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Local treatment of bone loss with an injection of a resorbable, calcium-based implant material to replace bone has a long history of clinical use. The in vivo discrimination of changes in bone versus implant is challenging with standard computed tomography (CT). However, spectral-CT techniques enable the separation between tissues of similar densities but different chemical compositions. Dual-layer spectral-CT imaging and postprocessing analysis methods were applied to investigate the separability of AGN1 (a triphasic calcium-based implant) and bone after AGN1 injection in n = 10 male cadaveric femurs ex vivo. Using the area under the curve (AUC) from receiver-operating characteristic (ROC) analyses, the separability of AGN1 from bone was assessed for AGN1 (postoperatively) versus compact and versus femoral neck cancellous bone (both preoperatively). CT techniques included conventional Hounsfield (HU) and density-equivalent units (BMD, mg hydroxyapatite [HA]/cm

To investigate the chewing efficiency and oral health-related quality of life of edentulous patients wearing complete dentures, successively supported by one, two, and three implants in the mandible.Thirteen (13) edentulous patients of at least 50 years of age received three implants in the mandible. After a conventional submerged healing period, the central implant was uncovered and connected to the denture base using a stud attachment. Two months later, chewing efficacy was evaluated, and the two lateral implants were uncovered and connected to the denture base. The central retention element was replaced by a short healing abutment with no connection to the denture base. Chewing efficiency was evaluated two months later. Afterward, the healing abutment of the central implant was replaced by a stud attachment and again connected to the denture base. Two months later, chewing efficacy was evaluated again. Oral health-related quality of life (OHRQoL) was measured at each recall visit using the summary score of the oral health impact profile. For statistical analysis of chewing efficacy, the changes from baseline (with no implants) to one, two, and three implants were used and tested by analysis of variance with repeated mesurements.Chewing efficacy clearly increased after implant loading, with a significant increase when two implants were loaded (p ≤ .05), compared to the chewing efficacy with no implants. OHRQoL also significantly improved after implant loading.Within the limitations of the present clinical trial regarding the number of patients, chewing efficacy as well OHRQoL of edentulous patients improve after implant placement in the mandible, irrespective of the number of implants. The best chewing efficacy was achieved with two implants.

Correlation between standard clinicopathological and genome instability parameters.

Test for proportional hazards.

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The ability of human γδ T cells from healthy donors to kill pancreatic ductal adenocarcinoma (PDAC) in vitro and in vivo in immunocompromised mice requires the addition of γδ T-cell–stimulating antigens. In this study, we demonstrate that γδ T cells isolated from patients with PDAC tumor infiltrates lyse pancreatic tumor cells after selective stimulation with phosphorylated antigens. We determined the absolute numbers of γδ T-cell subsets in patient whole blood and applied a real-time cell analyzer to measure their cytotoxic effector function over prolonged time periods. Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin. Supporting these observations, adoptive transfer of γδ T cells with the Her2/Vγ9 antibody reduced growth of pancreatic tumors grafted into SCID-Beige immunocompromised mice. Taken together, our results show how bispecific antibodies that selectively recruit γδ T cells to tumor antigens expressed by cancer cells illustrate the tractable use of endogenous γδ T cells for immunotherapy. Cancer Res; 74(5); 1349–60. ©2014 AACR.

PDF file - 2448K, Phenotype of established gamma delta T-cells and PDAC-cell lines (S1); Design and purification of the recombinant Her2xCD3 bsscFv (S2); Her2xCD3 bsscFv enhances the gamma delta T-cell lysis of Panc89 cells (S3); Design and purification of the recombinant (Her2)2xVγ9 tribody (S4); (Her2)2xVγ9 does not mediate lysis of antigen-negative lymphoma cells (S5); Increase of gamma delta T-cell cytotoxicity against Panc89 cells by tribody (Her2)2xVγ9 (S6); Tribody (Her2)2xVγ9 enhances CD107a expression on gamma delta Tcell lines co-cultured with PancTu-I cells (S7).

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Zusammenfassung Einleitung Konsekutiv zu unserer Publikation „Reifegrade des Qualitäts- und Risikomanagementsystems am Universitätsklinikum Schleswig-Holstein“ aus dem Jahr 2018 stellen wir die Weiterentwicklung unseres Reifegradmodells vor. Qualitäts- und Risikomanagement (QRM) in Krankenhäusern sind nicht nur gesetzlich gefordert, sondern führen maßgeblich zu einer optimierten patienten- und ablauforientierten Krankenversorgung. Methode Durch einen strukturierten Erhebungsbogen zur Eigenbewertung erfolgte an 46 Kliniken mit direkter Patientenversorgung an den beiden Standorten des UKSH (Kiel und Lübeck) eine Analyse von insgesamt neun Qualitätskriterien. Vier von diesen Kriterien (Qualitätssicherung (QS), Critical Incident Reporting System (CIRS), Beschwerdemanagement (BM) und Prozessmanagement (PM)) wurden bereits 2016 erhoben und in 2020 um fünf neue Aspekte erweitert – Audits und Begehungen, Verantwortlichkeiten, Morbiditäts- und Mortalitätskonferenzen, Hygieneschulungen und OP-Checklisten. Jedes Qualitätskriterium wurde in vier Kategorien von A (voll implementiert) bis D (nicht implementiert) eingeteilt. Ergebnisse Im direkten Ergebnisvergleich der vier Qualitätskriterien und des Gesamtreifegrades von 2016 und 2020 zeigten sich statistisch signifikante Verbesserungen in 2020 in den Kriterien QS (p=0,013), CIRS (p=0,026), PM (p=0,000) und dem Gesamtreifegrad (p=0,019). Im Bereich BM wurden keine statistisch signifikanten Unterschiede festgestellt, jedoch zeigte sich eine positive Entwicklung. In den in 2020 zusätzlich erhobenen fünf Qualitätskriterien wurden die Reifegrade A (voll implementiert) und B (zum großen Teil implementiert) jeweils in folgenden Häufigkeiten angegeben: Audits und Begehungen 100%, Verantwortlichkeiten 95,6%, Morbiditäts- und Mortalitätskonferenzen 65,2%, Hygieneschulungen 95,6% und OP-Checklisten 100%. Schlussfolgerung Das integrierte QRM ist seit Jahren fester Bestandteil am UKSH. Die Wirksamkeitsüberprüfungen der initiierten zielgerichteten Maßnahmen stellen jedoch eine Herausforderung dar. Aus diesem Grund erscheint es notwendig, wirkungsvolle und ressourcenschonende Ansätze für eine Evaluation von Maßnahmen und für die Identifikation von Verbesserungspotentialen zu entwickeln. Die erkannten Verbesserungspotentiale sollen risikopriorisiert und mit umsetzbaren Maßnahmen ausgeschöpft werden. Diesen Grundsätzen folgend konzipierten wir 2016 ein qualitatives Reifegradmodell zur Evaluation des QRM-Systems am UKSH, dessen Weiterentwicklung wir hier aufzeigen.

© 2021 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.Aims: Various studies have reported that young European women are more likely to develop early-onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype-by-sex (G × S) interactions contribute to the increased prevalence and severity. Materials and methods: Using the case-only design, we tested for differences in genetic effects between men and women in 896 North-West European early-onset cases, using imputed genotypes from the OmniExpress genotyping array. Population-representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population. Results: In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S-associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome-wide-associated with heel bone mineral density (CPEB4, MECOM), waist-to-hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13). Conclusions: Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis.

ImportanceApproximately 50% of all patients with cancer have an indication for radiotherapy, and approximately 50% of radiotherapy is delivered with palliative intent, with the aim of alleviating symptoms. Symptoms are best assessed by patient-reported outcomes (PROs), yet their reliable interpretation requires adequate reporting in publications.ObjectiveTo investigate the use and reporting of PROs in clinical trials of palliative radiotherapy.Evidence ReviewThis preregistered systematic review searched PubMed/Medline, EMBASE, and the Cochrane Center Register of Controlled Trials for clinical trials of palliative radiotherapy published from 1990 to 2020. Key eligibility criteria were palliative setting, palliative radiotherapy as treatment modality, and clinical trial design (per National Institutes of Health definition). Two authors independently assessed eligibility. Trial characteristics were extracted and standard of PRO reporting was assessed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. The association of the year of publication with the use of PROs was assessed by logistic regression. Factors associated with higher CONSORT-PRO adherence were analyzed by multiple regression. This study is reported following the PRISMA guidelines.FindingsAmong 7377 records screened, 225 published clinical trials representing 24 281 patients were eligible. Of these, 45 trials (20%) used a PRO as a primary end point and 71 trials (31%) used a PRO as a secondary end point. The most prevalent PRO measures were the Numeric Rating Scale/Visual Analogue Scale (38 trials), European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (32 trials), and trial-specific unvalidated measures (25 trials). A more recent year of publication was significantly associated with a higher chance of PROs as a secondary end point (odds ratio [OR], 1.04 [95% CI, 1.00-1.07]; P = .03) but not as primary end point. Adherence to CONSORT-PRO was poor or moderate for most items. Mean (SD) adherence to the extension adherence score was 46.2% (19.6%) for trials with PROs as primary end point and 31.8% (19.8%) for trials with PROs as a secondary end point. PROs as a primary end point (regression coefficient, 9.755 [95% CI, 2.270-17.240]; P = .01), brachytherapy as radiotherapy modality (regression coefficient, 16.795 [95% CI, 5.840-27.751]; P = .003), and larger sample size (regression coefficient, 0.028 [95% CI, 0.006-0.049]; P = .01) were significantly associated with better PRO reporting per extension adherence score.Conclusions and RelevanceIn this systematic review of palliative radiotherapy trials, the use and reporting of PROs had room for improvement for future trials, preferably with PROs as a primary end point.

OBJECTIVES The aim of this study was to assess single right ventricular (RV) function in a large cohort of hypoplastic left heart syndrome (HLHS) patients after the completion of total cavopulmonary connection by analysing serial cardiovascular magnetic resonance (CMR) studies. METHODS CMR studies from 95 HLHS patients were analysed. RV end-diastolic and end-systolic volumes (RVEDV, RVESV), ejection fraction (RVEF) and long-axis strain (LAS) were measured from cine images. RESULTS All 95 patients had at least 2 CMR scans and 35 patients had 3 CMR scans. The median age (first quartile–third quartile) at the 3 examinations was 4.2 (3.3–6.1), 9.4 (6.1–11.4) and 14.6 (11.8–16.8) years. RV indexed volumes (RVEDVi and RVESVi) increased from first to the second and from the first and second examination to the third examination in patients with >10 years of age (P CONCLUSIONS Serial assessment of CMR studies in HLHS patients after total cavopulmonary connection completion demonstrate an increase in indexed RV volumes in older HLHS patients but only mild reduction in RVEF and LAS. The correlation of indexed RV volumes with RVEF and LAS together with the significant increase in RV volumes over time suggests that indexed RV volumes might be superior to RV functional markers to monitor the RV in HLHS patients.

OBJECTIVES Tissue reaction to transcatheter mitral valve replacement in the mitral annulus remains to be elucidated. METHODS Trileaflet porcine pericardial valves were sewn onto self-expanding d-shaped nitinol stents, which were delivered transapically and in an off-pump fashion into the mitral position of 10 pigs. After at least 4 weeks of follow-up, gross pathological assessment and histological examination were performed. The specimens were stained with Movat’s pentachrome, Elastica-van-Gieson and von Kossa staining. The leucocytes, B cells, T cells or macrophages were detected by specific immunohistochemical staining. RESULTS Proper stent positioning in the mitral annulus was achieved in 9/10 animals. Nine of 10 animals survived the desired observation period. In all but one, the mitral valve stent was well integrated into the left atrium and perpendicularly embedded into the annulus by 85 ± 24%. One animal had minor fractures in the nitinol struts and another animal showed tearing of 1 of 4 tethers. Histological examination demonstrated no major tissue reaction with the nitninol struts but well-preserved overall structures around the mitral annulus in 8/9 cases. CONCLUSIONS This is the first report demonstrating good in-growth of transcatheter-delivered anatomically shaped mitral valve stents after at least 4 weeks of follow-up. Histological examination demonstrated progressive healing and neointimalization.

The basis of phenotypic variation of periodontitis is genetic variability. Disease relevant effects of individual risk alleles are considered to result from genetic interactions. We investigated gene × gene (G×G) interactions of suggestive periodontitis susceptibility alleles.We used the case-only design and investigated single-nucleotide polymorphism (SNPs) that showed associations in our recent genome-wide association study (GWAS) and GWAS meta-analysis with p 5 × 10SNPs at the genes sialic acid binding Ig-like lectin 5 (SIGLEC5) and plasminogen (PLG) showed G×G interactions with rs1122900 at the long non-coding RNA (lncRNA) CTD-2353F22. Associated chromatin cis-activated CTD-2353F22.1 6.5-fold (p = .003), indicating CTD-2353F22.1 as target gene of this interaction. CTD-2353F22.1 regulated GADD45A (pCTD-2353F22.1 mediates interaction of SIGLEC5 and PLG, together with genes that function in periodontal wound healing.

Up to 50% of radiotherapy courses are delivered in palliative intent for various indications. Despite the large number of treated patients, we know little about the choice of endpoints in trials of palliative radiotherapy. Our primary aim was, therefore, to analyze primary endpoints in trials of palliative radiotherapy.We conducted a pre-registered (https://doi.org/10.17605/OSF.IO/GMCAF) meta-research analysis searching Pubmed/MEDLINE, EMBASE, CENTRAL, and "ClinicalTrials.gov" for clinical trials of palliative radiotherapy published 1990-2020. Endpoints were categorized in "patient-centered endpoints", including overall survival and patient-reported outcomes, and "tumor-centered endpoints" such as local control. The remainder were "other endpoints" including toxicity or observer-rated symptoms. We applied descriptive statistics to summarize data and logistic regression to assess if year of publication predicted the choice of primary endpoints.Of 7379 records screened, 292 were eligible. Trials were characterized by small sample sizes and use of external beam radiotherapy for metastases or thoracic primaries. Median patient age was 64 and median ECOG was 1. Only 64.4%(145/225) of published trials clearly stated their primary endpoint. Published trials employed a "patient-centered primary endpoint" in 45.5%(66/145) and a "tumor-centered primary endpoint" in 17.3%(25/145) of the cases. There was no statistically significant trend in time for the use of "patient-centered primary endpoints". Registered ongoing trials used a "patient-centered primary endpoint" in 32.8%(22/67) and a "tumor-centered primary endpoint" in 26.9%(18/67) of the cases.Although "patient-centered primary endpoints" appear relatively prevalent in published trials of palliative radiotherapy, their use is still suboptimal and appears to be lower in currently ongoing trials.

Objectives The aim of this study is to analyze the esthetic perception of selected canine features, namely crown length, shade, inclination, and angle of incisal edge tip. Materials and methods The anterior maxillary teeth of a Central European woman were photographed and digitally modified in order to investigate esthetic perceptions of the above four categories. Three groups of examiners with different levels of experience in the field of dentistry (laypersons/inexperienced dental students, advanced dental students, dentists) evaluated the photographs twice with the help of visual analogue scales. Results The best-evaluated canines have approximately the same length as the central incisor, have the same shade as the other anterior teeth, are best embedded in a lighter overall tooth shade, are neutral to slightly palatal inclined, and have a right angled to rounded incisal edge (≥ 90°). The canines evaluated as least esthetic, however, are longer than the central incisors, darker, inclined labially, and have a tapered incisal edge. No significant differences could be found between the evaluations of the groups with regard to the four feature categories. Conclusions Laypersons, advanced dental students, and dentists generally evaluate according to the same esthetic standards. Gender does not have a significant influence on evaluation. Clear definitions of esthetically favored shades, incisal edge shapes, inclination, and lengths of the canines can be given. Clinical relevance Since the esthetics of the smile line play a critical role for patients, dentists, dental technicians, and their supplying industry, knowledge of the esthetically preferred morphology of canines is essential. Clinical significance The aim of this study is to give clear definitions of esthetically favored shades, incisal edge shapes, and lengths of the canines, as the esthetics of the smile line play a critical role for patients, dentists, dental technicians, and their supplying industry (e.g., denture tooth manufacturers). Precise knowledge of esthetic preferences is important in clinical practice for both dentists and dental technicians, for example, in order to adequately advise patients regarding esthetic corrections. Also, in the case of missing teeth, this knowledge is essential for optimal and satisfactory restorations. Thus, this study can contribute to the satisfaction of general practitioners and patients.

To test a newly introduced implant-abutment material combination against bacterial endotoxin leakage in a human whole blood assay.Two dental implant systems with internal connections and the following material combinations at the implant-abutment interface (IAI) were used (implant material/abutment material): yttrium-stabilized tetragonal zirconium dioxide (Y-TZP)/polyetherketoneketone (PEKK), and titanium (Ti/Ti). Test implants were inoculated with lipopolysaccharide (LPS) and sealed and submerged in human whole blood. Untreated implants served as the control groups. Changes in gene expression levels of inflammatory markers indicating LPS leakage were assessed after 1, 8, and 24 hours using quantitative real-time polymerase chain reaction.In the Y-TZP/PEKK test group, a significant influence of the implant system (P.001) on increases in gene expression indicating leakage were detected after 8 hours for TLR-4 and after 24 hours for interleukin 1-β and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), indicating microleakage of LPS at the IAI. In the Ti/Ti test group, differences in gene expression were found only for NF-κB after 8 hours.The internal hexalobe IAI of two-piece dental implants fabricated from Y-TZP and PEKK do not prevent LPS molecular microleakage.

Background Elevated pre-procedural high-sensitivity troponin T (hs-TnT) levels predict adverse outcomes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). It is unknown whether elevated troponin levels still provide prognostic information during follow-up after successful TAVR. We evaluated the long-term implications of elevated hs-TnT levels found at 1-year post-TAVR. Methods and results The study included 349 patients who underwent TAVR for severe AS from 2010–2019 and for whom 1-year hs-TnT levels were available. Any required percutaneous coronary interventions were performed > 1 week before TAVR. The primary endpoint was survival time starting at 1-year post-TAVR. Optimal hs-TnT cutoff for stratifying risk, identified by ROC analysis, was 39.4 pg/mL. 292 patients had hs-TnT p = 0.010). Multivariate analysis identified 1-year hs-TnT ≥ 39.4 pg/mL (hazard ratio 2.93, 95% CI 1.91–4.49, p 300 pg/mL, male sex, an eGFR < 60 mL/min/1.73 m2 and chronic obstructive pulmonary disease as independent risk factors for long-term mortality after TAVR. Conclusions Elevated hs-TnT concentrations at 1-year after TAVR were associated with a higher long-term mortality. Graphic abstract

Following upon our publication "Maturity Levels of Quality and Risk Management at the University Hospital Schleswig-Holstein" in 2018, we present the further development of the maturity model. Quality and risk management in hospitals is not only required by law but also plays a significant role in an optimized patient- and process-oriented health care.A questionnaire-based self-assessment was carried out by 46 clinical units of the UKSH (location Kiel and Lübeck) for the analysis of nine quality criteria overall. Four of these criteria (quality assurance (QS), critical incident reporting system (CIRS), complaint management (BM) and process management (PM)) were already analysed in 2016 and were extended to the five new aspects, namely audits and on-site inspections, responsibilities, morbidity and mortality conferences, hygiene training and surgical safety checklist. Every quality item was graded into four categories from "A" (fully implemented) to "D" (not implemented at all).The comparison of the results for quality criteria QS, CIRS, BM, PM and the overall maturity level between 2016 and 2020 demonstrated statistically significant improvements in 2020 concerning the criteria QS (p=0.013), CIRS (p=0.026), PM (p=0.000) and the overall maturity levels (p=0.019). The criteria BM did not show any statistically significant improvement. The five newly added quality criteria demonstrated maturity levels "A" (fully implemented) and "B" (largely implemented) the following: audits and on-site inspections (100%), responsibilities (95.6%), morbidity and mortality conferences (65.2%), hygiene training (95.6%), and surgical safety checklist (100%).An integrated quality and risk management has already been a firm element of UKSH for years. Nevertheless, review of effectiveness of the initiated targeted measures is still a challenge. This is the reason why it is necessary to develop effective and resource-saving approaches for the evaluation of measures and the identification of potential for improvement. The recognised potential for improvement should be risk-prioritized and completely exploited using sustainable measures. Following this principle, we designed a qualitative model of maturity levels for the evaluation of our quality and risk management system at the UKSH in 2016, whose further development we demonstrate here.Konsekutiv zu unserer Publikation „Reifegrade des Qualitäts- und Risikomanagementsystems am Universitätsklinikum Schleswig-Holstein“ aus dem Jahr 2018 stellen wir die Weiterentwicklung unseres Reifegradmodells vor. Qualitäts- und Risikomanagement (QRM) in Krankenhäusern sind nicht nur gesetzlich gefordert, sondern führen maßgeblich zu einer optimierten patienten- und ablauforientierten Krankenversorgung.Durch einen strukturierten Erhebungsbogen zur Eigenbewertung erfolgte an 46 Kliniken mit direkter Patientenversorgung an den beiden Standorten des UKSH (Kiel und Lübeck) eine Analyse von insgesamt neun Qualitätskriterien. Vier von diesen Kriterien (Qualitätssicherung (QS), Critical Incident Reporting System (CIRS), Beschwerdemanagement (BM) und Prozessmanagement (PM)) wurden bereits 2016 erhoben und in 2020 um fünf neue Aspekte erweitert – Audits und Begehungen, Verantwortlichkeiten, Morbiditäts- und Mortalitätskonferenzen, Hygieneschulungen und OP-Checklisten. Jedes Qualitätskriterium wurde in vier Kategorien von A (voll implementiert) bis D (nicht implementiert) eingeteilt.Im direkten Ergebnisvergleich der vier Qualitätskriterien und des Gesamtreifegrades von 2016 und 2020 zeigten sich statistisch signifikante Verbesserungen in 2020 in den Kriterien QS (p=0,013), CIRS (p=0,026), PM (p=0,000) und dem Gesamtreifegrad (p=0,019). Im Bereich BM wurden keine statistisch signifikanten Unterschiede festgestellt, jedoch zeigte sich eine positive Entwicklung. In den in 2020 zusätzlich erhobenen fünf Qualitätskriterien wurden die Reifegrade A (voll implementiert) und B (zum großen Teil implementiert) jeweils in folgenden Häufigkeiten angegeben: Audits und Begehungen 100%, Verantwortlichkeiten 95,6%, Morbiditäts- und Mortalitätskonferenzen 65,2%, Hygieneschulungen 95,6% und OP-Checklisten 100%.Das integrierte QRM ist seit Jahren fester Bestandteil am UKSH. Die Wirksamkeitsüberprüfungen der initiierten zielgerichteten Maßnahmen stellen jedoch eine Herausforderung dar. Aus diesem Grund erscheint es notwendig, wirkungsvolle und ressourcenschonende Ansätze für eine Evaluation von Maßnahmen und für die Identifikation von Verbesserungspotentialen zu entwickeln. Die erkannten Verbesserungspotentiale sollen risikopriorisiert und mit umsetzbaren Maßnahmen ausgeschöpft werden. Diesen Grundsätzen folgend konzipierten wir 2016 ein qualitatives Reifegradmodell zur Evaluation des QRM-Systems am UKSH, dessen Weiterentwicklung wir hier aufzeigen.

Purpose Every year, about 4.6 million people are diagnosed with cancer in Europe. However, based on preclinical changes and using appropriate examination procedures certain cancers can be detected in symptom-free patients at an early stage and treatment initiated. In Germany, various cancer screening examinations are currently offered to the relevant age groups and sexes free of charge. Participation rates are affected by a number of factors and barriers. The study aimed at identifying potential obstacles and barriers to uptake, taking into account demographic and socio-economic variables. Materials and methods Data collection was conducted in the context of routine examination appointments at the City of Kiel Occupational Health Department from September 2013 to September 2014 using an anonymised questionnaire. In addition to recording socio-demographic data and tobacco consumption, the questionnaire also catalogued participation in statutory health insurance cancer screening examinations using the “stages of change” from the Transtheoretical Model. Eight potential barriers to participation were recorded. Results The results are based on 718 completed questionnaires. It was found that women, older age, and non-smoking status were associated with a higher probability of participating in cancer screening. It was also found that various barriers affecting (regular) participation were perceived significantly different according to the individual stages of change. This influence of the stages was moderated by gender. Conclusion The results showed interesting trends in the different barriers and how they are influenced by socioeconomic factors and the stages of change. Especially the stages require different gender-specific approaches to mobilisation for cancer screening.

Simple Summary Atopic dermatitis, also called neurodermatitis, is one of the best-known chronic inflammatory skin diseases with eczema, strong itch and dry skin. It is based on an impaired skin barrier with changes in the fats and proteins of the horny layer, which leads to a disturbed water balance. Prurigo nodularis is a less common and intractable chronic skin disease with very itchy nodules. It can be associated with atopic dermatitis (so called atopic prurigo) or with many other diseases. The aim of this study was to compare these three skin diseases classic atopic dermatitis, atopic prurigo and non-atopic prurigo nodularis with healthy control subjects with regard to their skin barrier. In all three disease groups, we then found marked disease severity, reduced water content and increased water loss through the skin, thickening and inflammation of the skin, altered levels of certain proteins and reduced fat layers, all of which demonstrate a severe disturbance of the skin barrier. The main therapeutic consequence is that basic barrier repair, as established for patients with atopic dermatitis in the form of consistent skincare, could also be crucial for patients with non-atopic prurigo nodularis due to this verified skin barrier damage. Abstract A deficient epidermal barrier is a key feature of atopic dermatitis (AD) and comprises altered lipid and protein content and composition of the stratum corneum resulting in disturbed water balance. Clinically, eczematous lesions on dry skin and pruritus develop. Pruritic nodules occur in prurigo nodularis (PN), another chronic skin disease, which can be associated with atopy. We aimed at comparing the three clinical pictures, classic AD, atopic prurigo (AP), and non-atopic PN, to healthy controls regarding the epidermal barrier. We determined clinical parameters and performed biophysical measurements, histology/immunohistochemistry, electron microscopy, and molecular biological analysis. We found distinctively elevated clinical scores, reduced hydration and increased transepidermal water loss, epidermal hyperplasia and inflammation reduced filaggrin and increased loricrin and involucrin expression, as well as reduced intercellular lipid lamellae in all three disease groups. These findings show a severe disruption in epidermal barrier structure and function in all three disorders so that epidermal barrier impairment is now proven not only for AD but also for PN.

OBJECTIVESFemale gender is reported as an independent risk factor for a poor outcome after coronary artery bypass grafting. We analysed the influence of gender on surgical outcome in patients with single-vessel disease undergoing minimally invasive direct coronary artery bypass (MIDCAB).METHODSFrom January 1998 to December 2016, a total of 607 consecutive patients with single-vessel disease (31.9% women) underwent MIDCAB at our institution. Major adverse cardiac and cerebrovascular events (MACCE) were recorded during a median follow-up period of 8.0 years. Survival time was estimated for all patients and after applying propensity score matching (138 women vs 138 men). Multivariable Cox regression analysis identified risk factors predicting a long-term mortality rate.RESULTSIn women, a longer surgical time (125 vs 113 min; P CONCLUSIONSFemale patients showed no adverse outcomes after MIDCAB, although risk factors were gender-specific. Overall, MIDCAB demonstrated excellent short- and long-term results as a treatment for single-vessel disease in both genders.

Objective Therapy of complex aortic root pathologies remains a great surgical challenge. Though different graft materials are available to replace the often-destroyed aortic root, long durability and freedom from reoperation of the latter are still under debate. The aim of our study was to investigate patients' postoperative outcome after implantation of the BioIntegral conduit in complex aortic root pathologies. Methods From February 2014 to May 2017, 33 consecutive patients (69.7% male) with a median age of 73 (57.5; 76.2) years underwent aortic root replacement with the BioIntegral conduit at our institution. Severe aortic valve endocarditis (78.8%) was the predominant indication for surgery. In 28 patients (84.9%), implantation was performed as redo or in 87.8% as urgent and emergent surgery. Primary end-point was the 30-day survival time, evaluated by Cox regression analysis. Secondary midterm outcome and graft-related reoperation were analyzed. Results Median follow-up for all patients was 178 (8; 659) days. Median EuroScore II was 19.9% (13.4; 29.9). Freedom from reoperation was 97%. The overall 30-day mortality rate was 33% mainly caused by multiorgan failure in six (18.2%) patients and cardiac failure in five (15.1%) patients. One further death occurred during follow-up at day 156. None was directly conduit-related. Graft reinfection after the 4th surgery with basal abscess formation occurred in only one patient (3%). Early echocardiographic assessment of the valve revealed good functional results. A higher EuroScore II was significantly associated with a poorer 30-day survival time (hazard ratio, 1.039; 95% confidence interval, 1.015–1.063, p = 0.001). Conclusion Aortic root replacement for complex pathologies is associated with substantial 30-day mortality, but survival of patients after discharge from hospital was stable. Early functional status of the BioIntegral valve was good. Though freedom from re-operation was low, long-term outcome and long-term functional status have to be further evaluated.

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of ‘transcriptomic’ MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10− 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis. Electronic supplementary material The online version of this article (10.1007/s00439-019-01994-x) contains supplementary material, which is available to authorized users.

Background and Purpose— We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods— Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0–2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs—a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results— The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P =0.0007; odds ratio=0.89; 95% CI, 0.82–0.95 and SiGN/GISCOME: P =0.0036; odds ratio=0.94; 95% CI, 0.91–0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80–0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89–0.98) whereas imbalance without ohnologs lacked such an association. Conclusions— Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

ObjectiveTo test the hypothesis that ventricular and atrial function are different between patients with transposition of the great arteries (TGA) after arterial switch operation (ASO) and healthy controls.Methods103 consecutive patients with TGA (median age: 16.7 years, 4.3–39.6 years, 71.8% male) were compared with 77 controls (median age: 15.4 years, 6.3–43.2 years, 66.2% male). Biventricular and biatrial function were assessed using standard cardiovascular magnetic resonance (CMR) techniques and feature tracking. Group comparison was performed with conventional non-parametrical statistics and machine learning methods to find the variables most discriminative between patients and controls. These variables were used to build a multivariable logistic regression model to assess the case–control status.ResultsMarkers of left and right ventricular function (LV; RV) (ejection fraction, MAPSE, TAPSE, LV long-axis strain) as well as LV global longitudinal (−20.7 (−24.1; −17.9) vs −23.7 (−26.1; −21.6), pConclusionsBiventricular and biatrial function are largely preserved after ASO for TGA. Using a comprehensive CMR protocol along with statistical machine learning methods and a regression approach, only RV longitudinal function and LA function are significantly impaired.

Case-only (CO) studies are a powerful means to uncover gene-environment (G × E) interactions for complex human diseases. Moreover, such studies may in principle also draw upon genotype imputation to increase statistical power even further. However, genotype imputation usually employs healthy controls such as the Haplotype Reference Consortium (HRC) data as an imputation base, which may systematically perturb CO studies in genomic regions with main effects upon disease risk. Using genotype data from 719 German Crohn Disease (CD) patients, we investigated the level of imputation accuracy achievable for single nucleotide polymorphisms (SNPs) with or without a genetic main effect, and with varying minor allele frequency (MAF). Genotypes were imputed from neighbouring SNPs at different levels of linkage disequilibrium (LD) to the target SNP using the HRC data as an imputation base. Comparison of the true and imputed genotypes revealed lower imputation accuracy for SNPs with strong main effects. We also simulated different levels of G × E interaction to evaluate the potential loss of statistical validity and power incurred by the use of imputed genotypes. Simulations under the null hypothesis revealed that genotype imputation does not inflate the type I error rate of CO studies of G × E. However, the statistical power was found to be reduced by imputation, particularly for SNPs with low MAF, and a gradual loss of statistical power resulted when the level of LD to the SNPs driving the imputation decreased. Our study thus highlights that genotype imputation should be employed with great care in CO studies of G × E interaction. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02294-z.

Aims Increased shedding of extracellular vesicles (EVs)—small, lipid bilayer-delimited particles with a role in paracrine signalling—has been associated with human pathologies, e.g. atherosclerosis, but whether this is true for cardiac diseases is unknown. Methods and results Here, we used the surface antigen CD172a as a specific marker of cardiomyocyte (CM)-derived EVs; the CM origin of CD172a+ EVs was supported by their content of cardiac-specific proteins and heart-enriched microRNAs. We found that patients with aortic stenosis, ischaemic heart disease, or cardiomyopathy had higher circulating CD172a+ cardiac EV counts than did healthy subjects. Cellular stress was a major determinant of EV release from CMs, with hypoxia increasing shedding in in vitro and in vivo experiments. At the functional level, EVs isolated from the supernatant of CMs derived from human-induced pluripotent stem cells and cultured in a hypoxic atmosphere elicited a positive inotropic response in unstressed CMs, an effect we found to be dependent on an increase in the number of EVs expressing ceramide on their surface. Of potential clinical relevance, aortic stenosis patients with the highest counts of circulating cardiac CD172a+ EVs had a more favourable prognosis for transcatheter aortic valve replacement than those with lower counts. Conclusion We identified circulating CD172a+ EVs as cardiac derived, showing their release and function and providing evidence for their prognostic potential in aortic stenosis patients.