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Summary: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Myeloid cell accumulation and lymphocyte decline are widely recognized phenomena in septic patients. However, the fate of specific immune cells remains unclear. Here, we report the results of a human explorative study of patients with septic peritonitis and patients undergoing abdominal surgery without sepsis. We analyzed pairwise peritoneal fluid and peripheral blood taken 24 h after surgery to characterize immediate immune cell changes. Our results show that myeloid cell expansion and lymphocyte loss occur in all patients undergoing open abdominal surgery, indicating that these changes are not specific to sepsis. However, B1-like lymphocytes were specifically increased in the peritoneal fluid of septic patients, correlating positively with sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE-II) clinical severity scores. In support of this notion, we identified an accumulation of peritoneal B1b lymphocytes in septic mice.

Introduction Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysis Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and dissemination The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492.

Introduction Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host–pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose–response trial is necessary to assess the potential harm of this drug in this new indication.Methods and analysis Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive.Ethics and dissemination The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT05033808.

Abstract Strategies to contain the current SARS-CoV-2 pandemic rely, beside vaccinations, also on molecular and serological testing. For any kind of assay development, screening for the optimal antigen is essential. Here we describe the verification of a new protein microarray with different commercially available preparations significant antigens of SARS-CoV-2 that can be used for the evaluation of the performance of these antigens in serological assays and for antibody screening in serum samples. Antigens of other pathogens that are addressed by widely used vaccinations were also included. To evaluate the accuracy of 21 different antigens or antigen preparations on the microarray, receiver operating characteristics (ROC) curve analysis using ELISA results as reference were performed. Except for a single concentration, a diagnostic sensitivity of 1 was determined for all antigen preparations. A diagnostic specificity, as well as an area under the curve (AUC) of 1 was obtained for 16 of 21 antigen preparations. For the remaining five, the diagnostic specificity ranged from 0.942 to 0.981 and AUC from 0.974 to 0.999. The optimized assay was subsequently also applied to determine the immune status of previously tested individuals and/or to detect the immunization status after COVID-19 vaccination. Microarray evaluation of the antibody profiles of COVID-19 convalescent and post vaccination sera showed that the IgG response differed between these groups, and that the choice of the test antigen is crucial for the assay performance. Furthermore, the results showed that the immune response is highly individualized, depended on several factors (e.g., age or sex), and was not directly related to the severity of disease. The new protein microarray provides an ideal method for the parallel screening of many different antigens of vaccine-preventable diseases in a single sample and for reliable and meaningful diagnostic tests, as well as for the development of safe and specific vaccines.

BackgroundQuarantine is one of the most effective interventions to contain an infectious disease outbreak, yet it is one of the most disruptive. We investigated the quarantine of an entire village to better understand risk communication requirements for groups.MethodsWe conducted a cross-sectional, mixed-methods survey study on a single cohort of adult residents in Neustadt am Rennsteig, Germany, six weeks after the removal of a 14-day mandatory community quarantine. The survey response rate was 33% (289/883 residents).FindingsSurvey participants reported a lack of information on the quarantine implementation process. What authorities communicated was not necessarily what residents desired to know. While inhabitants used social media and telephones to communicate with each other, the official information sources were regional radio, television, newspapers and official websites. Public health authorities did not employ social media communication to engage with their communities. Despite a lack of information, the majority of respondents stated that they had complied with the quarantine and they expressed little sympathy for those who violated the quarantine. After lifting the quarantine, many respondents continued to avoid places where they suspected a significant risk of infection, such as family and friends' homes, doctor's offices and grocery stores.InterpretationThe survey participants utilised existing social networks to disseminate vital information and stabilise its group identity and behaviour (quarantine compliance). The authorities communicated sparsely in a unidirectional, top-down manner, without engaging the community. Despite the lack of official information, the social coherency of the group contributed to considerate and compliant conduct, but participants expressed dissatisfaction with official leadership and asked for more attention.ConclusionPublic health risk communication must engage with communities more effectively. This necessitates a deeper comprehension of groups, their modes of communication and their social needs.

Understanding persistent cellular and humoral immune responses to SARS-CoV-2 will be of major importance to terminate the ongoing pandemic. Here, we assessed long-term immunity in individuals with mild COVID-19 up to 1 year after a localized SARS-CoV-2 outbreak. CoNAN was a longitudinal population-based cohort study performed 1.5 months, 6 months, and 12 months after a SARS-CoV-2 outbreak in a rural German community. We performed a time series of five different IgG immunoassays assessing SARS-CoV-2 antibody responses on serum samples from individuals that had been tested positive after a SARS-CoV-2 outbreak and in control individuals who had a negative PCR result. These analyses were complemented with the determination of spike-antigen specific TH cell responses in the same individuals. All infected participants were presented as asymptomatic or mild cases. Participants initially tested positive for SARS-CoV-2 infection either with PCR, antibody testing, or both had a rapid initial decline in the serum antibody levels in all serological tests but showed a persisting TH cell immunity as assessed by the detection of SARS-CoV-2 specificity of TH cells for up to 1 year after infection. Our data support the notion of a persistent T-cell immunity in mild and asymptomatic cases of SARS-CoV-2 up to 1 year after infection. We show that antibody titers decline over 1 year, but considering several test results, complete seroreversion is rare.Trial registrationGerman Clinical Trials Register DRKS00022416.

Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse (Mus musculus) macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.

Abstract Background Monitoring pathogens of bloodstream infections (BSI) and their antibiotic susceptibility is important to guide empiric antibiotic treatment strategies and prevention programs. This study assessed the epidemiology of BSI and antibiotic resistance patterns at the German Federal State of Thuringia longitudinally. Methods A surveillance network consisting of 26 hospitals was established to monitor BSIs from 01/2015 to 12/2019. All blood culture results, without restriction of age of patients, of the participating hospitals were reported by the respective microbiological laboratory. A single detection of obligate pathogens and a repeated detection of coagulase-negative staphylococci, Bacillus spp., Corynebacterium spp., Micrococcus spp. and Propionibacterium spp., within 96 h were regarded as a relevant positive blood culture. If one of the aforementioned non-obligate pathogens has been detected only once within 96 h, contamination has been assumed. Logistic regression models were applied to analyse the relationship between resistance, year of BSI and hospital size. Generalized estimating equations were used to address potential clustering. Results A total of 343,284 blood cultures (BC) of 82,527 patients were recorded. Overall, 2.8% (n = 9571) of all BCs were classified as contaminated. At least one relevant pathogen was identified in 13.2% (n = 45,346) of BCs. Escherichia coli (25.4%) was the most commonly detected pathogen, followed by Staphylococcus aureus (15.2%), Staphylococcus epidermidis (8.1%) and Klebsiella pneumoniae (4.6%). In S. aureus, we observed a decline of methicillin resistance (MRSA) from 10.4% in 2015 to 2.5% in 2019 (p

Pathogens, their toxic byproducts, and the subsequent immune reaction exert different forms of stress and damage to the tissue of the infected host. This stress can trigger specific transcriptional and post-transcriptional programs that have evolved to limit the pathogenesis of infectious diseases by conferring tissue damage control. If these programs fail, infectious diseases can take a severe course including organ dysfunction and damage, a phenomenon that is known as sepsis and which is associated with high mortality. One of the key adaptive mechanisms to counter infection-associated stress is the unfolded protein response (UPR), aiming to reduce endoplasmic reticulum stress and restore protein homeostasis. This is mediated via a set of diverse and complementary mechanisms, i.e. the reduction of protein translation, increase of protein folding capacity, and increase of polyubiquitination of misfolded proteins and subsequent proteasomal degradation. However, UPR is not exclusively beneficial since its enhanced or prolonged activation might lead to detrimental effects such as cell death. Thus, fine-tuning and time-restricted regulation of the UPR should diminish disease severity of infectious disease and improve the outcome of sepsis while not bearing long-term consequences. In this review, we describe the current knowledge of the UPR, its role in infectious diseases, regulation mechanisms, and further clinical implications in sepsis.

Plasmodium falciparum (P. falciparum) and hepatitis B virus (HBV) co-infection is on the rise among pregnant women in northern Ghana. Mono-infection with either of these two pathogens results in unique metabolic alterations. Thus, we aimed to explicate the effects of this co-infection on the metabolome signatures of pregnant women, which would indicate the impacted metabolic pathways and provide useful prognostic or diagnostic markers. Using an MS/MS-based targeted metabolomic approach, we determined the serum metabolome in pregnant women with P. falciparum mono-infection, HBV mono-infection, P. falciparum, and HBV co-infection and in uninfected (control) women. We observed significantly decreased sphingolipid concentrations in subjects with P. falciparum mono-infection, whereas amino acids and phospholipids were decreased in subjects with HBV mono-infection. Co-infections were found to be characterized distinctively by reduced concentrations of phospholipids and hexoses (mostly glucose) as well as altered pathways that contribute to redox homeostasis. Overall, PC ae C40:1 was found to be a good discriminatory metabolite for the co-infection group. PC ae C40:1 can further be explored for use in the diagnosis and treatment of malaria and chronic hepatitis B co-morbidity as well as to distinguish co-infections from cases of mono-infections.

Abstract Background Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients. The aim of this study was to assess current evidence to determine whether antiviral therapy is associated with better outcomes in these patients. Methods MEDLINE, ISI Web of Science, Cochrane Database and ClinicalTrials.gov were searched from inception to 25 May 2020. All clinical studies investigating the effects of antiviral therapy on the outcome of mechanically ventilated ICU patients in whom HSV was detected in the respiratory tract were eligible for inclusion, regardless of study design, publication status or language. Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed and data extracted. We performed a random-effects meta-analysis to estimate relative risks (RRs) with corresponding 95% confidence intervals (CIs). The primary endpoint was hospital all-cause mortality. Results Nine studies were included in the meta-analysis (one randomized controlled trial, eight cohort studies). Antiviral treatment was associated with lower hospital mortality (with antiviral treatment, 40.6% (189 out of 465 patients); without, 52.7% (193 out of 366 patients); RR 0.74 [0.64, 0.85]; eight studies, low quality of evidence). Furthermore, antiviral treatment was associated with lower 30-day mortality (RR 0.75 [0.59, 0.94]; three studies, very low quality of evidence). We did not observe evidence for differences in ICU mortality (RR 0.73 [0.51, 1.05]; three studies, very low quality of evidence). Conclusions This meta-analysis of the available data shows that antiviral therapy might result in lower hospital and 30-day all-cause mortality in mechanically ventilated ICU patients who are positive for HSV in the respiratory tract. However, this result must be interpreted with great caution due to the high risk of bias and limited number of patients. Large, well-designed randomized controlled clinical trials are urgently needed. Trial registration The study was registered in advance on International Prospective Register of Systematic Reviews (CRD42020180053) .

The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more specific and more effective immune response upon the reencounter, reducing the severity of infectious diseases. Over the last 15 years, an increasing amount of evidence has accumulated showing that the innate immune system also has features of a memory. In contrast to the memory of adaptive immunity, innate immune memory is mediated by restructuration of the active chromatin landscape and imprinted by persisting adaptations of myelopoiesis. While originally described to occur in response to pathogen-associated molecular patterns, recent data indicate that host-derived damage-associated molecular patterns, i.e. alarmins, can also induce an innate immune memory. Potentially this is mediated by the same pattern recognition receptors and downstream signaling transduction pathways responsible for pathogen-associated innate immune training. Here, we summarize the available experimental data underlying innate immune memory in response to damage-associated molecular patterns. Further, we expound that trained immunity is a general component of innate immunity and outline several open questions for the rising field of pathogen-independent trained immunity.

The atomizing gas dynamics and the applied process energy have a significant influence on the produced particles. The melting process of the two wires can be influenced by current modulation. As for arc welding processes, more and more electronic and software-controlled machines are being used for arc spraying and will have replaced conventional power sources in the future. Due to the highly dynamic, fast regulating computing technology in the latest energy source, technology arcs can be operated with different current forms and types. The modern machines allow process-stable, reproducible variation of the particles and heat input into the substrate. Constant and pulsed current can be used as current forms. Usable current types are direct current (DC) and alternating current (AC). The electrical parameters must be analyzed to evaluate the process behavior. The consumable used is a wire-shaped iron-based alloy with a diameter of 1.6 mm. Relevant process parameters such as basic current Iground, pulse current Ipulse, pulse duration tpulse, impulse frequency fpulse, and alternating current frequency, fAC, are varied and recorded using appropriate measurement technology. The aim is to change the process performance and thereby the particle formation in a broad band. High-speed images are used to observe the arc and the deposition process. In addition, particle sizes are determined.

Objective: The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis. Methods: We developed a mouse strain, referred herein as FthR26 fl/fl, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5′end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult FthR26Δ/Δ mice, testing whether FTH is required for maintenance of organismal homeostasis. Results: Under standard nutritional Fe supply, Fth deletion in adult FthR26Δ/Δ mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue. Conclusion: The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation. Keywords: Iron metabolism, Redox homeostasis, Adipose tissue, Energy expenditure, Adipose tissue, Mitochondria

Background: Sepsis, the most severe form of infection, involves endothelial dysfunction which contributes to organ failure. To improve therapeutic prospects, elucidation of molecular mechanisms underlying endothelial vascular failure is of essence. Methods: Polymicrobial contamination induced sepsis mouse model and primary endothelial cells incubated with sepsis serum were used to study SHP-2 in sepsis-induced endothelial inflammation. SHP-2 activity was assessed by dephosphorylation of pNPP, ROS production was measured by DCF oxidation and protein interactions were assessed by proximity ligation assay. Vascular inflammation was studied in the mouse cremaster model and in an in vitro flow assay. Findings: We identified ROS-dependent inactivation of the tyrosine phosphatase SHP-2 to be decisive for endothelial activation in sepsis. Using in vivo and in vitro sepsis models, we observed a significant reduction of endothelial SHP-2 activity, accompanied by enhanced adhesion molecule expression. The impaired SHP-2 activity was restored by ROS inhibitors and an IL-1 receptor antagonist. SHP-2 activity inversely correlated with the adhesive phenotype of endothelial cells exposed to IL-1β as well as sepsis serum via p38 MAPK and NF-κB. In vivo, SHP-2 inhibition accelerated IL-1β-induced leukocyte adhesion, extravasation and vascular permeability. Mechanistically, SHP-2 directly interacts with the IL-1R1 adaptor protein MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3-K to MyD88. Interpretation: Our data show that SHP-2 inactivation by ROS in sepsis releases a protective break, resulting in endothelial activation. Fund: German Research Foundation, LMU Mentoring excellence and FöFoLe Programme, Verein zur Förderung von Wissenschaft und Forschung, German Ministry of Education and Research. Keywords: Endothelial cells, IL-1β, MyD88, ROS, SHP-2, Sepsis

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

Staphylococcus aureus bloodstream infections are associated with a high morbidity and mortality. Nevertheless, significance of a positive blood culture with this pathogen is often underestimated or findings are misinterpreted as contamination, which can result in inadequate diagnostic and therapeutic consequences. We here review and discuss current diagnostic and therapeutic key elements and open questions for the management of Staphylococcus aureus bloodstream infections.

Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H2S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H2S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P. aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase (Cse) gene (Cse-/-) and wild-type mice with a physiological expression (Cse+/+). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse+/+ donor; c) treatment with H2S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H2S compared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H2S higher and less than 5.3 μΜ (p = 7 x 10-6). In mice expression of Cse and application of STS afforded protection against infection with multidrug-resistant P. aeruginosa. Cyclophosphamide pretreatment eliminated the survival benefit of Cse+/+ mice, whereas BMT increased the survival of Cse-/- mice. Cse-/- mice had increased pathogen loads compared to Cse+/+ mice. Phagocytic activity of leukocytes from Cse-/- mice was reduced but was restored after H2S supplementation. An H2S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H2S is a potential independent parameter correlating with the outcome of P. aeruginosa. H2S provides resistance to infection by MDR bacterial pathogens.

Abstract Objectives Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a de facto innate immune memory, and its effects in non‐muscle‐invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette‐Guérin (BCG). Methods EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX‐01294 was used to investigate the effect on trained immunity responses in vitro. Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP‐qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX‐01294‐treated monocytes ex vivo. Results The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX‐01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands in vitro. This was accompanied by decreased H3K9me2 at the promoters of pro‐inflammatory genes. G9a inhibition was also associated with amplified ex vivo trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon ex vivo G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro‐inflammatory genes. Conclusion Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients.

BackgroundSeparating ill or possibly infectious people from their healthy community is one of the core principles of non-pharmaceutical interventions. However, there is scarce evidence on how to successfully implement quarantine orders. We investigated a community quarantine for an entire village in Germany (Neustadt am Rennsteig, March 2020) with the aim of better understanding the successful implementation of quarantine measures.MethodsThis cross-sectional survey was conducted in Neustadt am Rennsteig six weeks after the end of a 14-day mandatory community quarantine. The sample size consisted of 562 adults (64% of the community), and the response rate was 295 adults, or 52% (33% of the community).FindingsNational television was reported as the most important channel of information. Contact with local authorities was very limited, and partners or spouses played a more important role in sharing information. Generally, the self-reported information level was judged to be good (211/289 [73.0%]). The majority of participants (212/289 [73.4%]) approved of the quarantine, and the reported compliance was 217/289 (75.1%). A self-reported higher level of concern as well as a higher level of information correlated positively with both a greater acceptance of quarantine and self-reported compliant behaviour.InterpretationThe community quarantine presented a rare opportunity to investigate a public health intervention for an entire community. In order to improve the implementation of public health interventions, public health risk communication activities should be intensified to increase both the information level (potentially leading to better compliance with community quarantine) and the communication level (to facilitate rapport and trust between public health authorities and their communities).

Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.

We present here a 64-year-old male participant of the CoNAN study who experienced a PCR-confirmed mild SARS-CoV-2 infection but did not develop any measurable antibody response. Additionally, after vaccination with ChAdOx1 (AstraZeneca, Cambridge, UK) 11 months later, no antibodies were detected in six serological tests three weeks after the vaccination. When we assessed T-helper (Th) cell immunity, SARS-CoV-2-specific Th cells produced detectable amounts of IFNγ and TNF six weeks after the infection. A robust T-cell immunity remained detectable at least until six months after the infection and was boosted by the vaccination thereafter. This case report points out that an assessment of a prior infection or a vaccine response based solely on antibody detection might have limitations in individual patients.

The development of new brazing fillers requires knowledge about their properties in comparison to well established fillers. Therefore, the determination of the spreading and flow behavior is necessary. By now, different measuring techniques are combined in order to reach a comprehensive understanding of the mechanisms. Especially in case of flux brazing, conventional measuring techniques cannot be used. Due to the industrial demand of application-related experiments, the intended setup should be simple and easily to arrange. This paper deals with the development of a new procedure to determine the spreading and flow behavior of brazing fillers employing flux. The experimental setup, which consists of a commercially available induction heater, equipped with a temperature controller, is mounted inside a gas and vacuum tight chamber. A CCD camera system is used to record the spreading and flow behavior on surfaces as well as inside narrow gaps. The results of experiments using different fillers and base materials are presented. The measurements of the spreading area and the flow velocity under defined conditions allow a quantitative evaluation of the properties of the fillers. Thus, the comparison of different fillers among each other is possible.

Humoral immunity after infection or after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been attributed a key part in mitigating the further transmission of the virus. In this study, we used a commercial anti-Spike immunoglobulin G (S-IgG) assay and developed a cell culture-based neutralization assay to understand the longitudinal course of neutralizing antibodies in both SARS-CoV2 infected or vaccinated individuals. We show that even more than one year after infection, about 78% of observed study participants remained seropositive concerning S-IgG antibodies. In addition, the serum of the individuals had stable neutralization capacity in a neutralization assay against a SARS-CoV-2 patient isolate from March 2020. We also examined volunteers after either homologous BNT162b2 prime-boost vaccination or heterologous AZD1222 prime/mRNA-based booster vaccination. Both the heterologous and the homologous vaccination regimens induced higher levels of neutralizing antibodies in healthy subjects when compared to subjects after a mild infection, showing the high effectiveness of available vaccines. In addition, we could demonstrate the reliability of S-IgG levels in predicting neutralization capacity, with 94.8% of seropositive samples showing a neutralization titer of ≥10, making it a viable yet cheap and easy-to-determine surrogate parameter for neutralization capacity.

Acute pancreatitis is a severe systemic disease triggered by a sterile inflammation and initial local tissue damage of the pancreas. Immune cells infiltrating into the pancreas are main mediators of acute pancreatitis pathogenesis. In addition to their antimicrobial potency, macrolides possess anti-inflammatory and immunomodulatory properties which are routinely used in patients with chronic airway infections and might also beneficial in the treatment of acute lung injury. We here tested the hypothesis that the macrolide antibiotic azithromycin can improve the course of acute experimental pancreatitis via ameliorating the damage imposed by sterile inflammation, and could be used as a disease specific therapy. However, our data show that azithromycin does not have influence on caerulein induced acute pancreatitis in terms of reduction of organ damage, and disease severity. Furthermore Infiltration of immune cells into the pancreas or the lungs was not attenuated by azithromycin as compared to controls or ampicillin treated animals with acute experimental pancreatitis. We conclude that in the chosen model, azithromycin does not have any beneficial effects and that its immunomodulatory properties cannot be used to decrease disease severity in the model of caerulein-induced pancreatitis in mice.

β-Glucan derived from cell walls of Candida albicans is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.

Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection.

Development of organ dysfunction discriminates sepsis from uncomplicated infection. The paradigm shift implicated by the new sepsis-3 definition holds that initial impairment of any organ can pave the way for multiple organ dysfunction and death. Moreover, the role of the systemic inflammatory response, central element in previous sepsis definitions, has been questioned. Most strikingly, a so far largely underestimated defense mechanism of the host, i.e., “disease tolerance,” which aims at maintaining host vitality without reducing pathogen load, has gained increasing attention. Here, we summarize evidence that a dysregulation of critical cellular signaling events, also in non-immune cells, might provide a conceptual framework for sepsis-induced dysfunction of parenchymal organs in the absence of significant cell death. We suggest that key signaling mediators, such as phosphoinositide 3-kinase, mechanistic target of rapamycin, and AMP-activated protein kinase, control the balance of damage and repair processes and thus determine the fate of affected organs and ultimately the host. Therapeutic targeting of these multifunctional signaling mediators requires cell-, tissue-, or organ-specific approaches. These novel strategies might allow stopping the domino-like damage to further organ systems and offer alternatives beyond the currently available strictly supportive therapeutic options.

Brazing has a long tradition at the Institute of Material Science and Engineering of the University of Chemnitz, Germany. During the last years, comprehensive and innovative knowledge in brazing and soldering technologies were generated. Originating from high-temperature brazing, topics like metal-ceramic and light metal brazing, ultrasound assisted joining processes through to brazing of metal matrix composites were examined. In addition, new topics like joining by nanoparticles or corrosion behavior of brazed heat exchangers are in the focus of research. Prof. Bernhard Wielage managed the institute for 22 years. Today, Prof. Guntram Wagner introduces new topics like friction stir welding and continues the activities in brazing. Trendy badawcze w procesach lutowania miękkiego i twardego Streszczenie Tradycje związane z tematyką lutowania twardego w Instytucie Materiałoznawstwa i Inżynierii Uniwersytetu w Chemnitz (Niemcy) są długie. W ciągu ostatnich lat wygenerowano kompleksową i innowacyjną wiedzę dotyczącą technologii lutowania miękkiego i twardego. Zajmowano się problematyką badawczą wywodzącą się od lutowania wysokotemperaturowego, taką m.in. jak: lutowanie twarde metali lekkich z ceramiką i wspomaganie procesu spajania ultradźwiękami w lutowaniu kompozytów metalowych. Obecnie przedmiotem badań są nowe zagadnienia, takie jak: spajanie nanocząsteczkami oraz zachowanie odporności korozyjnej wymienników ciepła lutowanych na twardo. Profesor Bernhard Wielage zarządzał Instytutem przez ostatnie 22 lata. Obecnie, nowy Dyrektor Instytutu Profesor Guntram Wagner zajmuje się takimi zagadnieniami, tjak np. zgrzewaniem tarciowym z wymieszaniem materiału zgrzeiny (FSW) i kontynuuje prace badawcze związane z lutowaniem twardym.

Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms.

Cobalt-based superalloys are used under high-temperature service conditions. It is often necessary to join parts made of these alloys to construct components with complex geometries. High-temperature brazing is a suitable joining technology. To ensure a good corrosion resistance, the brazing filler and the base material should have similar chemical compositions. This paper deals with the development of near eutectic cobalt-based brazing fillers based on the alloy system Co-ZrC-TaC. The alloys are prepared by arc-melting on a water-cooled copper hearth in an argon atmosphere using a non-consumable tungsten electrode. Geometrical shaping is done by suction casting into a sectioned copper mould. Microstructure and melting behaviour are characterized by means of light microscopy and differential scanning calorimetry. Luty na bazie kobaltu Abstrakt Nadstopy na bazie kobaltu są stosowane do pracy w wysokiej temperaturze. Często pojawia się konieczność łączenia elementów wykonanych z tych materiałów w celu uzyskania zaprojektowanej konstrukcji. Lutowanie twarde jest odpowiednią metodą łączenia tych stopów, ponieważ zapewnia dobrą odporność na korozję, przy czym zarówno materiał dodatkowy, jak i materiał lutowany powinny mieć taki sam skład chemiczny. W artykule przedstawiono wy- niki prac nad trójskładnikowym lutem przyeutektycznym opracowanym na bazie stopu kobaltu – Co-ZrC-TaC. Stopy wytwarzane są przez topienie łukowe elektrodą wolframową na podkładce miedzianej chłodzonej wodą i w osłonie argonu. Kształt geometryczny nadawany jest w procesie odlewania próżniowego do dzielonej miedzianej formy. Mikrostruktura i zachowanie się topionego metalu analizowano z wykorzystaniem mikroskopii świetlnej i kalorymetrii skaningowej.

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.

Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis.The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls.S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups.Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development.