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Vaccination is considered one of the most important achievements of modern medicine and has saved millions of lives. As a result, the age-old fear of severe or fatal infectious diseases has largely been forgotten in society; however, the pandemic triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shows how quickly this fear can return. Also, many people have reservations about medical measures, especially if they are directed against vague dangers. Paradoxically, the success of vaccinations jeopardizes the acceptance. To counteract this development, this article provides information on basic vaccination principles, legal frameworks and components of vaccines. It explains the most important categories, goals, core elements of vaccination programs and the most important recommendations of the Standing Committee on Vaccination at the Robert Koch Institute (STIKO). It explains the current state of knowledge with respect to required resources, assessment of vaccine reactions, complication management and possible vaccine damage.

Was ist neu? Erregerspektrum, Verlauf, Therapieoptionen Prinzipiell können Bakterien, Viren oder Parasiten eine Reisediarrhö verursachen. Im Vordergrund steht die symptomatische Behandlung der Reisediarrhö. Krankheitsbild und Erregerart beeinflussen das weitere Vorgehen. Diagnostik Eine spezifische Erregerdiagnostik ist bei unkomplizierten Durchfällen mit häufiger Selbstlimitierung meist nicht erforderlich. Kommt es zu prolongierten und blutigen Durchfällen, Fieber oder Exsikkose, ist eine spezielle Diagnostik indiziert. Präventionsmaßnahmen und reisemedizinische Beratung Umfassend und qualifiziert sollte sie vor jeder größeren Fernreise stattfinden und Präventionsmaßnahmen, Malaria-Chemoprophylaxe, Impfungen, Möglichkeiten der Selbsttherapie und Verhalten bei reiseassoziierten Erkrankungen beinhalten. Therapiestrategien Sie umfassen den Flüssigkeits- und Elektrolytausgleich, die Gabe von Antidiarrhoika und die antimikrobielle Therapie.

ZusammenfassungDie Formale Begriffsanalyse vermag aus den Daten zu Gegenständen und deren Merkmalen eine Datenstruktur zu ermitteln. Es wird ein weitgehend automatisierbares Verfahren vorgestellt, das ausgehend von Elementarsätzen in Form von RDF-Tripeln in einem iterativen Bottom-up-Prozess mittels Semantischer Netze und der Formalen Begriffsanalyse zu einem Ontologieschema führt. Neben der Taxonomie der Klassen wird hierbei auch eine Taxonomie der Relationstypen erstellt. Die durch die Formale Begriffsanalyse automatisch erstellten Merkmalimplikationen können für die Qualitätssicherung herangezogen werden. Führt diese zu Korrekturen und Erweiterungen der Elementarsätze, wird der Prozess wiederholt. Das resultierende Ontologieschema wird in ein Entity-Relationship-Diagramm überführt, das die Grundlage für ein konzeptionelles Datenbankschema liefert. Zur Demonstration des Verfahrens wird exemplarisch eine Ontologie eines Wissensgebiets erstellt.Alle Überlegungen zur Erstellung des Ontologieschemas lassen sich prinzipiell auch bei der Erstellung und Ausarbeitung beliebiger semantischer Datenschemata anwenden. Somit bietet diese Bottom-up-Methode die Chance, die Generierung des Datenbankschemas algorithmisch durch Beispielsammlungen zu unterstützen. Da jeder Schritt im Verfahren nachvollziehbar und somit von der Person des Modellierers unabhängig ist, liefert das Verfahren einen Beitrag zur Automatisierung der Modellierung, insbesondere von Ontologien.

Introduction: Cryptosporidiosis has emerged as a major cause of diarrheal disease worldwide. It has especially serious health consequences for young, malnourished children living in endemic areas and for individuals with highly impaired T-cell function, such as HIV-positive individuals with low CD4 counts or immunosuppressed solid-organ transplant recipients.Areas covered: A selective literature search using PubMed was performed to review the available therapeutics to treat cryptosporidiosis, as well as related advances in drug development.Expert opinion: The only FDA-approved antiparasitic treatment in immunocompetent patients is nitazoxanide; however, it has failed to demonstrate convincing effectiveness among HIV-positive patients, immunosuppressed individuals and malnourished children. Thus, restoring HIV-positive patients' cellular immune response through effective antiretroviral therapy (ART), or reducing or changing immunosuppressive drugs, is important. Several new targets have been identified for chemotherapy, and the development of drugs for these targets has progressed, including parasite kinases, nucleic acid synthesis and processing, proteases and lipid metabolism. Candidate drugs that have been shown to be effective and safe in a neonatal calf model will most likely constitute the next advance for clinical trials in humans. However, developing an effective and inexpensive vaccination, as well as complementing structural preventive measures, would most decisively reduce the global cryptosporidiosis burden.

Background Pyogenic liver abscesses (PLAs) represent potentially life-threatening abdominal conditions that require immediate diagnosis and therapy. European and American incidence figures vary between one and 15 per 100,000 per year. Structured epidemiological data for European countries are not available. Objective To systematically characterize the epidemiology and clinical outcome of PLA in Germany. Methods In representative statutory health insurance data from four million people in 2013-2019, the prevalence and incidence with clinical coding of International Statistical Classification of Diseases and Related Health Problems (ICD)-10 code K75.0 were selected (n = 1118). Furthermore, demographics, relevant comorbidities, hospitalizations, mortality and complications were determined within one year. Results The incidence of PLA was approximately seven per 100,000. The average age at diagnosis was 66 years; 65% were male. Of these, biliary disease was documented in over 60% and infectious intestinal diseases were found in 21% within the same or previous calendar year. PLA patients had high comorbidity indices. Liver transplant status, malignancies of the liver and biliary system, liver cirrhosis and pancreatitis were strongly associated. Intensive care was documented in 27% of PLA cases. Nine percent died within 12 months, most with an underlying malignant disease. Conclusion Pyogenic liver abscess is a rare disease with high morbidity. Predisposing and risk factors include intestinal and biliary diseases as well as hepatic malignancies. Further research should focus on PLA therapy within prospective surveys and controlled clinical trials.

Zusammenfassung Ziel der Studie Ziel dieser Studie war es, die Empfehlungen eines etablierten ABS-Teams während der wöchentlichen Routinevisiten zu evaluieren sowie ihre Umsetzungsrate und die Gründe der Nichtumsetzung zu untersuchen. Methodik Die Visiten eines multiprofessionellen ABS-Teams (Infektiologie, Mikrobiologie, Apotheke und Krankenhaushygiene) wurden über 8 Wochen auf 9 intensivmedizinischen und peripheren Stationen eines Universitätsklinikums (1451 Betten) begleitet. Die Empfehlungen des ABS-Teams wurden prospektiv analysiert und bei fehlender Umsetzung Gründe standardisiert von den behandelnden Ärzten erfragt. Ergebnisse Während des Beobachtungszeitraums fanden bei 262 Patienten 359 ABS-Visiten statt. Im Median nahmen 4 Ärzte und 1 Apotheker (Q25/Q75: 4/6) an den ABS-Visiten teil. Bei 177/359 (49%) ABS-Visiten erfolgte mindestens eine Empfehlung zur Antiinfektivatherapie. Insgesamt wurden 210 Empfehlungen ausgesprochen. Am häufigsten waren mit 38% (80/210) Empfehlungen zur Einhaltung der festgesetzten Therapiedauer. Je mehr unterschiedliche Berufsgruppen an der ABS-Visite teilnahmen, je eher wurde eine Empfehlung ausgesprochen (p=0,016; Odds Ratio=1,018 (1,003–1,033)). 62/210 (30%) der Empfehlungen des ABS-Teams wurden vom behandelnden Arzt nicht umgesetzt. Als häufigster Grund wurde mit 32% (20/62) eine bewusst von der Empfehlung abweichende Therapieentscheidung angegeben. Schlussfolgerung Die hohe Empfehlungsrate von knapp 50% zeigt den Bedarf an Therapieoptimierung durch ABS-Teams in der Routine. Je multiprofessioneller diese besetzt sind, desto häufiger werden auch Empfehlungen ausgesprochen. Gründe für die fehlende Umsetzung von Empfehlungen sollten kritisch hinterfragt werden – sowohl seitens des ABS-Teams als auch seitens der behandelnden Ärzte auf Station.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04492-1.

Purpose Infectious complications are as high as 30% in elective colorectal surgery. In recent years, several studies have discussed the topic of preoperative bowel decontamination prior to colorectal surgery in order to reduce postoperative infectious complications and have found significant effects of oral antibiotic administration with a large variety of drugs used. No study has evaluated the combination of oral paromomycin and metronidazole in this context. Methods We performed a prospective single-center study with a matched-pair retrospective cohort to evaluate postoperative infectious complications (superficial site infections, organ space abscess, anastomotic leakage) in elective colorectal surgery. Patients A total of 120 patients were available for study inclusion; 101 gave informed consent and were included. A total of 92 patients were matched and subsequently analyzed. We could show a reduction in overall infectious complications in the intervention group (15.2% vs 30.8%, p = 0.018; odds ratio 0.333, 95% CI 0.142–0.784) as well as a reduction in superficial surgical site infections (8.7 vs 19.6%, p = 0.041, OR 0.333, 95% CI 0.121–0.917). The frequency of the other infectious complications such as intraabdominal abscesses and anastomotic leakage showed a tendency towards decreased frequencies in the intervention group (OR 0.714, 95% CI 0.235–2.169 and OR 0.571; 95% CI 0.167–1.952, respectively). Finally, the oral antibiotic administration led to an almost significantly reduced length of stay (12.24 days vs 15.25 days; p = 0.057). Conclusions Oral paromomycin and metronidazole with intravenous ertapenem effectively reduce infectious complications in elective colorectal surgery. Trial registration The study was registered at Clinicaltrials.gov (NCT03759886) December 17, 2018

Hypomethylating agents (HMA) have become the backbone of nonintensive acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) treatment, also by virtue of their activity in patients with adverse genetics, for example, monosomal karyotypes, often with losses on chromosome 7, 5, or 17. No comparable activity is observed with cytarabine, a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMAs decitabine and azacitidine. An unbiased RNA-sequencing approach was developed to interrogate decitabine-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3–1, with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. Decitabine globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3–1 and RIG-I mRNA was also observed during decitabine treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived monosomal karyotype AML murine xenografts, decitabine treatment resulted in superior survival rates compared with cytarabine. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over cytarabine in this difficult-to-treat patient group. Significance: These findings unravel the molecular mechanism underlying the intriguing clinical activity of HMAs in AML/MDS patients with chromosome 7 deletions and other monosomal karyotypes. See related commentary by O'Hagan et al., p. 813

Die chronischen myelomonozytaren Leukamien (CMML) sind klonale Stammzellerkrankungen mit persistierendem Nachweis einer Monozytose im peripheren Blut. Die Festlegung der Klassifikation CMML‑0, CMML‑I und CMML-II erfolgt in Abhangigkeit vom medullaren und peripheren Blastengehalt. Je nach Leukozytenwert (

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, with a variable probability of transformation into acute leukemia, which is, in the vast majority of cases, of myeloid lineage. Nevertheless, rare cases of acute lymphoblastic leukemia in patients with previously diagnosed MDS have been reported. We describe a series of 3 cases of MDS/CMML marked with evolution to acute lymphoblastic leukemia (ALL) and provide a comprehensive review of the 49 cases documented in the literature so far. These sporadic events have only been published as single-case reports or small series to date. Such atypical cases emphasize the possibility of major phenotypic switches arising at the leukemic stem cell (LSC) and/or early progenitor levels, as a consequence of epigenetic and genomic events driving these changes in the bone marrow niche.

Es wird der Fall einer 48-jahrigen Reiseruckkehrerin aus Bangladesch mit uber Monate persistierender Polyarthralgie und -arthritis infolge einer Chikungunya-Virus-Infektion dargestellt. Die Infektion manifestiert sich meist mit hohem Fieber und muskuloskeletalen Beschwerden, welche Monate bis Jahre persistieren konnen. Die Therapie der chronisch entzundlichen Form orientiert sich an den Empfehlungen fur andere chronisch entzundliche Gelenkerkrankungen. Infolge der zunehmenden Verbreitung des Virus und seiner Vektoren sowie der ungebrochenen Reiseaktivitat ist auch in Europa gehauft mit importierten Fallen bzw. einer Etablierung des Erregers zu rechnen.

Aufgrund der ungebrochenen Reisefreudigkeit spielen reisespezifische Erkrankungen in Deutschland weiterhin eine grose Rolle. Oft ist die Leber dabei primar oder sekundar betroffen. Als Ausloser kommen so gut wie alle Erregerklassen und viele toxische Substanzen infrage: Die Hepatitis A gehort zu den wichtigsten vermeidbaren viralen Hepatitiden. Andere Hepatitisviren (HBV/HDV, HCV, HEV) und Erreger viraler und bakterieller Begleithepatitiden (Zytomegalievirus [CMV], Epstein-Barr-Virus [EBV], humanes Immundefizienzvirus [HIV], Flaviviren, Rickettsien, Brucellen, Treponemen, Leptospiren etc.) konnen ebenfalls relevant sein. Insbesondere Leberabszesse durch Entamoeba histolytica und hypervirulente Klebsiellen mussen schnell erkannt werden. Auch parasitare Wurmer konnen unter bestimmten Expositionsbedingungen etliche hepatobiliare Erkrankungen (Helminthosen) verursachen. Dazu gehoren z. B. Leber- und Parchenegel sowie bestimmte Faden- und Bandwurmer. Bei unklaren (Leber‑)Symptomen und passender Reiseanamnese sollten Malaria und die viszerale Form der Leishmaniose bedacht werden. Auch Leberintoxikationen durch Pflanzen‑, Pilz- und Umweltgifte sowie Drogen sind in der Reisemedizin bekannt. Aufgrund potenziell schwerwiegender Komplikationen sollten reisespezifische Lebererkrankungen rechtzeitig erkannt bzw. im Sinne der Primarprophylaxe durch professionelle Reiseberatung verhindert werden.

Angesichts der zunehmenden antimikrobiellen Resistenzentwicklung ist Antibiotic Stewardship (ABS) eine wichtige Masnahme gegen die Ausbreitung resistenter Erreger und die Entstehung von Multiresistenz. Fur Deutschland und Osterreich steht eine 2018 aktualisierte umfangreiche S3-Leitlinie zur Verfugung. Die Steuerung des Antibiotika‑/Antiinfektivaeinsatzes im Krankenhausbereich sollen ABS-Teams begleiten. ABS beinhaltet auf Krankenhausebene die fortlaufende Analyse lokaler Antibiotikaverbrauchs- und Resistenzdaten. Daraus sollen Empfehlungen fur lokal angepasste Therapieschemata abgeleitet werden. In regelmasigen Visiten diskutieren Mitglieder des ABS-Teams am Krankenbett Indikation, Dosierung, Applikationsweg und Dauer einer antimikrobiellen Therapie. Herausfordernd ist der „sparsame“ Umgang mit Antibiotika, ohne den Patienten zu gefahrden. Digitalisierung und kunstliche Intelligenz bieten neue Moglichkeiten fur ABS. Wichtig ist auch die Adaptierung stationarer Konzepte an die ambulante Versorgung.

Antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. The most important ABS tools include the implementation of local guidelines, the development of a house-related list of anti-infective agents, regular ABS visits and practice-oriented internal training events. Effective strategies for therapy optimization include indication testing and therapy evaluation, dose optimization as well as determining an appropriate duration of therapy. Oralization of anti-infectives (sequence therapy) should be supported by consistent clinical criteria in in-house guidelines. The incidence of Clostridioides difficile infections (CDI) can be more than halved by restricting the so-called "4C antibiotics". Point-of-care tests help to minimize the use of antibiotics in the outpatient setting. Vaccination reduces the need for antibiotic therapy.

PURPOSE High CD33 expression in acute myeloid leukemia (AML) with mutated NPM1 provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in NPM1-mutated AML. PATIENTS AND METHODS Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all- trans-retinoic acid with or without GO. The early ( P = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment. RESULTS Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; P = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( P = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( P = .005), with no difference in the cumulative incidence of death ( P = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and FLT3 internal tandem duplication–negative patients with respect to EFS and CIR. CONCLUSION The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.

We report the case of a 65-year-old female patient with hepatic alveolar echinococcosis (AE) caused by Echinococcus multilocularis. This infrequent zoonosis has a considerable morbidity and mortality. The malignant appearing hepatic mass was initially misdiagnosed as cholangiocarcinoma of the right hepatic lobe (segments VII, VIII, and IVa, sized 10.9 cm × 7.6 cm) involving the right and middle hepatic vein and extending close to the left hepatic vein. During exploratory laparotomy, the frozen-section biopsy was indicative of AE (World Health Organization [WHO] classification: stage P3N0M0). Due to the high operative risk, it was decided to pretreat the patient with albendazole as inductive therapy in order to remove the AE secondarily in accordance with the patient’s request. After year-long treatment with albendazole (under strict control of the maximum blood levels), a right hemihepatectomy was successfully performed. Postoperative treatment with albendazole had to be stopped prematurely after 11 months due to considerable subjective intolerance and a more-than-tenfold elevation of transaminases despite normal therapeutic albendazole blood levels. A 18F-FDG-PET/CT scan revealed no evidence of AE residues. Conducting follow-up examinations by 18F-FDG-PET/CT scans every 2 years is planned in order to recognize possible recurrence at an early stage.

Zu den haufigsten Gesundheitsstorungen auf Fernreisen gehort die akute Reisediarrho, die je nach geographischer Region mit einer Pravalenz von >50 % auftreten kann. Dieses uberwiegend bakteriell (v. a. durch enteropathogene Escherichia coli, Campylobacter spp., Shigella, Salmonella) bzw. manchmal viral (durch Noro- oder Rotaviren) oder seltener parasitar (durch Giardien/Lamblien, Entamoben) verursachte Krankheitsbild verlauft in den meisten Fallen unkompliziert und selbstlimitierend. Eine persistierende Diarrho ist jedoch der haufigste Grund fur eine arztliche Vorstellung nach Fernreisen in der Praxis. Fur bestimmte Personengruppen, wie Immunsupprimierte oder Schwangere, ist auch eine scheinbar banale Reisediarrho immer abklarungsbedurftig. Dann ist eine gezielte Stuhldiagnostik gerechtfertigt, ebenso bei Fieber und blutigem Stuhl. Die Therapie ist meistens symptomatisch (Flussigkeits- und Elektrolytersatz); selten sind Antibiotika indiziert. Im Rahmen einer qualifizierten Reiseberatung sollten Praventionsmasnahmen (Destinationswahl, Hygieneverhalten, Impfungen) im Vorfeld besprochen werden.

ZusammenfassungDie humane intestinale Mikrobiota hat wichtige metabolische und immunologische Funktionen für das Individuum und ist Bestandteil der Abwehr gegenüber pathogenen Erregern im Gastrointestinaltrakt. Antibiotika, Probiotika, diätetische Maßnahmen wie Präbiotika sowie als relativ neu etablierte Methode der fäkale Mikrobiom-Transfer (FMT, auch fäkale Mikrobiota-Transplantation) können die Zusammensetzung des intestinalen Mikrobioms beeinflussen. Als FMT wird die Übertragung von Stuhlmikroorganismen, vornehmlich Bakterien, aber auch Bakteriophagen, Pilzen und Viren eines gesunden humanen Spenders in den Gastrointestinaltrakt eines Patienten bezeichnet. Diese Maßnahme soll der Wiederherstellung einer normalen Darmmikrobiota bei Patienten mit einer Dysbiose-assoziierten Erkrankung dienen. Die bislang einzige Indikation für einen FMT ist die multipel rezidivierende Clostridioides difficile-Infektion (CDI). Über 85 % betroffener Patienten können in dieser Situation durch eine „Stuhltransplantation“ erfolgreich und dauerhaft geheilt werden. Als mögliche weitere Anwendungsgebiete werden chronisch-entzündliche und funktionelle Darmerkrankungen, nicht-alkoholisch bedingte Fettlebererkrankung, Insulinresistenz, morbide Adipositas, multiple Sklerose (MS) oder idiopathische thrombozytopenische Purpura (ITP) diskutiert. Die Evaluation in klinischen Studien ist noch unvollständig. Die Durchführung des FMT unterliegt in Deutschland dem Arzneimittelgesetz (AMG) als individuelle Heilmittelzubereitung, an deren Herstellung und Durchführung der behandelnde Arzt verantwortlich und persönlich beteiligt sein muss. Notwendig ist eine sorgfältige Spenderselektion durch genaue Anamnese, klinische Untersuchung, Blut- und Stuhluntersuchungen.

The prevalence of alveolar echinococcosis (AE) and cystic echinococcosis (CE) in Germany is increasing. The number of cases in northern and eastern regions is low, so there is little experience with regard to diagnosis and therapy. The objective of this paper was to evaluate the management of suspected and/or diagnosed echinococcosis at a university center in a low-prevalence region. All the patients at the Leipzig University Hospital between 2004 and 2018 who had been serologically examined for echinococci were included in a retrospective cohort study. Clinical course, imaging, histology, therapeutic characteristics, relevant comorbidities and risk factors for AE and CE were evaluated. A time-staggered prevalence estimation, as well as sensitivity and specificity calculations for the serological tests, were performed. A total of 382 patients were enrolled, with 11 AE and 7 CE cases identified. The mean prevalence rate of AE in this cohort was 2.9 % and that of CE was 1.8 %. Among the patients, 56 % had known risk factors for AE and CE. The serological tests showed a sensitivity of 86 % and a specificity of 91 %. Two patients with false-negative serology were diagnosed by biopsy. All CE and 5 AE patients (45 %) were operated on. Six AE patients received long-term treatment with albendazole. AE and CE are rare diseases in the greater Leipzig region; however, case numbers are on the rise. Due to favorable factors such as the escalation of migration, a further increase is expected. Diagnosis and therapy are challenging and should be supported by specialists (experienced infectiologists, imaging experts and skilled hepatobiliary surgeons) who should be integrated in a German network.EINFüHRUNG : Die Prävalenz der alveolären (AE) und zystischen Echinokokkose (CE) in Deutschland nimmt zu, aber die Gesamtzahl der Fälle in den nördlichen und östlichen Bundesländern ist noch immer gering. Betroffene Patienten werden überwiegend in wenigen spezialisierten Zentren in Süddeutschland behandelt, sodass in anderen Regionen Deutschlands bislang nur relativ wenig klinische Erfahrung mit AE und CE vorhanden ist.Ziel unserer Studie war es, das derzeitige Management von Patienten mit Verdacht auf oder bestätigter Echinokokkose an einem Zentrum der tertiären Versorgungsstufe in einer Niedrigprävalenzregion zu bewerten, um eine Verbesserung des Vorgehens bei Verdacht auf AE/CE bzw. bereits gesicherter Diagnose zu erreichen.Alle Patienten, die am Universitätsklinikum Leipzig zwischen dem 01.01.2004 und dem 30.09.2018 infektionsserologisch auf Echinokokken untersucht wurden oder die Diagnose „AE“ bzw. „CE“ erhalten hatten, wurden in eine retrospektive Kohortenstudie eingeschlossen. Klinischer Verlauf, bildgebende sowie histopathologische Befunde, Therapiecharakteristika, relevante Begleiterkrankungen und mögliche Risikofaktoren für AE bzw. CE wurden bewertet. Die Datenanalyse umfasste weiter eine zeitlich gestaffelte Prävalenzabschätzung für unser Zentrum sowie Sensitivitäts- und Spezifitätsberechnungen für die durchgeführten serologischen Tests.Insgesamt wurden 382 Patienten in die Analyse einbezogen. 11 AE- und 7 CE-Fälle wurden identifiziert. Die mittlere Prävalenzrate der AE in dieser Kohorte lag bei 2,9 % und die der CE bei 1,8 %. Bei 4 Patienten war die Diagnose bereits auswärtig gesichert worden und eine gezielte Überweisung zur spezialisierten Behandlung erfolgt. 56 % der Patienten wiesen bekannte Risikofaktoren für CE bzw. AE auf. Mit Ausnahme eines Falls waren alle CE-Fälle Migranten mit ausländischer Herkunft. Die durchgeführten serologischen Tests zeigten für beide Erkrankungen eine Sensitivität von 86 % und eine Spezifität von 91 %. 2 Patienten mit zunächst falsch negativer Diagnose (einer mit AE und einer mit CE) wurden durch ultraschallgestützte Biopsie korrekt diagnostiziert. Alle CE-Fälle und 5 AE-Fälle (45 %) wurden unter Albendazolschutz chirurgisch versorgt. Die restlichen 6 AE-Fälle erhielten eine Langzeitbehandlung mit Albendazol. Es wurden keine Todesfälle infolge Echinokokkose beobachtet.Sowohl AE als auch CE sind im Großraum Leipzig seltene Erkrankungen, wenngleich ein Anstieg der Fallzahlen an unserem Zentrum zu verzeichnen ist. Aufgrund unterschiedlicher begünstigender Faktoren wie z. B. Zunahme der Migration ist in Zukunft mit einem weiteren Anstieg zu rechnen. Diagnosestellung und Therapiemanagement stellen sowohl für die AE als auch für die CE eine Herausforderung dar und sollten von einem Expertenteam begleitet werden, darunter erfahrene Infektiologen, Bildgebungsspezialisten und versierte hepatobiliäre Chirurgen. Der Aufbau eines deutschen Echinokokkosenetzwerks wäre sinnvoll.

Zecken sind Ubertrager einer Vielzahl humanpathogener Krankheitserreger mit einer grosen Bandbreite klinischer Symptome. Das Verbreitungsgebiet der einzelnen Erreger ist vom Vorkommen der Vektoren und Wirte abhangig. Aufgrund verschiedener Faktoren ist es in den letzten Jahren zum Teil zu einer Ausdehnung der Endemiegebiete gekommen. Am weitesten verbreitet sind Zecken-ubertragene Rickettsiosen, welche v.a. in der Reisemedizin eine Rolle spielen. Die haufigsten Zecken-ubertragbaren Erkrankungen in Deutschland und Europa sind Lyme-Borreliose und Fruhsommer-Meningoenzephalitis (FSME). Meist verlaufen die Infektionen mild oder sind — im Falle bakterieller Infektionen — gut behandelbar. Die wichtigsten praventiven Masnahmen bei Aufenthalten in einem Risikogebiet sind der Schutz vor Zeckenstichen und im Falle der FSME die sehr gut wirksame Impfung.

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

BACKGROUND: COVID-19 prediction models based on clinical characteristics, routine biochemistry and imaging, have been developed, but little is known on proteomic markers reflecting the molecular pathophysiology of disease progression. METHODS: The multicentre (six European study sites) Prospective Validation of a Proteomic Urine Test for Early and Accurate Prognosis of Critical Course Complications in Patients with SARS-CoV-2 Infection Study (Crit-COV-U) is recruiting consecutive patients (≥ 18 years) with PCR-confirmed SARS-CoV-2 infection. A urinary proteomic biomarker (COV50) developed by capillary-electrophoresis-mass spectrometry (CE-MS) technology, comprising 50 sequenced peptides and identifying the parental proteins, was evaluated in 228 patients (derivation cohort) with replication in 99 patients (validation cohort). Death and progression along the World Health Organization (WHO) Clinical Progression Scale were assessed up to 21 days after the initial PCR test. Statistical methods included logistic regression, receiver operating curve (ROC) analysis and comparison of the area under the curve (AUC). FINDINGS: In the derivation cohort, 23 patients died, and 48 developed worse WHO scores. The odds ratios (OR) for death per 1 standard deviation (SD) increment in COV50 were 3·52 (95% CI, 2·02-6·13, p

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.

In patients with critical or mild COVID19 (WHO stages 6-8 [n=53] and stages 1-3 [n=66]), 593 urinary peptides significantly affected by disease severity were identified, reflecting the molecular pathophysiology associated with the course of the infection. The peptide profiles were similar compared with those observed in kidney disease, a prototype of target organ damage with major microvascular involvement, thereby confirming the observation that endothelial damage is a hallmark of COVID19. The clinical corollary is that COVID19 is an indication for anti-oxidative, anti-inflammatory and immunosuppressive treatment modalities protecting the endothelial lining.

Background In 2019, 1.5 billion international tourist trips were counted worldwide. Germany, with 70.8 million vacations lasting ≥ 5 days, was one of the populations most willing to travel. These days, even elderly and multimorbid persons regularly travel long-distance, which can be associated with significant health risks. By advising travelers and implementing preventive measures, the risk of illness can be reduced significantly. Methods A selective survey of PubMed was performed to identify publications on medical advice for travelers between 2000 and 2020. We included guidelines, studies, and recommendations that mainly deal with the preventive aspects of travel medicine and have a high level of practical relevance and the highest possible level of evidence. Previously published guidelines (based on the GRADE criteria) were adopted, and recommendations not based on the results of scientific studies were characterized as Good Clinical Practice (GCP). Results Many medical recommendations for travelers still rely on individualized, experience-based, or consensus-based assessments. Apart from a review of medical history and vaccination status, a risk analysis is performed, travel fitness is evaluated individually, and a prevention plan is designed. Particular attention is devoted to malaria prophylaxis, vector protection, and traveler's diarrhea. Medical advice before travel is especially important for the elderly, children, pregnant women, the chronically ill, long-term and adventure travelers as well as migrants from malaria-endemic areas who are returning home. Conclusion The health risks associated with travel can be minimized by specialist medical advice. Many recommendations are empirical in nature and require further research.

Decitabine (5-aza-2′-deoxycytidine) is a hypomethylating agent used in the treatment of acute myeloid leukemia (AML). Decitabine inhibits DNA methyltransferases, causing DNA hypomethylation, and limiting the transcription of tumor suppressor genes, leading to gene silencing. Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy. The initial authorization in 2012 was based on the results of the open-label, randomized, multicenter phase 3 DACO-016 trial, and supported by data from the supportive phase 2 open-label DACO-017 trial. Compared with standard care, decitabine significantly improved overall survival, event-free survival, progression-free survival, and response rate. Decitabine was generally well tolerated, offering a valuable treatment option in patients with AML irrespective of age, especially for patients achieving a complete response. Several observational “real-life” studies confirmed these results. In contrast to standard chemotherapy, the presence of adverse-risk karyotypes or TP53 mutations does not negatively impact sensitivity to hypomethylating therapy albeit with lower durability. Data suggest a potential positive effect of decitabine in patients with monosomal karyotype-positive AML. For the time being, decitabine is an appropriate option as monotherapy for patients with AML who are unfit to receive more intensive combination therapies, but emerging data suggest that decitabine-based doublet or triplet combinations may be future treatment options for patients with AML.

Although, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called “cytokine storm”, with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned those elevated inflammatory molecules might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity-2 (sST2) and 20S proteasome at hospital admission and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. Furthermore, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality (sST2, AUC = 0.73, HSP27, AUC = 0.59, 20S proteasome = 0.67). Elevated sST2, HSP27, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation (OR = 1.8, p &lt, 0.001, OR = 1.1, p = 0.04, OR = 1.03, p = 0.03, respectively). These findings could help to identify high-risk patients early in the course of COVID-19.

Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection (CDI). Here, we report in a prospective observational cohort study the incidence of CDI and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients ≥ 50 years receiving newly initiated antibiotic treatment with penicillins plus a beta-lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones or clindamycin from 34 European hospitals. The estimated 90-day cumulative incidences of a first CDI episode is 1.9% (95% CI 1.1-3.0). Carbapenem treatment (Hazard Ratio (95% CI): 5.3 (1.7-16.6)), toxigenic C. difficile rectal carriage (10.3 (3.2-33.1)), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (5.4 (2.1-18.7)), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (9.7 (3.2-29.7)), but not normalized urinary 3-indoxyl sulfate levels, predicts an increased CDI risk., Here, the authors report the incidence of Clostridioides difficile infection (CDI) and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients of 50 years and above receiving newly initiated antibiotic treatment.

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD–mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

Highlights • Deep learning technology applied to diagnosis of Acute Promyelocytic Leukemia (APL). • Convolutional neural networks (Mask R-CNN) may diagnose APL in bone marrow smear images with a high precision. • Data augmentation and pre-trained approach improves diagnostic accuracy., Background Serological severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays differ in the target antigen specificity, e.g. of antibodies directed against the viral spike or the nucleocapsid protein, and in the spectrum of detected immunoglobulins. The aim of the study was to evaluate the performance of two different routinely used immunoassays in hospitalized and outpatient COVID-19 cases. Methods The test characteristics of commercially available spike1 protein-based serological assays (Euroimmun, EI-assays), determining IgA or IgG and nucleocapsid-based assays (Virotech, VT-assays) determining IgA, IgM or IgG were compared in 139 controls and 116 hospitalized and outpatient COVID-19 cases. Results Hospitalized COVID-19 patients (n = 51; 115 samples) showed significantly higher concentrations of antibodies against SARS-CoV-2 and differed from outpatient cases (n = 65) by higher age, higher disease severity scores and earlier follow up blood sampling. Sensitivity of the two IgG assays was comparable in hospitalized patients tested ≥ 14 days (EI-assay: 88%, CI95% 67.6–99.9; VT-assay: 96%, CI95% 77.7–99.8). In outpatient COVID-19 cases sensitivity was significantly lower in the VT-assay (86.2%, CI95% 74.8–93.1) compared with the EI-assay (98.5%, CI95% 90.6–99.9). Assays for IgA and IgM demonstrated a lack of specificity or sensitivity. Conclusions Our results indicate that SARS-CoV-2 serological assays may need to be optimized to produce reliable results in outpatient COVID-19 cases who are low or even asymptomatic. Assays for IgA and IgM have limited diagnostic performance and do not prove an additional value for population-based screening approaches.

SARS-CoV-2 infection results in a mild-to-moderate disease course in most patients, allowing outpatient self-care and quarantine. However, in approx. 10% of cases a two- or three-phasic critical disease course with starting from day 7 to 10 is observed. To facilitate and plan outpatient care, biomarkers prognosing such worsening at an early stage appear of outmost importance. In this accelerated article, we report on the identification of urinary peptides significantly associated with SARS-CoV-2 infection, and the development of a multi-marker urinary peptide based test, COVID20, that may enable prognosis of critical and fatal outcomes in COVID-19 patients. COVID20 is composed of 20 endogenous peptides mainly derived from various collagen chains that enable differentiating moderate or severe disease from critical state or death with 83% sensitivity at 100% specificity. Based on the performance in this pilot study, testing in a prospective study on 1000 patients has been initiated. This article is protected by copyright. All rights reserved.

We analyzed Clostridioides difficile infection (CDI) rates and various antimicrobials’ application densities from 2013 to 2019 at Leipzig University Hospital, Germany, by using multivariate linear regression. Ceftriaxone application was the only independent predictor of CDI incidence. Thus, antibiotics’ specific pharmacokinetic and pharmacodynamic properties such as biliary excretion of ceftriaxone in its active form should be considered when determining their potential to cause CDI.

We investigated potential transmissions of a symptomatic SARS-CoV-2–positive physician in a tertiary-care hospital who worked for 15 cumulative hours without wearing a face mask. No in-hospital transmissions occurred, despite 254 contacts among patients and healthcare workers. In conclusion, exposed hospital staff continued work, accompanied by close clinical and virologic monitoring.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.

IntroductionStaphylococci are the most commonly identified pathogens in bloodstream infections. Identification of Staphylococcus aureus in blood culture (SAB) requires a prompt and adequate clinical management. The detection of coagulase-negative staphylococci (CoNS), however, corresponds to contamination in about 75% of the cases. Nevertheless, antibiotic therapy is often initiated, which contributes to the risk of drug-related side effects. We developed a computerised clinical decision support system (HELP-CDSS) that assists physicians with an appropriate management of patients with Staphylococcus bacteraemia. The CDSS is evaluated using data of the Data Integration Centers (DIC) established at each clinic. DICs transform heterogeneous primary clinical data into an interoperable format, and the HELP-CDSS displays information according to current best evidence in bacteraemia treatment. The overall aim of the HELP-CDSS is a safe but more efficient allocation of infectious diseases specialists and an improved adherence to established guidelines in the treatment of SAB.Methods and analysisThe study is conducted at five German university hospitals and is designed as a stepped-wedge cluster randomised trial. Over the duration of 18 months, 135 wards will change from a control period to the intervention period in a randomised stepwise sequence. The coprimary outcomes are hospital mortality for all patients to establish safety, the 90-day disease reoccurrence-free survival for patients with SAB and the cumulative vancomycin use for patients with CoNS bacteraemia. We will use a closed, hierarchical testing procedure and generalised linear mixed modelling to test for non-inferiority of the CDSS regarding hospital mortality and 90-day disease reoccurrence-free survival and for superiority of the HELP-CDSS regarding cumulative vancomycin use.Ethics and disseminationThe study is approved by the ethics committee of Jena University Hospital and will start at each centre after local approval. Results will be published in a peer-reviewed journal and presented at scientific conferences.Trial registration numberDRKS00014320.

Background Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy. Case presentation A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered. Conclusions Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.

TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p

Die rasche Zunahme multiresistenter Gram-negativer Erreger (MRGN) ist ein drangendes und weitgehend ungelostes globales Problem. Die Behandlungsoptionen bei diesen Erregern sind sehr stark eingeschrankt. Nur wenige neue Substanzen sind zugelassen worden oder befinden sich aktuell in klinischen Phase-II/III-Studien. Ubersichtliche Vorstellung der bislang vorliegenden Daten zu den neuen β‑Laktam-Antibiotika und β‑Laktamase-Inhibitor-Kombinationen. Die neuen Makrolide, Ketolide und Aminoglykoside werden nicht adressiert. Selektive Literaturrecherche zu den Substanzen Ceftazidim/Avibactam, Ceftolozan/Tazobactam, Imipenem/Cilastatin + Relebactam, Meropenem/Vaborbactam, Aztreonam/Avibactam und Cefiderocol unter Einbeziehung aktuell registrierter Studien mit klinischer Auswertung und Datenanalyse. Die Entwicklung neuer Substanzen zur Therapie von Infektionen durch MRGN eroffnet neue Optionen bei Infektionen durch besonders schwierig zu behandelnde Erreger, insbesondere Erreger, die Carbapenemasen vom Klebsiella-pneumoniae-Carbapenemase (KPC) und OXA-48-Typ bilden. β‑Laktamase-Bildner werden durch die neuen Substanzen oder Kombinationen unterschiedlich stark gehemmt; allerdings fehlen noch immer ausreichende Therapieoptionen fur Metallo-β-Laktamase-Bildner sowie Infektionen durch multiresistente Pseudomonas-aeruginosa- und Acinetobacter-spp.-Stamme. Vielfach sind die klinischen Daten noch indifferent und stammen aus uneinheitlich definierten Patientenkollektiven. Direkte Vergleiche mit etablierten Behandlungsstrategien wie dem „Last-resort-Einsatz“ von Polymyxinen sind kaum moglich. Leider sind auch bereits Falle einer raschen Resistenzentwicklung beschrieben. Der Stellenwert der Toxizitat und optimalen Dosierung – auch bei Organversagen oder Organersatzverfahren wie Dialyse – ist vielfach noch unklar.

The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.

Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression in vitro. Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% (P=0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling (P=0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 versus 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1–0.9); P=0.03]. In vitro decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia.

Was ist neu? Epidemiologie Clostridium-difficile-Infektionen (CDI) gehen auch in Deutschland mit unverändert hoher Krankheitslast und einem Anstieg der Zahl schwerer bzw. letaler Verläufe einher. Der Anteil ambulant erworbener CDI steigt weltweit weiter an und umfasst selten auch Patienten mit einer Reisediarrhö. Es gibt eine gute Evidenz dafür, dass nosokomiale Fälle durch Implementierung von Antibiotic-Stewardship- (ABS-) Programmen stark verringert werden können. Diagnostik Nur Patienten mit unklarer, neu aufgetretener Diarrhö sollten getestet werden. Die mikrobiologische Untersuchung auf toxigene C.-difficile-Stämme sollte mehrstufig erfolgen, d. h. mittels Glutamatdehydrogenase- (GDH-) Test plus Toxinnachweis oder Nukleinsäureamplifikationstests (NAAT), oder NAAT plus Toxinnachweis. Von einem alleinigen Toxinnachweis mittels Enzymimmunoassay (EIA) oder einem alleinigen Einsatz von NAAT wird abgeraten. Neue Therapieleitlinien Nach den 2017/18 aktualisierten US-amerikanischen Leitlinien gilt oral verabreichtes Vancomycin inzwischen als Mittel der ersten Wahl. Fidaxomicin ist ähnlich wirksam wie Vancomycin, sein Vorteil besteht jedoch in der geringeren Rate an Rezidiven. Weitere Behandlungsoptionen und Impfung Es konnte gezeigt werden, dass die zusätzliche Gabe des monoklonalen Antikörpers Bezlotoxumab die Rezidivrate signifikant senkt. Neue Antibiotika, die die Darmmikrobiota besser schützen, werden derzeit in klinischen Studien getestet. Für die Therapie multipel rezidivierender CDI bestehen gesicherte Behandlungserfolge von ≥ 90 % durch den fäkalen Mikrobiomtransfer (FMT). Da der FMT in Deutschland zurzeit lediglich den Status eines individuellen Heilversuchs hat, ist eine evidenzbasierte generelle Empfehlung für die klinische Praxis nicht möglich. Wahrscheinlich wird sich die Applikation kryokonservierter FMT-Kapseln längerfristig durchsetzen. Es ist zu erwarten, dass Toxoid-Impfstoffe CDI wirksam verhindern können; allerdings wurde bislang noch keine Zulassungsstudie abgeschlossen.