Applying Machine Learning to Blood Count Data Predicts Sepsis with ICU Admission.

BACKGROUND: Timely diagnosis is crucial for sepsis treatment. Current machine learning (ML) models suffer from high complexity and limited applicability. We therefore created an ML model using only complete blood count (CBC) diagnostics. METHODS: We collected non-intensive care unit (non-ICU) data from a German tertiary care centre (January 2014 to December 2021). Using patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells), we trained a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature. RESULTS: After exclusion, 1 381 358 laboratory requests (2016 from sepsis cases) were available. The CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857-0.887). External validations show AUROCs of 0.805 (95% CI, 0.787-0.824) for University Medicine Greifswald and 0.845 (95% CI, 0.837-0.852) for MIMIC-IV. The model including PCT revealed a significantly higher AUROC (0.857; 95% CI, 0.836-0.877) than PCT alone (0.790; 95% CI, 0.759-0.821; P < 0.001). CONCLUSIONS: Our results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.

Imaging Markers Derived From MRI-Based Automated Kidney Segmentation­an Analysis of Data From the German National Cohort (NAKO Gesundheitsstudie)

BACKGROUND: Population-wide research on potential new imaging biomarkers of the kidney depends on accurate automated segmentation of the kidney and its compartments (cortex, medulla, and sinus). METHODS: We developed a robust deep-learning framework for kidney (sub-)segmentation based on a hierarchical, three-dimensional convolutional neural network (CNN) that was optimized for multi-scale problems of combined localization and segmentation. We applied the CNN to abdominal magnetic resonance images from the population-based German National Cohort (NAKO) study. RESULTS: There was good to excellent agreement between the model predictions and manual segmentations. The median values for the body-surface normalized total kidney, cortex, medulla, and sinus volumes of 9934 persons were 158, 115, 43, and 24 mL/m2. Distributions of these markers are provided both for the overall study population and for a subgroup of persons without kidney disease or any associated conditions. Multivariable adjusted regression analyses revealed that diabetes, male sex, and a higher estimated glomerular filtration rate (eGFR) are important predictors of higher total and cortical volumes. Each increase of eGFR by one unit (i.e., 1 mL/min per 1.73 m2 body surface area) was associated with a 0.98 mL/m2 increase in total kidney volume, and this association was significant. Volumes were lower in persons with eGFR-defined chronic kidney disease. CONCLUSION: The extraction of image-based biomarkers through CNN-based renal sub-segmentation using data from a population-based study yields reliable results, forming a solid foundation for future investigations.

Prevalence of infectious diseases, immunity to vaccine-preventable diseases and chronic medical conditions among Ukrainian refugees in Germany - A cross sectional study from the German Network University Medicine (NUM).

BACKGROUND: Vulnerability to infectious diseases in refugees is dependent on country of origin, flight routes, and conditions. Information on specific medical needs of different groups of refugees is lacking. We assessed the prevalence of infectious diseases, immunity to vaccine-preventable diseases, and chronic medical conditions in children, adolescents, and adult refugees from Ukraine who arrived in Germany in 2022. METHODS: Using different media, we recruited Ukrainian refugees at 13 sites between 9-12/2022. An antigen test for acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, serologies for a range of vaccine-preventable diseases, as well as interferon gamma release assays (IGRAs) for tuberculosis (TB), and SARS-CoV-2 were performed. We assessed personal and family history of chronic medical conditions, infectious diseases, vaccination status, and conditions during migration. RESULTS: Overall, 1793 refugees (1401 adults and 392 children/adolescents) were included. Most participants were females (n = 1307; 72·3%) and from Eastern or Southern Ukraine. TB IGRA was positive in 13% (n = 184) of the adults and in 2% (n = 7) of the children. Serology-based immunological response was insufficient in approximately 21% (360/1793) of the participants for measles, 32% (572/1793) for diphtheria, and 74% (1289/1793) for hepatitis B. CONCLUSIONS: We show evidence of low serological response to vaccine-preventable infections and increased LTBI prevalence in Ukrainian refugees. These findings should be integrated into guidelines for screening and treatment of infectious diseases in migrants and refugees in Germany and Europe. Furthermore, low immunity for vaccine-preventable diseases in Ukrainians independent of their refugee status, calls for tailor-made communication efforts.

Whole-body metabolic modelling reveals microbiome and genomic interactions on reduced urine formate levels in Alzheimer's disease.

In this study, we aimed to understand the potential role of the gut microbiome in the development of Alzheimer's disease (AD). We took a multi-faceted approach to investigate this relationship. Urine metabolomics were examined in individuals with AD and controls, revealing decreased formate and fumarate concentrations in AD. Additionally, we utilised whole-genome sequencing (WGS) data obtained from a separate group of individuals with AD and controls. This information allowed us to create and investigate host-microbiome personalised whole-body metabolic models. Notably, AD individuals displayed diminished formate microbial secretion in these models. Additionally, we identified specific reactions responsible for the production of formate in the host, and interestingly, these reactions were linked to genes that have correlations with AD. This study suggests formate as a possible early AD marker and highlights genetic and microbiome contributions to its production. The reduced formate secretion and its genetic associations point to a complex connection between gut microbiota and AD. This holistic understanding might pave the way for novel diagnostic and therapeutic avenues in AD management.

Body composition markers are associated with changes in inflammatory markers but not vice versa: A bi-directional longitudinal analysis in a population-based sample.

BACKGROUND AND AIM: Growing body of evidence consistently link obesity and inflammation, Although the direction of the association is still unclear. We aimed to investigate longitudinal associations of body anthropometric, composition and fat distribution parameters with inflammatory markers and vice versa. METHOD AND RESULTS: We used data from 2464 individuals of the SHIP-TREND cohort with a median follow-up of 7 years. Linear regression models adjusted for confounders were used to analyze associations of standardized body composition markers derived from classic anthropometry, bioelectrical impedance analysis (BIA) and magnetic resonance imaging (MRI) at baseline with changes in inflammatory markers (C-reactive protein (CRP), white blood cell (WBC), fibrinogen) and vice versa. Higher level of anthropometric markers at baseline were associated with an increase in the change of inflammatory markers. A 13.5 cm higher waist circumference (WC), 16.0 kg body weight and 7.76 % relative fat mass (FM) at baseline was associated with a change in CRP of 0.52 mg/L (95 % confidence interval [CI]: 0.29 to 0.74), 0.51 mg/L (95 % CI: 0.29; 0.74) and 0.58 mg/L (95 % CI: 0.34; 0.82) respectively. Absolute FM showed the strongest association with changes in serum fibrinogen levels (ß for 8.69 kg higher FM: 0.07 g/L; 95 % CI: 0.05; 0.09). Baseline inflammatory markers were only associated with changes in hip circumference. CONCLUSION: Our study indicates the importance of anthropometric, body composition and fat distribution markers as a risk factor for the development of inflammation. To prevent inflammatory-related complications, important is to take measures against the development of obesity.

Higher Parametric Thyroid Feedback Quantile-based Index is a predictor of type 2 diabetes in a German population sample.

BACKGROUND: Type 2 diabetes has been described to be associated with hypothyroidism but we recently found that a decrease in pituitary sensitivity to thyroid hormone is associated with diabetes, obesity, and the metabolic syndrome.We aim to assess the longitudinal nature of this association in the population-based Study of Health in Pomerania(SHIP) in Germany. MATERIALS AND METHODS: 77% of a population-based sample of 4308 participants between 20 and 79 years was followed for 5 years. We studied 2542 participants without diabetes or thyroid medication at baseline and complete data in the variables of interest. Data of baseline thyroxine(fT4) and thyrotropin(TSH) were used to calculate the Parametric Thyroid Feedback Quantile-based Index(PTFQI), which measures whether TSH remains elevated despite fT4 being high. It uses the average population response as reference. PTFQI association with incidence of type 2 diabetes over 5 years was estimated with Poisson regression models adjusted for age, sex, and body mass index(BMI). RESULTS: Compared with the 1st PTFQI quartile, Incidence Rate Ratios (IRR) for diabetes were 1.54(95% CI 0.97 to 2.46), 1.55(0.94 to 2.57), and 1.97(1.27 to 3.10) for the upper quartiles (p-trend=0.004) after adjusting for age and sex. The association remained statistically significant after additionally adjusting for BMI: 1.64(1.05 to 2.59) for the 4th vs the 1st quartile (p-trend=0.043). CONCLUSIONS: An elevation of the pituitary TSH-inhibition threshold is associated with incident type 2 diabetes independently of BMI. The PTFQI might have clinical potential for prognosis and metabolic status monitoring.

The Association Between C24:0/C16:0 Ceramide Ratio and Cardiorespiratory Fitness is Robust to Effect Modifications by Age and Sex.

Ceramides and cardiorespiratory (CR) fitness are both related to cardiovascular diseases. The associations of three blood plasma ceramides (C16:0, C22:0, and C24:0) with CR fitness in the population-based Study of Health in Pomerania (SHIP-START-1; n = 1,102; mean age 50.3 years, 51.5% women) are investigated. In addition, subgroup analysis according to age (

Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes.

White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based Study of Health in Pomerania (SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified hsa-miR-425-5p as directly associated with WMLs. In subsequent analyses, hsa-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the SH3PXD2A gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced hsa-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia.

Estimates of protection levels against SARS-CoV-2 infection and severe COVID-19 in Germany before the 2022/2023 winter season: the IMMUNEBRIDGE project.

PURPOSE: Despite the need to generate valid and reliable estimates of protection levels against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real time. METHODS: In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n = 33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses ("confirmed exposures"). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest. RESULTS: Most participants were seropositive against the spike antigen; 37% of the participants ≥ 79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4-28% of participants having less than three confirmed exposures. CONCLUSION: Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups.

Sleep characteristics and parameters of bone turnover and strength in the adult population: results from the Study of Health in Pomerania-TREND.

Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea-hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.

Diagnostic sample transport via pneumatic tube systems: data logger and their algorithms are sensitive to transport effects.

OBJECTIVES: Many hospitals use pneumatic tube systems (PTS) for transport of diagnostic samples. Continuous monitoring of PTS and evaluation prior to clinical use is recommended. Data loggers with specifically developed algorithms have been suggested as an additional tool in PTS evaluation. We compared two different data loggers. METHODS: Transport types - courier, conventional (cPTS) and innovative PTS (iPTS) - were monitored using two data loggers (MSR145® logger, CiK Solutions GmbH, Karlsruhe, Germany, and a prototype developed at the University Medicine Greifswald). Data loggers differ in algorithm, recording frequencies and limit of acceleration detection. Samples from apparently healthy volunteers were split among the transport types and results for 37 laboratory measurands were compared. RESULTS: For each logger specific arbitrary units were calculated. Area-under-the-curve (AUC)-values (MSR145®) were lowest for courier and highest for iPTS and increased with increasing recording frequencies. Stress (St)-values (prototype logger) were obtained in kmsu (1,000*mechanical stress unit) and were highest for iPTS as well. Statistical differences between laboratory measurement results of transport types were observed for three measurands sensitive for hemolysis. CONCLUSIONS: The statistical, but not clinical, differences in the results for hemolysis sensitive measurands may be regarded as an early sign of preanalytical impairment. Both data loggers record this important interval of beginning mechanical stress with a high resolution indicating their potential to facilitate early detection of preanalytical impairment. Further studies should identify suitable recording frequencies. Currently, evaluation and monitoring of diagnostic sample transport should not only rely on data loggers but also include diagnostic samples.

Association of spermidine blood levels with microstructure of sleep-implications from a population-based study.

Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer's disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50-81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.

Serum lipoprotein subfractions are associated with the periodontal status: Results from the population-based cohort SHIP-TREND.

AIM: To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1 H-NMR) spectroscopy with periodontitis and tooth loss. MATERIALS AND METHODS: A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1 H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing. RESULTS: While only spurious associations between lipoprotein levels from conventional blood tests were found-that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1 H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity. CONCLUSIONS: Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.

[Laboratory diagnostics of lipid metabolism disorders]. / Labordiagnostik von Fettstoffwechselstörungen.

Clinically, disorders of lipid metabolism often remain without symptoms. Typical skin lesions, however, can be indicative. Secondary hyperlipoproteinemias (HLP) are more common than primary hyperlipoproteinemias; they can (partially) be improved by treating the underlying disease. Basic diagnostics consist of the determination of cholesterol, triglycerides, LDL cholesterol and HDL cholesterol. To exclude secondary HLP, glucose, HbA1C, TSH, transaminases, creatinine, urea, protein and protein in the urine are useful. Since virtually all routine methods for LDL-C are biased by high triglycerides, lipoprotein electrophoresis is indicated for triglycerides above 400 mg/dl (4.7 mmol/l). Primary HLPs have known or yet unknown genetic causes. Primary hyperlipidemias should be taken into consideration especially in young patients with an LDL cholesterol concentration are above 190 mg/dl (4.9 mmol/l) and/or triglycerides above 400 mg/dl (10 mmol/l) and secondary HLP (obesity, alcohol, diabetes mellitus, kidney disease) is excluded. The basic diagnostics is meaningfully extended by the measurement of lipoprotein (a) (Lp(a)). It is indicated in moderate and high risk of vascular disease, progression of atherosclerosis in "well-controlled" LDL cholesterol, familial clustering of atherosclerosis or high Lp(a), evidence for elevated Lp(a) coming from lipoprotein electrophoresis, aortic stenosis and in patients in whom statins have a poor effect. Genetic diagnostics needs to be considered if primary HLP is suspected. It is most frequently conducted for suspected familial hypercholesterolemia and has already been recommended in guidelines.

Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study.

Rationale & Objective: Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Study Design: Prospective cohort study. Setting & Participants: A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio >300mg/g or equivalent). Exposures: Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Outcomes: Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF. Analytical Approach: HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.08-2.75). Limitations: Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. Conclusions: In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD. Plain-Language Summary: A blood sample-based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample-based strategy to identify patients with kidney disease at high cardiovascular risk.

Correction: Analysis of epidemiological association patterns of serum thyrotropin by combining random forests and Bayesian networks.

[This corrects the article DOI: 10.1371/journal.pone.0271610.].

Periodontitis and systemic inflammation as independent and interacting risk factors for mortality: evidence from a prospective cohort study.

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.