IDH1 mutation is associated with improved resection rates, progression-free survival and overall survival in patients with anaplastic astrocytomas.

PURPOSE: The introduction of molecular markers in to the diagnosis of gliomas has changed the therapeutic approach to this tumors. The aim of this study was to examine the impact of surgery on anaplastic astrocytomas (AA), which has not previously been fully elucidated. METHODS: This was a retrospective study involving a total of 143 patients who underwent surgery for primary AA in our department between 1995 and 2020. RESULTS: Total tumor resection was achieved more often in patients with IDH-mutant tumors (41.09%) than in patients with IDH-wildtype tumors (30.76%). The median PFS was 1876 days for patients with IDH1 mutations and 238 days for patients with IDH-wildtype tumors. The 1-, 3-, 5- and 10-year PFS were longer in patients with total tumor resection and IDH-mutant AA (86.2%, 69%, 65.5% and 44.8%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (83.3%, 55.6%, 41.7% and 25%, respectively) and even longer compared to all IDH-wildtype tumors. The median OS was 2472 days for patients with IDH1 mutations and 434 days for patients with IDH-wildtype tumors. The 3-, 5- and 10-year OS times were longer in patients with total tumor resection and IDH-mutant AA (89.2%, 85.2% and 72.6%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (85.9%, 73.7% and 52.6%, respectively) and were even longer compared to all IDH-wildtype tumors. CONCLUSION: Total tumor resection is more common with IDH-mutant AA than with IDH-wildtype tumors. Patients with IDH-mutant AA had significantly better PFS and OS after total tumor resection than after subtotal tumor resection and biopsy.

Sociodemographic and Environmental Determinants of Regional Prevalence of Psoriasis in Germany: A Spatiotemporal Study of Ambulatory Claims Data.

There are regional differences in the prevalence of psoriasis between countries, as well as within countries. However, regional determinants of differences in prevalence are not yet understood. The aim of this study was to identify sociodemographic and environmental determinants of regional prevalence rates for psoriasis. Analyses were based on German outpatient billing data from statutory health insurance, together with data from databases on sociodemographic and environment factors at the county level (N = 402) for 2015-2017. Descriptive statistics were calculated for all variables. To identify determinants for prevalence at the county level, spatiotemporal regression analysis was performed, with prevalence as the dependent variable, and the number of physicians, mean age, mean precipitation, sunshine hours, mean temperature, level of urbanity, and the German Index of Socioeconomic Deprivation (GISD) as independent variables. Mean prevalence of psoriasis increased from 168.63 per 10,000 in 2015 to 173.54 per 10,000 in 2017 for Germany as a whole, with high regional variation. Five determinants were detected (p < 0.05). The prevalence increased by 4.18 per 10,000 persons with SHI with each GISD unit, and by 3.76 per 10,000 with each year increase in age. Each additional hour of sunshine resulted in a decrease of 0.04 and each °C increase in mean temperature resulted in an increase of 4.22. Each additional dermatologist per 10,000 inhabitants resulted in a decrease of 0.07. In conclusion, sociodemographic and environmental factors result in significant differences in prevalence of psoriasis, even within-country.

Which factors influence the participation in statutory skin cancer screenings in Germany?

BACKGROUND AND OBJECTIVES: Due to increasing skin cancer incidence, Germany implemented a statutory nationwide routine skin cancer screening (rSCS) in 2008. The present study aims (1) to analyze which patient factors are associated with the participation in rSCS in Germany and (2) to investigate reasons for nonparticipation. PATIENTS AND METHODS: Participants and nonparticipants of rSCS (≥ 35 years) were recruited in routine care in nine dermatological outpatient clinics. Reasons for (non-)participation, knowledge about skin cancer as well as clinical and socioeconomic data were obtained. Stratified by groups, descriptive analyses and binary logistic regression analyses for associations with participation were performed. RESULTS: Of the 294 rSCS participants and 162 non-participants, 46.5% were male with a mean age of 54.5 ± 12.7 years. In total, 87.1% had sunburns in childhood and 47.1% used sunbeds before. Higher age, female gender, previous sunbed use, and concern for and knowledge of skin cancer were significantly associated with previous rSCS participation. Of the non-participants, 46% were unaware of the option for free rSCS and 40% justified their nonparticipation on the basis of feeling healthy. CONCLUSIONS: The reasons for nonparticipation in rSCS, such as sociodemographic characteristics and risk behavior, should be known in order to optimize rSCS programs.

Case-only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD-2353F22.1 implying the importance of periodontal wound healing for disease aetiology.

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.

[Further Development of Maturity Levels of Quality and Risk Management System at the University Hospital Schleswig-Holstein]. / Weiterentwicklung der Reifegrade des Qualitäts ­ und Risikomanagementsystems am Universitätsklinikum Schleswig-Holstein.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.

Evaluation of skin cancer screening in Germany - Spatiotemporal associations between skin cancer screening and skin cancer mortality based on ambulatory claims data.

BACKGROUND: There are regional differences in skin cancer screening uptake in Germany. So far, it is unclear whether a high uptake of screening services leads to a reduction in mortality. This article presents study results on the investigation of spatiotemporal associations between skin cancer screening and mortality. The methods used are discussed regarding their suitability. MATERIAL AND METHODS: The basis is ambulatory claims data on the utilization of early skin cancer detection as well as data on skin cancer mortality from the cause-of-death statistics of the years 2011-2015 at county level in Germany. In addition to a descriptive evaluation, spatiotemporal cluster analyses and regression models were used to investigate the relationship between the uptake of early detection and mortality. In addition to age, adjustments were also made for other selected socio-economic and socio-graphical variables. RESULTS: The descriptive results show striking spatial patterns of skin cancer screening and mortality. Cluster analyses identified regions with significantly higher and lower cases of early detection and skin cancer mortality. The spatiotemporal regression analyses show no clear association. Only early detection by a dermatologist, adjusted for age, shows an association with mortality. CONCLUSIONS: No clear association between early skin cancer detection and mortality can be derived from the results. However, the study design used with a spatiotemporal cluster and regression analysis has shown that these methods allow in-depth statements about the relationship between early skin cancer detection and mortality.

Evaluation of early skin cancer detection in Germany with cancer registry data - challenges, solutions and current trends.

BACKGROUND AND AIMS: The evidence for the benefit of the skin cancer screening introduced in Germany in 2008 is weak. We investigate to what extent data from the German epidemiological cancer registries are suitable to contribute to the evaluation of skin cancer screening and report these evaluation results. MATERIAL AND METHODS: Skin cancer-related cancer registry data from 1999-2019 were described in terms of completeness and comprehensiveness. Regional pools with data of different validity were defined, missing data were multiply imputed where appropriate, and temporal trends were analyzed. In addition, data from the cause of death statistics were used. RESULTS: Reliable estimates of completeness are only available for malignant melanoma (ICD-10: C43). Based on a regional data pool covering approximately 21% of the German population, melanoma-related incidence can be validly described since 2005. Sufficient information for multiple imputation is available for T-stage and localization. The trend analyses show incidence changes that can be expected in the short term in the temporal context of the introduction of early detection, which changes into a long-lasting high incidence. The rate of advanced stages does not decrease significantly. From 2014 onwards, the melanoma mortality rate, which had been rising until then, decreases. CONCLUSIONS: Adequately selected and processed cancer registry data are suitable for population-based evaluation of skin cancer screening. An explanation of the persistently high incidence level is not possible based on the cancer registry data. Overdiagnosis or an increase in the background incidence can be considered. The benefit of skin cancer screening remains open.

Evaluation of skin cancer screening in Germany - participation, tumor detection and interval tumors based on SHI data.

BACKGROUND AND GOALS: The rising incidence of skin cancer in Germany has increased the need for secondary prevention measures. For this purpose, a statutory skin cancer screening for insured persons aged 35 and older was introduced on 1 June 2008. The aim of this work package in the Innovation Fund project "Perspectives of a multimodal evaluation of early skin cancer detection" (Pertimo) was to test an evaluation of skin cancer screening using secondary data. PATIENTS AND METHODS: The data basis was statutory insured persons of the DAK Health from the age of 35 who were insured as of 31 December 2010 and were followed up until the end of 2015. The rates of participation, skin tumors detected in skin cancer screening (tumor detections), and interval tumors that occurred within two years after a finding-free skin cancer screening were calculated. RESULTS: The biennial skin cancer screening take-up rate in 2014 and 2015 was 33.6% for women and 32.6% for men. Of those screened, 4.2% had a skin cancer finding (tumor detection) in the course of skin cancer screening. Of all incident skin cancer diagnoses (2012-2015), 50.1% were detected in skin cancer screening. In 1.5% of the insured persons with skin cancer screening without findings, an incidental skin tumor was diagnosed in the following two years (interval tumor). CONCLUSIONS: The data from the statutory health insurance mapped the skin cancer screening occurrence in Germany and highlighted the importance of dermatologists in the screening process. The analysis provided important new insights.

Health services in older psoriasis patients before and after nursing home admission : A retrospective analysis of health insurance data.

BACKGROUND AND OBJECTIVE: Demographic change confers significance to healthcare management of chronic diseases like psoriasis. There are few studies on the care of older people with psoriasis, particularly for the nursing home setting. It was investigated whether the number of psoriasis patients with specialist contact changes before vs. after nursing home admission. MATERIAL AND METHODS: We analyzed claims data of a German health insurance company including a cohort of newly admitted nursing home residents aged 65 years and older between 2011 and 2014, who received a diagnosis of psoriasis 1 year before nursing home admission. Outpatient care was compared between the years before vs. after nursing home admission. We conducted a multivariate regression analysis for identifying predictors for dermatological care. RESULTS: The study cohort included 718 insured persons (Ø83 years). Proportion of patients who had contact to a dermatologist significantly decreased after nursing home entry (44.6% before vs. 40.1% after nursing home entry). Strongest predictors for dermatological care after entry were a previously existing dermatological contact (odds ratio, OR 3.87, 95% confidence interval, CI 2.70-5.54) and prescription for topical steroids (OR 1.61, 95% CI 1.14-2.28). CONCLUSION: The analysis of health insurance data showed a pertinent decrease in the use of outpatient dermatological care after institutionalization. The evaluation of the adequacy of care is difficult due to the used database without clinical information. As long as no further investigations of this vulnerable patient group are available, the care of psoriasis patients of old age should be closely monitored. Dermatological knowledge of the skin in old age is an essential prerequisite for this.

Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Influence of the number of implants in the edentulous mandible on chewing efficacy and oral health-related quality of life-A within-subject design study.

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.

Myocardial hypoxic stress mediates functional cardiac extracellular vesicle release.

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.

Investigation of the esthetic perception of different canine parameters.

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.

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Genotype imputation in case-only studies of gene-environment interaction: validity and power.

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.

High Levels of Chromosomal Copy Number Alterations and TP53 Mutations Correlate with Poor Outcome in Younger Breast Cancer Patients.

Prognosis in young patients with breast cancer is generally poor, yet considerable differences in clinical outcomes between individual patients exist. To understand the genetic basis of the disparate clinical courses, tumors were collected from 34 younger women, 17 with good and 17 with poor outcomes, as determined by disease-specific survival during a follow-up period of 17 years. The clinicopathologic parameters of the tumors were complemented with DNA image cytometry profiles, enumeration of copy numbers of eight breast cancer genes by multicolor fluorescence in situ hybridization, and targeted sequence analysis of 563 cancer genes. Both groups included diploid and aneuploid tumors. The degree of intratumor heterogeneity was significantly higher in aneuploid versus diploid cases, and so were gains of the oncogenes MYC and ZNF217. Significantly more copy number alterations were observed in the group with poor outcome. Almost all tumors in the group with long survival were classified as luminal A, whereas triple-negative tumors predominantly occurred in the short survival group. Mutations in PIK3CA were more common in the group with good outcome, whereas TP53 mutations were more frequent in patients with poor outcomes. This study shows that TP53 mutations and the extent of genomic imbalances are associated with poor outcome in younger breast cancer patients and thus emphasize the central role of genomic instability vis-a-vis tumor aggressiveness.

Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans.

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.

Improvement of renal function after transcatheter aortic valve replacement and its impact on survival.

BACKGROUND: Chronic kidney disease as well as acute kidney injury are associated with adverse outcomes after transcatheter aortic valve replacement (TAVR). However, little is known about the prognostic implications of an improvement in renal function after TAVR. METHODS: Renal improvement (RI) was defined as a decrease in postprocedural creatinine in µmol/l of ≥1% compared to its preprocedural baseline value. A propensity score representing the likelihood of RI was calculated to define patient groups which were comparable regarding potential confounders (age, sex, BMI, NYHA classification, STS score, log. EuroSCORE, history of atrial fibrillation/atrial flutter, pulmonary disease, previous stroke, CRP, creatinine, hsTNT and NT-proBNP). The cohort was stratified into 5 quintiles according to this propensity score and the survival time after TAVR was compared within each subgroup. RESULTS: Patients in quintile 5 (n = 93) had the highest likelihood for RI. They were characterized by higher creatinine, lower eGFR, higher NYHA class, higher NT-proBNP, being mostly female and having shorter overall survival time. Within quintile 5, patients without RI had significantly shorter survival compared to patients with RI (p = 0.002, HR = 0.32, 95% CI = [0.15-0.69]). There was no survival time difference between patients with and without RI in the whole cohort (p = 0.12) and in quintiles 1 to 4 (all p > 0.16). Analyses of specific subgroups showed that among patients with NYHA class IV, those with RI also had a significant survival time benefit (p < 0.001, HR = 0.15; 95%-CI = [0.05-0.44]) compared to patients without RI. CONCLUSIONS: We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit.

Protocol for evaluating women with female genital mutilation seeking asylum.

Rapid immigration from countries that practice female genital mutilation/cutting (FGM/C) has introduced new populations requiring culturally sensitive health care. Clinicians play an important role in providing documentation and expert testimony for women seeking asylum on the basis on FGM/C. The intent of this paper is to provide instruction to providers aiming to evaluate an individual seeking asylum based on FGM/C. This document provides guidance about the three primary parts of evaluation: the interview, exam, and report. Other goals of investigation include preventing and ending suffering, compensation, and psychological or physical rehabilitation.

Case-only analysis of gene-gene interactions in inflammatory bowel disease.

BACKGROUND: 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'. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.