Michael F. Leitzmann

Background: Cardio-kidney-metabolic (CKM) diseases share risk factors, but their shared and distinct risk factors for disease progression remain unclear. We examined whether classical risk factors predict baseline CKM indicators and their longitudinal changes in a population-based German National Cohort (NAKO) sample. Methods: In 2,650 NAKO-IMMEDIATE participants selected for deep-phenotyping, baseline values and 5-year changes in — glycated hemoglobin (HbA1c), systolic blood pressure (SBP), pulse wave velocity (PWV), and estimated glomerular filtration rate (eGFR) were linearly regressed on age, sex, education, alcohol and tobacco consumption, body mass index (BMI), and residuals of BMI-adjusted waist circumference (WC) with mutual adjustment. Results: Baseline values for HbA1c were 34.6±5.8 mmol/mol, for PWV 8.3±1.5 m/s, for SBP 128.0±15.7 mmHg and for eGFR 96.0±14.6 ml/min/1.73 m². Cross-sectionally, all risk factors were associated with one or more of the CKM indicators, with age and BMI being associated with all four indicators. Over 5 years, HbA1c (1.2±4.2 mmol/mol), PWV (0.5±1.2 m/s) and SBP (0.6± 14.2 mmHg) increased, whereas eGFR (−2.3±9.5 ml/min/1.73 m²) decreased. Age (0.03 m/s per 5 year, 95% CI 0.01, 0.06 m/s) was associated with higher and BMI (−0.02 m/s per 1kg/m2, −0.03, −0.01) with lower PWV changes. No other risk factors were associated with CKM indicator changes. Conclusion: Classical risk factors were more frequently related to baseline CKM indicators than to their 5-year changes. Within longitudinal analyses, only age and BMI were related to PWV 5-year changes. Clinical Perspective: It is well established that classical risk factors are associated with cardio-kidney and metabolic (CKM) diseases whereas their associations with longitudinal changes in CKM indicators are less well understood. This study examines to what extent age, sex, education, alcohol and tobacco consumption, BMI and waist circumference are associated with glycated hemoglobin, systolic blood pressure, pulse wave velocity and estimated glomerular filtration rate at baseline and their 5-year changes. Only age and BMI were associated with changes in PWV, while other longitudinal associations were non-significant, suggesting that classical CKM risk factors have greater utility for assessing cross-sectional CKM function than for predicting prospective changes in CKM function in the general population.

Aim: To evaluate regional disparities in the prevalence, severity and extent of probing depths (PDs) as well as tooth loss in German adults aged 19–74, using data from the baseline study of the German National Cohort (NAKO; 2014–2019). Methods: Dental examinations were recorded at two levels: Level 1 (18/18 centres; N = 184,871; tooth counts including third molars and dental interview) and Level 2 (8/18 centres, not geographically representative; N = 18,389; recording of PDs). We evaluated differences by sex, age and study region. All data were survey‐weighted. For individuals aged 65–74, we supplemented tooth loss data from the Fifth German Oral Health Study and the Study of Health in Pomerania. Results: Among Level 1 participants, the prevalence of edentulism was 1.7% (95% confidence interval: 1.6–1.9). The average mean PD was 1.89 mm (1.87–1.91). Both edentulism and PDs increased with increasing age. There were clear regional disparities, with the lowest prevalence of both in Augsburg/Regensburg in the south (1.3% and 1.64 mm) and the highest in Neubrandenburg in the north‐east (2.3% and 2.31 mm). Conclusion: Clear regional disparities emerged. In light of demographic changes, these results highlight the importance of incorporating region‐specific oral health burdens into future healthcare planning and treatment concepts.

Background: Insufficient physical activity is a leading global cause of premature mortality, yet how light-, moderate-, and vigorous-intensity activity differ in their associations with mortality and the implications of reallocating time across intensities remain unclear. Methods: We prospectively analysed individually pooled baseline device-measured physical activity from 147,414 participants aged 40–74 years in the German National Cohort (NAKO) and UK Biobank, the largest pooled accelerometer dataset to date. Multivariable Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) for mortality across activity intensities and under time-reallocation models holding total active time constant. Results: Over a mean follow-up of 7.9 years, 5,545 deaths occurred. Compared with no activity, 150 min per week of moderate-intensity activity was associated with lower mortality (HR: 0.70; 95% CI: 0.67, 0.72). Similar associations were observed for approximately 510 min per week of light-intensity activity or 12 min per week of vigorous-intensity activity. Additional activity beyond these levels was associated with further risk reduction. Replacing 15–60 min per week of light- or moderate-intensity activity with vigorous-intensity activity was associated with 18–30% lower mortality risk. Conclusions: Physical activity at all intensities was associated with lower mortality, with vigorous-intensity activity showing strong inverse associations even at low volumes. Shifting modest amounts of active time toward higher intensities was associated with further risk reductions. These findings provide quantitative evidence to inform the interpretation of physical activity recommendations.

Background: Post-COVID Condition (PCC) affected 10–30% of individuals after SARS-CoV-2 infection, and pre-infection predictors of who goes on to develop it are not well established. We compared pre-infection structural brain variation and baseline psychiatric phenotype as candidate predictors of PCC within a common multi-modal framework in the German National Cohort (NAKO). Both are candidate “first hits” under the second-hit hypothesis, which motivates the comparison; this is a prediction study, not a test of that hypothesis. Methods: In 8,464 SARS-CoV-2-infected NAKO neuroimaging participants, of whom 2,304 (27.2%) met PCC criteria (weighted post-COVID syndrome (PCS) score > 10.75) and the rest were symptom-free controls, ten pre-infection modalities (T1-weighted volumetric brain MRI across six parcellations, baseline mental health (PHQ-9, GAD-7), demographics, and seven further biomedical and socioeconomic domains) entered a stacked ensemble with 10 × 5 nested cross-validation (primary metric: the area under the precision–recall curve, PR-AUC). Pre-specified analyses assessed transportability to a non-imaging cohort and robustness to the mental-health symptom trajectory and to unmeasured confounding. SARS-CoV-2 infection status and the PCC outcome were ascertained by self-report; no clinically confirmed diagnoses were available. Results: Baseline mental health, assessed 3–8 years before infection, was the strongest predictor (38.0% of feature importance; standalone ROC-AUC = 0.640), whereas all six brain-MRI parcellations performed at or near chance (ROC-AUC 0.496–0.516). The multi-modal model achieved moderate, well-calibrated discrimination (ROC-AUC = 0.665, 95% CI 0.653–0.677; PR-AUC = 0.413, 0.392–0.434; ECE = 0.013). A four-modality non-imaging version, applied without retraining to NAKO participants without MRI, retained discrimination (ROC-AUC = 0.660, 0.654–0.665), meeting all three pre-specified equivalence criteria, the calibration intercept narrowly. The baseline mental-health odds ratio was 2.06 (1.83–2.32; E-value 2.66) and essentially unchanged under an alternative control definition (2.07); adjusting for the full mental-health symptom trajectory reduced it to a conservative lower bound of 1.38 (1.20–1.58) that remained independently significant. Baseline mental health did not predict objectively measured hyposmia in participants screened before their infection (0.89) while predicting self-reported smell loss in the same participants (1.92). Conclusions: Baseline mental health years before infection is the strongest pre-infection predictor of PCC among the infected, and the association held across the pre-specified sensitivity analyses. Whether it acts specifically on COVID-19 sequelae is a separate question this design cannot answer, and the indirect evidence points away from specificity: the association is undiminished after mild infection but absent among the hospitalized, and baseline mental health predicts current mental-health symptom load slightly less strongly in infected than in non-infected participants. The volumetric structural candidate is not supported: prepandemic T1-weighted volumetry carried no predictive signal in this single neuroimaging cohort. Risk stratification may benefit from incorporating baseline psychiatric phenotype; whether treating it reduces PCC incidence requires interventional study.

Assessing exposures that are considered potential health hazards in professional sports poses substantial challenges. This is particularly true for contact sports such as football (soccer), where a...

Background Obesity is a risk factor for pancreatic cancer, but mechanisms remain unclear. We investigated how anthropometric traits, individually and combined, relate to pancreatic cancer risk and whether associations are mediated by metabolic biomarkers. Methods We analysed 462,300 adults (40–69 years) in the UK Biobank. Principal component analysis derived three body shape phenotypes combining body mass index (BMI), height, weight, waist and hip circumference, and waist-to-hip ratio (WHR). Mediation was assessed using four-way decomposition. Results Over a median follow-up of 10.9 years, 1115 pancreatic cancer cases occurred. Each one-standard-deviation (SD) increase in BMI or WHR was associated with a higher incidence of pancreatic cancer, with hazard ratios (HRs) of 1.20 (confidence interval, CI: 1.12–1.28) and 1.24 (CI: 1.14–1.36), respectively. Body shape characterizing overall obesity showed a similar association (HR = 1.20; CI: 1.12–1.28 per 1-SD), with glucose and HbA1c accounting for mediated proportions (mediated interaction + pure indirect effect) of 12.2% (CI: 3.4–21.0%) and 15.0% (CI: 5.7–24.2%), respectively. For BMI, glucose accounted for 15.9% (CI: 2.8–28.9%) and HbA1c for 20.0% (CI: 6.3–33.7%) of the association. Conclusions Glucose and HbA1c mediate a large proportion of the obesity-pancreatic cancer association, highlighting the important role of glycemic control in obesity-related pancreatic carcinogenesis and targeted interventions in at-risk populations.

Objectives: Low physical activity (PA) and poor cognitive function are associated with higher mortality risks. However, little is known about their interaction, including whether PA may moderate cognition-related mortality risks. This study examines the combined associations of PA and cognition with all-cause mortality, with attention to sex differences. Methods: Using data from the German National Cohort and its mortality follow-up, we analyzed mortality risk based on: a) baseline low vs. sufficient PA (assessed via the global physical activity questionnaire using a threshold of < vs. ≥ 600 MET-minutes/week), b) baseline low vs. medium vs. high semantic memory (SM) and executive function/processing speed (EF/PS), assessed through factor analyses of a neurocognitive test battery, and c) their interaction on mortality in individuals aged 65 + up to 10 years of follow-up (N = 28,892). Cox models were estimated both in the total sample and stratified by sex, adjusting for relevant confounders and reporting both distinct and combined associations. Results: During follow-up, 1,605 individuals (5.6%) died: 1,097 men (7.5%) and 508 women (3.6%). Compared to individuals with low cognitive function, those with high SM (Hazard Ratio (HR) = 0.83 [95%CI: 0.67–1.02]), as well as high EF/PS (HR = 0.66 [0.53–0.83]) and medium EF/PS (HR = 0.68 [0.60–0.78]) had lower mortality risks. PA was associated with a 29% decreased mortality risk (HR = 0.71 [0.62–0.82]) compared to low PA. PA moderated the elevated risk from low cognition, with regard to EF/PS (low EF/PS*PA: HR = 0.65 [0.50–0.84] vs. low EF/PS*low PA: HR = 1 (ref.)) and SM (low SM*PA: HR = 0.60 [0.46–0.77] vs. low SM*low PA: HR = 1 (ref.)). The associations did not differ between men and women. Conclusion: Maintaining cognitive function and PA in older age is relevant for reducing mortality risk in both men and women. PA may offset risks linked to low cognition in both sexes, though mechanisms require further study. Trial registration: Clinical trial number: not applicable.

Tobacco use, second‐hand tobacco smoke (SHS) exposure and alcohol consumption are well‐established carcinogens and major public health concerns. In the European Union (EU), tobacco and alcohol use are the leading preventable causes of cancer and four other major noncommunicable diseases (NCDs), significantly contributing to NCD‐related morbidity and mortality. Despite declining prevalence, consumption of these substances is still high in the region, especially among the most deprived. There is strong evidence that quitting smoking, minimising exposure to SHS and eliminating or reducing alcohol intake substantially lowers the risk of cancer. Comprehensive public health strategies at both the individual and population level are crucial to prevent cancer and other NCDs. Scientific evidence leads to two recommendations for individual action on tobacco in the European Code Against Cancer, 5th edition: (1) ‘Do not smoke. Do not use any form of tobacco, or vaping products. If you smoke, you should quit’; and (2) ‘Keep your home and car free of tobacco smoke’; and one on alcohol: (3) ‘Avoid alcoholic drinks’.

Diet, body weight, physical activity, sedentary behavior, and breastfeeding are modifiable factors influencing the cancer burden in the European Union, shaped by underlying social, commercial, environmental, and behavioral conditions. Excess body weight has reached epidemic levels, significantly influenced by widespread intake of sugar‐sweetened beverages and ultra‐processed foods rich in sugar, fat, and salt. Consumption of red and processed meat also commonly exceeds dietary recommendations. Physical inactivity and prolonged sedentary behavior are widespread. Breastfeeding rates vary widely across Europe but are generally low, particularly in high‐income countries. To reduce cancer risk, the European Code Against Cancer, 5th edition (ECAC5) recommends a diet rich in whole grains, vegetables, legumes, and fruits, while limiting red meat and avoiding processed meat. Intake of vegetables, legumes, and fruits prevents aerodigestive tract cancers, while diets high in whole grains and low in red and processed meat reduce colorectal cancer risk. Avoiding excess body weight through diet and physical activity, and limiting prolonged sitting, decreases risk of numerous cancers. Promoting and supporting sustained breastfeeding contributes to lowering breast cancer risk. Key policy interventions, such as fiscal incentives, urban planning, marketing restrictions, and public awareness campaigns, are central to creating supportive environments for cancer prevention.