Longitudinal change in SARS-CoV-2 seroprevalence in 3-to 16-year-old children: the Augsburg Plus study

BACKGROUND: Currently, more than 30,200,000 COVID-19 cases have been diagnosed in Germany alone. However, data regarding prevalence of COVID-19 in children, both in Germany and internationally, are sparse. We sought to evaluate the number of infected children by measuring IgG antibodies. METHODS: Oropharyngeal swabs were collected between December 2020 and August 2021 to measure SARS-CoV-2, and capillary blood for the detection of SARS-CoV-2 antibodies (by rapid test NADAL® and filter paper test Euroimmun® ELISA); venous blood was taken for validation (Roche® ECLIA and recomLine Blot) in 365 German children aged 3–16 years from 30 schools and preschools. We used multiple serological tests because the filter paper test Euroimmun® ELISA performs better in terms of sensitivity and specificity than the rapid test NADAL®. The Roche® ECLIA test is used to detect SARS-CoV-2 spike protein, and the recomLine Blot test is used to rule out the possibility of infection by seasonal SARS-viruses and to test for specific SARS-CoV-2 proteins (NP, RBD and S1). In addition, one parent each (n = 336), and 4–5 teachers/caregivers (n = 90) per institution were tested for IgG antibodies from capillary blood samples. The total study duration was 4 months per child, including the first follow-up after 2 months and the second after 4 months. RESULTS: Of 364 children tested at baseline, 3.6% (n = 13) were positive for SARS-CoV-2 IgG antibodies using Euroimmun® ELISA. Seven children reported previously testing positive for SARS-CoV-2; each of these was confirmed by the Roche® Anti-SARS-CoV-2-ECLIA (antibody to spike protein 1) test. SARS-CoV-2 IgG antibodies persisted over a 4-month period, but levels decreased significantly (p = 0.004) within this timeframe. The median IgG values were 192.0 BAU/ml [127.2; 288.2], 123.6 BAU/ml [76.6; 187.7] and 89.9 BAU/ml [57.4; 144.2] at baseline, 2 months and 4 months after baseline, respectively. During the study period, no child tested positive for SARS-CoV-2 by oropharyngeal swab. A total of 4.3% of all parents and 3.7% of teachers/caregivers tested positive for IgG antibodies by Euroimmun® ELISA at baseline. CONCLUSION: We noted a rather low seroprevalence in children despite an under-reporting of SARS-CoV-2 infections. Measurement of IgG antibodies derived from capillary blood appears to be a valid tool to detect asymptomatic infections in children. However, no asymptomatic active infection was detected during the study period of 4 months in the whole cohort. Further data on SARS-CoV-2 infections in children are needed, especially in the group of <5-year-olds, as there is currently no licensed vaccine for this age group in Germany. The Robert Koch Institute’s Standing Commission on Vaccination (STIKO) recommended COVID-19 vaccination for 12–17 and 5–11 year olds in August 2021 and May 2022 respectively

Association between fatigue and cytokine profiles in patients with ischemic stroke

Background Chronic fatigue is a common symptom after a stroke. Studies suggested that chronic fatigue is caused by inflammatory or immunological processes but data are limited and contradictory. Thus, the present study aimed to identify specific biomarkers associated with fatigue in post-stroke patients and replicated the findings in a population-based study. Methods We investigated associations between 39 circulating biomarkers of inflammation and fatigue in 327 patients after an ischemic stroke included in the Stroke Cohort Augsburg (SCHANA) study and the “Metabolism, Nutrition and Immune System in Augsburg” (MEIA) study (n = 140). The Fatigue Assessment Scale (FAS) was used to assess the severity of fatigue. The serum concentrations of the biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel (Bio-Rad, USA). Multiple linear regression models adjusted for possible confounders were used to examine associations. Results In patients with stroke, SCGFb was inversely associated [−1.67, 95% confidence interval (CI) (−3.05; −0.29) p = 0.018], and in healthy subjects, G-CSF was positively associated [1.56, 95% CI (0.26; 2.87), p = 0.020] with an increasing FAS-score, while SCF was positively related in both samples [1.84, 95% CI (0.27; 3.42), p = 0.022 and 1.40, 95% CI (0.29; 2.52), p = 0.015]. However, after correction for multiple testing, all of these associations lost statistical significance. Conclusion The present findings suggested an association between the growth factor SCF and fatigue. Future research on cytokines as possible markers of fatigue should focus on a longitudinal design including a sufficiently large number of study participants to enable testing associations between certain cytokines and sub-groups of chronic fatigue

Post-COVID-19 fatigue and SARS-CoV-2 specific humoral and T-cell responses in male and female outpatients

BACKGROUND: Information on the clinical characteristics and pathophysiological mechanisms underlying post-COVID-19 fatigue are scarce. The main objective of this study was to evaluate sex-specific humoral and T-cell responses associated with post-COVID-19 fatigue in a sample of individuals treated as outpatients. METHODS: At a median time of 279 (179;325) days after the acute infection, a total of 281 individuals (45.9% men) aged 18-87 years old were included in the analysis. The participants were examined at the University Hospital of Augsburg, Southern Germany. Fatigue was assessed using the Fatigue Assessment Scale (FAS). Levels of anti-SARS-CoV2-spike IgG antibodies were measured by an enzyme-linked immunosorbent assay (ELISA), and for exploration of the SARS-CoV2-specific T-cell response, ex vivo ELISpot/FLUOROspot assays were conducted using an interferon-γ (IFN-γ) and interleukin-2 (IL-2) SARS-CoV-iSpot kit. RESULTS: Women more significantly suffered from post-COVID-19 fatigue in comparison to men (47.4% versus 25.6%, p=0.0002). Females but not males with fatigue showed a significantly lower number of T-cells producing IFN-γ, IL-2 or both IL-2 and IFNγ in comparison with females without fatigue. In both sexes, serum levels of anti-SARS-CoV2-spike IgG antibodies did not differ significantly between participants with or without fatigue. CONCLUSIONS: Development of fatigue after acute COVID-19 disease might be associated with SARS-CoV-2-specific T-cell responses in women, but not men after a mild infection course treated outpatient

Association between fatigue and cytokine profiles in patients with ischemic stroke

BackgroundChronic fatigue is a common symptom after a stroke. Studies suggested that chronic fatigue is caused by inflammatory or immunological processes but data are limited and contradictory. Thus, the present study aimed to identify specific biomarkers associated with fatigue in post-stroke patients and replicated the findings in a population-based study.MethodsWe investigated associations between 39 circulating biomarkers of inflammation and fatigue in 327 patients after an ischemic stroke included in the Stroke Cohort Augsburg (SCHANA) study and the “Metabolism, Nutrition and Immune System in Augsburg” (MEIA) study (n = 140). The Fatigue Assessment Scale (FAS) was used to assess the severity of fatigue. The serum concentrations of the biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel (Bio-Rad, USA). Multiple linear regression models adjusted for possible confounders were used to examine associations.ResultsIn patients with stroke, SCGFb was inversely associated [−1.67, 95% confidence interval (CI) (−3.05; −0.29) p = 0.018], and in healthy subjects, G-CSF was positively associated [1.56, 95% CI (0.26; 2.87), p = 0.020] with an increasing FAS-score, while SCF was positively related in both samples [1.84, 95% CI (0.27; 3.42), p = 0.022 and 1.40, 95% CI (0.29; 2.52), p = 0.015]. However, after correction for multiple testing, all of these associations lost statistical significance.ConclusionThe present findings suggested an association between the growth factor SCF and fatigue. Future research on cytokines as possible markers of fatigue should focus on a longitudinal design including a sufficiently large number of study participants to enable testing associations between certain cytokines and sub-groups of chronic fatigue

Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity

CCDC6 was originally identified upon rearrangement with RET in human thyroid papillary carcinomas generating the RET/PTC1 oncogene. We have previously reported that CCDC6 interacts with CREB1 and represses its transcriptional activity. Since the function of at least one allele of CCDC6 is lost following RET/PTC1 rearrangements, we aimed at the generation of mice, carrying a CCDC6 mutant gene. Previous studies suggested that the coiled-coil domain of CCDC6, mainly encoded by human exon 2, is required for the protein function. Therefore, we engineered a murine Ccdc6 construct, carrying a deletion of the exon 2, that was able to exert only a mild repression on CREB1 transcriptional activity, with respect to the wild type Ccdc6. Subsequently, we generated Ccdc6-ex2 knock-in mice. These mice developed thyroid hyperplasia associated with an enhanced CREB1 activity and an increased expression of the CREB-1 regulated genes. These results strongly support a CCDC6 promoting role, ascribed to its functional impairment, in the development of thyroid papillary carcinomas harboring the RET/PTC1 oncogene

The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias

We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

Critical role of bevacizumab scheduling in combination with pre-surgical chemo-radiotherapy in MRI-defined high-risk locally advanced rectal cancer: Results of the BRANCH trial.

BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC. Patients received three biweekly cycles of OXATOM/FUFA during RT. Bevacizumab was given 2 weeks before the start of chemo-radiotherapy, and on the same day of chemotherapy for 3 cycles (concomitant-schedule A) or 4 days prior to the first and second cycle of chemotherapy (sequential-schedule B). Primary end point was pathological complete tumor regression (TRG1) rate. RESULTS: The accrual for the concomitant-schedule was early terminated because the number of TRG1 (2 out of 16 patients) was statistically inconsistent with the hypothesis of activity (30%) to be tested. Conversely, the endpoint was reached with the sequential-schedule and the final TRG1 rate among 46 enrolled patients was 50% (95% CI 35%-65%). Neutropenia was the most common grade ≥ 3 toxicity with both schedules, but it was less pronounced with the sequential than concomitant-schedule (30% vs. 44%). Postoperative complications occurred in 8/15 (53%) and 13/46 (28%) patients in schedule A and B, respectively. At 5 year follow-up the probability of PFS and OS was 80% (95%CI, 66%-89%) and 85% (95%CI, 69%-93%), respectively, for the sequential-schedule. CONCLUSIONS: These results highlights the relevance of bevacizumab scheduling to optimize its combination with preoperative chemo-radiotherapy in the management of LARC.The study was a no-profit trial partially supported by research grants from the Italian Ministry of Health to A. Avallone (RF-2009-1539464) and to A. Budillon (RF- 2011-02346914)

Terrestrial Very-Long-Baseline Atom Interferometry:Workshop Summary

This document presents a summary of the 2023 Terrestrial Very-Long-Baseline Atom Interferometry Workshop hosted by CERN. The workshop brought together experts from around the world to discuss the exciting developments in large-scale atom interferometer (AI) prototypes and their potential for detecting ultralight dark matter and gravitational waves. The primary objective of the workshop was to lay the groundwork for an international TVLBAI proto-collaboration. This collaboration aims to unite researchers from different institutions to strategize and secure funding for terrestrial large-scale AI projects. The ultimate goal is to create a roadmap detailing the design and technology choices for one or more km-scale detectors, which will be operational in the mid-2030s. The key sections of this report present the physics case and technical challenges, together with a comprehensive overview of the discussions at the workshop together with the main conclusions