Estimates of protection levels against SARS-CoV-2 infection and severe COVID-19 in Germany before the 2022/2023 winter season: the IMMUNEBRIDGE project.

PURPOSE: Despite the need to generate valid and reliable estimates of protection levels against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real time. METHODS: In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n = 33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses ("confirmed exposures"). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest. RESULTS: Most participants were seropositive against the spike antigen; 37% of the participants ≥ 79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4-28% of participants having less than three confirmed exposures. CONCLUSION: Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups.

Bridging the gap - estimation of 2022/2023 SARS-CoV-2 healthcare burden in Germany based on multidimensional data from a rapid epidemic panel.

OBJECTIVES: Throughout the SARS-CoV-2 pandemic, Germany like other countries lacked adaptive population-based panels to monitor the spread of epidemic diseases. METHODS: To fill a gap in population-based estimates needed for winter 2022/23 we resampled in the German SARS-CoV-2 cohort study MuSPAD in mid-2022, including characterization of systemic cellular and humoral immune responses by interferon-γ-release assay (IGRA) and CLIA/IVN assay. We were able to confirm categorization of our study population into four groups with differing protection levels against severe COVID-19 courses based on literature synthesis. Using these estimates, we assessed potential healthcare burden for winter 2022/23 in different scenarios with varying assumptions on transmissibility, pathogenicity, new variants, and vaccine booster campaigns in ordinary differential equation models. RESULTS: We included 9921 participants from eight German regions. While 85% of individuals were located in one of the two highest protection categories, hospitalization estimates from scenario modeling were highly dependent on viral variant characteristics ranging from 30-300% compared to the 02/2021 peak. Our results were openly communicated and published to an epidemic panel network and a newly established modeling network. CONCLUSIONS: We demonstrate feasibility of a rapid epidemic panel to provide complex immune protection levels for inclusion in dynamic disease burden modeling scenarios.

Decision aid and cost compensation influence uptake of PSA-based early detection without affecting decisional conflict: a cluster randomised trial.

International guidelines recommend to inform men about the benefits and harms of prostate specific antigen (PSA) based early detection of prostate cancer. This study investigates the influence of a transactional decision aid (DA) or cost compensation (CC) for a PSA test on the decisional behaviour of men. Prospective, cluster-randomised trial to compare two interventions in a 2 × 2 factorial design: DA versus counselling as usual, and CC versus noCC for PSA-testing. 90 cluster-randomised physicians in the administrative district of Muenster, Germany recruited 962 participants aged 55-69 yrs. in 2018. Primary endpoint: the influence of the DA and CC on the decisional conflict. Secondary endpoints: factors which altered the involvement of the men regarding their decision to take a PSA-test. The primary endpoint was analysed by a multivariate regression model. The choice to take the PSA test was increased by CC and reduced by the DA, the latter also reduced PSA uptake in men who were offered CC. The DA led to an increase of the median knowledge about early detection, changed willingness to perform a PSA test without increasing the level of shared decision, giving participants a stronger feeling of having made the decision by themselves. The DA did not alter the decisional conflict, as it was very low in all study groups. DA reduced and CC increased the PSA uptake. The DA seemed to have a greater impact on the participants than CC, as it led to fewer PSA tests even if CC was granted.Trial registration: German Clinical Trial Register (Deutsches Register Klinischer Studien DRKS00007687). Registered: 06/05/2015. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007687 .

The Mode of Detection Is Not Associated with Quality of Life in Women with Breast Cancer.

INTRODUCTION: Apart from saving lives, mammography screening programs (MSP) are expected to reduce negative side effects of treatment by detecting cancer earlier, when it is more responsive to less aggressive treatment. This study compared quality of life (QoL) among women with breast cancers that were detected either by screening mammography, as interval cancers, or clinically among women not participating in the MSP. METHODS: Retrospective study of first-ever invasive breast cancers detected among MSP-eligible women aged 50-69 years between 2006 and 2012 in Münster, Germany. EORTC QLQ-C30 and -BR23 questionnaires were mailed to 1,399 cases still alive in 2015 (response rate 64.1%). RESULTS: Women's responses were obtained on average 6.1 years after diagnosis. Mean crude and age-adjusted scores for overall QoL, breast and body image (BBI), and five functional scales (FS) were comparable between groups of detection mode. Clearly lower adjusted means for most scores were observed in women with interval cancers, if time since diagnosis was less than 5 years. Cases younger than 60 years showed lower values for some FS, particularly among interval and screen-detected cases. DISCUSSION/CONCLUSION: In summary, cases with breast cancer showed health-related score values that were similar to the general population of the same age. There was also no indication that mode of detection markedly influenced these scores. However, after adjusting for tumor stage and other influential factors, screening participants appeared more susceptible to score declines after a diagnosis of cancer than non-participants.

Development and Prospective Randomized Evaluation of a Decision Aid for Prostate-specific Antigen-based Early Detection of Prostate Cancer in Men Aged Between 55 and 69Yr: The PSAInForm Trial.

For men interested in early detection of prostate cancer, the potential impact on decisional conflict of a decision aid with or without cost compensation for the prostate-specific antigen test will be investigated.

Polyamine-independent Expression of Caenorhabditis elegans Antizyme.

Degradation of ornithine decarboxylase, the rate-limiting enzyme of polyamine biosynthesis, is promoted by the protein antizyme. Expression of antizyme is positively regulated by rising polyamine concentrations that induce a +1 translational frameshift required for production of the full-length protein. Antizyme itself is negatively regulated by the antizyme inhibitor. In our study, the regulation of Caenorhabditis elegans antizyme was investigated, and the antizyme inhibitor was identified. By applying a novel GFP-based method to monitor antizyme frameshifting in vivo, we show that the induction of translational frameshifting also occurs under stressful conditions. Interestingly, during starvation, the initiation of frameshifting was independent of polyamine concentrations. Because frameshifting was also prevalent in a polyamine auxotroph double mutant, a polyamine-independent regulation of antizyme frameshifting is suggested. Polyamine-independent induction of antizyme expression was found to be negatively regulated by the peptide transporter PEPT-1, as well as the target of rapamycin, but not by the daf-2 insulin signaling pathway. Stress-dependent expression of C. elegans antizyme occurred morely slowly than expression in response to increased polyamine levels, pointing to a more general reaction to unfavorable conditions and a diversion away from proliferation and reproduction toward conservation of energy. Interestingly, antizyme expression was found to drastically increase in aging individuals in a postreproductive manner. Although knockdown of antizyme did not affect the lifespan of C. elegans, knockdown of the antizyme inhibitor led to a significant reduction in lifespan. This is most likely caused by an increase in antizyme-mediated degradation of ornithine decarboxylase-1 and a resulting reduction in cellular polyamine levels.

Comparative analysis of macrophage migration inhibitory factors (MIFs) from the parasitic nematode Onchocerca volvulus and the free-living nematode Caenorhabditis elegans.

The macrophage migration inhibitory factors (MIFs) from the filarial parasite Onchocerca volvulus (OvMIF) were compared to the MIFs from the free-living nematode Caenorhabditis elegans (CeMIF) with respect to molecular, biochemical and immunological properties. Except for CeMIF-4, all other MIFs demonstrated tautomerase activity. Surprisingly, OvMIF-1 displayed oxidoreductase activity. The strongest immunostaining for OvMIF-1 was observed in the outer cellular covering of the adult worm body, the syncytial hypodermis; moderate immunostaining was observed in the uterine wall. The generation of a strong humoral immune response towards OvMIF-1 and reduced reactivity to OvMIF-2 was indicated by high IgG levels in patients infected with O. volvulus and cows infected with the closely related Onchocerca ochengi, both MIFs revealing identical amino acid sequences. Using Litomosoides sigmodontis-infected mice, a laboratory model for filarial infection, MIFs derived from the tissue-dwelling O. volvulus, the rodent gut-dwelling Strongyloides ratti and from free-living C. elegans were recognized, suggesting that L. sigmodontis MIF-specific IgM and IgG1 were produced during L. sigmodontis infection of mice and cross-reacted with all MIF proteins tested. Thus, MIF apparently functions as a target of B cell response during nematode infection, but in the natural Onchocerca-specific human and bovine infection, the induced antibodies can discriminate between MIFs derived from parasitic or free-living nematodes.

Filarial parasites possess an antizyme but lack a functional ornithine decarboxylase.

In eukaryotes, the key player in polyamine metabolism is the ornithine decarboxylase (ODC) that catalyses the first and rate limiting step in cellular polyamine synthesis. The half life of ODC is strictly regulated by the antizyme (AZ), which promotes its degradation. Older reports on the polyamine situation in filarial parasites indicate a lack of ornithine decarboxylation activity and an increased uptake of polyamines. Our in silico analysis of the Brugia malayi genome revealed only an ODC-like protein that lacks essential residues. Consequently, the recombinant protein had no enzymatic ODC activity. Furthermore, only ODC-like genes were found in the available draft genomes of other filarial parasites. In this ODC-free scenario, we set out to investigate the AZ of O. volvulus (OvAZ). The expression of the recombinant protein allowed us to analyse the localization of OvAZ in different O. volvulus stages as well as to identify it as target for the human humoral immune response. Strong immunostaining was observed in the outer zone of the uterine epithelium as well as in the uterus lumen around the periphery of the developing parasite, indicating a potential role of the OvAZ in the control of polyamine levels during embryonic development. By employing a novel in vivo method using Caenorhabditis elegans, we postulate that the OvAZ enters the secretory pathway. Even though the ODCs are absent in filarial parasites, OvAZ has the ability to bind to various ODCs, thereby demonstrating the functionality of the conserved AZ-binding domains. Finally, pull-down assays show an interaction between B. malayi AZ and the B. malayi ODC-like protein, indicating that the B. malayi ODC-like protein might function as an AZI. Taken together, our results suggest that filarial species do not possess the ODC while retaining the ODC-regulatory proteins AZ and AZI. It is tempting to speculate that both proteins are retained for the regulation of polyamine transport systems.

Functional characterization and immune recognition of the extracellular superoxide dismutase from the human pathogenic parasite Onchocerca volvulus (OvEC-SOD).

Onchocerca volvulus is a human pathogenic filarial nematode causing chronic onchocerciasis, a disease characterized by chronic skin and eye lesions. Despite attempts to control this infection from many perspectives, it still remains a threat to public health because of adverse effects of available drugs and recent reports of drug resistance. Under control of an intact immune system, O. volvulus survives for a long time in the host by employing a variety of strategies including the utility of antioxidant enzymes. In the present study, we focus on the extracellular superoxide dismutase from O. volvulus (OvEC-SOD) found in the excretory/secretory products of adult worms. Contrary to previous studies, the OvEC-SOD was found to have a 19 amino acid long signal peptide that is cleaved off during the process of maturation. To validate this result, we designed a novel method based on Caenorhabditis elegans cup5(ar465) mutants to specifically evaluate signal peptide-mediated secretion of nematodal proteins. Following purification, the recombinant OvEC-SOD was active as a dimer. Site-directed mutagenesis of the three cysteines present in the OvEC-SOD shows that enzyme activity is markedly reduced in the Cys-192 mutant. A homology model of the OvEC-SOD underlines the importance of Cys-192 for the stabilization of the adjacent active site channel. The generation of a humoral immune response to secretory OvEC-SOD was indicated by demonstrating IgG reactivity in sera from patients infected with O. volvulus while the cross-reactivity of IgG in plasma samples from cows, infected with the most closely related parasite Onchocerca ochengi, occurred only marginally. High IgG1 and IgM titres were recorded in sera from mice infected with the filaria Litomosoides sigmodontis, however, low or no cellular proliferative responses were observed. Thus, the present data suggest that secretory OvEC-SOD is a target of the humoral immune response in human onchocerciasis and induced strongest IgG responses in hyperreactive onchocerciasis. Furthermore, humoral response during murine infection induced SOD-specific IgG that cross-reacted with OvEC-SOD.