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MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
Get PDFDisruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution.Peer Reviewe
Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication
Get PDFHepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.Peer Reviewe
Protein G affinity chromatography is an underrated but very potent purification method for a broad range of species-independent and tag-less Fab-fragments
Get PDFBecause of their superior properties for certain biological applications small antibody derivatives like fragment of antigen binding (Fab) have found widespread use in basic research and as therapeutics. However, generation of Fab-fragments is still a rather complex matter, reflected by the fact that a variety of methods and purification techniques are necessary for the production of all the different classes of Fab-fragments (kappa/lambda light chains, type of species). Here we demonstrate that Fab-fragments derived from six different antibodies of human or murine origin produced by transient expression in HEK cells can be purified in a single step to a high degree of purity by standard protein G affinity chromatography. This is most likely due to alternative contact sites for protein G located in the CH1 domain of the Fab heavy chain. Our data demonstrate that protein G affinity chromatography as for whole antibodies is a robust method for the purification of tag-less Fab-fragments independent of species, significantly simplifying the process of Fab-fragment purification.Peer Reviewe
Effectiveness and efficiency of immunisation strategies to prevent RSV among infants and older adults in Germany: a modelling study
No full textBackground:
Recently, several novel RSV immunisation products that protect infants and older adults against RSV disease have been licensed in Europe. We estimated the effectiveness and efficiency of introducing these RSV immunisation strategies in Germany.
Methods:
We used a Bayesian framework to fit a deterministic age-structured dynamic transmission model of RSV to sentinel surveillance and RSV-specific hospitalisation data in Germany from 2015 to 2019. The calibrated model was used to evaluate different RSV intervention strategies over 5 years: long-acting, single-dose monoclonal antibodies (mAbs) in high-risk infants aged 1–5 months; long-acting mAbs in all infants aged 1–5 months; seasonal vaccination of pregnant women and one-time seasonal vaccination of older adults (75 + /65 + /55 + years). We performed sensitivity analysis on vaccine uptake, seasonal vs. year-round maternal vaccination, and the effect of under-ascertainment for older adults.
Results:
The model was able to match the various RSV datasets. Replacing the current short-acting mAB for high-risk infants with long-acting mAbs prevented 1.1% of RSV-specific hospitalisations in infants per year at the same uptake. Expanding the long-acting mAB programme to all infants prevented 39.3% of infant hospitalisations per year. Maternal vaccination required a larger number to be immunised to prevent one additional hospitalisation than a long-acting mAB for the same uptake. Vaccination of adults older than 75 years at an uptake of 40% in addition to Nirsevimab in all infants prevented an additional 4.5% of all RSV hospitalisations over 5 years, with substantial uncertainty in the correction for under-ascertainment of the RSV burden.
Conclusions:
Immunisation has the potential to reduce the RSV disease burden in Germany.Peer Reviewe
A seroprevalence study indicates a high proportion of clinically undiagnosed MPXV infections in men who have sex with men in Berlin, Germany
No full textIntroduction:
During the mpox outbreak in 2022, the highest number of cases in Germany were registered in Berlin, almost all of them in men who have sex with men (MSM). However, the frequency of clinically undiagnosed infections is unknown.
Methods:
A cross-sectional study was conducted among MSM in Berlin, Germany. Participants were recruited from private practices and community-based checkpoints specialised in HIV and STI care for MSM. They were asked to complete an online questionnaire on socio-demographic data, mpox diagnosis, vaccination history and sexual behaviour, and to provide a blood sample for serological analysis. The samples were tested for antibodies against a range of antigens to distinguish between antibodies induced by mpox infection and MVA vaccination, with pre-immune sera from childhood smallpox vaccination as a confounding factor. Associations of behavioural variables with reported and suspected mpox diagnosis as the outcome were tested using univariable and multivariable logistic regression models.
Results:
Between the 11th April and 1st July 2023, 1,119 participants were recruited in eight private practices and two community-based checkpoints in Berlin. All participants provided a blood sample for serological testing. Information for the online questionnaire was provided by 728 participants; core data on age and mpox history for participants who did not provide questionnaire data were provided by the practices for an additional 218 participants. A previous diagnosis of mpox was reported for/by 70 participants (7.4%). Using a conservative and strict case definition, we serologically identified an additional 91 individuals with suspected undiagnosed mpox infection. Individuals with reported or suspected mpox infections reported more condomless anal sex partners in the past 3 months (OR = 5.93; 95% CI 2.10-18.35 for 5–10 partners; OR = 9.53; 95% CI 2.72–37.54 for > 10 partners) and were more likely to report sexual contact with partners diagnosed with mpox (OR = 2.87; 95% CI 1.39–5.84).
Conclusion:
A substantial proportion of mpox infections were clinically undiagnosed. The number of condomless anal sex partners was strongly associated with both confirmed and suspected undiagnosed mpox infection. Therefore, mpox control measures based on clinical diagnosis of mpox are likely to have limited effectiveness in preventing mpox transmission in outbreak situations because many infections remain unrecognised and undiagnosed.Peer Reviewe
Guidance on how to efficiently find, choose, and use available systematic reviews was developed
No full textObjectives:
The aim of this paper is to provide clinicians and authors of clinical guidelines or patient information with practical guidance on searching and choosing systematic reviews(s) (SR[s]) and, where adequate, on making use of SR(s).
Study Design and Setting:
At the German conference of the Evidence-Based Medicine Network (EbM Network) a workshop on the topic was held to identify the most important areas where guidance for practice appears necessary. After the workshop, we established working groups. These included SR users with different backgrounds (eg, information specialists, epidemiologists) and working areas. Each working group developed and consented a draft guidance based on their expert knowledge and experiences. The results were presented to the entire group and finalized in an iterative process.
Results:
We developed a practical guidance that answers questions that usually arise when choosing and using SR(s). (1) How to efficiently find high-quality SRs? (2) How to choose the most appropriate SR? (3) What to do if no SR of sufficient quality could be identified? In addition, we developed an algorithm that links these steps and accounts for their interaction. The resulting guidance is primarily directed at clinicians and developers of clinical practice guidelines or patient information resources.
Conclusion:
We suggest practical guidance for making the best use of SRs when answering a specific research question. The guidance may contribute to the efficient use of existing SRs. Potential benefits when using existing SRs should be always weighted against potential limitations.Peer Reviewe
ARE-Wochenbericht KW 01
No full textDie ARE-Aktivität in den letzten Wochen ergibt sich aus der hohen Zahl an COVID-19, Influenza und RSV-Erkrankungen. Die Influenza-Aktivität nahm seit der 49. KW deutlich zu, die Grippewelle 2023/24 hat laut RKI-Definition mit der 50. KW 2023 begonnen und hält an. Von Influenzaerkrankungen sind bisher vornehmlich Kinder im Schulalter und junge Erwachsene betroffen. Influenza A(H1N1)pdm09-Viren werden am häufigsten detektiert. Die RSV-Aktivität ist weiterhin hoch, bei der COVID-19-Aktivität mehren sich Hinweise für einen Rückgang. Insbesondere Kinder unter zwei Jahren sind von einer Krankenhaus-einweisung mit RSV-Infektion betroffen, bei älteren Menschen führt weiterhin COVID-19 am häufigsten zu schwer verlaufenden Erkrankungen. Die weitere Entwicklung der Grippewelle in Deutschland kann in den kommenden Wochen besser beurteilt werden, da in der 1. KW 2024 die meisten Bundesländer noch Schulferien hatten.
Die Aktivität akuter respiratorischer Erkrankungen (ARE) in der Bevölkerung ist von der 52. KW 2023 zur 1. KW 2024 insgesamt gesunken, jedoch bei den Kindern relativ stabil geblieben. Im ambulanten Bereich ist die Zahl der Arztbesuche wegen ARE von der 52. KW 2023 zur 1. KW 2024 wie auch in den Vorjahren üblich wieder gestiegen.
Im NRZ für Influenzaviren wurden in der 1. KW 2024 in insgesamt 78 der 140 eingesandten Sentinelproben respiratorische Viren identifiziert, darunter hauptsächlich Influenzaviren (21 %), RSV (20 %) und SARS-CoV-2 (9 %).
Im Rahmen der ICD-10-Code basierten Krankenhaussurveillance (ICOSARI) ist die Zahl schwerer akuter respiratorischer Infektionen (SARI) in der 1. KW 2024 im Vergleich zur Vorwoche insgesamt und in fast allen Altersgruppen zurückgegangen. In der Altersgruppe der Schulkinder blieb die Zahl der SARI-Fälle stabil auf hohem Niveau. Unter allen in der 1. KW 2024 wegen einer schweren Atemwegserkrankung hospitalisierten Patientinnen und Patienten lag der Anteil der RSV-Diagnosen bei 17 %. Bei Kindern unter zwei Jahren war der Anteil der RSV-Diagnosen mit 75 % weiterhin hoch. Der Anteil der COVID-19-Diagnosen geht seit der 51. KW 2023 zurück und lag in der 1. KW 2024 bei 14 %. Influenzadiagnosen wurden in der 1. KW bei 11 % aller SARI-Fälle vergeben und damit ähnlich häufig wie in den Wochen vor dem Jahreswechsel.
Bei den Daten aus dem Meldewesen gemäß IfSG setzte sich der steigende Trend bei Influenza in der 1. KW 2024 fort. In der Abwassersurveillance ist nach einem stetigen Anstieg seit Ende Juni 2023 (26. KW) seit Mitte Dezember 2023 (50. KW) ein Rückgang der SARS-CoV-2-Viruslast zu beobachten
Epidemiologische Situation der RSV-Infektionen auf Basis der Meldedaten für die erste Saison 2023/24 nach Einführung der RSV-Meldepflicht in Deutschland
Get PDFDas Respiratorische Synzytial-Virus (RSV) ist ein weltweit verbreiteter Erreger akuter respiratorischer Erkrankungen in jedem Lebensalter und einer der bedeutendsten Erreger akuter Infektionen der unteren Atemwege, insbesondere bei Säuglingen und Kleinkindern. Nach aktuellen Schätzungen erkranken weltweit jährlich 33,1 Millionen Kleinkinder unter 5 Jahren an einer RSV-Infektion, was zu etwa 3,2 Millionen Krankenhauseinweisungen und 200.000 Todesfällen führt. Die Einführung der bundesweiten RSV-Meldepflicht ermöglicht die Erfassung von laborbestätigten RSV-Infektionen in Deutschland. Auf der Grundlage der erfassten Meldedaten wird die epidemiologische Situation der RSV-Infektionen in der ersten Saison nach Einführung der RSV-Meldepflicht beschrieben und durch den Vergleich mit bestehenden Sentinelsurveillancesystemen besser eingeordnet.Peer Reviewe
Speicheldrüsenkarzinome - Inzidenz und Überleben in Deutschland
No full textSpeicheldrüsenkarzinome sind eine seltene und sehr heterogene Gruppe verschiedener Tumore, zu der es in der internationalen Literatur nur wenig aktuelle epidemiologische Daten gibt. Hierfür möchten wir angelehnt an unsere Anträge 5.03.04/0003#0030 und 5.03.04/0003#0031 aggregierte Daten zu den verschiedenen Entitäten der Speicheldrüsenkarzinome zusammen mit den Kollegen des Landeskrebsregisters NRW untersuchen.
Wir möchten die Daten zur Inzidenz, TNM Stadien, Lokalisation, Überleben und Rezidiven von den verschiedenen Entitäten der Speicheldrüsenkarzinomen untersuchen (analog zu unserer Untersuchung zu Nasennebenhöhlenkarzinomen 5.03.04/0003#0030 und Plattenepithelkarzinomen 5.03.04/0003#0031 der Speicheldrüsen). Hierdurch möchten wir aktuelle und umfangreiche epidemiologische Daten zu dieser seltenen Entität gewinnen und wissenschaftlich veröffentlichen. Die Auswertung und Verarbeitung der Daten wir hierbei durch die Kollegen des Landeskrebsregisters NRW erfolgen