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Aim: 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. Materials and Methods: 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 × 10−6. CRISPR‐dCas9 gene activation followed by RNA‐sequencing and gene‐set enrichment analyses elucidated differentially expressed genes and gene networks. With the databases of SNPInspector and Transfac professional, luciferase reporter gene assays and antibody electrophoretic mobility shift experiments, we analysed allele‐specific effects on transcription factor binding. Results: SNPs 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 (padj < 4.9 × 10−11, log2 fold change (FC) = −0.55), THBS1, SERPINE1 and Tissue Factor F3 (padj < 5 × 10−7, log2 FC ≥ −0.35) and the gene set "angiogenesis" (area under the curve = 0.71, padj = 8.2 × 10−5). rs1122900 effect C‐allele decreased reporter gene activity (5.5‐fold, p =.0003) and PRDM14 binding (76%). Conclusions: CTD‐2353F22.1 mediates interaction of SIGLEC5 and PLG, together with genes that function in periodontal wound healing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide 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  < 0.05). There was a slight decrease in RVEF and LAS throughout the examinations, but this was not statistically significant. Correlations were found between RVEF and LAS (r  = −0.23; P  < 0.01). Both RVEF and LAS correlated with RVEDVi and RVESVi (r  = −0.17 to 0.43; P  < 0.05). 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gene–gene interactions (G × G) potentially play a role in the etiology of complex human diseases, including inflammatory bowel disease (IBD), and may partially explain their 'missing heritability'. Using the largest genotype dataset available for IBD (16,636 Crohn's disease (CD) and 12,888 ulcerative colitis (UC) cases) we analyzed G × G with the powerful case-only (CO) design. We studied 169 single nucleotide polymorphisms (SNPs) for CD (156 for UC), previously shown to be associated with the respective diseases. To ensure the validity of the CO design, we confined our analysis to pairs of unlinked SNPs. We used principal component analysis at the center level to adjust for possible causes of genotypic association other than G × G, such as population stratification and genotyping batch effects. Results from center-wise logistic regression analyses were combined by a random effects meta-analysis. A number of nominally significant (p <.05) G × G interactions were observed, but none of these withstood the Bonferroni multiple testing correction. However, one SNP pair, comprising rs26528 in the IL27 gene and rs9297145 in the KPNA7 gene region was characterized by an interaction odds ratio of 1.18 (95% CI: 1.10–1.27) for CD and a p-value of 7.75 × 10−6. Owing to the concurrent role of the IL27 and KPNA7 genes in NF-κB signaling, a master regulator of pro- and anti-inflammatory processes in IBD, the observed interaction also has biological plausibility. We were able to exemplify the utility of the CO design for analyzing G × G, but had to recognize that such interactions are probably scarce for IBD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. The significance of concomitant tricuspid regurgitation (TR) in the context of transcatheter aortic valve replacement (TAVR) remains unclear. This study aimed to analyze the severity of TR before and after TAVR with regard to short- and long-term survival and to analyze the influencing factors. Methods. In our retrospective analysis, TR before and after TAVR was examined and patients were classified into groups accordingly. Special attention was paid to patients with post-interventional changes in TR. Mortality after TAVR was considered the primary endpoint of the analysis and major complications according to the Valve Academic Research Consortium 3 (VARC3) were compared. Moreover, biomarkers and risk factors for worsening or improvement of TR through TAVR were analyzed. Results. Among 775 patients who underwent TAVR in our center between January 2009 and December 2019, 686 patients (89%) featured low- and 89 patients (11%) high-grade TR. High-grade pre-TAVR TR was associated with worse short- (30-day), mid- (2-year) and long-term survival up to 8 years. Even though in nearly half of the patients with high-grade TR the regurgitation improved within seven days after TAVR (n = 42/89), this did not result in a survival benefit for this subgroup. On the other hand, a worsening of low-grade TR was seen in more than 10% of the patients (n = 73/686), which was also associated with a worse prognosis. Predictors of worsening of TR after TAVR were adipositas, impaired right ventricular function and the presence of mild TR. Age, atrial fibrillation, COPD, impaired renal function and elevated cardiac biomarkers were risk factors for mortality after TAVR independent from the grade of TR. Conclusions. Not only pre-interventional, but also post-TAVR high-grade TR is associated with a worse prognosis after TAVR. TAVR can change concomitant tricuspid regurgitation, but improvement does not have any impact on short- and long-term survival. Worsening of TR after TAVR is possible and impairs the prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Cancer risk assessment for ulcerative colitis patients by evaluating histological changes through colonoscopy surveillance is still challenging. Thus, additional parameters of high prognostic impact for the development of colitis-associated carcinoma are necessary. This meta-analysis was conducted to clarify the value of aneuploidy as predictor for individual cancer risk compared with current surveillance parameters. Methods: A systematic web-based search identified studies published in English that addressed the relevance of the ploidy status for individual cancer risk during surveillance in comparison to neoplastic mucosal changes. The resulting data were included into a meta-analysis, and odds ratios (OR) were calculated for aneuploidy or dysplasia or aneuploidy plus dysplasia. Results: Twelve studies addressing the relevance of aneuploidy compared to dyplasia were comprehensively evaluated and further used for meta-analysis. The meta-analysis revealed that aneuploidy (OR 5.31 [95 % CI 2.03, 13.93]) is an equally effective parameter for cancer risk assessment in ulcerative colitis patients as dysplasia (OR 4.93 [1.61, 15.11]). Strikingly, the combined assessment of dysplasia and aneuploidy is superior compared to applying each parameter alone (OR 8.99 [3.08, 26.26]). Conclusions: This meta-analysis reveals that aneuploidy is an equally effective parameter for individual cancer risk assessment in ulcerative colitis as the detection of dysplasia. More important, the combined assessment of dysplasia and aneuploidy outperforms the use of each parameter alone. We suggest image cytometry for ploidy assessment to become an additional feature of consensus criteria to individually assess cancer risk in UC. [ABSTRACT FROM AUTHOR]

Aim Risk assessment of patients undergoing transcatheter aortic valve implantation ( TAVI) remains difficult. Biomarkers have been shown to provide potential prognostic information . Here, we aimed to analyze whether the biomarker high-sensitivity Troponin T (hs TNT) could be used to improve risk stratification. Method We prospectively enrolled 267 patients undergoing TAVI. Biomarkers (hs TNT and NTpro BNP) were measured 1 day before, and 3 and 7 days postprocedure. All possible prognostic factors upon survival time were analyzed by Cox regression analysis. Results A total of 259 patients (mean age 82±6.1 years) were available for complete follow-up. The median Logistic Euro SCORE (Log ES) and Log ES II were 21.16% (Q1=13.92; Q3=34.27) and 6.42% (Q1=3.89; Q3=11.07), respectively. Median follow-up was 290 (Q1=88; Q3=529) days. A total of 71 deaths occurred during follow-up, and the 30-day mortality was 5.8%. Median baseline hs TNT was 27.4 pg/mL (Q1=16.2; Q3=46 pg/mL). From all potential mortality-associated factors, only preprocedural hs TNT level ( P=.001), elevated Log ES ( P=.03) as well as acute kidney injury ( P<.001) and chronic obstructive pulmonary disease ( COPD) ( P=.039) emerged as independent prognostic parameters for adverse outcome. We also tested whether the Valve Academic Research Consortium-2 ( VARC- II) cutoff for myocardial damage (hs TNT peak value exceeding 15× the upper reference limit + at least 50% increase) was of prognostic relevance. At 72-hours post- TAVI, 36.2% of the patients matched these VARC- II criteria of myocardial damage. However, these patients did not display a difference in survival compared to patients without significant myocardial injury. Conclusion Elevated preprocedural hs TNT represents an independent risk predictor of all-cause death while periprocedural hs TNT elevation failed to show prognostic relevance. [ABSTRACT FROM AUTHOR]

Gene-environment interactions (G × E) have attracted considerable research interest in the past owing to their scientific and public health implications, but powerful statistical methods are required to successfully track down G × E, particularly at a genome-wide level. Previously, a case-only (CO) design has been proposed as a means to identify G × E with greater efficiency than traditional case-control or cohort studies. However, as with genotype-phenotype association studies themselves, hidden population stratification (PS) can impact the validity of G × E studies using a CO design. Since this problem has been subject to little research to date, we used comprehensive simulation to systematically assess the type I error rate, power and effect size bias of CO studies of G × E in the presence of PS. Three types of PS were considered, namely genetic-only (PS), environment-only (PS), and joint genetic and environmental stratification (PS). Our results reveal that the type I error rate of an unadjusted Wald test, appropriate for the CO design, would be close to its nominal level (0.05 in our study) as long as PS involves only one interaction partner (i.e., either PS or PS). In contrast, if the study population is stratified with respect to both G and E (i.e., if there is PS), then the type I error rate is seriously inflated and estimates of the underlying G × E interaction are biased. Comparison of CO to a family-based case-parents design confirmed that the latter is more robust against PS, as expected. However, case-parent trios may be particularly unsuitable for G × E studies in view of the fact that they require genotype data from parents and that many diseases with an environmental component are likely to be of late onset. An alternative approach to adjusting for PS is principal component analysis (PCA), which has been widely used for this very purpose in past genome-wide association studies (GWAS). However, resolving genetic PS properly by PCA requires genetic data at the population level, the availability of which would conflict with the basic idea of the CO design. Therefore, we explored three modified Wald test statistics, inspired by the genomic control (GC) approach to GWAS, as an alternative means to allow for PS. The modified statistics were benchmarked against a stratified Wald test assuming known population affiliation, which should provide maximum power under PS. Our results confirm that GC is capable of successfully and efficiently correcting the PS-induced inflation of the type I error rate in CO studies of G × E. [ABSTRACT FROM AUTHOR]

Purpose: Aneuploidy has long been suggested as an independent prognostic marker for colorectal cancer (CRC) patients and could thus aid for individualized medicine. However, due to a large spectrum of deviating studies, expert panels do not recommend ploidy assessment. In order to clarify a potential bias of stage-specific frequency of aneuploidy, we now conducted a meta-analysis combined with a systematic review regarding aneuploidy and prognosis. Methods: A systematic, web-based search process retrieved 1935 studies published in English between 1990 and 2011. The defined endpoint for the meta-analysis was an increase in aneuploidy frequency between early- (Dukes A, B and UICC I, II; n = 3632 samples) and late-stage (Dukes C, D and UICC III, IV; n = 3440 samples) colorectal carcinomas. Results: Of 1935 studies initially identified, 17 image (2130 patients) and 20 (7023 patients) flow cytometric studies were analyzed in detail. The meta-analysis (7072 patients) revealed late-stage CRC to be more frequently aneuploid than early-stage CRC (odds ratio 1.51, 95 % CI 1.37-1.67; p = 0.0007). Independent of tumor stage, the overall range of aneuploidy was 39 to 81 % (median 58 %), and altogether, 21 (54.1 %) studies described a significant prognostic impact of aneuploidy for overall, disease-specific, and recurrence-free survival, respectively. Conclusions: A substantial number of studies showed a prognostic importance of aneuploidy in CRC. Furthermore, the higher frequency of aneuploidy in late-stage CRC implies an increase in genomic instability with CRC progression, indicating aneuploidy to be also a stage-specific prognostic marker. [ABSTRACT FROM AUTHOR]

Gene-environment ( G × E) interactions have been invoked to account, at least in part, for the gap between the known heritability of common human diseases and the phenotypic variation hitherto explained by genetic variants. Noteworthy in this context, a case-only (CO) design has been proposed in the past as a means to detect G × E interactions possibly more efficiently than by using classical case-control and cohort designs. So far, however, most CO studies have followed a candidate (or single) gene approach, and the genome-wide utility of the CO design is still more or less unknown. In particular, the way in which linkage disequilibrium (LD) impacts upon the chance to detect G × E interaction through the analysis of proxy markers has not been studied in much detail before. Therefore, we systematically assessed the power to indirectly detect a given G × E interaction through exploiting LD in a CO design. Our simulations revealed a strong relationship between LD and detection power that was subsequently validated in a real colorectal cancer data set. [ABSTRACT FROM AUTHOR]

Aim Periodontitis ( PD) is influenced by genetic as well as lifestyle and socio-economic factors. Epidemiological studies show that men are at greater risk of severe forms of PD, suggesting interplay between sex and genetic factors. We aimed to systematically analyse patients with aggressive periodontitis (AgP) for gene-sex interactions. Materials and Methods Three hundred and twenty-nine German AgP cases and 983 controls were genotyped with Affymetrix 500K Arrays and were analysed by logistic regression analysis. The most significant gene-sex interaction was replicated in an independent sample of 382 German/Austrian AgP cases and 489 controls. Results Ten single-nucleotide polymorphisms ( SNPs) in strong linkage disequilibrium ( r 2 > 0.85) upstream the gene neuropeptide Y ( NPY) suggested gene-sex interaction ( p < 5 × 10−5). SNP rs198712 showed the strongest association in interaction with sex ( p = 5.4 × 10−6) with odds ratios in males and females of 1.63 and 0.69 respectively. In the replication, interaction of sex with rs198712 was verified with p = 0.022 (pooled p = 4.03 × 10−6) and similar genetic effects. Analysis of chromatin elements from ENCODE data revealed tissue-specific transcription at the associated non-coding region. Conclusion This study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD. [ABSTRACT FROM AUTHOR]

Objectives: Endodontically treated teeth (ETT) used as abutments for removable partial dental prostheses (RPDPs) have an increased fracture risk as compared to vital abutments. One suggested explanation is that ETT exhibit a lower threshold level for tactile sensitivity than vital teeth. Therefore, this study compared the threshold for tactile sensitivity of vital teeth and ETT in the same individuals. Methods: Forty participants with double crown-retained RPDPs fixed to vital teeth and ETT were included in the study. Each subject had at least one vital and one corresponding contralateral endodontically treated abutment tooth in the same jaw. After removal of the RPDP, an increasing centric force (0 cN to max. 2000 cN) was separately applied axially to both free-standing abutment teeth using a force gauge while the patient was asked to give three acoustic signals: (1) when noticing the first contact, (2) when noticing pressure and (3) when the pressure became displeasing. Afterwards, the same trial was performed with an eccentric force applied parallel to the tooth axis. Results: Statistical analysis revealed no significant differences in the threshold of tactile sensitivity of vital teeth and ETT to either centric or eccentric loading (p > 0.05). Eccentric loading showed lower mean threshold values compared to centric loading. A large variability of tactile sensitivity between individuals was noted. However, there were no gender-related significant differences in tactile sensitivity (p > 0.05). Conclusions: The tactile sensitivity of vital and non-vital teeth seems comparable. Clinical significance: The assumption that a lower threshold level for tactile sensitivity in ETT than in vital teeth is responsible for their increased fracture risk could not be confirmed. Therefore, other reasons, e.g. loss of hard tissue due to root canal treatment, have to be considered responsible for the increased fracture risk of ETT. [ABSTRACT FROM AUTHOR]

In this article we consider three nonparametric maximum likelihood estimators based on mixed-case interval-censored data. Apart from the unrestricted estimator, we consider estimators under the assumption that the underlying distribution function of event times is concave or unimodal. Characterizations of the estimates are derived, and algorithms are proposed for their computation. The estimators are shown to be asymptotically consistent, and the benefits of additional constraints are illustrated through simulations. Finally, the estimators are used as an ingredient in a nonparametric comparison of two samples. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor concerning the increased heritability of gallstone disease in early onset cases is presented.

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. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this laboratory study was to evaluate the influence of the attachment design and material on the retention of resin-bonded attachments (RBAs) before and after dynamic loading. Materials and methods: Forty-eight caries-free human premolars were prepared for RBAs fabricated either from a CoCr alloy or from zirconia ceramic. Specimens were divided into three groups (n = 16 each). Two groups had a standard attachment design for alloys (group M made from a CoCr alloy and group Z1 made from zirconia ceramic). The third group had an attachment design optimized for zirconia ceramic (group Z2 made from zirconia ceramic). Attachments were bonded to the acid-etched enamel of the premolars using a phosphate monomer containing adhesive resin. Subgroups of eight specimens each were either debonded using a tensile force in a universal testing machine at a cross-head speed of 2 mm/min (S) or were exposed to dynamic loading with 50 N over 1200,000 loading cycles in a chewing simulator prior to debonding (D). Results: There were no significant differences in the initial failure loads of groups. With the exception of subgroup Z1-D, all specimens survived the dynamic loading. Statistical analysis showed that dynamic loading caused a significant decrease of failure loads in group Z1. In contrast, subgroup Z2-D exhibited significantly higher failure loads compared to the subgroup Z1-D. Conclusions: The results suggest that zirconia RBAs fabricated with an optimized attachment design may be a valid clinical alternative to metal RBAs. Clinical relevance: Clinical data on the long-term potential of zirconia RBAs is required before these restorations can be recommended for general use. [ABSTRACT FROM AUTHOR]

Objectives: Sonic/ultrasonic devices are essential tools in today's endodontics. This prospective trial evaluated for the first time the impact of practitioners' proficiency levels and patient-related factors on complications associated with a high frequency polyamide sonic irrigant activation device. Methods: In total 334 patients (females:158, males:176; age:18–95 years) received in the course of their endodontic therapy an intracanal irrigation, using a high frequency polyamide sonic irrigant activation device, by practitioners of different proficiency levels (undergraduate students, general practitioners or endodontists). Intracanal bleeding (yes/no), postoperative pain (0–10 scale), emphysema (yes/no) and polyamide tip fractures (yes/no) were recorded and related to proficiency levels, age, gender, tooth type, smoking-status, systemic conditions affecting healing ability, baseline pain, swelling, fistula, sensitivity to percussion and diagnosis. Results: Intracanal bleeding was associated with patients' age (p<0.05), baseline pain level (OR = 1.14, 95%CI = 0.91–1.22) and baseline swelling (OR = 2.73, 95%CI = 0.14–0.99; p<0.05) but not proficiency level, gender, tooth type, smoking, systemic conditions, baseline fistula or sensitivity to percussion (p>0.05). Postoperative pain development was related to proficiency level (p<0.05) and baseline pain level (p<0.001), with no influence of age, gender, tooth type, smoking, systemic conditions, baseline fistula, swelling or sensitivity to percussion (p>0.05). Emphysema and polyamide tip fractures were not reported. Conclusions: Within the current study's limitations, younger patients with higher baseline pain and swelling, were associated with higher intracanal bleeding. Apart from higher postoperative pain observed with less experienced practitioners, proficiency level had no influence on bleeding, polyamide tip fracture or emphysema, endorsing the high frequency polyamide sonic irrigation device as a safe therapeutic device. [ABSTRACT FROM AUTHOR]

Objective The aim of this laboratory study was to evaluate the horizontal and vertical effects of the polymerization shrinkage of three-unit temporary fixed dental prostheses (FDPs) on the position of the prepared teeth. In addition, the reduction of these effects by using different fabrication techniques was evaluated. Methods A total of 192 temporary FDPs were fabricated using one methacrylate (MA) and two dimethacrylate (DMA) materials. Each material group (n = 64) was divided into two groups according to the fabrication methods (M1: curing on the prepared teeth, M2: curing in a silicone mold). Each fabrication group was divided into four subgroups (n = 8) according to the relining method used (B: no relining, S: spacer foil 300 μm, DG: grinding-out with 500 μm cutting depth, and FG: free grinding). The experimental apparatus consisted of two abutment teeth lowered at right angles into a silicone mold. One prepared tooth was embedded in silicone to simulate the periodontium and permit slight horizontal tooth movement. The dimensional changes were recorded with an optical microscope. The test images were superimposed and measured using image analysis software. Results The statistical analysis showed that there were significantly higher horizontal changes for the MA than the DMA resins in M1, while there was none in M2. Regarding the vertical changes, there were significant differences between the baseline group and all relining and fabrication groups in all materials. Significance Relining of directly fabricated temporary FDPs significantly reduces the effect of polymerization shrinkage and thus secures the position of the prepared teeth. [ABSTRACT FROM AUTHOR]

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

• Systematic meta-research analysis on endpoints in trials of palliative radiotherapy. • Trials are dominated by small sample sizes and external-beam radiotherapy. • "Patient-centered primary endpoints" are relatively often used in published trials. • Surrogate "tumor-centered primary endpoints" seem common in ongoing trials. 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. [ABSTRACT FROM AUTHOR]

Background. Today, many adhesive systems with different coupling agents for tooth structures and restorative materials are available. The purpose of this in vitro study was to evaluate the tensile bond strength (TBS) of different universal adhesive systems to etched lithium disilicate ceramic. Methods. The authors etched and bonded 96 disk-like lithium disilicate ceramic specimens (IPS e.max CAD, Ivoclar Vivadent) with 4 different adhesive bonding systems to Plexiglas tubes filled with a composite resin. The authors stored the specimens in water at 37°C for 3 days without thermal cycling or for 30 or 150 days with 7,500 or 37,500 thermal cycles between 5°C and 55°C, respectively. Then, all specimens underwent TBS testing. The authors performed statistical analysis by using Kruskal-Wallis and Wilcoxon tests with a Bonferroni-Holm correction for multiple testing. Results. Initially, all adhesive systems exhibited considerable TBS, but some showed a significant reduction after 30 days of storage. After 3,30, and 150 days, the Monobond Plus and Multilink Automix (Ivoclar Vivadent) silane-containing adhesive system showed significantly higher bond strengths to lithium disilicate ceramic than did the other universal adhesive systems, some of which do not contain silanes. Conclusions. The bond strength to lithium disilicate ceramic is affected significantly by the adhesive bonding system used. Practical Implications. Universal adhesive systems that do not contain a silane should be avoided for bonding lithium disilicate ceramic restorations because of their inferior bond strength. [ABSTRACT FROM AUTHOR]

Aims: Transcatheter aortic valve implantation (TAVI) has emerged as a treatment of aortic stenosis in patients at high surgical risk. However, risk stratification in this elderly population is challenging, as patients at extreme risk might not benefit from TAVI. While several clinical criteria have been proposed for estimating the outcome, prediction of individual risk remains difficult. Therefore, our aim was to assess the prognostic value of the biomarker growth differentiation factor 15 (GDF15).Methods and Results: Over a 2.9-year period, we prospectively enrolled 217 patients undergoing TAVI. Clinical parameters, risk scores, and biomarkers (NT-proBNP and GDF15) were measured at baseline. The primary endpoint was survival time; prognostic factors were analysed by Cox regression analysis. Mean age of study participants was 81.8 ± 6.0 years. Median Logistic EuroSCORE was 20.1 (Q1-Q3 13.6-32.6). Thirty-day mortality was 6.9%; 30.4% of the patients died during follow-up [median 349 days (Q1-Q3 106-660)]. Median pre-procedural GDF15 values were 2256 pg/mL (1585-3082). High GDF15 levels were associated with numerous factors that could contribute to poor outcome. Analyses comparing the upper quartile with the lower three quartiles for biomarker levels revealed a hazard ratio (HR) of increased GDF15 for adverse outcome of 2.4 [95% confidence interval (CI) 1.5-3.9, P < 0.001]. Of note, in multiple analyses, elevated GDF15 levels were superior to NT-proBNP for predicting negative outcome (adjusted HR of GDF15 1.97, 95% CI 1.2-3.3; P = 0.009).Conclusion: Elevated GDF15 levels were superior to NT-proBNP for TAVI risk stratification and provided additional prognostic information. Thus, patient selection for TAVI may benefit from measurement of GDF15. [ABSTRACT FROM AUTHOR]

Introduction: Different devices and techniques are available for endovascular treatment of ischemic stroke. In this in vitro study, we examined the stent-thrombus interaction and the influence of additional aspiration on the efficiency of mechanical thrombectomy with established stent retrievers. Methods: Human blood thrombi were made in a Chandler loop. The thrombi were placed into the middle cerebral artery of a vascular silicon phantom. A programmable piston pump was used to acquire physiological flow in the model. Resistances were interposed to gain physiological pressure. The stent retrievers Trevo, Solitaire FR, Separator 3D, and Aperio were used to perform thrombectomy under direct visual control. For the additional aspiration, we used intermediate catheters. Results: Ten attempts per device were made with and without aspiration under standardized conditions, a total of n = 80. For all thrombectomy maneuvers, it was demonstrated that the thrombus was pushed by the stent struts against the vessel wall and was retracted along it. The stent-thrombus interaction was only superficial for all devices. Using additional distal aspiration, the amount of distal embolism and rate of embolism in new territories was significantly lower than without. Moreover, additional aspiration reduced the number of recanalization maneuvers and the recanalization time. Conclusion: Distal aspiration with intermediate catheters increases the efficacy of mechanical thrombectomy with stent retrievers significantly. In contrary to earlier suggestions, the interaction between the thrombus and the stent retriever is only superficial, rather than an integration of the thrombus into the retriever. No significant differences between the proven devices could be shown in our model. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The purpose of this in vitro study was to evaluate the bond strength and durability of adhesive bonding systems to amorphous and crystalline PEKK and fiber-reinforced PEEK using five types of surface conditioning methods. Methods: One hundred and fifty specimens of each material were conditioned mechanically and chemically, bonded with Multilink Automix to Plexiglas tubes, filled with Multicore Flow, and stored in water at 37°C for 3, 30 and 150 days. The long-term storage series were thermal cycled between 5 and 55°C for 10,000 times (30 days) or for 37,500 times (150 days) prior to tensile bond strength test (TBS). Statistical analysis was performed using Kruskal–Wallis and Wilcoxon tests with a Bonferroni–Holm correction for multiple testing (α =0.05). Results: Fiber-reinforced PEEK exhibited higher bond strengths in all five conditioning groups and at all three storage times than crystalline and amorphous PEKK, which showed lowest TBS. Highest TBS was achieved after conditioning with silica coating and priming (Rocatec Soft, Monobond Plus, Luxatemp Glaze & Bond; TBS up to 23.6MPa). Significance: The conditioning method has a significant influence to the bond strength of the bonding to the amorphous and crystalline PEKKs and fiber-reinforced PEEKs. [Copyright &y& Elsevier]

Current prostate cancer risk classifications rely on clinicopathological parameters resulting in uncertainties for prognostication. To improve individual risk stratification, we examined the predictive value of selected proteins with respect to tumor heterogeneity and genomic instability. We assessed the degree of genomic instability in 50 radical prostatectomy specimens by DNA-Image-Cytometry and evaluated protein expression in related 199 tissue-microarray (TMA) cores. Immunohistochemical data of SATB1, SPIN1, TPM4, VIME and TBB5 were correlated with the degree of genomic instability, established clinical risk factors and overall survival. Genomic instability was associated with a GS ≥ 7 (p = 0.001) and worse overall survival (p = 0.008). A positive SATB1 expression was associated with a GS ≤ 6 (p = 0.040), genomic stability (p = 0.027), and was a predictor for increased overall survival (p = 0.023). High expression of SPIN1 was also associated with longer overall survival (p = 0.048) and lower preoperative PSA-values (p = 0.047). The combination of SATB1 expression, genomic instability, and GS lead to a novel Prostate Cancer Prediction Score (PCP-Score) which outperforms the current D'Amico et al. stratification for predicting overall survival. Low SATB1 expression, genomic instability and GS ≥ 7 were identified as markers for poor prognosis. Their combination overcomes current clinical risk stratification regimes. [ABSTRACT FROM AUTHOR]

Purpose: Presently, no markers exist to predict metachronous metastasis at the time a primary colorectal cancer is diagnosed. While aneuploidy indicates poor survival prognosis and elevated carcinoembryonic antigen (CEA) levels the presence of recurrent disease, the predictive value of both markers regarding imminent metachronous metastases is unclear. Methods: Sixty patients with distant recurrence throughout a 5-year follow-up (TM+) were randomly chosen and 60 patients without metastasis matched to this cohort (TM−). In addition, an enlarged collective ( n = 217; n = 85, n = 132) with median follow-up of 79.2 months was assessed by logistic regression regarding metachronous metastases. Univariate and stepwise regression analyses included clinicopathological characteristics, preoperative CEA levels and aneuploidy assessed by DNA image cytometry. Results: The matched-pair collective showed aneuploidy in 71.1 % (TM−) and 85.0 % (TM+; p = 0.076), and elevated CEA in 24.5 % (TM−) and 52.2 % [TM+; odds ratio (OR), 3.414; p = 0.007]. The enlarged collective presented aneuploidy in 71.2 % (TM−) and 83.5 % (TM+; OR 2.050, p = 0.038), and elevated CEA in 28.6 % (TM−) and 48.9 % (TM+; OR 2.391, p = 0.020). Elevated CEA and aneuploidy did not show any association ( p = 0.919). In contrast, logistic regression analyses demonstrated that besides increased T category (OR 1.745, p = 0.019), both elevated CEA level (OR 2.633, p = 0.015) and aneuploidy (OR 1.929, p = 0.058) were independent predictive markers for metachronous metastasis. Conclusions: Our data show that aneuploidy and elevated CEA levels besides increased T category could serve for individual risk assessment to predict metachronous metastases. The fact that still aneuploidy missed the significance level by a small margin emphasizes the need for larger validation studies. [ABSTRACT FROM AUTHOR]

Introduction. Aneuploidy has been suggested as independent prognostic marker in ulcerative colitis (UC) patients for developing UC-associated colorectal carcinomas (UCCs). UCCs are associated with a poorer prognosis and more frequently present with synchronous carcinomas when compared with sporadic colorectal carcinomas (SCCs). The authors therefore investigated if the adjacent non-malignant mucosa of aneuploid UCCs and aneuploid SCCs shows differences regarding the frequency of aneuploidy and if this aneuploidy is associated with histomorphological alterations. Methods. Primary tumors of 25 UCCs and 20 SCCs were selected showing exclusively aneuploid DNA patterns and matching DNA stemlines. The UCCs' ( n = 82) and SCCs' ( n = 40) adjacent non-malignant mucosa were evaluated for histopathology and assessed for DNA ploidy status by image cytometry. Results. UCCs' non-malignant mucosa showed dysplasia in 31.7% and aneuploidy in 89%. In contrast, SCCs' non-malignant mucosa revealed no dysplasia and aneuploidy in only 5%. Irrespective of dysplastic lesions, aneuploidy was observed more frequently in adjacent non-malignant mucosa of UCCs than of SCCs ( p < 0.001). Neither a correlation between aneuploidy and inflammation ( p = 0.916) nor between aneuploidy and dysplastic lesions ( p = 0.159) could be observed. Conclusion. Aneuploidy is more frequent in adjacent non-malignant mucosa of aneuploid UCCs than in adjacent non-malignant mucosa of aneuploid SCCs. Furthermore, aneuploidy seems to be irrespective of inflammation or dysplasia. The results therefore emphasize the importance of aneuploidy for UC-associated carcinogenesis and its potential as new diagnostic target. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Transcatheter pulmonary valve replacement has become a valid treatment option for right ventricular outflow tract diseases. However, some limitations occur in patients with wide, compliant right ventricular outflow tracts that might be amenable to treatment with self-expanding valved protheses. An experimental ovine study was designed to evaluate a novel dip-coated, low-profile trileaflet polycarbonate urethane (PCU) heart valve mounted into a self-expandable nitinol stent. METHODS The PCU valves were produced by a dip-coating technique, mounted in a conical-shaped nitinol stent and provided with a leaflet thickness of 100–150 µm. The valved stents were implanted percutaneously via transfemoral access in 6 consecutive sheep divided into 2 groups. Three animals were followed up for 1 month and the remainder, for 6 months. Angiographic measurements and transthoracic echocardiography were performed before and after implantation and at the end of the 1- or 6-month observation period, respectively. RESULTS Orthotopic positioning of the valve was achieved in all animals. All except 1 had competent valves during the follow-up period. The peak-to-peak gradient across the PCU valved stents was 4.6 ± 1.0 mmHg after 1 month and 4.4 ± 2.3 mmHg after 6 months of follow-up. Macroscopic and microscopic post-mortem evaluation indicated good morphological and structural results. There were no stent fractures, leaflet calcification or thrombus formation. CONCLUSIONS This study demonstrates successful transcatheter pulmonary valve replacement with a novel dip-coated valved nitinol stent. The trileaflet PCU prostheses indicated good functional and biocompatible properties after a 6-month observation period. [ABSTRACT FROM AUTHOR]

Objectives: The knowledge about the influence of dental treatment on health-related quality of life (HRQoL) is still limited. The aim of this multicenter randomized controlled clinical trial was to assess the effect of stabilizing an existing complete denture, by means of a single mandibular implant, on HRQoL. Furthermore, the impact of the loading protocol, i.e., immediate or delayed loading, in edentulous patients was evaluated. Methods: One hundred fifty-eight participants aged 60–89 years were randomly assigned to study group A (immediate loading; n = 81) and to group B (delayed loading; n = 78). All participants received a single midline implant in the mandible. The implants were either immediately loaded (group A) or after a closed healing period of 3 months (group B) by connecting the existing mandibular complete dentures to ball attachments. HRQoL was assessed with the Short Form-36 questionnaire of health (SF-36) at baseline, 4 months, and 24 months after implant loading. Results: Improvement of HRQoL by means of a single implant-retained mandibular overdenture could not be demonstrated after 4 and 24 months of implant loading. Furthermore, the application of two different loading protocols did not influence HRQoL ratings of study participants. Conclusion: The loading protocol is not a factor, influencing HRQoL in patients treated by a single midline implant in the edentulous mandible. Clinical relevance: A single midline implant in the edentulous mandible, stabilizing a mandibular complete denture, cannot be recommended for improving HRQoL. [ABSTRACT FROM AUTHOR]

Hyperalgesia and allodynia are frequent in neuropathic pain. Some pain questionnaires such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and the Neuropathic Pain Scale (NPS) include self-assessment or bedside testing of hyperalgesia/allodynia. The aim of this study was to determine to what extent LANSS and NPS data are congruent with findings on quantitative sensory testing (QST). Self-reported presence of dynamic mechanical allodynia (DMA) and descriptors of hot, cold, or deep ongoing pain (the NPS and LANSS) as well as bedside findings of mechanical allodynia (LANSS) were compared with signs of DMA and thermal hyperalgesia on QST in 617 patients with neuropathic pain. Self-reported abnormal skin sensitivity (LANSS) showed a moderate concordance with DMA during bedside test (67.9%, κ = 0.391) or QST (52.8%, κ = 0.165). Receiver operating curve analysis for self-reported DMA yielded similar area-under-the-curve values for the LANSS (0.65, confidence interval: 0.59%-0.97%) and NPS (0.71, confidence interval: 0.66%-0.75%) with high sensitivity but low specificity. Self-reported deep pain intensity was higher in patients with blunt pressure hyperalgesia, but not in patients with DMA or thermal hyperalgesia. No correlations were observed between self-reported hot or cold pain quality and thermal hyperalgesia on QST. Self-reported abnormal skin sensitivity has a high sensitivity to identify patients with DMA, but its low specificity indicates that many patients mean something other than DMA when reporting this symptom. Self-reported deep pain is related to deep-tissue hypersensitivity, but thermal qualities of ongoing pain are not related to thermal hyperalgesia. Questionnaires mostly evaluate the ongoing pain experience, whereas QST mirrors sensory functions. Therefore, both methods are complementary for pain assessment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Gut microbiota represent a potential novel target for future prediabetes and type 2 diabetes therapies. In that respect, niacin has been shown to beneficially affect the host-microbiome interaction in rodent models.Research Design and Methods: We characterized more than 500 human subjects with different metabolic phenotypes regarding their niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and their gut microbiome. In addition, NA and NAM delayed-release microcapsules were engineered and examined in vitro and in vivo in two human intervention studies (bioavailability study and proof-of-concept/safety study).Results: We found a reduced α-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.Conclusion: Targeted microbiome intervention by delayed-release NA might represent a future therapeutic option for prediabetes and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers ( n = 12) and patients with early- ( n = 7) and late-stage ( n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected ( p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities ( p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls ( n = 15), early-stage CRCs ( n = 15), late-stage CRCs ( n = 15)]. Two proteins-clusterin and glutathione synthetase (GSH-S)-featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial. [ABSTRACT FROM AUTHOR]

Background: Nuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible transcription factor being essential in regulating cell homeostasis. Thus, acute induction of Nrf2 in epithelial cells exposed to inflammation confers protection from oxidative cell damage and mutagenesis supporting an anti-tumorigenic role for Nrf2. However, pancreatic ductal adenocarcinoma (PDAC) is characterized by persistent Nrf2 activity conferring therapy resistance which points to a pro-tumorigenic role of Nrf2. A similar dichotomous role in tumorigenesis is described for the Transforming Growth Factor-beta 1 (TGF-β1). The present study therefore aimed at elucidating whether the switch of Nrf2 function towards a tumor promoting one relates to the modulation of TGF-β1 induced cell responses and whether this might occur early in PDAC development.Methods: In situ analysis comprised immunohistochemical stainings of activated (phosphorylated) Nrf2 and Ki67 in pancreatic tissues containing normal ducts and pancreatic intraepithelial neoplasia (PanINs). In vitro, Nrf2 levels in benign (H6c7-pBp), premalignant (H6c7-kras) and malignant (Colo357) pancreatic ductal epithelial cells were modulated by Nrf2 specific siRNA or Nrf2 overexpression. Then, the effect of Nrf2 alone and in combination with TGF-β1 on cell growth and survival was investigated by cell counting, Ki67 staining and apoptosis assays. The underlying cell signaling was investigated by western blotting. Statistical analysis was performed by Shapiro-Wilk test for normal distribution. Parametric data were analyzed by one-way ANOVA, while non-parametric data were analyzed by Kruskal-Wallis one-way ANOVA on ranks.Results: Significantly elevated expression of activated Nrf2 and Ki67 could be detected in PanINs but not in normal pancreatic ductal epithelium. While the effect of Nrf2 on basal cell growth of H6c7-pBp, H6c7-kras and Colo357 cells was minor, it clearly attenuated the growth inhibiting effects of TGF-β1 in all cell lines. This enhanced Nrf2-mediated cell survival was predominantly based on an enhanced proliferative activity. Accordingly, expression of p21 expression along with expression of phospho-p38 and phospho-Smad3 was diminished whereas Erk-phosphorylation was enhanced under these conditions.Conclusions: Overall, our data demonstrate that Nrf2 being elevated in early precursor lesions counteracts the growth inhibiting function of TGF-β1 already in benign and premalignant pancreatic ductal epithelial cells. This could represent one fundamental mechanism underlying the functional switch of both- TGF-β1 and Nrf2 - which may manifest already in early stages of PDAC development. [ABSTRACT FROM AUTHOR]

I Cardiovascular Research i , cvab290, https://doi.org/10.1093/cvr/cvab290 I Cardiovascular Research i , 2021,https://doi.org/10.1093/cvr/cvab290 In the originally published version of this article, an error was noted. The following text should read: "whereas an FiO SB 2 sb of 0.16 resulted in mild hypoxaemia (hx; PaO SB 2 sb , 75 ± 16 mmHg; SaO SB 2 sb , 89 ± 3%) (4-6 mice per group)" instead of "whereas an FiO SB 2 sb of 0.16 resulted in mild hypoxaemia (hx; PaO SB 2 sb , 104 ± 15 mmHg; SaO SB 2 sb , 92 ± 3%) (4-6 mice per group)". [Extracted from the article]

Highlights: [•] lincRNAs are transcripts from non-coding DNA. [•] We found that IL-6 and TNF-α regulate different types of lincRNAs in vivo. [•] Our data suggest a role for lincRNA in the pathophysiology of RA. [•] Our data indicate lincRNAs to be specifically regulated by pharmaceutical agents. [Copyright &y& Elsevier]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP. [ABSTRACT FROM AUTHOR]

Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance. [ABSTRACT FROM AUTHOR]

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 immunocom-promised 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. [ABSTRACT FROM AUTHOR]

Y-chromosomal and mitochondrial DNA (mtDNA) polymorphisms have been used for population studies for a long time. However, there is another possibility to define the origin of a population: autosomal single-nucleotide polymorphisms (SNPs) whose allele frequencies differ considerably in different populations. In an attempt to compare the usefulness of these approaches we studied a population from Madagascar using all the three mentioned approaches. Former investigations of Malagasy maternal (mtDNA) and paternal (Y chromosome) lineages have led to the assumption that the Malagasy are an admixed population with an African and Asian-Indonesian heritage. Our additional study demonstrated that more than two-third of the Malagasy investigated showed clearly a West African genotype regarding only the autosomal SNPs despite the fact that 64% had an Asian mtDNA and more than 70% demonstrated an Asian-Indonesian heritage in either mtDNA or Y-chromosomal haplogroup or both. Nonetheless, the admixture of the Malagasy could be confirmed. A clear African or Asian-Indonesian heritage according to all the three DNA approaches investigated was only found in 14% and 1% of male samples, respectively. Not even the European or Northern African influences, detected in 9% of males (Y-chromosomal analysis) and 11% of samples (autosomal SNPs) were consistent. No Malagasy in our samples showed a European or Northern African origin in both categories. So, the analysis of autosomal SNPs could confirm the admixed character of the Malagasy population, even if it pointed to a greater African influence as detectable by Y-chromosomal or mtDNA analysis. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study was to evaluate the linear and volumetric dimensional changes of six denture base resins processed by their corresponding injection-molding systems at 3 time intervals of water storage. Materials and methods: Two heat-curing (SR Ivocap Hi Impact and Lucitone 199) and four auto-curing (IvoBase Hybrid, IvoBase Hi Impact, PalaXpress, and Futura Gen) acrylic resins were used with their specific injection-molding technique to fabricate 6 specimens of each material. Linear and volumetric dimensional changes were determined by means of a digital caliper and an electronic hydrostatic balance, respectively, after water storage of 1, 30, or 90 days. Means and standard deviations of linear and volumetric dimensional changes were calculated in percentage (%). Statistical analysis was done using Student's and Welch's t tests with Bonferroni–Holm correction for multiple comparisons (α =0.05). Results: Statistically significant differences in linear dimensional changes between resins were demonstrated at all three time intervals of water immersion (p ≤0.05), with exception of the following comparisons which showed no significant difference: IvoBase Hi Impact/SR Ivocap Hi Impact and PalaXpress/Lucitone 199 after 1 day, Futura Gen/PalaXpress and PalaXpress/Lucitone 199 after 30 days, and IvoBase Hybrid/IvoBase Hi Impact after 90 days. Also, statistically significant differences in volumetric dimensional changes between resins were found at all three time intervals of water immersion (p ≤0.05), with exception of the comparison between PalaXpress and Futura Gen. Significance: Denture base resins (IvoBase Hybrid and IvoBase Hi Impact) processed by the new injection-molding system (IvoBase), revealed superior dimensional precision. [Copyright &y& Elsevier]

Introduction: Lung-protective ventilation aims at using low tidal volumes (VT) at optimum positive end-expiratory pressures (PEEP). Optimum PEEP should recruit atelectatic lung regions and avoid tidal recruitment and end-inspiratory overinflation. We examined the effect of VT and PEEP on ventilation distribution, regional respiratory system compliance (CRS), and end-expiratory lung volume (EELV) in an animal model of acute lung injury (ALI) and patients with ARDS by using electrical impedance tomography (EIT) with the aim to assess tidal recruitment and overinflation. Methods: EIT examinations were performed in 10 anaesthetized pigs with normal lungs ventilated at 5 and 10 ml/kg body weight VT and 5 cmH2O PEEP. After ALI induction, 10 ml/kg VT and 10 cmH2O PEEP were applied. Afterwards, PEEP was set according to the pressure-volume curve. Animals were randomized to either low or high VT ventilation changed after 30 minutes in a crossover design. Ventilation distribution, regional CRS and changes in EELV were analyzed. The same measures were determined in five ARDS patients examined during low and high VT ventilation (6 and 10 (8) ml/kg) at three PEEP levels. Results: In healthy animals, high compared to low VT increased CRS and ventilation in dependent lung regions implying tidal recruitment. ALI reduced CRS and EELV in all regions without changing ventilation distribution. Pressure-volume curve-derived PEEP of 21±4 cmH2O (mean±SD) resulted in comparable increase in CRS in dependent and decrease in non-dependent regions at both VT. This implied that tidal recruitment was avoided but end-inspiratory overinflation was present irrespective of VT. In patients, regional CRS differences between low and high VT revealed high degree of tidal recruitment and low overinflation at 3±1 cmH2O PEEP. Tidal recruitment decreased at 10±1 cmH2O and was further reduced at 15±2 cmH2O PEEP. Conclusions: Tidal recruitment and end-inspiratory overinflation can be assessed by EIT-based analysis of regional CRS. [ABSTRACT FROM AUTHOR]

The characterization of externally visible traits by DNA analysis is already an important tool when investigating ancient skeletal remains and may gain similar importance in future forensic DNA analysis. This, however, depends on the different legal regulations in the different countries. Besides eye or hair color, the population origin can provide crucial information in criminal prosecution. In this study, we present the analysis of 16 single-nucleotide polymorphisms (SNPs) combined to two robust SNaPshot assays with a detection threshold of 25-pg DNA. This assay was applied to 891 people from seven different populations (West Africa, North Africa, Turkey, Near East, Balkan states, North Europe, and Japan) with a thorough statistical evaluation. The prediction model was validated by an additional 125 individuals predominantly with an ancestry from those same regions. The specificity of these SNPs for the prediction of all population origins is very high (>90 %), but the sensitivity varied greatly (more than 90 % for West Africa, but only 25 % for the Near East). We could identify West Africans with a certainty of 100 %, and people from North Africa, the Balkan states, or North Europe nearly with the same reliability while determination of Turks or people from the Near East was rather difficult. In conclusion, the two SNaPshot assays are a powerful and reliable tool for the identification of people with an ancestry in one of the above listed populations, even from degraded DNA. [ABSTRACT FROM AUTHOR]

Microleakage has been discussed as a major contributing factor for inflammatory reactions at the implant-abutment connection. In previous studies, the tightness against corpuscular bodies (viable bacteria) has been successfully investigated under static and dynamic conditions. The aim of this study was to investigate the tightness against endotoxins of two implant systems (AstraTech and Ankylos) with conical internal connections under static conditions. The inner parts of eight implants of each system were inoculated with endotoxin. Implants were screwed together with the respective abutments and stored under isostatic conditions in a supernatant of pyrogen-free water for 168 h. Supernatant samples were taken after 5 min, 24 h, 72 h, and 168 h, and endotoxin contamination was determined by the amebocyte-lysate test. Only one implant in the AstraTech group showed no sign of endotoxin contamination after 168 h, while the other implants showed contamination after varying storage times, respectively. The implants in the Ankylos group showed endotoxin contamination after only 5 min of storage in the supernatant solution. The tested internal conical implant-abutment connections appear to be unable to prevent endotoxin leakage. In average, Astra implants showed a higher tightness than Ankylos implants. [ABSTRACT FROM AUTHOR]

Genetic matching potentially provides a means to alleviate the effects of incomplete Mendelian randomization in population-based gene–disease association studies. We therefore evaluated the genetic-matched pair study design on the basis of genome-wide SNP data (309 790 markers; Affymetrix GeneChip Human Mapping 500K Array) from 2457 individuals, sampled at 23 different recruitment sites across Europe. Using pair-wise identity-by-state (IBS) as a matching criterion, we tried to derive a subset of markers that would allow identification of the best overall matching (BOM) partner for a given individual, based on the IBS status for the subset alone. However, our results suggest that, by following this approach, the prediction accuracy is only notably improved by the first 20 markers selected, and increases proportionally to the marker number thereafter. Furthermore, in a considerable proportion of cases (76.0%), the BOM of a given individual, based on the complete marker set, came from a different recruitment site than the individual itself. A second marker set, specifically selected for ancestry sensitivity using singular value decomposition, performed even more poorly and was no more capable of predicting the BOM than randomly chosen subsets. This leads us to conclude that, at least in Europe, the utility of the genetic-matched pair study design depends critically on the availability of comprehensive genotype information for both cases and controls.European Journal of Human Genetics (2009) 17, 967–975; doi:10.1038/ejhg.2008.266; published online 21 January 2009 [ABSTRACT FROM AUTHOR]

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. 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. [ABSTRACT FROM AUTHOR]