The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Increased Glomerular Production or Permeability in Diabetes Mellitus?

Background: A previous report showed that the urine output of HPLBII-P in patients with diabetes mellitus and SARS-CoV-2 infection was increased as a sign of glomerular dysfunction. The aim of this report was to investigate the relation of the urine output of HPLBII-P to diabetes mellitus in two large community-based elderly populations, i.e., the ULSAM and PIVUS cohorts. Methods: HPLBII-P was measured by an ELISA in the urine of a community-based cohort of 839 men (ULSAM) collected at 77 years of age and in the urine of a community-based cohort of 75-year-old men, n = 387, and women, n = 401 (PIVUS). KIM-1, NGAL, and albumin were measured in urine and cathepsin S and cystatin C in serum. Results: HPLBII-P was significantly raised among males with diabetes in the ULSAM (p < 0.0001) and PIVUS cohorts (p ≤ 0.02), but not in the female cohort of PIVUS. In the female subpopulation of insulin-treated diabetes, HPLBII-P was raised (p = 0.02) as compared to women treated with oral antidiabetics only. In the ULSAM cohort, HPLBII-P was correlated to NGAL, KIM-1, and albumin in urine both in non-DM (all three biomarkers; p < 0.0001) and in DM (NGAL; p = 0.002, KIM-1; p = 0.02 and albumin; p = 0.01). Plasma glucose and HbA1c in blood showed correlations to U-HPLBII-P (r = 0.58, p < 0.001 and r = 0.42, p = 0.004, respectively). U-HPLBII-P and cathepsin S were correlated in the ULSAM group (r = 0.50, p < 0.001). No correlations were observed between U-HPLBII-P and serum creatinine or cystatin C. Conclusions: The urine measurement of HPLBII-P has the potential to become a novel and useful biomarker in the monitoring of glomerular activity in diabetes mellitus.

Analysis of plasma metabolomes from 11 309 subjects in five population-based cohorts.

Plasma metabolomics holds potential for precision medicine, but limited information is available to compare the performance of such methods across multiple cohorts. We compared plasma metabolite profiles after an overnight fast in 11,309 participants of five population-based Swedish cohorts (50-80 years, 52% women). Metabolite profiles were uniformly generated at a core laboratory (Metabolon Inc.) with untargeted liquid chromatography mass spectrometry and a comprehensive reference library. Analysis of a second sample obtained one year later was conducted in a subset. Of 1629 detected metabolites, 1074 (66%) were detected in all cohorts while only 10% were unique to one cohort, most of which were xenobiotics or uncharacterized. The major classes were lipids (28%), xenobiotics (22%), amino acids (14%), and uncharacterized (19%). The most abundant plasma metabolome components were the major dietary fatty acids and amino acids, glucose, lactate and creatinine. Most metabolites displayed a log-normal distribution. Temporal variability was generally similar to clinical chemistry analytes but more pronounced for xenobiotics. Extensive metabolite-metabolite correlations were observed but mainly restricted to within each class. Metabolites were broadly associated with clinical factors, particularly body mass index, sex and renal function. Collectively, our findings inform the conduct and interpretation of metabolite association and precision medicine studies.

Are there lost opportunities in chronic kidney disease? A region-wide cohort study.

OBJECTIVES: Identify the windows of opportunity for the diagnosis of chronic kidney disease (CKD) and the prevention of its adverse outcomes and quantify the potential population gains of such prevention. DESIGN AND SETTING: Observational, population-wide study of residents in the Stockholm and Skåne regions of Sweden between 1 January 2015 and 31 December 2020. PARTICIPANTS: All patients who did not yet have a diagnosis of CKD in healthcare but had CKD according to laboratory measurements of CKD biomarkers available in electronic health records. OUTCOME MEASURES: We assessed the proportions of the patient population that received a subsequent diagnosis of CKD in healthcare, that used guideline-directed pharmacological therapy (statins, renin-angiotensin aldosterone system inhibitors (RAASi) and/or sodium-glucose cotransporter-2 inhibitors (SGLT2i)) and that experienced adverse outcomes (all-cause mortality, cardiovascular mortality or major adverse cardiovascular events (MACE)). The potential to prevent adverse outcomes in CKD was assessed using simulations of guideline-directed pharmacological therapy in untreated subsets of the study population. RESULTS: We identified 99 382 patients with undiagnosed CKD during the study period. Only 33% of those received a subsequent diagnosis of CKD in healthcare after 5 years. The proportion that used statins or RAASi was of similar size to the proportion that didn't, regardless of how advanced their CKD was. The use of SGLT2i was negligible. In simulations of optimal treatment, 22% of the 21 870 deaths, 27% of the 14 310 cardiovascular deaths and 39% of the 22 224 MACE could have been avoided if every patient who did not use an indicated medication for their laboratory-confirmed CKD was treated with guideline-directed pharmacological therapy for CKD. CONCLUSIONS: While we noted underdiagnosis and undertreatment of CKD in this large contemporary population, we also identified a substantial realisable potential to improve CKD outcomes and reduce its burden by treating patients early with guideline-directed pharmacological therapy.

FEV1 and FVC as robust risk factors for cardiovascular disease and mortality: Insights from a large population study.

INTRODUCTION: Data is limited on influence of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in a large adult population, including individuals with normal spirometry at baseline. METHODS: Using the UK Biobank cohort, a multivariable Cox regression analysis was conducted on 406,424 individuals to examine the association between FEV1 and FVC, categorized into three groups based on their percentage of predicted values (%pred) (≥80, 60-80 and < 60), and overall mortality, cardiovascular mortality, myocardial infarction, stroke, and heart failure over approximately 12.5 years. Moreover, a subgroup analysis was conducted on 295,459 individuals who had normal spirometry. RESULTS: Reduced FEV1 and FVC %pred values were associated with an elevated risk across all studied outcomes. Individuals with the lowest FEV1 and FVC %pred values (<60 %) exhibited HR of 1.83 (95 % CI 1.74-1.93) and 1.98 (95 % CI 1.76-2.22) for overall mortality, and 1.96 (95 % CI 1.83-2.1) and 2.26 (95 % CI 1.94-2.63) for cardiovascular mortality. Moreover, a graded association was observed between lower FEV1 and FVC %pred, even among never smokers and individuals with normal spirometry at baseline. DISCUSSION: Reduced FEV1 and FVC represent robust risk factors for cardiovascular disease and mortality. The fact that the increased risk was evident also at FEV1 and FVC levels exceeding 80 %pred challenges the contemporary classification of lung function categories and the notion that the entire FEV1- and FVC-range above 80 % of predicted represents a normal lung function.

Short physical performance battery is not associated with falls and injurious falls in older persons: longitudinal data of the SCOPE project.

INTRODUCTION: Falls and fall-related injuries in older persons are a major public health problem. Our objective was to study the predictive value of the Short Physical Performance Battery (SPPB) in the cohort of the SCOPE project on falls, injurious falls, and possible difference of prediction between indoors and outdoors falls. METHODS: For this sub-study of the SCOPE project participants reporting no falls at baseline, and survey data on falls at the 12-month and 24-month follow-up were included. Participant´s characteristics were assessed during the baseline interview and medical examinations. Falls as well as injurious falls and fall circumstances were obtained self-reported. SPPB and its association with fallers vs. no fallers at 12 and at 24 months were studied with logistic regression models. RESULTS: The 1198 participants had a median age of 79 years (77-82), and a median SPPB of 10 (8-11), with a 52.5% of female. A total of 227 and 277 falls (12- and 24- month visits, respectively) were reported. In the crude model, the SPPB sum scores (p < 0.001) as well as most single item scores were significant different between fallers and non-fallers over time. However, the association was attenuated in models adjusted for age, sex, marital status, number of medications, quality of life, handgrip strength, and muscle mass [e.g., 12 months; OR 0.94 (0.87-1.02)]. While SPPB fails to differentiate between injurious and non-injurious falls (p = 0.48), a lower SPPB score was associated with falls at home (p < 0.01) after 24 months. CONCLUSION: SBPP was not able to significantly predict the risk of falling as well as experiencing an injurious fall. TRIAL REGISTRATION: This study was registered prospectively on 25th February 2016 at clinicaltrials.gov (NCT02691546).

Prevalence of Sarcopenia in Chronic Heart Failure and Modulating Role of Chronic Kidney Disease.

INTRODUCTION: Sarcopenia, heart failure (HF), and chronic kidney disease (CKD) are common among the older people. Our objective was to evaluate the frequency of sarcopenia, among community-dwelling older adults with HF, possible causative factors, and the additive factor of CKD. METHODS: A cross-sectional analysis of 1,420 older people living in the community was carried out. Participants (aged 75 years and more) came from a European multicenter prospective cohort (SCOPE study). Global geriatric assessment including short physical performance battery, handgrip strength test, and bioelectrical impedance analysis was performed. Previous known HF was defined as physician-diagnosed HF registered in the patient's medical record or the use of HF-related medications, regardless of left ventricular ejection fraction (LVEF). Sarcopenia was defined by the updated criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Estimated glomerular filtration rate was calculated using Berlin Initiative Study (BIS) to define the stages of CKD. Two-year mortality was also collected. RESULTS: A total of 226 (15.9%) participants had a prior chronic HF diagnosis, with a median age of 80.0 (5.0), and 123 (54.4%) were women. Using EWGSOP2 definition, 11.5% HF and 10.7% in non-HF participants met diagnostic criteria for sarcopenia. In multivariate analyses, only a lower body mass index (BMI) (odds ratios [OR], 0.82; 95% confidence interval [CI], 0.73-0.93) and lower short physical performance battery score (OR, 0.81; 95% CI, 0.69-0.96) were associated with sarcopenia. Patients with HF and sarcopenia have a similar all-cause mortality risk but higher 2-year cardiovascular mortality risk (p = 0.047). DISCUSSION/CONCLUSION: One out of ten community-dwelling older adults with concurrent clinical stable chronic HF, without considering LVEF, have sarcopenia. Lower BMI and poor physical performance are associated with sarcopenia in this population, but not CKD.

Accelerometer-based physical activity is associated with the gut microbiota in 8416 individuals in SCAPIS.

BACKGROUND: Previous population-based studies investigating the relationship between physical activity and the gut microbiota have relied on self-reported activity, prone to reporting bias. Here, we investigated the associations of accelerometer-based sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity with the gut microbiota using cross-sectional data from the Swedish CArdioPulmonary bioImage Study. METHODS: In 8416 participants aged 50-65, time in SED, MPA, and VPA were estimated with hip-worn accelerometer. Gut microbiota was profiled using shotgun metagenomics of faecal samples. We applied multivariable regression models, adjusting for sociodemographic, lifestyle, and technical covariates, and accounted for multiple testing. FINDINGS: Overall, associations between time in SED and microbiota species abundance were in opposite direction to those for MPA or VPA. For example, MPA was associated with lower, while SED with higher abundance of Escherichia coli. MPA and VPA were associated with higher abundance of the butyrate-producers Faecalibacterium prausnitzii and Roseburia spp. We observed discrepancies between specific VPA and MPA associations, such as a positive association between MPA and Prevotella copri, while no association was detected for VPA. Additionally, SED, MPA and VPA were associated with the functional potential of the microbiome. For instance, MPA was associated with higher capacity for acetate synthesis and SED with lower carbohydrate degradation capacity. INTERPRETATION: Our findings suggest that sedentary and physical activity are associated with a similar set of gut microbiota species but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain gut microbiota species. FUNDING: European Research Council, Swedish Heart-Lung Foundation, Swedish Research Council, Knut and Alice Wallenberg Foundation.

Circulating leptin is associated with adverse vascular changes in young adult survivors of childhood cancer.

INTRODUCTION: Proteomics may help discover novel biomarkers and underlying mechanisms for cardiovascular disease. This could be useful for childhood cancer survivors as they show an increased risk of cardiovascular disease. The aim of this study was to investigate circulating cardiovascular proteins in young adult survivors of childhood cancer and their relationship to previously reported subclinical cardiovascular disease. METHODS: Ninety-two cardiovascular proteins were measured in 57 childhood cancer survivors and in 52 controls. For proteins that were significantly different between childhood cancer survivors and controls, we performed correlations between protein levels and measures of peripheral arterial stiffness (carotid distensibility and stiffness index, and augmentation index) and endothelial dysfunction (reactive hyperemia index). RESULTS: Leptin was significantly higher in childhood cancer survivors compared to controls (normalized protein expression units: childhood cancer survivors 6.4 (1.5) versus 5.1 (1.7), p < 0.0000001) after taking multiple tests into account. Kidney injury molecule-1, MER proto-oncogene tyrosine kinase, selectin P ligand, decorin, alpha-1-microglobulin/bikunin precursor protein, and pentraxin 3 showed a trend towards group differences (p < 0.05). Among childhood cancer survivors, leptin was associated with anthracycline treatment after adjustment for age, sex, and body mass index (p < 0.0001). Higher leptin correlated with lower carotid distensibility after adjustment for age, sex, body mass index, and treatments with radiotherapy and anthracyclines (p = 0.005). CONCLUSION: This proteomics approach identified that leptin is higher in young asymptomatic adult survivors of childhood cancer than in healthy controls and is associated with adverse vascular changes. This could indicate a role for leptin in driving the cardiovascular disease burden in this population.

Heart failure outcomes by left ventricular ejection fraction in a contemporary region-wide patient cohort.

AIMS: This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF. METHODS AND RESULTS: Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population-based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90 days of their first HF diagnosis, and patients with prevalent HF within 5 years prior to the index date. The 13 375 patients with prevalent HF (39.2% women, mean age 73.9 years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3 years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system. CONCLUSIONS: This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Kidney function and other associated factors of sarcopenia in community-dwelling older adults: The SCOPE study.

AIM: Sarcopenia is associated with several factors and medical conditions among older adults, though previous research has shown limitations and inconsistencies, especially regarding chronic kidney disease (CKD). We investigated the clinical and laboratory variables associated with sarcopenia and severe sarcopenia in older adults, focusing on kidney function measures. METHODS: Data from community-dwelling adults aged ≥75 years participating in the SCOPE multicenter prospective cohort study were assessed cross-sectionally. Comprehensive geriatric assessment was conducted; sociodemographic and lifestyle factors, clinical variables and comorbidities, anthropometric and bioelectrical impedance analysis, blood and urine laboratory variables were collected. EWGSOP2 revised criteria were used to define sarcopenia and its severity. Estimated glomerular filtration rate (eGFR) was calculated using creatinine and non-creatinine-based equations, and CKD stages were defined accordingly. RESULTS: 1420 participants were included, prevalence of sarcopenia was 10.6 %, and 6 % had severe sarcopenia. Multivariate logistic regression analysis showed that age [OR =1.14; 95 %CI (1.09-1.19)], body mass index (BMI) [0.83 (0.79-0.88)], disability performing instrumental activities of daily living (IADL) [2.61 (1.69-4.06)], Mini Mental State Examination (MMSE) score <24 [2.75 (1.62-4.67)], osteoporosis [2.39 (1.55-3.67)], and stage 4 CKD defined by CKD-EPIBTP-B2M, a non-creatinine-based eGFR equation [2.88 (1.11-7.49)], were independently associated with sarcopenia; as were specifically with severe sarcopenia, with more pronounced associations. CONCLUSIONS: In community-dwelling older adults, sarcopenia is a relevant condition and is associated with severe CKD, older age, IADL, cognitive impairments, osteoporosis and low BMI. These factors should be assessed for proper identification and management of older patients with sarcopenia, and even more so with severe sarcopenia.

Plasma Protein Profiling of Incident Cardiovascular Diseases: A Multisample Evaluation.

BACKGROUND: Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs. METHODS: Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure. RESULTS: Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors. CONCLUSIONS: Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Diabetes and factors associated with cognitive and functional decline. The screening for CKD among older people across Europe (SCOPE) study.

BACKGROUND: Type 2 diabetes mellitus (DM) in older people is a heterogeneous condition that exhibits differential characteristics in comparison with younger adults. DM increases the risk of disability, is associated with dementia and loss of function, and cognition may often be interrelated and more pronounced in older patients with DM than in those without. AIMS: Our aim was to evaluate the incidence of functional and/or cognitive impairment in older adults with and without DM, and its associated factors in DM participants. METHODS: A 2-year prospective analysis was conducted in a European multicenter prospective cohort (SCOPE study). Older community-dwelling adults (aged ≥ 75 years) underwent a comprehensive geriatric assessment. New functional and/or cognitive decline was explored. RESULTS: Of 1611 participants, 335 (22.0%) had DM at baseline. The percentage of participants scoring at least one ADL impairment and/or cognitive impairment (MMSE < 24) was similar in both groups (9.6%). Factors associated with any new disability in participants with DM in the multivariate analysis were female sex (OR 3.28, 95% CI 1.42-7.56), history of stroke (OR 4.58, 95% CI 1.64-12.7), and greater IADL dependency (OR 1.08 95% CI 1.02-1.15). DISCUSSION: Association between DM and cognitive or functional decline in outpatients of 75 years and older was not found, but factors such as female gender, history of stroke, and IADL dependency could be related. CONCLUSION: Decline in functional and cognitive status of community-dwelling older adults with DM was similar to participants without DM in a short period of 2 years of follow-up, though several clinical factors may increase its risk in this population.

The C-reactive protein Albumin ratio was not consistently associated with cardiovascular and all-cause mortality in two community-based cohorts of 70-year-olds.

C-reactive protein (CRP)/Albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, which we aimed to study. As method we use a prospective study design; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 912, women 50%; mean age 70 years, baseline 2001 and 2004, median follow-up 15.0 years, end of follow-up 2019) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 924 mean age 71 years, baseline 1991-1995, median follow-up 15.6 years, end of follow-up 2016). Serum samples were used for analyses of CRP and Albumin. Cox regression analyses were performed for cardiovascular and all-cause mortality in models adjusting for several factors (age; physical activity; Interleukin-6; cardiovascular (CVD) risk factors: smoking, BMI level, systolic blood pressure, LDL-cholesterol, and diabetes), with 95% confidence interval (CI). When adjusting for age and CVD risk factors, CAR was significantly associated with cardiovascular mortality for meta-analyzed results from PIVUS and ULSAM, HR 1.09 (95% 1.01-1.18), but neither in PIVUS (HR 1.14, 95% CI 0.99-1.31) nor in ULSAM (1.07, 95% CI 0.98-1.17). Additionally, CAR was significantly associated with all-cause mortality in ULSAM 1.31 (95% CI 1.12-1.54) but not in PIVUS HRs 1.01 (95% 0.089-1.15). The predictive value of CAR was similar to CRP alone in PIVUS and ULSAM and slightly better than albumin for the prediction of CVD-mortality in ULSAM. In conclusion, CAR was not consistently associated with cardiovascular and all-cause mortality in the two cohorts. The prognostic value of CAR for long-term CVD-mortality was similar to CRP.

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation.

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Poor recognition and undertreatment of anemia in patients with chronic kidney disease managed in primary care.

BACKGROUND: Anemia is a common complication of chronic kidney disease (CKD), but limited awareness and treatment options may hinder its management among CKD patients followed in primary care. METHODS: We evaluated adults with CKD stages 3-5 attending primary care in Stockholm, Sweden, 2012-2018. We assessed the incidence of anemia, clinical reactions, and association with subsequent major adverse cardiovascular events (MACE) and death. RESULTS: We identified 45,637 patients with CKD stages 3-5 free from anemia (mean age 78 years; 64% females; 79% CKD stage 3b). During a median follow-up of 2.4 years, 26% of patients developed anemia, and 10.4% developed severe anemia (hemoglobin <10 g/dL). Within 6 months from the anemia event, iron tests were infrequent; ferritin and transferrin saturation were tested in 27% and 11% of anemia cases, respectively, and 49% and 24% of severe anemia cases. Few patients were recognized with a clinical diagnosis (15% of anemia cases; 68% of severe anemias). Only 19% of patients with anemia received treatment, primarily iron (10%) and blood transfusions (7%); erythropoietin-stimulating agent use was anecdotal (∼1%). Treatment rates for severe anemia were higher, but 43% of patients still failed to receive treatment. Developing anemia was associated with a higher risk of MACE and death. CONCLUSION: Anemia was common and associated with adverse outcomes among patients with CKD stages 3-5 managed in primary care. Iron stores were infrequently tested, and a large proportion of patients with anemia remained untreated/under-recognized.

Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.

AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. METHODS: We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2). RESULTS: A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. CONCLUSIONS/INTERPRETATION: A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.