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Improving accuracy and timeliness for osteoporosis diagnosis could help prevent fragility fractures, morbidity, and mortality for older individuals. Osteoporosis is an often silent health condition, especially as regards vertebral fractures, and WHO issued a call to action for primary care to lead efforts in screening, assessing, and managing diseases such as osteoporosis. We used a machine learning method, Stochastic Gradient Boosting (SGB), to identify what diagnoses in a primary care setting predict a new osteoporosis diagnosis, using a sex- and age-matched case-control design. Cases of new osteoporosis (ICD-10 code: M80, M81, M82) were identified across all outpatient care settings during 2012-2019. We included individuals aged ≥ 40 years old, stratified by sex and age-groups 40-65 years and > 65 years old. Controls were sampled from outpatients that did not have osteoporosis at any time during 2010-2019. Using the SGB model, we ranked the most important diagnoses related to newly diagnosed osteoporosis, presented as the normalized relative influence (NRI) score with a corresponding odds ratio of marginal effects (OR_ME) of being newly diagnosed with osteoporosis. A train-test approach was used to develop the model, with the performance evaluated using area under the curve (AUC). In total, we included 30,741 patients with osteoporosis aged ≥ 40 years. AUC was high, > 0.899 for all age and sex stratas. The number of visits to primary care in the year prior to the osteoporosis diagnosis contributed with the most predictive information for all age and sex stratas. For all age groups several other factors also showed high NRI and OR_ME and among them many unspecific diagnoses such as Dorsalgia showed high NRI, (2.6-9.0%) and other painful musculoskeletal disorders. However, our study also showed that the diagnosis of Hypertension had a very high NRI for patients aged > 65 years but not in patients 40-65 years of age. In this AI study, including only diagnoses from patients seen in primary health care centres, we found that the number of consultations in primary care had high predictive information as well unspecific diagnoses including muscle and skeletal pain predicted high risk for osteoporosis in all age groups.

BACKGROUND: Joint pain and chronic back pain are highly prevalent in the aging population and have a large impact on life quality. As the underlying mechanisms are not fully understood, this exploratory cross-sectional study aimed to discover proteins and pathways associated with these two pain conditions in Swedish 70-year-old men.

METHODS: Plasma proteins (n = 720) were measured in participants from the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 931) using Olink target panels. Participants self-reported current joint pain or continuous back pain during the past year. We used logistic regression with multiple testing adjustments and RIDGE regression (selecting ~10% highest-ranking proteins) to identify proteins associated with either joint or chronic back pain, which were then investigated for clusters and pathway enrichments.

RESULTS: Out of 931 subjects with protein data, 131 reported joint pain and 31 reported chronic back pain. We identified 19 (significant after multiple testing adjustment) and 25 (nominally significant) highest-ranking proteins associated with joint and chronic back pain, respectively. Enriched pathways included immune responses, inflammation, lipid, coagulation and rheumatoid arthritis pathways. Similar pathways were found for both joint and chronic back pain, even though only two proteins were associated with both these pain conditions.

CONCLUSIONS: This exploratory proteomics study provides support for systemic inflammation as a common underlying mechanism for joint and chronic back pain. Although similar pathways were found for both pain conditions, the selected proteins differed. Nevertheless, caution is advised due to low sample size and validation in larger studies including both women and men is needed.

SIGNIFICANCE STATEMENT: Logistic and RIDGE regression analyses indicated that joint pain and chronic back pain were associated with different proteins, which were enriched for similar inflammatory pathways.

Introduction: Children born with lower birth weight face an increased risk of developing cardiovascular disease later in life. We hypothesize that cardiovascular protein biomarkers in cord blood, associated with birth weight SDS and systolic cardiac function, may reveal mechanisms behind early programming of cardiovascular function. Methods: We investigated the association between birth weight SDS and plasma levels of 184 circulating proteins determined by Proximity Extension Assay (PEA) in cord blood from 48 children. The birth weight-associated proteins were correlated with left ventricular longitudinal strain (LVLS) determined by echocardiography at birth and 3 months of age. Results: We identified seven cardiovascular protein biomarkers associated with birth weight SDS: stem cell factor, leptin, elafin, insulin-like growth factor-binding protein-1, follastatin, paraoxonase, and epithelial cell adhesion molecule (Ep-CAM). Among these, Ep-CAM significantly correlated with LVLS at 3 months of age. Conclusion: PEA successfully identified both established and novel proteins associated with fetal growth and birth size, including one novel protein related to LVLS. This indicates that our approach is promising for uncovering biological pathways that may be involved in direct programming of cardiovascular function in children and affect the risk of cardiovascular disease in adulthood.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions.

METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution.

FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant).

INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity.

FUNDING: Gates Foundation and Bloomberg Philanthropies.

Background: Decades of steady improvements in life expectancy in Europe slowed down from around 2011, well before the COVID-19 pandemic, for reasons which remain disputed. We aimed to assess how changes in risk factors and cause-specific death rates in different European countries related to changes in life expectancy in those countries before and during the COVID-19 pandemic. Methods: We used data and methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to compare changes in life expectancy at birth, causes of death, and population exposure to risk factors in 16 European Economic Area countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Portugal, Spain, and Sweden) and the four UK nations (England, Northern Ireland, Scotland, and Wales) for three time periods: 1990–2011, 2011–19, and 2019–21. Changes in life expectancy and causes of death were estimated with an established life expectancy cause-specific decomposition method, and compared with summary exposure values of risk factors for the major causes of death influencing life expectancy. Findings: All countries showed mean annual improvements in life expectancy in both 1990–2011 (overall mean 0·23 years [95% uncertainty interval [UI] 0·23 to 0·24]) and 2011–19 (overall mean 0·15 years [0·13 to 0·16]). The rate of improvement was lower in 2011–19 than in 1990–2011 in all countries except for Norway, where the mean annual increase in life expectancy rose from 0·21 years (95% UI 0·20 to 0·22) in 1990–2011 to 0·23 years (0·21 to 0·26) in 2011–19 (difference of 0·03 years). In other countries, the difference in mean annual improvement between these periods ranged from –0·01 years in Iceland (0·19 years [95% UI 0·16 to 0·21] vs 0·18 years [0·09 to 0·26]), to –0·18 years in England (0·25 years [0·24 to 0·25] vs 0·07 years [0·06 to 0·08]). In 2019–21, there was an overall decrease in mean annual life expectancy across all countries (overall mean –0·18 years [95% UI –0·22 to –0·13]), with all countries having an absolute fall in life expectancy except for Ireland, Iceland, Sweden, Norway, and Denmark, which showed marginal improvement in life expectancy, and Belgium, which showed no change in life expectancy. Across countries, the causes of death responsible for the largest improvements in life expectancy from 1990 to 2011 were cardiovascular diseases and neoplasms. Deaths from cardiovascular diseases were the primary driver of reductions in life expectancy improvements during 2011–19, and deaths from respiratory infections and other COVID-19 pandemic-related outcomes were responsible for the decreases in life expectancy during 2019–21. Deaths from cardiovascular diseases and neoplasms in 2019 were attributable to high systolic blood pressure, dietary risks, tobacco smoke, high LDL cholesterol, high BMI, occupational risks, high alcohol use, and other risks including low physical activity. Exposure to these major risk factors differed by country, with trends of increasing exposure to high BMI and decreasing exposure to tobacco smoke observed in all countries during 1990–2021. Interpretation: The countries that best maintained improvements in life expectancy after 2011 (Norway, Iceland, Belgium, Denmark, and Sweden) did so through better maintenance of reductions in mortality from cardiovascular diseases and neoplasms, underpinned by decreased exposures to major risks, possibly mitigated by government policies. The continued improvements in life expectancy in five countries during 2019–21 indicate that these countries were better prepared to withstand the COVID-19 pandemic. By contrast, countries with the greatest slowdown in life expectancy improvements after 2011 went on to have some of the largest decreases in life expectancy in 2019–21. These findings suggest that government policies that improve population health also build resilience to future shocks. Such policies include reducing population exposure to major upstream risks for cardiovascular diseases and neoplasms, such as harmful diets and low physical activity, tackling the commercial determinants of poor health, and ensuring access to affordable health services. Funding: Gates Foundation. © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Chronic care manages long-term, progressive conditions, while acute care addresses short-term conditions. Chronic conditions increasingly strain health systems, which are often unprepared for these demands. This study examines the burden of conditions requiring acute versus chronic care, including sequelae. Conditions and sequelae from the Global Burden of Diseases Study 2019 were classified into acute or chronic care categories. Data were analysed by age, sex, and socio-demographic index, presenting total numbers and contributions to burden metrics such as Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost (YLL). Approximately 68% of DALYs were attributed to chronic care, while 27% were due to acute care. Chronic care needs increased with age, representing 86% of YLDs and 71% of YLLs, and accounting for 93% of YLDs from sequelae. These findings highlight that chronic care needs far exceed acute care needs globally, necessitating health systems to adapt accordingly. © The Author(s) 2025.

Introduction: Falls among older adults are frequent and will remain a health concern. We describe fall characteristics among older adults living independently in the community based on location, severity, and sex. Methods: As part of the SCOPE study, fall occurrence, location, causes, circumstances, and consequences were reported by 1,754 community-dwelling older adults across Europe at baseline (F0), 12-month follow-up (FU12), and 24-month follow-up (FU24). A geriatric assessment that included demographics, clinical and medication assessment, depression, Cumulative Illness Rating Scale, blood and urine examination, hand grip strength, and fear of falling was performed. Falls characteristics were described, and a multivariate logistic regression analysis was performed to examine the probability of being severely injured because of a fall, inside or outdoors. Results: Data on falls revealed 938 falls at baseline, 773 falls at FU12, and 797 falls at FU24. Approximately 70% of these falls resulted in no injury or untreated injuries, while 8.5% led to bone fractures. Most falls (54.8%) occurred outdoors, primarily during ambulation (64.6%). About 50% of the falls were due to trips, slips, or bumping into objects, while 20.3% were due to balance and gait impairments. Women experienced falls about 30% more frequently than men. Conclusions: Our findings offer new insights into the patterns of falls by location, sex, and injury type. This may help suggest ways of preventing falls. It is reasonable to recommend that older adults train their balance and specifically balance reactive responses to a situation whenever balance is lost accidently and unexpectedly. © 2025 The Author(s). Published by S. Karger AG, Basel.

BACKGROUND: Studies examining the association of chronic kidney disease (CKD) with cancer risk have demonstrated conflicting results.

METHODS: This was an individual participant data meta-analysis including 54 international cohorts contributing to the CKD Prognosis Consortium. Included cohorts had data on albuminuria [urine albumin-to-creatinine ratio (ACR)], estimated glomerular filtration rate (eGFR), overall and site-specific cancer incidence, and established risk factors for cancer. Included participants were aged 18 years or older, without previous cancer or kidney failure.

RESULTS: Among 1,319,308 individuals, the incidence rate of overall cancer was 17.3 per 1000 person-years. Higher ACR was positively associated with cancer risk [adjusted hazard ratio 1.08 (95% CI 1.06-1.10) per 8-fold increase in ACR]. No association of eGFR with overall cancer risk was seen. For site-specific cancers, lower eGFR was associated with urological cancer and multiple myeloma, whereas higher ACR was associated with many cancer types (kidney, head/neck, colorectal, liver, pancreas, bile duct, stomach, larynx, lung, hemolymphatic, leukaemia, and multiple myeloma). Results were similar in a 1-year landmark analysis.

DISCUSSION: Albuminuria, but not necessarily eGFR, was independently associated with the subsequent risk of cancer. Our results warrant an investigation into mechanisms that explain the link between albuminuria and cancer.

BACKGROUND AND AIMS: The relationship between uncommon phenotypes, such as metabolically healthy obesity and normal weight with metabolic syndrome (MetS), and cardiovascular disease (CVD) risk, remains unclear. We investigated how different combinations of body mass index (BMI) and MetS are associated with overall and specific CVDs and how the number of MetS components influences CVD risk in individuals with obesity.

METHODS AND RESULTS: We performed separate analyses and a meta-analysis of 36,233 individuals from four Swedish cohorts to assess the risk of incident CVDs across BMI/MetS combinations (normal-weight, overweight or obese/MetS yes or no). Participants were followed for CVDs and death through linkage to the Swedish National Registers. Compared to normal weight without MetS, overweight and obesity without MetS had most pronounced association with the risk of heart failure [multivariable hazard ratios, HR (95 % CI) = 1.37 (1.16-1.63) and 1.85 (1.37-2.48), respectively, p < 0.001]. In obese individuals, the risk of incident CVD (composite endpoint) increased with an increasing number of MetS components, but this relationship was not statistically significant in obese participants without additional MetS components, likely due to the small at-risk group. Normal-weight individuals with MetS had an increased risk of myocardial infarction [HR (95 % CI) 2.0 (1.51-2.64)], p < 0.001, and stroke [HR (95 % CI) 1.63 (1.17-2.28), p = 0.004].

CONCLUSIONS: Overweight and obesity without MetS showed a greater impact on the risk of heart failure, whereas normal-weight individuals with MetS had a higher risk of myocardial infarction and stroke. In obese individuals, CVD risk increased as the number of MetS components increased.

IMPORTANCE: Estimated glomerular filtration rates (eGFRs) can differ according to whether creatinine or cystatin C is used for the eGFR calculation, but the prevalence and importance of these differences remain unclear.

OBJECTIVES: To evaluate the prevalence of a discordance between cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr), identify characteristics associated with greater discordance, and evaluate associations of discordance with adverse outcomes.

DATA SOURCES: Participants in the Chronic Kidney Disease Prognosis Consortium (CKD-PC).

STUDY SELECTION: Participants with concurrent cystatin C and creatinine measurements and clinical outcome measurement.

DATA EXTRACTION AND SYNTHESIS: Between April 2024 and August 2025, data were synthesized using individual-level meta-analysis.

MAIN OUTCOMES AND MEASURES: The primary independent measurement was a large negative eGFR difference (eGFRdiff), defined as an eGFRcys that was at least 30% lower than eGFRcr. Secondary (dependent) outcomes included all-cause and cardiovascular mortality, atherosclerotic cardiovascular disease, heart failure, and kidney failure with replacement therapy.

RESULTS: A total of 821 327 individuals from 23 outpatient cohorts (mean [SD] age, 59 [12] years; 48% female; 13.5% with diabetes; 40% with hypertension) and 39 639 individuals from 2 inpatient cohorts (mean [SD] age, 67 [16] years; 31% female; 30% with diabetes; 72% with hypertension) were included. Among outpatient participants, 11% had a large negative eGFRdiff (range, 3%-50%). Among inpatients, 35% had a large negative eGFRdiff. Among outpatient participants, at a mean (SD) follow-up of 11 (4) years, a large negative eGFRdiff, compared with an eGFRdiff between -30% and 30%, was associated with higher rates of all-cause mortality (28.4 vs 16.8 per 1000 person-years [PY]; hazard ratio [HR], 1.69 [95% CI, 1.57-1.82]), cardiovascular mortality (6.1 vs 3.8 per 1000 PY; HR, 1.61 [95% CI, 1.48-1.76]), atherosclerotic cardiovascular disease (13.3 vs 9.8 per 1000 PY; HR, 1.35 [95% CI, 1.27-1.44]), heart failure (13.2 vs 8.6 per 1000 PY; HR, 1.54 [95% CI, 1.40-1.68]), and kidney failure with replacement therapy (2.7 vs 2.1 per 1000 PY; HR, 1.29 [95% CI, 1.13-1.47]).

CONCLUSIONS AND RELEVANCE: In the CKD-PC, 11% of outpatient participants and 35% of hospitalized patients had an eGFRcys that was at least 30% lower than their eGFRcr. In the outpatient setting, presence of eGFRcys at least 30% lower than eGFRcr was associated with significantly higher rates of all-cause mortality, cardiovascular events, and kidney failure.