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Eileen Moritz,1,2,* Gabriele Jedlitschky,1,* Josefine Negnal,1 Mladen V Tzvetkov,1 Günter Daum,3,4 Marcus Dörr,2,5 Stephan B Felix,2,5 Henry Völzke,2,6 Matthias Nauck,2,7 Edzard Schwedhelm,4,8 Peter Meisel,9 Thomas Kocher,9 Bernhard H Rauch,1,2,10,* Birte Holtfreter9,* 1Institute of Pharmacology, Department of General Pharmacology, University Medicine Greifswald, Greifswald, Germany; 2German Center for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany; 3Clinic and Polyclinic for Vascular Medicine, University Heart Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany; 5Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; 6Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; 7Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany; 8Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Humburg, Germany; 9Dental Clinics, Department of Periodontology, University Medicine Greifswald, Greifswald, Germany; 10Carl von Ossietzky Universität Oldenburg, Department of Human Medicine, Section of Pharmacology and Toxicology, Oldenburg, Germany*These authors contributed equally to this workCorrespondence: Bernhard H RauchCarl von Ossietzky Universität Oldenburg, Department of Human Medicine, Section of Pharmacology and Toxicology, Carl-von-Ossietzky-Str. 9-11, Oldenburg, 26129, GermanyTel +49 (0) 441 798 4930Fax +49 (0) 441 798 3088Email Bernhard.Rauch@uni-oldenburg.dePurpose: Periodontitis is an inflammatory disease of the oral cavity with an alarmingly high prevalence within the adult population. The signaling lipid sphingosine-1-phosphate (S1P) plays a crucial role in inflammatory and immunomodulatory responses. In addition to cardiovascular disease, sepsis and tumor entities, S1P has been recently identified as both mediator and biomarker in osteoporosis. We hypothesized that S1P may play a role in periodontitis as an inflammation-prone bone destructive disorder. The goal of our study was to evaluate associations between periodontitis and S1P serum concentrations in the Study of Health in Pomerania (SHIP)-Trend cohort. In addition, we investigated the expression of S1P metabolizing enzymes in inflamed gingival tissue.Patients and Methods: We analyzed data from 3371 participants (51.6% women) of the SHIP-Trend cohort. Periodontal parameters and baseline characteristics were assessed. Serum S1P was measured by liquid chromatography tandem mass spectrometry. The expression of S1P metabolizing enzymes was determined by immunofluorescence staining of human gingival tissue.Results: S1P serum concentrations were significantly increased in subjects with both moderate and severe periodontitis, assessed as probing depth and clinical attachment loss. In contrast, no significant association of S1P was seen with caries variables (number and percentage of decayed or filled surfaces). S1P concentrations significantly increased with increasing high-sensitivity C-reactive protein (hs-CRP) levels. Interestingly, inflamed compared to normal human gingival tissue exhibited elevated expression levels of the S1P-generating enzyme sphingosine kinase 1 (SphK1).Conclusion: We report an intriguingly significant association of various periodontal parameters with serum levels of the inflammatory lipid mediator S1P. Our data point towards a key role of S1P during periodontitis pathology. Modulation of local S1P levels or its signaling properties may represent a potential future therapeutic strategy to prevent or to retard periodontitis progression and possibly reduce periodontitis-related tooth loss.Keywords: sphingosine-1-phosphate, lipid mediator, periodontitis, inflammation

Objective: To explore associations between diabetes etiology (type 1 diabetes mellitus [T1DM] vs. T2DM) and glycemic control in the prediction of 5-year periodontal status change.Research Design and Methods: The Study of Health in Pomerania (SHIP) is a population-based stratified sample of German men and women. Healthy participants and those determined to have T2DM arose from the SHIP cohort, and T1DM participants were recruited from diabetes clinics in the catchment area that gave rise to SHIP. Dentate participants (n = 2,626; 53% women; 20-81 years of age) were included. Diabetes was determined via physician diagnosis and/or HbA(1c) ≥6.5% (uncontrolled diabetes >7.0%). Examiners blinded to diabetes status performed random half-mouth periodontal examinations, assessing probing depth (PD) and attachment loss (AL) (four sites/tooth) at baseline and follow-up. Participants were categorized into six groups as follows: 1) diabetes free (n = 2,280), 2) incident T2DM (n = 79), 3) controlled T2DM (n = 80), 4) uncontrolled T2DM (n = 72), 5) controlled T1DM (n = 43), and 6) uncontrolled T1DM (n = 72). In multivariable regressions, mean PD change (ΔMPD), mean AL change (ΔMAL), or incident tooth-loss values were regressed across the aforementioned diabetes categories.Results: Mean (SD) ΔMPD and ΔMAL values among all participants were -0.08 ± 0.5 mm and 0.08 ± 1.03 mm, respectively, and 34% lost one or more teeth. Relative to diabetes-free participants, those with uncontrolled T2DM experienced greater ΔMPD ± SE (P < 0.05), whereas participants with either uncontrolled T1DM or uncontrolled T2DM realized greater ΔMAL (P < 0.05). Uncontrolled T1DM and T2DM were both associated with an increased risk of future tooth loss (P < 0.05).Conclusions: Diabetes control, but not etiology, was associated with future tooth loss and accelerated AL progression. [ABSTRACT FROM AUTHOR]

Objective: Infection may be a type 2 diabetes risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to A1C progression in diabetes-free participants.Research Design and Methods: The Study of Health in Pomerania (SHIP) is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20-81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percentage of sites per mouth with attachment loss >or=5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463, and 479 (241 participants were edentulous). Mean absolute changes (year 5 minus baseline) in A1C (DeltaA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, sex, smoking, obesity, physical activity, and family history).Results: Across baseline periodontal disease categories, DeltaA1C +/- SEM values were 0.023 +/- 0.02, 0.023 +/- 0.02, 0.065 +/- 0.03, and 0.106 +/- 0.03 (P(trend) = 0.02), yielding an approximate fivefold increase in the absolute difference in DeltaA1C when dentate participants in the highest versus lowest periodontal disease category were compared; these results were markedly stronger among participants with high-sensitivity C-reactive protein >or=1.0 mg/l (P(interaction) = 0.01). When individuals who had neither baseline periodontal disease nor deterioration in periodontal status at 5 years were compared with individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean DeltaA1C values were 0.005 vs. 0.143% (P = 0.003).Conclusions: Periodontal disease was associated with 5-year A1C progression, which was similar to that observed for a 2-SD increase in either waist-to-hip ratio or age in this population. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is one of the most common causes of hospital-acquired infections. At the same time, 25% of healthy persons are symptom-free S. aureus carriers, and they have an increased risk of developing nosocomial S. aureus septicemia. Paradoxically, their prognosis is much better than that of noncarriers. We compared the antibody profiles for carriers and noncarriers toward S. aureus superantigens. In carriers, we found high titers of neutralizing antibodies specific for those superantigens that are expressed by their colonizing strain. The results show that carriage status confers strain-specific humoral immunity, which may contribute to protection during S. aureus septicemia. Copyright © 2006 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

OBJECTIVE: Oral leukoplakia is an oral lesion with a premalignant character. Besides smoking and alcohol, diabetes could be a risk factor. The aim is to search for such an association. RESEARCH DESIGN AND METHODS: Subjects with leukoplakia (N = 123) from the population-based Study of Health in Pomerania (SHIP) were matched 1:2 for age and sex with unaffected control subjects. Behavioral and lifestyle factors were assessed by a questionnaire. Lipoprotein concentrations, glycemia, and inflammation parameters were determined. RESULTS Subjects with oral leukoplakia showed higher levels of diabetes-related metabolites, a higher LDL/HDL cholesterol ratio (P = 0.004), and higher A1C (P = 0.002), and they were more frequently smokers (P < 0.001). Assessed by conditional logistic regression, the probability of leukoplakia increases with current smoking (odds ratio 2.20 [95% CI 1.16-4.17]) and higher levels of A1C (1.51 [95% CI 1.08-2.12]), revealing interaction between both factors (P = 0.012). CONCLUSIONS: Diabetes is associated with the risk of oral leukoplakia, which is exaggerated by smoking. The risk is positively correlated with A1C concentrations. [ABSTRACT FROM AUTHOR]

Background: We investigated the efficacy of two different cold atmospheric pressure jet plasma devices (CAP09 and CAPmed) and an air polishing device with glycine powder (AP) either applied as monotherapies or combined therapies (AP + CAP09; AP + CAPmed), in microbial biofilm removal from discs with anodised titanium surface., Methods: Discs covered with 7-day-old microbial biofilm were treated either with CAP09, CAPmed, AP, AP + CAP09 or AP + CAPmed and compared with negative and positive controls. Biofilm removal was assessed with flourescence and electron microscopy immediately after treatment and after 5 days of reincubation of the treated discs., Results: Treatment with CAP09 or CAPmed did not lead to an effective biofilm removal, whereas treatment with AP detached the complete biofilm, which however regrew to baseline magnitude after 5 days of reincubation. Both combination therapies (AP + CAP09 and AP + CAPmed) achieved a complete biofilm removal immediately after cleaning. However, biofilm regrew after 5 days on 50% of the discs treated with the combination therapy., Conclusion: AP treatment alone can remove gross biofilm immediately from anodised titanium surfaces. However, it did not impede regrowth after 5 days, because microorganisms were probably hidden in holes and troughs, from which they could regrow, and which were inaccessible to AP. The combination of AP and plasma treatment probably removed or inactivated microorganisms also from these hard to access spots. These results were independent of the choice of plasma device., (© 2024. The Author(s).)

Background: Recent studies have highlighted the role of low-grade systemic inflammation in linking periodontitis to cardiovascular disease (CVD) outcomes, but many aspects remain unclear. This study examines the independent and reciprocal associations of periodontitis and low-grade systemic inflammation with all-cause and CVD mortality in a large-scale cohort., Methods: A total of 3047 participants from the prospective, population-based Study of Health in Pomerania (SHIP-START) were followed for a period of 13.0 ± 2.4 years. For the association between various inflammation/periodontitis measures and mortality, hazard ratios (HRs) were obtained from covariate-adjusted Cox proportional hazards models. Interactions were analysed in joint models: on the multiplicative scale, HRs were reported and on the additive scale, relative excess risks due to interaction (RERI) were calculated. Subject and variable-specific interval records were used to account for time-varying exposures and covariates., Results: During the observation period, 380 (12.5%) individuals died from CVD (n = 125) or other causes (n = 255). All markers of periodontitis and inflammation showed apparent associations with all-cause mortality (HRs per SD-increase: mean PPD: 1.068 (95% confidence interval (CI): 0.988-1.155), mean CAL: 1.205 (95% CI: 1.097-1.323), missing teeth: 1.180 (95% CI: 1.065-1.307), periodontitis score: 1.394 (95% CI: 1.202-1.616), leukocytes: 1.264 (95% CI: 1.163-1.374), fibrinogen: 1.120 (95% CI: 1.030-1.218), CRP: 1.231 (95% CI: 1.109-1.366), inflammation score: 1.358 (95% CI: 1.210-1.523)). For CVD mortality, all PPD related variables showed significant associations. Interaction modelling revealed some variation with respect to mortality type and exposure combinations. On the additive scale, RERIs for periodontitis score and inflammation score implied 18.9% and 27.8% excess mortality risk for all-cause and CVD mortality, respectively. On the multiplicative scale, the HRs for interaction were marginal., Conclusions: Both periodontitis and inflammation were significantly associated with all-cause mortality and CVD mortality. On the additive scale, a substantial excess risk was observed due to the interaction of periodontitis and inflammation, suggesting that the greatest treatment benefit may be achieved in patients with both periodontitis and high systemic inflammation. As periodontal therapy has been reported to also reduce systemic inflammation, the possibility of a reduction in CVD mortality risk by anti-inflammatory treatments, including periodontal interventions, seems worthy of further investigation., (© 2023. The Author(s).)

Aim: Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis., Materials and Methods: As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed., Results: Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296)., Conclusion: In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nolde, Alayash, Reckelkamm, Kocher, Ehmke, Holtfreter, Baurecht, Georgakis and Baumeister.)

Purpose: Cortisol has obesogenic, hyperglycemic and immunomodulating effects. Preclinical and observational research suggested that it is associated with periodontitis but the evidence for potential causality in humans is sparse. We triangulated results from prospective observational and Mendelian randomization (MR) analyses to further explore this., Methods: Using pooled data from 3,388 participants of two population cohort studies embedded in the Study of Health in Pomerania (SHIP) project, we associated serum cortisol levels with periodontal outcomes measured after a median follow-up time of 6.9 years, adjusting for confounding and selection bias using propensity score weighting and multiple imputation. We further examined the effect of genetically proxied plasma morning cortisol levels on periodontitis using two-sample MR of 17,353 cases and 28,210 controls., Results: In SHIP, we found that cortisol levels were positively associated with follow-up levels of mean clinical attachment level (CAL), deep interdental CAL and bleeding on probing but were unrelated to mean probing pocket depth and deep periodontal pockets. In MR analysis, cortisol was not associated with periodontitis., Conclusion: The observational study revealed a prospective association of spot cortisol with makers of periodontitis. Contrary to observational studies, genetically instrumented, long-term cortisol was unrelated to periodontitis. Our results find no univocal evidence that cortisol plays a role in periodontitis pathology, casting doubt on cortisol-related pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baumeister, Reckelkamm, Grabe, Nauck, Klinger-König, Völzke, Kocher, Friedrich and Holtfreter.)

Aim: To investigate the effect of genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) on the risk of periodontitis., Materials and Methods: Genetic instruments were selected from the vicinity of TNFR superfamily member 1A (TNFRSF1A) gene (chromosome 12; base pairs 6,437,923-6,451,280 as per GRCh37 assembly) based on their association with C-reactive protein (N= 575,531). Summary statistics of these variants were obtained from a genome-wide association study (GWAS) of 17,353 periodontitis cases and 28,210 controls to estimate the effect of TNFR1 inhibition on periodontitis using a fixed-effects inverse method., Results: Considering rs1800693 as an instrument, we found no effect of TNFR1 inhibition on periodontitis risk (Odds ratio (OR) scaled per standard deviation increment in CRP: 1.57, 95% confidence interval (CI): 0.38;6.46). Similar results were derived from a secondary analysis that used three variants (rs767455, rs4149570, and rs4149577) to index TNFR1 inhibition., Conclusions: We found no evidence of a potential efficacy of TNFR1 inhibition on periodontitis risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alayash, Baumeister, Holtfreter, Kocher, Baurecht, Ehmke, Reckelkamm and Nolde.)

Peri-implantitis-associated inflammation can lead to bone loss and implant failure. Current decontamination measures are ineffective due to the implants' complex geometry and rough surfaces providing niches for microbial biofilms. A modified water jet system (WaterJet) was combined with cold plasma technology (CAP) to achieve superior antimicrobial efficacy compared to cotton gauze treatment. Seven-day-old multi-species-contaminated titanium discs and implants were investigated as model systems. The efficacy of decontamination on implants was determined by rolling the implants over agar and determining colony-forming units supported by scanning electron microscopy image quantification of implant surface features. The inflammatory consequences of mono and combination treatments were investigated with peripheral blood mononuclear cell surface marker expression and chemokine and cytokine release profiles on titanium discs. In addition, titanium discs were assayed using fluorescence microscopy. Cotton gauze was inferior to WaterJet treatment according to all types of analysis. In combination with the antimicrobial effect of CAP, decontamination was improved accordingly. Mono and CAP-combined treatment on titanium surfaces alone did not unleash inflammation. Simultaneously, chemokine and cytokine release was dramatically reduced in samples that had benefited from additional antimicrobial effects through CAP. The combined treatment with WaterJet and CAP potently removed biofilm and disinfected rough titanium implant surfaces. At the same time, non-favorable rendering of the surface structure or its pro-inflammatory potential through CAP was not observed.

Background: Observational and in-vivo research suggested a bidirectional relationship between depression and periodontitis. We estimated the genetic correlation and examined directionality of causation., Methods: The study used summary statistics from published genome wide association studies, with sample sizes ranging from 45,563 to 797,563 individuals of European ancestry. We performed linkage disequilibrium score regression (LDSC) to estimate global correlation and used Heritability Estimation from Summary Statistics (ρ-HESS) to further examine local genetic correlation. Latent Heritable Confounder Mendelian randomization (LHC-MR), Causal Analysis using Summary Effect estimates (CAUSE), and conventional MR approaches assessed bidirectional causation., Results: LDSC observed only weak genetic correlation (r g = 0.06, P-Value = 0.619) between depression and periodontitis. Analysis of local genetic correlation using ρ-HESS did not reveal loci of significant local genetic covariance. LHC-MR, CAUSE and conventional MR models provided no support for bidirectional causation between depression and periodontitis, with odds ratios ranging from 1.00 to 1.06 in either direction., Conclusions: Results do not support shared heritability or a causal connection between depression and periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nolde, Holtfreter, Kocher, Alayash, Reckelkamm, Ehmke, Baurecht and Baumeister.)

Background: Peri-implantitis therapy is a major problem in implantology. Because of challenging rough implant surface and implant geometry, microorganisms can hide and survive in implant microstructures and impede debridement. We developed a new water jet (WJ) device and a new cold atmospheric pressure plasma (CAP) device to overcome these problems and investigated aspects of efficacy in vitro and safety with the aim to create the prerequisites for a clinical pilot study with these medical devices., Methods: We compared the efficiency of a single treatment with a WJ or curette and cotton swab (CC) without or with adjunctive use of CAP (WJ + CAP, CC + CAP) to remove biofilm in vitro from rough titanium discs. Treatment efficacy was evaluated by measuring turbidity up to 72 h for bacterial re-growth or spreading of osteoblast-like cells (MG-63) after 5 days with scanning electron microscopy. With respect to application safety, the WJ and CAP instruments were examined according to basic regulations for medical devices., Results: After 96 h of incubation all WJ and CC treated disks were turbid but 67% of WJ + CAP and 46% CC + CAP treated specimens were still clear. The increase in turbidity after WJ treatment was delayed by about 20 h compared to CC treatment. In combination with CAP the cell coverage significantly increased to 82% (WJ + CAP) or 72% (CC + CAP), compared to single treatment 11% (WJ) or 10% (CC)., Conclusion: The newly developed water jet device effectively removes biofilm from rough titanium surfaces in vitro and, in combination with the new CAP device, biologically acceptable surfaces allow osteoblasts to grow. WJ in combination with CAP leads to cleaner surfaces than the usage of curette and cotton swabs with or without subsequent plasma treatment. Our next step will be a clinical pilot study with these new devices to assess the clinical healing process., (© 2022. The Author(s).)

The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.

Background: Periodontitis is among the most common chronic diseases worldwide, and it is one of the main reasons for tooth loss. Comprehensive profiling of the metabolite content of the saliva can enable the identification of novel pathways associated with periodontitis and highlight non-invasive markers to facilitate time and cost-effective screening efforts for the presence of periodontitis and the prediction of tooth loss., Methods: We first investigated cross-sectional associations of 13 oral health variables with saliva levels of 562 metabolites, measured by untargeted mass spectrometry among a sub-sample (n = 938) of the Study of Health in Pomerania (SHIP-2) using linear regression models adjusting for common confounders. We took forward any candidate metabolite associated with at least two oral variables, to test for an association with a 5-year tooth loss over and above baseline oral health status using negative binomial regression models., Results: We identified 84 saliva metabolites that were associated with at least one oral variable cross-sectionally, for a subset of which we observed robust replication in an independent study. Out of 34 metabolites associated with more than two oral variables, baseline saliva levels of nine metabolites were positively associated with a 5-year tooth loss. Across all analyses, the metabolites 2-pyrrolidineacetic acid and butyrylputrescine were the most consistent candidate metabolites, likely reflecting oral dysbiosis. Other candidate metabolites likely reflected tissue destruction and cell proliferation., Conclusions: Untargeted metabolic profiling of saliva replicated metabolic signatures of periodontal status and revealed novel metabolites associated with periodontitis and future tooth loss., (© 2021. The Author(s).)

Objectives: It is still not clear why impaction of third molars occurs. Craniofacial morphology and facial parameters have been discussed to be strong predictors for third molar impaction. Thus, this study aimed to investigate the effect of craniofacial morphology on erupted or impacted third molars in a German population sample., Materials and Methods: Erupted and impacted third molars in 2,484 participants from the Study of Health in Pomerania were assessed by whole-body magnetic resonance imaging. Markers of facial morphology were determined in 619 individuals of those participants in whose 421 participants (16.7%) had at least one impacted third molar. Craniofacial morphology was estimated as linear measurements and was associated in a cross-sectional study design with impacted and erupted third molars by multinomial logistic regression models. Erupted third molars were used as reference outcome category and regression models were adjusted for age and sex., Results: Maximum Cranial Width (Eurion-Eurion distance) was significantly associated with impacted third molars (RR: 1.079; 95% confidence interval 1.028-1.132). This association was even more pronounced in the mandible. Individuals with a lower total anterior facial height (Nasion-Menton distance) and a lower facial index also have an increased risk for impacted third molars in the mandible (RR 0.953; 95% confidence interval 0.913-0.996 and RR: 0.943; 95% confidence interval 0.894-0.995). No significant associations of third molar status with facial width (Zygion-Zygion distance), and sagittal cranial dimension (Nasion-Sella distance; Sella-Basion distance) were observed., Conclusion: Individuals with an increased maximal cranial width have a higher risk for impaction of third molars in the mandible and in the maxilla. Individuals with a lower anterior total anterior facial height and lower facial index also have an increased risk for third molars impaction in the mandible. These findings could help orthodontic dentists, oral surgeons and oral and maxillofacial surgeons in decision-making for third molars removal in their treatment. These findings highlight the necessity of an additional analysis of the maximal cranial width by the Eurion- Eurion distance., Competing Interests: The authors have declared that no competing interests exist.

We estimated effects of diabetes mellitus and metabolic control on long-term change in coronal caries and restorative status using 11-year-follow-up data from the population-based Study of Health in Pomerania. Data of 3731 participants with baseline and 5- and 11-year follow-up information were included. Diabetes was defined via self-reported physician´s diagnosis or intake of glucose-lowering drugs or hemoglobin A1c (HbA1c) ≥6.5% or fasting blood glucose levels ≥11.1 mmol/l. The diabetes status was defined as no diabetes (HbA1c < 6.5% or non-fasting blood glucose <11.1 mmol/l), subjects with known or undetected diabetes mellitus and HbA1c ≤ 7% (well-controlled diabetes), and subjects with known or undetected diabetes mellitus and HbA1c > 7% (poorly-controlled diabetes). The caries status was clinically assessed using the half-mouth method and the Decayed Missing Filled Surfaces (DMFS) index and its component scores were determined. Covariate-adjusted linear mixed models were evaluated. Rates in change in DMFS were significantly higher in subjects with poorly-controlled diabetes compared to subjects without diabetes. Subjects with poorly- and well-controlled diabetes had significantly higher rates in change in Missing Surfaces (MS) compared to subjects without diabetes. For the DFS, rates in change were significantly lower for subjects with well-controlled diabetes and higher for subjects with poorly-controlled diabetes as compared to subjects without diabetes. Concordantly, all rates in change increased proportional to HbA1c levels. Effects were even more pronounced in subjects with diabetes duration of ≥5 years. Subjects with poorly-controlled diabetes are at higher risk for caries progression compared to subjects without diabetes, especially in case of longer disease duration.

Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10 -9 , OR = 1.36, 95% CI = [1.23-1.51]) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10 -9 , OR = 1.24, 95% CI = [1.15-1.34]). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.

Evidence for a shared genetic basis of association between coronary artery disease (CAD) and periodontitis (PD) exists. To explore the joint genetic basis, we performed a GWAS meta-analysis. In the discovery stage, we used a German aggressive periodontitis sample (AgP-Ger; 680 cases vs 3,973 controls) and the CARDIoGRAMplusC4D CAD meta-analysis dataset (60,801 cases vs 123,504 controls). Two SNPs at the known CAD risk loci ADAMTS7 (rs11634042) and VAMP8 (rs1561198) passed the pre-assigned selection criteria (P AgP-Ger  < 0.05; P CAD  < 5 × 10 -8 ; concordant effect direction) and were replicated in an independent GWAS meta-analysis dataset of PD (4,415 cases vs 5,935 controls). SNP rs1561198 showed significant association (PD[Replication]: P = 0.008 OR = 1.09, 95% CI = [1.02-1.16]; PD [Discovery + Replication]: P = 0.0002, OR = 1.11, 95% CI = [1.05-1.17]). For the associated haplotype block, allele specific cis-effects on VAMP8 expression were reported. Our data adds to the shared genetic basis of CAD and PD and indicate that the observed association of the two disease conditions cannot be solely explained by shared environmental risk factors. We conclude that the molecular pathway shared by CAD and PD involves VAMP8 function, which has a role in membrane vesicular trafficking, and is manipulated by pathogens to corrupt host immune defense.

Objectives: To improve understanding of periodontitis pathology, we need more profound knowledge of relative abundances of single prokaryotic species and colonization dynamics between habitats. Thus, we quantified oral microbes from two oral habitats to gain insights into colonization variability and correlation to the clinical periodontal status., Methods: We analyzed tongue scrapings and subgingival pocket samples from 237 subjects (35-54 years) with at least 10 teeth and no recent periodontal treatment from the 11-year follow-up of the Study of Health in Pomerania. Relative abundances of Porphyromonas gingivalis , Aggregatibacter actinomycetemcomitans , Fusobacterium nucleatum , Streptococcus sanguinis , total bacteria, and Archaea were correlated to clinically assessed pocket depths (PD) and clinical attachment levels (CAL)., Results: Increased relative abundances of P. gingivalis , A. actinomycetemcomitans , and F. nucleatum were linked to increased levels of PD and CAL (i) on the subject level (mean PD, mean CAL) and (ii) in subgingival pockets. Relative abundances of Archaea from tongue samples correlated negatively with mean PD or mean CAL. Detection and quantity of bacterial species correlated weakly to moderately between the tongue and subgingival pocket, except for Archaea ., Conclusions: Relative abundances of specific oral species correlated weakly to moderately between habitats. Single species, total bacteria, and Archaea were linked to clinically assessed severity of periodontitis in a habitat-dependent manner.

Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Lifespan is a complex trait, and longitudinal data for humans are naturally scarce. We report the results of Cox regression and Pearson correlation analyses using data of the Study of Health in Pomerania (SHIP), with mortality data of 1518 participants (113 of which died), over a time span of more than 10 years. We found that in the Cox regression model based on the Bayesian information criterion, apart from chronological age of the participant, six baseline variables were considerably associated with higher mortality rates: smoking, mean attachment loss (i.e. loss of tooth supporting tissue), fibrinogen concentration, albumin/creatinine ratio, treated gastritis, and medication during the last 7 days. Except for smoking, the causative contribution of these variables to mortality was deemed inconclusive. In turn, four variables were found to be associated with decreased mortality rates: treatment of benign prostatic hypertrophy, treatment of dyslipidemia, IGF-1 and being female. Here, being female was an undisputed causative variable, the causal role of IFG-1 was deemed inconclusive, and the treatment effects were deemed protective to the degree that treated subjects feature better survival than respective controls. Using Cox modeling based on the Akaike information criterion, diabetes, mean corpuscular hemoglobin concentration, red blood cell count and serum calcium were also associated with mortality. The latter two, together with albumin and fibrinogen, aligned with an"integrated albunemia" model of aging proposed recently.

Aggregatibacter actinomycetemcomitans is a Gram-negative commensal bacterium of the oral cavity which has been associated with the pathogenesis of periodontitis with severe alveolar bone destruction. The role of host factors such as reactive oxygen and nitrogen intermediates in periodontal A. actinomycetemcomitans infection and progression to periodontitis is still ill-defined. Therefore, this study aimed to analyze the role of NADPH oxidase and inducible nitric oxide synthase (iNOS) in a murine model of A. actinomycetemcomitans-induced periodontitis. NADPH oxidase-deficient (gp91 phox knockout [KO]), iNOS-deficient (iNOS KO), and C57BL/6 wild-type mice were orally infected with A. actinomycetemcomitans and analyzed for bacterial colonization at various time points. Alveolar bone mineral density and alveolar bone volume were quantified by three-dimensional micro-computed tomography, and the degree of tissue inflammation was calculated by histological analyses. At 5 weeks after infection, A. actinomycetemcomitans persisted at significantly higher levels in the murine oral cavities of infected gp91 phox KO mice than in those of iNOS KO and C57BL/6 mice. Concomitantly, alveolar bone mineral density was significantly lower in all three infected groups than in uninfected controls, but with the highest loss of bone density in infected gp91 phox KO mice. Only infected gp91 phox KO mice revealed significant loss of alveolar bone volume and enhanced inflammatory cell infiltration, as well as an increased number of osteoclasts. Our results indicate that NADPH oxidase is important to control A. actinomycetemcomitans infection in the murine oral cavity and to prevent subsequent alveolar bone destruction and osteoclastogenesis., (Copyright © 2017 American Society for Microbiology.)

Population-based studies on Staphylococcus aureus nasal colonization are scarce. We examined the prevalence, resistance, and molecular diversity of S. aureus in the general population in Northeast Germany. Nasal swabs were obtained from 3,891 adults in the large-scale population-based Study of Health in Pomerania (SHIP-TREND). Isolates were characterized using spa genotyping, as well as antibiotic resistance and virulence gene profiling. We observed an S. aureus prevalence of 27.2%. Nasal S. aureus carriage was associated with male sex and inversely correlated with age. Methicillin-resistant S. aureus (MRSA) accounted for 0.95% of the colonizing S. aureus strains. MRSA carriage was associated with frequent visits to hospitals, nursing homes, or retirement homes within the previous 24 months. All MRSA strains were resistant to multiple antibiotics. Most MRSA isolates belonged to the pandemic European hospital-acquired MRSA sequence type 22 (HA-MRSA-ST22) lineage. We also detected one livestock-associated MRSA ST398 (LA-MRSA-ST398) isolate, as well as six livestock-associated methicillin-susceptible S. aureus (LA-MSSA) isolates (clonal complex 1 [CC1], CC97, and CC398). spa typing revealed a diverse but also highly clonal S. aureus population structure. We identified a total of 357 spa types, which were grouped into 30 CCs or sequence types. The major seven CCs (CC30, CC45, CC15, CC8, CC7, CC22, and CC25) included 75% of all isolates. Virulence gene patterns were strongly linked to the clonal background. In conclusion, MSSA and MRSA prevalences and the molecular diversity of S. aureus in Northeast Germany are consistent with those of other European countries. The detection of HA-MRSA and LA-MRSA within the general population indicates possible transmission from hospitals and livestock, respectively, and should be closely monitored., (Copyright © 2016 Holtfreter et al.)

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objectives. The aim was to develop an instrument for quality control in dental practices. We compared the number of teeth of subjects of the Study of Health in Pomerania (SHIP-0) with those from patients of dental practices. Methods. Patients from seven dental practices (n = 1,497) were randomly sampled by age strata and gender for a period of two years. Dental status derived from patient files was transformed into practice profiles using age-specific number of teeth as a parameter. Practice profiles were compared with a nomogram, which was based on the age-specific number of teeth of 3,990 SHIP-0 participants regularly visiting the dentist. Further, negative binomial regression models were evaluated to model associations between the number of teeth with age and dental practices, including interactions. Results. The practice profiles ranged between the 45th and 95th quantile curves of the reference population SHIP-0. The rate ratios (RR) for the number of missing teeth ranged from 0.37 to 0.67 (p < 0.001) between the different dental practices, indicating lower risk for higher numbers of missing teeth in comparison to SHIP-0. Conclusions. This study showed considerable differences between dental practices and the reference population of SHIP-0 regarding the pattern of tooth loss and confirms the value of nomograms to compare age-specific numbers of teeth between patients of dental practices and a population-based-study as a tool for quality control. For further analyses, the socioeconomic status of patients and relevant risk factors will be used to adjust for structural differences in order to improve the validity of the comparisons.

Treatment of implants with peri-implantitis is often unsuccessful, because an instrumented implant surface and residual microbial biofilm impedes re-osseointegration. The application of cold atmospheric plasma (CAP) could be a simple and effective strategy to overcome the inherent problems of peri-implantitis treatment. CAP is able to destroy and eliminate bacterial biofilms. Additionally, it increases the wettability of titanium, which supports cellular attachment. In this study, the behaviour of osteoblasts on titanium discs was analysed after treatment of bacterial biofilms with CAP, brushing, or a combination of both. A human plaque biofilm was cultured on titanium discs. Treatment with a brush (BR), 1% oxygen/argon CAP (PL), or brushing combined with CAP (BR+PL) was used to eliminate the biofilm. Discs without biofilm (C), autoclaved biofilm (AUTO) and untreated biofilm (BIO) served as controls. Subsequently, human osteoblastic cell growth (MG-63) was observed after 1 and 24 h. Biofilm remnants on BR and PL impaired osteoblastic cell development, whereas the BR+PL provided an increased area of osteoblastic cells. A five-day cell growth was only detectable on BR+PL treated discs. The combination of established brushing and CAP application may be a promising strategy to treat peri-implantitis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Periodontitis is a multi-microbial oral infection with high prevalence among adults. Putative oral pathogens are commonly found in periodontally diseased individuals. However, these organisms can be also detected in the oral cavity of healthy subjects. This leads to the hypothesis, that alterations in the proportion of these organisms relative to the total amount of oral microorganisms, namely their abundance, rather than their simple presence might be important in the transition from health to disease. Therefore, we developed a quantitative molecular method to determine the abundance of various oral microorganisms and the portion of bacterial and archaeal nucleic acid relative to the total nucleic acid extracted from individual samples. We applied quantitative real-time PCRs targeting single-copy genes of periodontal bacteria and 16S-rRNA genes of Bacteria and Archaea. Testing tongue scrapings of 88 matched pairs of periodontally diseased and healthy subjects revealed a significantly higher abundance of P. gingivalis and a higher total bacterial abundance in diseased subjects. In fully adjusted models the risk of being periodontally diseased was significantly higher in subjects with high P. gingivalis and total bacterial abundance. Interestingly, we found that moderate abundances of A. actinomycetemcomitans were associated with reduced risk for periodontal disease compared to subjects with low abundances, whereas for high abundances, this protective effect leveled off. Moderate archaeal abundances were health associated compared to subjects with low abundances. In conclusion, our methodological approach unraveled associations of the oral flora with periodontal disease, which would have gone undetected if only qualitative data had been determined.

Background: Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the "Greifswald Approach to Individualized Medicine" (GANI&#95;MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice., Methods/design: Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI&#95;MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel.

A large body of evidence underlines an association between periodontal disease and cardiovascular disease. In contrast, data on its relation with endothelial dysfunction as a marker of early subclinical atherosclerosis is inconclusive and limited to patient-cohort studies. We therefore investigated the association between periodontal disease and flow-mediated dilation of the brachial artery (FMD) as a measure of endothelial dysfunction in a general population, and also addressed a possible mediation via inflammation. The study population comprised 1,234 subjects (50.5% men) aged 25-85 years from the 5-year follow-up of the Study of Health in Pomerania, a population-based cohort study. Clinical attachment loss (CAL) and pocket probing depth (PPD) as measures of periodontal disease were assessed half-mouth at four sites per tooth. Subjects were classified according to the periodontitis case definition proposed by Tonetti and Claffey (2005). Measurements of FMD and nitroglycerin-mediated dilation (NMD) were performed using standardized ultrasound techniques. High-sensitive C-reactive protein, fibrinogen and leukocyte count were measured. Fully adjusted multivariate linear regression analyses revealed significant associations of the percentage of sites with PPD ≥ 6 mm with FMD (p(trend)=0.048), with subjects within the highest category having a 0.74% higher FMD compared to subjects within the lowest category (p<0.05). Consistently, FMD values increased significantly across categories of the percentage of sites with CAL ≥ 6 mm (p(trend)=0.01) and the periodontitis case definition (p(trend)=0.006). Restrictions to subjects without antihypertensive or statin medication or current non-smokers confirmed previous results. Systemic inflammation did not seem to mediate the relation. Both PPD and CAL were not consistently associated with NMD. In contrast to previous studies, high levels of periodontal disease were significantly associated with high FMD values. This association was not mediated via systemic inflammation. This study revives the discussion on whether and how periodontitis contributes to endothelial dysfunction.

This study aimed to assess the potential association of periodontal diseases with lung volumes and airflow limitation in a general adult population. Based on a representative population sample of the Study of Health in Pomerania (SHIP), 1463 subjects aged 25-86 years were included. Periodontal status was assessed by clinical attachment loss (CAL), probing depth and number of missing teeth. Lung function was measured using spirometry, body plethysmography and diffusing capacity of the lung for carbon monoxide. Linear regression models using fractional polynomials were used to assess associations between periodontal disease and lung function. Fibrinogen and high-sensitivity C-reactive protein (hs-CRP) were evaluated as potential intermediate factors. After full adjustment for potential confounders mean CAL was significantly associated with variables of mobile dynamic and static lung volumes, airflow limitation and hyperinflation (p<0.05). Including fibrinogen and hs-CRP did not change coefficients of mean CAL; associations remained statistically significant. Mean CAL was not associated with total lung capacity and diffusing capacity of the lung for carbon monoxide. Associations were confirmed for mean probing depth, extent measures of CAL/probing depth and number of missing teeth. Periodontal disease was significantly associated with reduced lung volumes and airflow limitation in this general adult population sample. Systemic inflammation did not provide a mechanism linking both diseases.