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INTRODUCTION: Acute kidney injury (AKI) criteria and staging are based on serum creatinine and urine output, but serum cystatin C performs better at estimating glomerular filtration rate (GFR) in critically ill patients. Accordingly, a cystatin C-based AKI staging system was developed and its performance studied in critically ill patients.

METHODS: AKI stages according to Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria were converted to corresponding cystatin C-based stages using 14-day mortality in 9424 critically ill patients from 3 Swedish hospitals followed for 5.6 years (median interquartile range: 2.8-7.2). Model performance was evaluated using Cox regression on long-term mortality adjusted for age, gender, comorbidities, and unit type. An independent cohort (n = 434) was used for validation.

RESULTS: KDIGO stages corresponded to the following: Stage 1: increase in cystatin C 1.40 to 1.59 times baseline within 7 days or ≥ 0.44 mg/l within 48 hours; Stage 2: 1.60 to 2.09 times baseline; and Stage 3: above 2.10 times baseline or ≥ 2.80 mg/l. Cystatin C-based versus creatinine-based staging identified 11% more AKI and 10% more Stage 3. Patients reclassified to AKI by cystatin C from no AKI had a higher risk of death of 1.36 (1.24-1.49), whereas those reclassified vice versa had a lower risk 0.71 (0.56-0.91). These findings were consistent irrespective of infection status for 30-day mortality. In the validation cohort, reclassification to a higher stage by cystatin C was an independent predictor of increased risk of death.

CONCLUSION: In critically ill patients, cystatin C-based staging identified more AKI than KDIGO criteria, and these patients had increased short- and long-term mortality.

Objective: To examine if long-term constant low vitamin D status in the sunny season has a greater impact on bone mineral density (BMD) over time than long-term constant low vitamin D status in the dark season.

Patients and Methods: In a longitudinal cohort study conducted from November 3, 2003 to May 22, 2019, 1802 Swedish women living in Uppsala County (latitude 58°N) (mean baseline age of 65 years and average follow-up of 12 years) had vitamin D status measured by serum 25-hydroxyvitamin D concentration (S-25OHD). Participants were stratified by season of blood draw (dark [November-April] vs sunny [May-October]). We examined the association of long-term stable season-specific S-25OHD with 12-year changes in total hip BMD, measured by dual-energy x-ray absorptiometry, and investigated if increasing S-25OHD during follow-up influenced changes in BMD by baseline S-25OHD levels and season.

Results: Compared with longitudinally sunny season constant S-25OHD>70 nmol/L, women with sunny season constant S-25OHD<40 nmol/L displayed 10.0% (95% CI,3.8%-16.1%) lower total hip BMD at follow-up. No difference in BMD was observed by dark season S-25OHD. Among women with baseline sunny season S-25OHD<45 nmol/L, each 20 nmol/L increase in S-25OHD during follow-up was associated with a 2.5% increase in hip BMD (95% CI,0.5-4.6). This estimate was attenuated when increasing the low S-25OHD cut-off and was not observed with dark season samples.

Conclusion: Women with sunny season S-25OHD<40-50 nmol/L are a likely target group for vitamin D interventions to improve BMD. Blood samples taken during the dark season are less informative for determining future bone health. 

BACKGROUND: Studies in breast cancer patients have consistently shown that physical activity improves survival. We examined if change in physical activity from before to after a breast cancer diagnosis is associated with outpatient specialist care use and hospitalisations in women with type 2 diabetes mellitus (T2DM).

METHODS: This register-based cohort study included 2145 women with T2DM who self-reported frequency of walking 30 min/week, 1-3 years before and after their breast cancer diagnosis (diagnosed 2004-2018). Women were grouped as: maintained inactive (reference), increased activity, decreased activity, or maintained active. Using multivariable-adjusted Cox proportional hazards models, we assessed change in physical activity with time to 1) first hospital admission and 2) first outpatient specialist care/hospitalisation for 15 International Classification of Disease chapters in the National Patient Register.

RESULTS: Women who maintained active (hazard ratio[95% CI]: 0.68[0.58-0.80]) or increased (0.72[0.58-0.88]) activity, but not those who decreased (0.92[0.79-1.08]) activity, had a lower rate of hospitalisations during follow-up than inactive women. Results were similar for infection, malignancy, blood disorders, general symptoms, mental/behavioural health.

CONCLUSION: In breast cancer survivors, treated with curative intention, with T2DM, maintaining or increasing walking to ≥3times/week was associated with lower rates of hospitalisations overall and specialist outpatient care/hospitalisations across a range of diagnoses.

Background

How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death.

Methods

We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men.

Findings

The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass.

Interpretation

These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease.

This commentary refers to 'Plasma proteome and incident myocardial infarction: sex-specific differences', by O.E. Titova et al., https://doi.org/10.1093/eurheartj/ehae658 and the discussion piece 'Gender-specific associations and circulating proteins in myocardial infarction: potential causal relationships', by Y. Xu et al., https://doi.org/10.1093/eurheartj/ehaf111

Background: Circulating proteins are associated with type 2 diabetes (T2D) but causality has often not been investigated. Whether plasma proteins could be suitable targets for T2D prevention remains uncertain.

Objectives: We aimed to identify causal associations between plasma proteins and incident T2D and discover whether proteins may mediate associations between diet and T2D risk.

Methods: We measured 276 plasma proteins in 2 Swedish prospective cohorts. The discovery cohort consisted of 4103 females, and the replication cohort consisted of 1017 females and 4124 males. During follow-up, 189 females in the discovery cohort and 297 participants in the replication cohort developed T2D. Associations between proteins with incident T2D were estimated using Cox proportional hazards models. Mendelian randomization analyses using cis-protein quantitative trait loci were conducted to assess causal relevance, along with colocalization analyses to examine shared causal variants between proteins and T2D. We further assessed whether proteins could mediate associations between dietary patterns (DPs) derived from principle component analysis and incident T2D.

Results: Overall, 112 proteins were associated with incident T2D independent of age, sex and lifestyle factors in 2 cohorts. Genetically raised levels of tyrosine-protein kinase receptor TYRO3, intercellular adhesion molecule 2, sortilin (SORT1), and sialomucin core protein 24 were associated with increased T2D risk, whereas catechol O-methyltransferase, CD2-associated protein, matrix metalloproteinase-12, nectin-2 (NECTIN2), reticulon-4 receptor (RTN4R), and fibroblast growth factor 21 were inversely associated (false discovery rate-adjusted P < 0.05). Strong evidence (posterior hypothesis 4 of colocalization > 0.8) of shared genetic variants of NECTIN2, RTN4R, and SORT1 with T2D was found. Phenome-wide association investigation at the gene level confirmed associations of proteins with T2D traits. We identified a mediating role of proteins with genetic evidence in the association between a healthy DP (i.e., high consumption of vegetables, fruits, nuts, and whole grains) and T2D.

Conclusions: We provide novel and robust findings of proteins causally linked to T2D and their associations with habitual diet. These findings may guide nutritional strategies for T2D prevention.

AIMS/HYPOTHESIS: The aim of this study was to quantify the impact of childhood-onset type 1 diabetes on parental incomes in a Nordic welfare state.

METHODS: In this register-based quasi-experimental study, we included the parents of 13,358 children diagnosed with type 1 diabetes in Sweden from 1993 to 2014 together with 506,516 population-based matched control parents. A difference-in-differences approach was used to compare income trajectories between exposed parents and control parents. Work-related and pension-qualifying incomes (including parental benefits) were assessed during the first 7 years after diagnosis. The long-term incomes of parents of children diagnosed with type 1 diabetes in 1993-2004 were also investigated.

RESULTS: A sharp decline in work-related income was observed in both mothers and fathers of children diagnosed with type 1 diabetes. In the year after diagnosis, the mean yearly income difference (expressed in €100) was -15.4 for mothers (95% CI -17.2, -13.6) and -6.0 for fathers (95% CI -8.9, -3.2), representing a relative decrease of 6.6% and 1.6%, respectively. The effects on income were similar across sociodemographic groups and calendar periods. The pension-qualifying income of mothers increased in the first year after diagnosis by 28.7 (95% CI 27.1, 30.3), attributable to the parental care allowance, but gradually decreased during long-term follow-up (-10.9, 95% CI -16.6, -5.1, after 17 years).

CONCLUSIONS/INTERPRETATION: This study highlights the enduring financial consequences for parents caring for a child with type 1 diabetes in Sweden. While parental benefits in Sweden mitigated the short-term loss of maternal income, the current welfare system does not adequately address long-term consequences.

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1-30.2%) in women and 29.3% (95% CI 27.5-30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (>= 80 years). Without an algorithm, a naive estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections.

Objectives: Hip fractures are associated with a high burden of morbidity and mortality. Diet is essential for preventing fragility fractures, but the role of dietary fatty acids on the risk of hip fracture is uncertain. The aim was to investigate how intake of different dietary fatty acids relates to the risk of hip fracture. A relative validation of the long-term intake of dietary fatty acids estimated from food frequency questionnaires (FFQs) was also performed.

Design, settings and participants: We used data collected in two population-based cohorts, the Swedish Mammography Cohort and the Cohort of Swedish men (n = 83,603, 54% men, aged 45–82 years). Data from the repeated investigations in the cohorts and cross-sectional data from their clinical sub-cohorts were used.

Measurements: Diet data was collected in FFQs. Incident hip fractures were gathered by individual linkage to national registers. We performed Cox regression analysis to investigate associations between dietary fatty acids and hip fracture. Follow-up time was between January 1st, 1998 and December 31st, 2020. The validation was performed using correlation analyses, comparing fatty acids measured in adipose tissue with estimated fatty acid intakes from FFQs.

Results: During up to 23 years of follow-up (mean 18 years) and 1,538,627 person-years at risk, 7345 participants (2840 men) experienced a hip fracture. A low linoleic acid (LA) and high intakes of long-chain n-3 fatty acids were associated with higher hip fracture risk in a non-linear way. In quartile 4 compared to quartile 1 of LA, the multivariable-adjusted hazard ratio of hip fracture was 0.89 (95% Confidence Interval: 0.81, 0.97). The study confirmed the validity of FFQs to capture the intake of the specific dietary long-chain n-3 fatty acids. The estimated intake of LA, α-linolenic acid, and myristic acid were also adequately captured by the FFQs. Validity was confirmed in both women and men.

Conclusion: A low to moderate intake of linoleic acid and a higher intake of long-chain n-3 fatty acids were associated with a higher risk of hip fractures. The results indicate that attention should be paid to dietary fatty acid composition for the optimal prevention of fragility fractures.