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Background Patients who actively engage in their medical decision-making processes can experience better health outcomes. This exploratory study aimed to identify predictors of preferred and actual roles in decision-making in healthy women with BRCA1/2 pathogenic variants (PVs). Methods Women with BRCA1/2 PVs without a history of breast and/or ovarian cancer were recruited in six centres across Germany. Those returning the baseline questionnaires (T1) were randomly assigned to the intervention or control group (IG, CG). The IG completed a decision-coaching (DC) programme, the CG received standard care. A second survey (T2) followed after 12 weeks. Ordinal regression analyses were performed. Sociodemographic and outcome-related baseline variables were used to identify predictors of (i) desired role at T1 in the total group and (ii) actual role at T2 in the CG and the IG. Role preferences were measured with the Control Preferences Scale. Results 389 women completed the baseline questionnaires, 191 were randomised to the CG and 198 to the IG. At T1, high decisional conflict (OR 1.016, 95% CI 1.001–1.023, p  = 0.038) and a negative self-concept (OR 1.030, 95% CI 1.008–1.054, p  = 0.009) were significant predictors for preferring a more passive role. At T2, high baseline decisional conflict significantly predicted taking a more passive role in the CG, whereas in the IG, baseline decisional conflict showed no influence. Furthermore, in the IG, younger age (OR 1.049, 95% CI 1.001–1.098, p  = 0.044) and a non-academic education (OR 0.46, 95% CI 0.213–0.775, p = 0.006) were identified as significant predictors for taking a more active role. Conclusions High initial decisional conflict was identified as an important predictor for preferring and taking a passive role in decision-making among women with BRCA1/2 PVs. Participating in the DC programme can counteract passivating effects of an initially high decisional conflict and particularly support younger PV carriers and those with lower educational status to take an active role. With this profile, the DC programme expands the existing counselling and care concept to include a measure that can also specifically cover the support needs of younger women and those with a lower education level. Trial registration DRKS-ID: DRKS00015527. Registered 30/10/2019.

Background Disseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient’s pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow. Methods A total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab. Results At baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p  = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p  = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p  = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p  = 1.00). Conclusion This is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.

Purpose To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Methods A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. Results A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9–93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6–85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6–91.7), p  < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8–62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3–6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. Conclusions High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.

BackgroundDetermination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants.MethodsIn families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC. Aberrant fragments were sequenced. All coding exons and splice sites of BRCA1 and BRCA2 were analyzed. Screening for large rearrangements in both genes was performed by MLPA.ResultsOf 523 index patients, 121 (23.1%) were found to carry a pathogenic or likely pathogenic (class 4/5) mutation. A variant of unknown significance (VUS) was detected in 73/523 patients (13.9%). Two mutations p.Gln1756Profs*74 and p.Cys61Gly comprised 42.3% (n = 33/78) of all detected pathogenic mutations in BRCA1. Most of the other mutations were unique mutations. The most frequently detected mutation in BRCA2 was p.Val1283Lys (13.9%; n = 6/43). Altogether, 101 different neutral genetic variants were counted in BRCA1 (n = 35) and in BRCA2 (n = 66).ConclusionThe two most frequently detected mutations are founder mutations in Poland and Czech Republic. More similarities seem to be shared with our direct neighbor countries compared to other European countries. For comparison of the extended genotype, a shared database is needed.

Background HPV vaccination has been recommended and reimbursed for girls in Germany since 2007. In June 2018 the German Standing Committee on Vaccination (STIKO) recommended the gender-neutral vaccination of adolescents aged 9 to 14 years with catch-up through age 17. Objectives of this study were to describe the uptake of vaccination in boys before and during the COVID-19 pandemic. Methods The study used data from a proprietary electronic medical record database and a database with information on nationally dispensed vaccine doses. The monthly number of first doses of HPV vaccinations in boys and girls aged 9–17 years in the period from 01/2018 to 12/2021 was determined. In addition, for boys the cumulative vaccination rates were calculated for initiated and completed vaccination series. Results Four months after the introduction of mandatory reimbursement for boys, the monthly numbers of first doses were comparable to that of girls. Compared to the same month in 2019, the number of first doses declined by up to 49% (girls) in 2020 and 71% (boys) in 2021. At the end of 2021, the vaccination rate for 15-year-old boys (2006 birth cohort) reached 44.4% for initiated and 26.4% for completed series. Conclusion After an initial dynamic increase in HPV vaccinations in boys, the impact of COVID-19 was particularly strong in the second year of the pandemic. At the end of 2021 vaccination rates were still low. Efforts are needed to catch-up on adolescents that missed doses during the pandemic and to increase uptake.

In 2015, 4062 unaccompanied minor refugees were registered in Berlin, Germany. According to national policies, basic clinical examination and tuberculosis (TB) screening is a prerequisite to admission to permanent accommodation and schooling for every refugee. This article evaluates the use of an interferon-γ-release-assay (IGRA) during the initial examination and TB screening of 970 unaccompanied minor refugees. IGRA test were obtained during TB screening for 301 (31.0%) of 970 adolescents not previously screened for TB. Positive IGRA results were obtained in 13.9% (42/301). Most of the 42 IGRA-positive refugees originated from Afghanistan or Syria (n?20 and 10 respectively). Two IGRA-positive adolescents were lost to follow-up, 2 were diagnosed with TB and the remaining 38 diagnosed with latent TB infection (LTBI). Demographic features of the 40 patients with positive IGRA result were as follows: 39 male, median age 16.8 years (IQR 16.0-17.2y), none meeting underweight criteria (median BMI 21.3kg/m2). On initial chest X-ray 2/40 participants had signs of active TB, while in 38 active disease was excluded and the diagnosis of latent TB infection (LTBI) made. Active hepatitis B-co-infection was diagnosed in 3/38 patients. All patients with LTBI received Isoniazid and Rifampicin for 3 months without occurrence of severe adverse events. The most frequently observed side effect was transient upper abdominal pain (n = 5). Asymptomatic elevation of liver transaminases was seen in 2 patients. 29 patients completed treatment with no signs of TB disease at the end of chemoprevention and 9 were lost to follow up. Screening for TB infection in minor refugees was feasible in our setting with a relatively high rate of TB infection detected. Chemopreventive treatment was tolerated well regardless of underlying hepatitis-B-status. Minor refugees migrating to Germany should be screened for TB infection, instead of TB disease only, regardless of the background TB incidence.

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

Background Epilepsy and other seizure disorders account for a high disease burden in Germany. As a timely diagnosis and accurate treatment are crucial, improving the management of these disorders is important. Outside of Germany, outpatient long-term video EEGs (ALVEEGs) have demonstrated the potential to support the diagnosis and management of epilepsy and other seizure disorders. This study aims to evaluate the implementation of ALVEEGs as a new diagnostic pathway in eastern parts of Germany to diagnose epilepsy and other seizure disorders and to assess if ALVEEGs are equally effective as the current inpatient-monitoring gold standard, which is currently only available at a limited number of specialized centers in Germany. Methods ALVEEG is a prospective, multicenter, randomized controlled equivalence trial, involving five epilepsy centers in the eastern states of Germany. Patients will be randomized into either intervention (IG) or control group (CG), using a permuted block randomization. The sample size targeted is 688 patients, continuously recruited over the trial. The IG will complete an ALVEEG in a home setting, including getting access to a smartphone app to document seizure activity. The CG will receive care as usual, i.e., inpatient long-term video-EEG monitoring. The primary outcome is the proportion of clinical questions being solved in the IG compared to the CG. Secondary outcomes include hospital stays, time until video EEG, time until diagnosis and result discussion, patients’ health status, quality of life and health competence, and number and form of epilepsy-related events and epileptiform activity. Alongside the trial, a process implementation and health economic evaluation will be conducted. Discussion The extensive evaluation of this study, including an implementation and health economic evaluation, will provide valuable information for health policy decision-makers to optimize future delivery of neurological care to patients affected by epilepsy and other seizure disorders and on the uptake of ALVEEG into standard care in Germany. Trial registration German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023.

Northern latitude peatlands act as important carbon sources and sinks, but little is known about the greenhouse gas (GHG) budgets of peatlands that were submerged beneath the North Sea during the last glacial–interglacial transition. We found that whilst peat formation was diachronous, commencing between 13 680 and 8360 calibrated years before the present, stratigraphic layering and local vegetation succession were consistent across a large study area. Large carbon stores were measured. In situ methane (CH4) concentrations of sediment pore waters were widespread but low at most sites, with the exception of two locations. Incubation experiments in the laboratory revealed molecular signatures of methanogenic archaea, with strong increases in rates of activity upon methylated substrate amendment. Remarkably, methanotrophic activity and the respective diagnostic molecular signatures could not be detected. Heterotrophic Bathyarchaeota dominated the archaeal communities, and bacterial populations were dominated by candidate phylum JS1 bacteria. In the absence of active methanogenic microorganisms, we conclude that these sediment harbour low concentrations of widespread millennia-old CH4. The presence of large widespread stores of carbon and in situ methanogenic microorganisms, in the absence of methanotrophic microorganisms, holds the potential for microbial CH4 production if catalysed by a change in environmental conditions.

Background Epilepsy and other seizure disorders are medical conditions that impose a substantial health economic burden on society given their considerable costs of illness and use of healthcare resources. The ALVEEG trial aims to tackle resource shortages in clinical settings and optimize patient management by evaluating outpatient ambulatory long-term video electroencephalograms (ALVEEGs) as a new diagnostic pathway to diagnose and manage epilepsy and other seizure disorders. The health economic evaluation alongside this trial aims to determine the cost-effectiveness and cost-utility of ALVEEGs for affected patients presenting themselves at participating epilepsy centers in Germany. Methods This study protocol comprises the rationale and methods of the health economic evaluation of ALVEEGs embedded into the ALVEEG project. We will perform cost-effectiveness and cost-utility analyses, with the outcomes being a priori defined endpoint measures of the main trial. We will consider the proportion of solved clinical queries (primary endpoint), the number of hospital stays, the in-patient length of stay, and quality-adjusted life years for the here presented health economic evaluation. Costs will be collected by the participating health insurance companies alongside the trial, with the evaluation being conducted from a statutory health insurance perspective within the German healthcare system. The reporting of the economic evaluation follows the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Discussion The health economic evaluation of ALVEEGs for patients affected by epilepsy and other seizure disorders within the German healthcare system will deliver insightful evidence on the cost-effectiveness and cost-utility of the intervention and hence guide policy and decision makers regarding a potential inclusion of ALVEEGs into the health benefit basket of the statutory health insurance scheme. Trial registration German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023.