Immunogenity of the pneumococcal polysaccharide vaccine in COPD patients. The effect of systemic steroids

AbstractRationale: To investigate if systemic steroids influence the antibody response to the 23-valent pneumococcal polysaccaride vaccine (23-PPV) in COPD patients.Patients and methods: COPD patients on: (a)⩾10mg of prednisolone/day (SS, n=30); (b) inhalative steroids (IS, n=30); (c) controls without COPD (CG, n=29) were vaccinated with 23-PPV. The concentration (μg/ml) of capsular specific anti-pneumococcal IgG antibodies (AB) for the serotypes (PNC) 4,6B,9V,14,18C,19F,23F were measured by Elisa technique before, 3 and 12 months (m) after vaccination. Non-responders were defined when AB-concentrations did neither doubled nor reach ⩾1μg/ml.Results: N=24 (CG), n=29 (IS), n=18 (SS) patients completed the study (mean age 64yrs.). Serious adverse events were not observed. Geometric mean (GM) AB-concentration of all serotypes increased significantly (CG, IS, SS) 3 and 12m after vaccination (P<0.05). The percentage of non-responders ranged between 16% (PNC 19F, IS) and 65% (PNC 4, SS) after 3m and 21% (PNC 19F, IS) and 82% (PNC 4, CG) after 12m. Neither post-vaccine AB-concentrations (3 and 12m) nor the rate of non-responders differed significantly between patients on systemic steroids and the other groups (IS, CG).Conclusions: Systemic steroids did not influence the AB-response. In all groups mean AB-concentration increased significantly after vaccination but an important percentage of subjects of all three groups were non-responders

Numerical Analysis of Sub-critical Crack Growth in Particulate Ceramic Composites

AbstractThe strength of glass or ceramic containing materials can be affected by the environment (“stress corrosion”). Under applied stress, crack-like defects may grow (sub-critically) for stress intensity factors, KI, below the fracture toughness of the material, KIc. The aim of the present work was to develop a two-dimensional finite element model to analyze the subcritical crack growth behavior of ceramic-based particulate composites. The maximum tangential stress criterion (MTS) was used to predict the direction of the crack propagation, in the framework of linear elastic fracture mechanics. The modeled material was a Low Temperature Co-fired Ceramic (LTCC), containing alumina particles embedded in a glass matrix. The experimentally determined SCCG material behavior (i.e. v-KI data) was implemented in the numerical model. The effect of the elastic modulus of the particles on the subcritical crack propagation was investigated. The conclusions of this paper can contribute to a better understanding of the subcritical propagation of cracks in particulate composites

Molecular epidemiology of SARS-CoV-2: a regional to global perspective

Background After a year of the global SARS-CoV-2 pandemic, a highly dynamic genetic diversity is surfacing. Among nearly 1000 reported virus lineages, dominant lineages such as B.1.1.7 or B.1.351 attract media attention with questions regarding vaccine efficiency and transmission potential. In response to the pandemic, the Jena University Hospital began sequencing SARS-CoV-2 samples in Thuringia in early 2020.Methods Viral RNA was sequenced in tiled amplicons using Nanopore sequencing. Subsequently, bioinformatic workflows were used to process the generated data. As a genomic background, 9,642 representative SARS-CoV-2 genomes (1,917 of German origin) were extracted from more than 300.000 genomes.Results In a comprehensive bioinformatics analysis, we have set Thuringian isolates in the German, European and global context. In Thuringia, a largely rural German region without an international airport and a population density below the German average, we discovered many of the common “EU lineages”. German samples are scattered across eight major clades, and Thuringian samples occupy four of them.Conclusion The rapid emergence and spread of novel variants are of great concern as these lineages could transmit more efficiently, evade current vaccine efforts or undermine diagnostic test accuracy. To anticipate and mitigate these threats, a continuous molecular surveillance is essential.Key messagesBioinformatics analysis of 1,917, 4,251, and 3,474 SARS-CoV-2 genomes from Germany, the EU (except Germany), and non-EU, respectively, subsampled from more than 300,000 public genomes and placed in the context of Thuringian sequencesConstant antigenic drift for SARS-CoV-2 and no clear pattern or clustering is visible in Thuringia based on the current number of samplesCurrently over 100 described lineages are identified in Germany and only a subset (9) are detected in Thuringia so far, most likely due to genetic undersamplingFrom a national perspective, it is likely that high-frequency lineages, which are currently spreading throughout Europe, will eventually also reach ThuringiaSystematic and dense molecular surveillance via whole-genome sequencing is needed to detect concerning new lineages early, limit spread and adjust vaccines if necessaryCompeting Interest StatementThe authors have declared no competing interest.Funding StatementThe work is funded by the German Ministry of Education and Research (BMBF), grant number 01KX2021, and the Thuringian Region Government, grant number TZUZI82094.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:not applicableAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is available on GISAID.Introduction Methods - Nanopore sequencing and genome reconstruction - Time tree creation Results - Most highly prevalent SARS-CoV-2 lineages in Germany detected in Thuringia - Genetic divergence and current lineage distribution Discussio

Staphylococcus aureus induces tolerance in human monocytes accompanied with expression changes of cell surface markers

Exposure of human monocytes to lipopolysaccharide (LPS) or other pathogen-associated molecular pattern (PAMPs) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance (ET), associated with the pathogenesis of sepsis. In this study, we aimed to characterize the cellular state of human monocytes from healthy donors stimulated with Staphylococcus aureus in comparison to TLR2-specific ligands. We analyzed S. aureus induced gene expression changes after 2 and 24 hours by amplicon sequencing (RNA-AmpliSeq) and compared the pro-inflammatory response after 2 hours with the response in re-stimulation experiments. In parallel, glycoprotein expression changes in human monocytes after 24 hours of S. aureus stimulation were analyzed by proteomics and compared to stimulation experiments with TLR2 ligands Malp-2 and Pam3Cys and TLR4 ligand LPS. Finally, we analyzed peripheral blood monocytes of patients with S. aureus bloodstream infection for their ex vivo inflammatory responses towards S. aureus stimulation and their glycoprotein expression profiles. Our results demonstrate that monocytes from healthy donors stimulated with S. aureus and TLR ligands of Gram-positive bacteria entered the tolerant cell state after activation similar to LPS treatment. In particular reduced gene expression of pro-inflammatory cytokines (TNF, IL1β) and chemokines (CCL20, CCL3, CCL4, CXCL2, CXCL3 and CXCL8) could be demonstrated. Glycoprotein expression changes in monocytes tolerized by the different TLR agonists were highly similar while S. aureus -stimulated monocytes shared some of the PAMP-induced changes but also exhibited a distinct expression profile. 11 glycoproteins (CD44, CD274, DSC2, ICAM1, LAMP3, LILRB1, PTGS2, SLC1A3, CR1, FGL2, and HP) were similarly up- or downregulated in all four comparisons in the tolerant cell state. Monocytes from patients with S. aureus bacteremia revealed preserved pro-inflammatory responsiveness to S. aureus stimulation ex vivo, expressed increased CD44 mRNA but no other glycoprotein of the tolerance signature was differentially expressed

Towards a qAOP Framework for Predictive Toxicology - Linking Data to Decisions

The adverse outcome pathway (AOP) is a conceptual construct that facilitates organisation and interpretation of mechanistic data representing multiple biological levels and deriving from a range of methodological approaches including in silico, in vitro and in vivo assays. AOPs are playing an increasingly important role in the chemical safety assessment paradigm and quantification of AOPs is an important step towards a more reliable prediction of chemically induced adverse effects. Modelling methodologies require the identification, extraction and use of reliable data and information to support the inclusion of quantitative considerations in AOP development. An extensive and growing range of digital resources are available to support the modelling of quantitative AOPs, providing a wide range of information, but also requiring guidance for their practical application. A framework for qAOP development is proposed based on feedback from a group of experts and three qAOP case studies. The proposed framework provides a harmonised approach for both regulators and scientists working in this area

Serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study

Objective To examine whether acute dysglycaemia predicts death in people admitted to hospital with community acquired pneumonia

International Perspective on the New 2019 American Thoracic Society/Infectious Diseases Society of America Community-Acquired Pneumonia Guideline:A Critical Appraisal by a Global Expert Panel

In 2019, the American Thoracic Society (ATS) / Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite generalization of infectious disease guidelines is limited due substantial geographic differences in microbiological etiology and antimicrobial resistance, the ATS/IDSA guidelines are frequently applied outside the USA. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside of the USA. For this, an expert panel comprised of 14 international key opinion leaders in the field of CAP from 10 countries across 5 continents, who were not involved in the 2019 guideline, was asked to subjectively name the five most useful, the most critical and the recommendation that can not be applied to their respective region. There was no formal consensus process and the paper reflects different opinions. Recommendations welcomed by the vast majority of the international pneumonia experts included the abandonment of the concept of "health-care associated pneumonia" (HCAP), the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiological diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative

Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group

INTRODUCTION: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The “network of excellence on Community Acquired Pneumonia” (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research. METHODS: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat. RESULTS: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications. CONCLUSION: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients’ risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP