)).The results show that FTRD is a safe and effective instrument for use in the lower gastrointestinal tract. Limitations of the FTRD system concerning full thickness resection are scarring, fibrosis and thickness of the intestinal wall, especially in the lower rectum; therefore, it is suggested that a simulation with a tube similar in size to the FTRD should be performed during the screening colonoscopy in order to establish whether an endoscopic resection with FTRD is possible.

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide with a high mortality. Available therapeutical options are limited, thus the development of new, innovative therapeutic strategies is crucial. Based on the immune system's antitumoral effect, immunotherapy is a promising new treatment option. Specific antitumoral T-cell responses can be detected in patients with HCC, however, their impact on tumor control seems to be rather weak. Various different immunosuppressive mechanisms seem to contribute to the failure of tumor-specific T-cell responses. Thus, the aim of immunotherapeutic strategies is to address these mechanisms of T-cell failure and to induce new or to boost existing antitumoral immune responses.