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The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE e4-related sporadic AD and APOE e4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD. The amyloid hypothesis has been the dominant model for the pathogenesis of Alzheimer disease for several decades. In this Perspective, Giovanni Frisoni and colleagues examine evidence for and against this hypothesis before outlining an alternative model, the probabilistic model of Alzheimer disease.

SPRINT (Systolic Blood Pressure Intervention Trial) showed that intensive lowering of systolic blood pressure to P =0.012), as compared with the standard treatment (P Graphic Abstract: An online graphic abstract is available for this article.

The carotid-to-femoral pulse wave velocity, determined by pulse transit time (PTT) and distance, is a well-established measure of arterial stiffness and predicts adverse outcomes. However, its predictive value decreases with aging. To explore new risk indicator in the elderly, we investigated if the variation of carotid-to-femoral pulse wave velocity, registered as beat-to-beat variability of carotid-to-femoral PTT (cf-PTT), could predict outcome. Totally 3015 (median age, 72.4 years; 39.6% men) and 1181 (75.6 years; 42.2% men) subjects from communities of Malmö, Sweden, and Shanghai, China, were analyzed, respectively. Continuous pulse waves for 10 seconds were recorded sequentially at carotid and femoral arterial sites with applanation tonometry (SphygmoCor, Atcor, Australia). During a median of 6.6 and 10.2 years, 389 and 427 deaths occurred in the Malmö and Shanghai cohorts, respectively. Each one-SD increase in the log-transformed coefficient of variation of cf-PTT was associated with 24% (95% CI, 13%–37%) and 21% (10%–33%) increased risk for all-cause mortality in the Malmö and Shanghai subjects, and 60% (33%–91%) for cardiovascular mortality in the Malmö subjects. Adding the coefficient of variation of cf-PTT to the models including conventional risk factors and carotid-to-femoral pulse wave velocity significantly ( P

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33–0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.

AIMS: This study aimed to investigate the association between the 'Shrunken pore syndrome' (SPS) and risk of death, 30 day rehospitalization, and health-related quality of life (QoL) in heart failure (HF) patients. SPS is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C /eGFRcreatinine ratio.METHODS AND RESULTS: A total of 373 patients hospitalized for HF [mean age 74.8 (±12.1) years; 118 (31.6%) women] were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmo). Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used for estimation of glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatin C ≤ 60% of eGFRcreatinine . In Cox regression multivariate models, associations between SPS, risk of death (median follow-up time 1.8 years), and risk of 30 day rehospitalization were studied. Associations between SPS and impaired QoL were studied using multivariate logistic regressions. In multivariate models, SPS was associated with all-cause mortality [124 events; hazard ratio (HR) 1.99; 95% confidence interval (95% CI) 1.23-3.21; P = 0.005] and with 30 day rehospitalization (70 events; HR 1.82; CI 95% 1.04-3.18; P = 0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score < 50, revealed that SPS was associated with higher risk of low health-related QoL (odds ratios 2.15; CI 95% 1.03-4.49; P = 0.042).CONCLUSIONS: The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms. (Less)

The impact of age and 24‐h ambulatory blood pressure (ABPM) on arterial stiffness and carotid intima‐media thickness (cIMT) in ischemic stroke patients younger than 60 years of age is poorly explored. A total of 385 acute ischemic stroke patients (aged 49.6±9.7 years, 68% men) were prospectively included and grouped in younger (15–44 years, n = 93) and middle‐aged (45–60 years, n = 292). Arterial stiffness was measured by carotid‐femoral pulse wave velocity (PWV), and cIMT by carotid ultrasound. 24‐h ABPM was recorded. The middle‐aged stroke patients had higher prevalence of smoking, hypertension, diabetes mellitus, metabolic syndrome and hypercholesterolemia, and had higher PWV and cIMT (all p

Childless men are reported to have a higher risk of cardiovascular disease (CVD) and mortality. Information on inherited genetic risk for CVD has improved the predictive models. Presuming that childlessness is a proxy of infertility we aimed to investigate if childless men inherit more often genetic traits for CVD and if combining genetic and parenthood information improves predictive models for CVD morbidity and mortality. Data was sourced from a large prospective population-based cohort where genetic risk score (GRS) was calculated using two sets of either 27 (GRS 27) or 50 (GRS 50) single nucleotide polymorphisms (SNPs) previously found to be associated with CVD. Part of the participants (n = 2572 men) were randomly assigned to a sub-cohort with focus on CVD which served as an exploratory cohort. The obtained statistically significant results were tested in the remaining (confirmatory) part of the cohort (n = 9548 men). GRS distribution did not differ between childless men and fathers (p-values for interaction between 0.29 and 0.76). However, when using fathers with low GRS as reference high GRS was a strong predictor for CVD mortality, the HR (95% CI) increasing from 1.92 (1.10–3.36) for GRS 50 and 1.54 (0.87–2.75) for GRS 27 in fathers to 3.12 (1.39–7.04) for GRS50 and 3.73 (1.75–7.99) for GRS27 in childless men. The confirmatory analysis showed similar trend. Algorithms including paternal information and GRS were more predictive for CVD mortality at 5 and 10 years follow-ups when compared to algorithms including GRS only (AUC 0.88 (95% CI 0.84–0.92) and 0.86 (95% CI 0.84–0.90), and, AUC 0.81 (95% CI 0.75–0.87) and 0.78 (95% CI 0.73–0.82), respectively). Combining information on parental status and GRS for CVD may improve the predictive power of risk algorithms in middle-aged men. Childless men and those with severe infertility problem may be an important target group for prevention of CVD.

Introduction: The heart and arterial system are equally affected by arteriosclerosis/atherosclerosis. There is a constant interaction between the left ventricular (LV) function and the arterial system, termed ventricular-arterial coupling (VAC), which reflects the global cardiovascular efficiency. VAC is traditionally assessed by echocardiography as the ratio of effective arterial elastance (Ea) over end-systolic elastance (Ees) (Ea/Ees). However, the concept of VAC is evolving and new methods have been proposed such as the ratio of pulse wave velocity (PWV) to global longitudinal strain (GLS) and myocardial work index. Area covered: This clinical review presents the hemodynamic background of VAC, its clinical implications and the impact of therapeutic interventions to normalize VAC. The review also summarizes the detrimental effects of cardio-metabolic risk factors on the aorta and LV, and provides an update on arterial load and its impact on LV function. The narrative review is based upon a systemic search of the bibliographic database PubMed for publications on VAC. Expert opinion: Newer methods such as PWV/GLS-ratio may be a superior marker of VAC than the traditional echocardiographic Ea/Ees in predicting target organ damage and its association with clinical outcomes. Novel anti-diabetic drugs and optimal antihypertensive treatment may normalize VAC in high-risk patients. (Less)

Based on a nationwide register data we recently reported a link between male infertility and increased risk of early onset prostate cancer. However, mortality due to prostate cancer, which can be regarded as the ultimate proxy for its clinical significance, especially in the context of over-diagnosis and over-treatment, could not be explored in the previous study, since the follow-up period in most cases was too short. Data therefore must be retrieved from other cohorts, with longer follow-up. We sourced data from a population-based prospective cohort including 11,343 men aged over 45 years, enrolled in the 1970s. The results showed that childless men have higher risk for prostate cancer related mortality (HR: 1.49, 95% CI: 1.09–2.03, p = 0.01) compared to men with children, in particular when only married men, who most probably are involuntary childless, were considered (HR 1.54, 95% CI 1.13 − 2.10, p = 0.006). However, the prostate cancer incidence did not differ (HR = 1.04, 95% CI: 0.88–1.24). In conclusion, our results show that childless men are at higher risk for dying from prostate cancer, probably due to a more aggressive form of the disease. (Less)

Mediterranean diet protects from both cardiovascular disease (CVD) and cancer. In the 1960s, Ancel Keys defined the concept of Mediterranean diet in the South Italian region of Cilento and proposed it as a key factor for healthy ageing in the region. The aim of the current study was to compare the prevalence of CVD and cancer between a middle-aged population from Cilento and those of a Northern European population from Malmö, Sweden. We clinically characterized two middle-aged (50–67 years of age) population-based samples from Cilento (n = 809) and Malmö (n = 1025), Sweden, respectively. Logistic regression was used to calculate odds ratios (95% confidence interval) for disease prevalence in Malmö versus Cilento inhabitants adjusted for age and sex (model 1) and adjusted for all cardiometabolic risk factors (model 2). The prevalence of hypertension, current smoking, diabetes mellitus and levels of body mass index and triglycerides were lower, whereas HDL-cholesterol was higher in Malmö than in Cilento. LDL-cholesterol was higher and estimated glomerular filtration rate was lower in Malmö than in Cilento. The odds ratio for cardiovascular disease in Malmö versus Cilento inhabitants was 1.13 (0.69–1.87) (P = 0.62) in model 1, whereas it was significantly elevated in model 2 [2.03 (1.14–3.60) (P = 0.016)]. Moreover, the odds ratio for cancer in Malmö versus Cilento was 2.78 (1.81–4.27) (P P

Background We explored the association of N-terminal probrain natriuretic peptide (NT-proBNP) with metabolic traits in a bi-ethnic African-Caucasian cohort. Methods Baseline examinations of the Sympathetic activity and Ambulatory Blood Pressure in African (SABPA) prospective cohort study were performed between 2008 and 2009, and re-examination after a three-year follow up in South African teachers (black African, n = 194; Caucasian, n = 203). Results Each one standard deviation increment of NT-proBNP was significantly inversely associated with body mass index ( β -1.01), glycated haemoglobin ( β -0.14 %), waist circumference (β -1.82), HOMA-IR (β -0.47), insulin (β -1.66) and triglyceride levels (β -0.04). Each one standard deviation increment of NT-proBNP was also associated with reduced odds of incident diabetes, and subjects within the highest quartile of NT-proBNP were at lowest risk (OR: 0.24; 95% CI: 0.06-0.96; p = 0.041). Conclusions In the SABPA cohort, Africans and Caucasians had similar NT-proBNP levels; however, the associations for Africans were stronger. Those findings suggest that BNP may affect the propensity for metabolic disturbances differently in Africans and Caucasians.

Objective: To explore the longitudinal, as well as sex-specific, associations between circulating uric acid (UA) and diabetes incidence.Methods: A cohort study of the Malmo Diet Cancer-cardiovascular Cohort (Malmo, Sweden) consisting of 3140 individuals without diabetes at baseline, was followed up until the end of 2018. Incident diabetes cases were identified by linking to local and national diabetes registers. Cox proportional hazard regression was used to assess plasma UA levels in relation to diabetes incidence with adjustment for established confounders.Results: At baseline, with increasing levels of UA, subjects were more likely to be older and have significantly higher body mass index, waist circumference, triglycerides, C-reactive protein, fasting glucose and 2-h plasma glucose postoral glucose tolerance test, and lower levels of high-density lipoprotein. During a mean follow-up period of 8.09±2.24 years, 315 (10.0%) participants developed diabetes, and diabetes incidence rates were 7.89, 9.48 and 18.11 per 1000 person-years for subjects in the 1st, 2nd, and 3rd tertiles of UA, respectively (log-rank test: p

OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

Pulse wave velocity is an established marker of early vascular aging but may also help identifying individuals with supernormal vascular aging. We tested the hypothesis that individuals with the largest difference (Δ-age) between chronological and vascular age show the lowest rate of cardiovascular events and may thus be defined as supernormal vascular aging. Vascular age was defined as the predicted age in the best fitting multivariable regression model including classical risk factors and treatment and pulse wave velocity, in a subset of the Reference Values for Arterial Stiffness Collaboration Database (n=3347). Δ-age was then calculated as chronological age minus vascular age, and the 10th and 90th percentiles were used to define early (Δ-age6.8 years). The risk for fatal and nonfatal cardiovascular events associated with vascular aging categories was investigated in the Malmö Diet and Cancer Study cohort (n=2642). In the Malmö Diet and Cancer Study Cohort (6.6-year follow-up, 286 events), Δ-age was significantly ( P

Background Aortic stenosis (AS) is the most common valvular heart disease in developed countries, confers high mortality in advanced cases, but can effectively be reversed using endovascular or open-heart surgery. We evaluated the association between AS and neighborhood socioeconomic status (NSES). Methods We used Swedish population-based nationwide registers and an echocardiography screening cohort during the study period 1997–2014. NSES was determined by an established neighborhood deprivation index composed of education, income, unemployment, and receipt of social welfare. Multilevel adjusted logistic regression models determined the association between NSES and incident AS (according to ICD-10 diagnostic codes). Results The study population of men and women (n=6,641,905) was divided into individuals living in high (n = 1,608,815 [24%]), moderate (n = 3,857,367 [58%]) and low (n = 1,175,723 [18%]) SES neighborhoods. There were 63,227 AS cases in total. Low NSES (versus high) was associated with a slightly increased risk of AS (OR 1.06 [95% CI 1.03–1.08]) in the nationwide study population. In the echocardiography screening cohort (n = 1586), the association between low NSES and AS was markedly stronger (OR: 2.73 [1.05–7.12]). There were more previously undiagnosed AS cases in low compared to high SES neighborhoods (3.1% versus 1.0%). Conclusions In this nationwide Swedish register study, low NSES was associated with a slightly increased risk of incident AS. However, the association was markedly stronger in the echocardiography screening cohort, which revealed an almost three-fold increase of AS among individuals living in low SES neighborhoods, possibly indicating an underdiagnosis of AS among these individuals.

OBJECTIVE Hyperglycemia and diabetes mellitus associate with arterial stiffness. This observational study aimed to investigate such links in two related generations from a population-based study. METHODS Data from 2640 participants in the ongoing Malmo Offspring Study, Sweden, was used. The participants were direct descendants, that is, parents (median age 52.5 years) and children (26.9 years). In linear regressions, arterial stiffness measured through carotid--femoral pulse wave velocity was associated with markers of glucose metabolism (fasting glucose, glycated hemoglobin, skin autoflourescence of Advanced Glycation End products), adjusted for age, sex, smoking, BMI, lipids, SBP and antihypertensive medication. Analysis was first performed in all participants and then separately in each generation. T-tests with diabetes mellitus as the grouping variable were performed for all participants and per generation. RESULTS In all participants, pulse wave velocity was significantly associated with glucose (β = 0.007, P = 0.018) and hemoglobin (β = 0.017, P

Background Gout is predicted by a number of comorbidities and lifestyle factors. We aimed to identify discrete phenotype clusters of these factors in a Swedish population-based health survey. In these clusters, we calculated and compared the incidence and relative risk of gout. Methods Cluster analyses were performed to group variables with close proximity and to obtain homogenous clusters of individuals (n = 22,057) in the Malmö Preventive Project (MPP) cohort. Variables clustered included obesity, kidney dysfunction, diabetes mellitus (DM), hypertension, cardiovascular disease (CVD), dyslipidemia, pulmonary dysfunction (PD), smoking, and the use of diuretics. Incidence rates and hazard ratios (HRs) for gout, adjusted for age and sex, were computed for each cluster. Results Five clusters (C1–C5) were identified. Cluster C1 (n = 16,063) was characterized by few comorbidities. All participants in C2 (n = 750) had kidney dysfunction (100%), and none had CVD. In C3 (n = 528), 100% had CVD and most participants were smokers (74%). C4 (n = 3673) had the greatest fractions of obesity (34%) and dyslipidemia (74%). In C5 (n = 1043), proportions with DM (51%), hypertension (54%), and diuretics (52%) were highest. C1 was by far the most common in the population (73%), followed by C4 (17%). These two pathways included 86% of incident gout cases. The four smaller clusters (C2–C5) had higher incidence rates and a 2- to 3-fold increased risk for incident gout. Conclusions Five distinct clusters based on gout-related comorbidities and lifestyle factors were identified. Most incident gout cases occurred in the cluster of few comorbidities, and the four comorbidity pathways had overall a modest influence on the incidence of gout.

The metabolic syndrome (MetS) is an adverse metabolic state composed of obesity, hyperglycemia/pre-diabetes, hypertension, and dyslipidemia. It substantially increases the risk of type 2 diabetes, cardiovascular disease (CVD) and mortality, and has a huge impact on public health.The present review gives an update on the definition and prevalence of MetS, and its impact on cardiac structure and function as well as on the brain and central arteries. The association with CVD and mortality risk is discussed. Focus is mainly directed toward the subclinical target organ damage related to MetS. Data is also critically reviewed to provide evidence on the incremental prognostic value of overall MetS over its individual components.MetS is a clinical risk condition associated with subclinical and clinical CVD and mortality. Roughly, 30% of the world population suffer from MetS. As all components of the MetS are modifiable, optimal preventive and therapeutic measures should be initiated to improve CV risk control, particularly aggressively treating hypertension and hyperglycemia, and encouraging people to adopt healthy lifestyle as early as possible is of great importance.

Background In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. Aim To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. Setting/ methods Twenty-two healthy subjects were given 150 mL of full milk cream (54 g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 h (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. Results An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12–31) pmol/L (P and at 3 h for triglycerides of 0.60 (0.43–0.78) mmol/L (P Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46–78) pmol/L (P and plasma triglycerides at 3 h of 0.32 (0.18–0.45) mmol/L (P The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r = 0.49, P = 0.021) and olive oil (r = 0.55, P = 0.008), respectively. Conclusion Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.

We propose combining population-based register data with a nested clinical cohort to correct misclassification and unmeasured confounding through probabilistic quantification of bias. We have illustrated this approach by estimating the association between knee osteoarthritis and mortality. We used the Swedish Population Register to include all persons resident in the Skåne region in 2008 and assessed whether they had osteoarthritis using data from the Skåne Healthcare Register. We studied mortality through year 2017 by estimating hazard ratios. We used data from the Malmö Osteoarthritis Study (MOA), a small cohort study from Skåne, to derive bias parameters for probabilistic quantification of bias, to correct the hazard ratio estimate for differential misclassification of the knee osteoarthritis diagnosis and confounding from unmeasured obesity. We included 292,000 persons in the Skåne population and 1,419 from the MOA study. The adjusted association of knee osteoarthritis with all-cause mortality in the MOA sample had a hazard ratio of 1.10 (95% confidence interval (CI): 0.80, 1.52) and was thus inconclusive. The naive association in the Skåne population had a hazard ratio of 0.95 (95% CI: 0.93, 0.98), while the bias-corrected estimate was 1.02 (95% CI: 0.59, 1.52), suggesting high uncertainty in bias correction. Combining population-based register data with clinical cohorts provides more information than using either data source separately.

Background and Aim: Altered gut microbiota have been suggested as part of an etiology of irritable bowel syndrome (IBS), but studies have shown contrasting results. Our aim was to examine gut microbiota composition in a large population-based cohort, with respect to presence and severity of bowel symptoms. Methods: The study cohort consisted of 1988 participants of the Malmo Offspring Study (mean age 40 years, 53% women). From a questionnaire, 19% reported having bowel symptoms the last 2 weeks and 15% reported having IBS. Bowel symptoms were assessed by a validated set of questions with visual analog scales. Gut microbiota was assessed by 16S rRNA gene sequencing (300 bp*2 in V1–V3 region) from fecal samples. The association between abundance of bacteria at genus level and bowel symptoms was calculated by logistic regression or general linear model, adjusted for false discovery rate (q

We have summarized key studies regarding the assessment of subclinical macroangiopathic target organ damage (TOD) in type 1 diabetes mellitus (T1DM).Although chronic complications resulting from hyperglycemia, in particular macroangiopathies, are still the first cause of death in T1DM, there has been growing recognition of the role of hypoglycemia in cardiovascular morbidity and mortality. Subclinical TOD diagnosis ensures early implementation of the complex management aiming at either partial reversal of these complications or at least its downturn. To better identify patients with early TODs, several non-invasive diagnostic techniques are employed, including the ultrasonographic assessment of the intima-media thickness (IMT), computed tomography (CT) for coronary artery calcium (CAC) scores, and pulse wave velocity (PWV) measurement for arterial stiffness evaluation. Various studies reported that T1DM patients present an increased IMT. An increasing IMT fairly correlates with the cardiovascular (CV) events risk even after the adjustment to age, diabetes duration, quality of glucose control as well as the presence of hypertension, and chronic complications. Another, well established marker of the organ damage - CAC score is recommended by ACC/AHA guidelines to assess the overall CV risk in T1DM. Also, the arterial stiffness evaluation with PWV may further improve CV risk prediction, which has been reported in multiple studies including the Framingham Heart Study.There is shortage of data from prospective studies which could confirm the benefits of early treatment initiation based on the presence of the subclinical organ damage in T1DM. Most evidence comes from T2DM trials, where effective preventive measures were identified i.e.: smoking cessation, reasonable blood glucose control, efficacious hypertension treatment, and dyslipidemia management, as well as renoprotection. There is still a field for further research to see if routine assessment of asymptomatic vascular damage and early implementation of aggressive treatment would reduce mortality excess from CVD in T1DM.

Adult health is influenced by factors during fetal life affecting organ development and birth weight. We aimed to study such factors in relation to adult respiratory disease (ARD) risk. The Helsingborg Birth Cohort, Sweden, contributed baseline data collected by medical staff through clinical examination and questionnaires on maternal and birth characteristics 1964–1967. Register linkages were performed with completions of data on ARD by ICD 8–10 classifications (1969–2016), and/or ARD-related drug usage (2005–2016) enabling a 50-year follow-up time. Cox proportional hazard regression analyses were made to adjust for potential confounders, adjusted hazard ratio (aHR). A total of 3675 mothers and their offspring were included. Female offspring showed higher frequency of ARD than males, aHR 1.5 (95% CI 1.3–1.8). Maternal use of sedatives during second trimester, aHR 2.2 (95% CI 1.4–3.4), and maternal smoking during most of pregnancy, aHR 1.2 (95% CI 1.0–1.4), were associated with offspring ARD. Stratified by sex, large-for-gestational-age, aHR 1.4 (95% CI 1.0–1.9), was significantly associated with ARD in female offspring along with maternal sedative use during second trimester and maternal smoking during most of pregnancy. Maternal sedative use during second trimester or all trimesters were the only significant risk factors for male offspring. In conclusion, maternal sedative use in second trimester was independently associated with subsequent respiratory disease in adult offspring irrespective of sex. Electronic supplementary material The online version of this article (10.1007/s10654-020-00626-3) contains supplementary material, which is available to authorized users.

Objectives:We aimed to investigate possible associations between birth weight and adult life carotid-femoral pulse wave velocity (cfPWV) and augmentation pressure index (AIx).Design and method:This study included 1598 participants, that is, 340 elderly individuals from the Malmo Birth Data Cohort (MBDC) and 1258 young-middle aged individuals from the Malmo Offspring Study (MOS) with full data on birth weight and gestational age. Participants underwent cfPWV and AIx measurements with Sphygmocor (AtCor, Australia). Analysis of data was performed with multiple linear regression models including adjustments for age, sex, gestational age and risk factors. Furthermore, comparisons were made between participants born prematurely or at term or born small-for-gestational age (SGA) or appropriate-for-gestational age (AGA).Results:Birth weight was positively associated with cfPWV after full adjustment (β = 0.057; P < 0.001), a finding that remained significant in the younger age group 18-27 years (β = 0.138, P = 0.008). Furthermore, birth weight was inversely associated with AIx (β = -0.058, P = 0.001). Participants born SGA had significantly higher AIx (P = 0.007) and MAP (P = 0.037) compared with AGA born. Preterm-born participants showed significantly higher SBP compared with term-born (P = 0.034). Finally, birth weight was inversely associated with MAP (β = -0.058, P = 0.017) and SBP (β = -0.047, P = 0.031), respectively.Conclusion:Birth weight is positively associated with cfPWV, shown strongest in the youngest individuals, a finding that could possibly be explained by increasing trends for maternal overweight/obesity in recent decades. Furthermore, birth weight is inversely associated with AIx, a risk marker of cardiovascular disease. This calls for screening of risk factors in subjects with adverse conditions at birth. (Less)

Background:Central haemodynamics have in recent years emerged as a promising predictor of cardiovascular health and risk of cardiovascular disease (CVD). Central haemodynamics are affected early in the development of vascular aging and contributes to target organ damage. Carotid-femoral pulse wave velocity (c-f PWV), augmentation index (Aix) and central SBP (cSBP) are variables that reflect arterial stiffness and central haemodynamics.Aim:To study the association between patterns of central haemodynamics across three related generations focusing on c-f PWV.Methods:In all, 1131 participants from the Malmo Diet Cancer Study (MDCS) and Malmo Offspring Study (MOS) were included. c-f PWV was measured (Sphygmocor) in grandparents and in all offsprings. Correlation analyses of c-f PWV between offspring and c-f PWV in parents and grandparents were conducted. Parents and grandparents were stratified into quartiles by c-f PWV. Offspring c-f PWV means were compared with one-way ANOVA analyses. Multiple regression analyses were adjusted for age, sex, BMI, SBP and fasting glucose. Bonferroni corrections were used.Results:c-f PWV in offsprings was positively correlated with c-f PWV in parents (r = 0.26, P < 0.001) and in grandparents (r = 0.29, P < 0.001). Parents with high c-f PWV had offspring with significantly higher means of c-f PWV.Conclusion:A measure of aortic stiffness (c-f PWV) is positively correlated across three related generations in this population-based study. (Less)

Purpose Elevated plasma concentration of the vasopressin marker copeptin and low water intake are associated with elevated blood glucose and diabetes risk at a population level. Moreover, in individuals with low urine volume and high urine osmolality (u-Osm), water supplementation reduced fasting plasma (fp) copeptin and fp-glucose. In this observational study, we investigated if low total water intake or high u-Osm correlated with high fp-copeptin and components of the metabolic syndrome at the population level. Methods In the population-based Malmö Offspring Study (MOS, n = 2599), fp-copeptin and u-Osm from morning urine samples were measured, and diet and total water intake (from beverages and food moisture) was assessed by a 4-day web-based record. Results Increasing water intake by tertile was after adjustment for age and sex associated with low fp-triglycerides (p = 0.002) and high fp-HDL (p = 0.004), whereas there was no association with the other investigated metabolic traits (HbA1c, fp-glucose, BMI or waist circumference). Increasing u-Osm by tertile was, after adjustment for age and sex, associated with high fp-glucose (p = 0.007), and borderline significantly associated with high HbA1c (p = 0.053), but no association was observed with fp-HDL, fp-triglycerides, BMI or waist circumference. Fp-copeptin concentration correlated significantly with water intake (r = − 0.13, p r = 0.27, p p Conclusion Low concentrations of the vasopressin marker copeptin is linked to high water intake, low u-Osm, and a favorable metabolic profile, suggesting that vasopressin lowering lifestyle interventions, such as increased water intake, may promote metabolic health.

Aims Although the epidemiological association between Type 2 diabetes and congestive heart failure (CHF) as well as cardiovascular disease (CVD) is well established, associations between diabetes‐related single‐nucleotide polymorphisms (SNPs), CHF, and CVD have been surprisingly inconclusive. Our aim is to examine if 43 diabetes‐related SNPs were associated with prevalent diastolic dysfunction assessed by echocardiography and incident CVD and/or CHF. Methods and results We genotyped 43 SNPs that previously reported genome‐wide significant associations with Type 2 diabetes, in 1444 subjects from the population‐based Malmö Preventive Project‐Re‐examination Study (MPP‐RES) (mean age 68 years; 29% women, 36% prevalent diabetes) (discovery cohort) and in 996 subjects from the VARA cohort (mean age 51 years, 52% women, 7% prevalent diabetes) (replication cohort). Multivariable logistic regression was assessed. Genetic variants that reached significant association with diastolic dysfunction in both cohorts were then analysed for association with incident CVD/CHF in a larger sample of the MPP‐RES cohort (3,407 cases and 11,776 controls, median follow up >30 years) using Cox regression analysis. A common variant at the HNF1B [major allele (T) coded, also the risk allele for diabetes] was the only SNP associated with increased risk of prevalent diastolic dysfunction in both the discovery [MPP‐RES; odds ratio (OR) 1.21, P = 0.024), and the replication cohort (VARA; OR 1.38, P = 0.042]. Cox regression analysis showed that carriers of the T‐allele of rs757210 had an increased risk of future CVD (HR 1.05, P = 0.042). No significant association was seen for incident CHF. Conclusions The diabetes susceptibility locus HNF1B is associated with prevalent diastolic dysfunction in two independent Swedish cohorts as well as incident cardiovascular disease.

BackgroundObesity is a key risk factor for type 2 diabetes, however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI, and subsequently to test if lean individuals who carry an obese metabolome are at hidden high risk of obesity related diseases, such as diabetes.MethodsWe measured 109 metabolites in fasted plasma samples of 7663 individuals from two Swedish and one Italian population-based cohort. Ridge regression models were used to predict BMI using the plasma metabolites. Individuals with a predicted BMI either more than 5 kg/m2higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity related risk factors and future risk of diabetes and mortality.ResultsThe plasma metabolome could predict BMI in all cohorts (r2= 0.48, 0.26 and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, similar waist circumference, were not more likely to change weight over time but had a 2 times higher risk of future diabetes and an 80 % increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters.ConclusionsWe found that lean individuals with an obese metabolome, have an increased risk for diabetes and all-cause mortality compared to lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals, in order to initiate lifestyle and pharmacological interventions.

Background and AimTrigger finger (TF) or stenosing tenosynovitis has been associated with diabetes mellitus (DM), although today’s knowledge is mostly based on cross-sectional and case-control studies. Thus, the aim of the present population-based cohort study over more than 20 years was to investigate DM as a risk factor for TF.MethodsData from Malmö Diet and Cancer Study (MDCS), including 30,446 individuals, were analysed with regards to baseline DM and known or potential confounders. Information regarding TF diagnosis until study end date of Dec 31st, 2018, was retrieved from the Swedish National Patient Register (NPR) using ICD-codes. Survival probability was investigated in Kaplan-Meier plots. Cox proportional hazard regression model was used to evaluate DM as risk factor for TF, adjusted for several confounders and presented as Hazard Ratio (HR) with 95% confidence intervals (CI).ResultsAt baseline, 4.6% (1,393/30,357) participants had DM. In total, 3.2% (974/30,357) participants were diagnosed with TF during the study period. Kaplan-Meier plot showed that the probability for incident TF was significantly higher in participants with baseline DM compared with individuals without baseline DM. Adjusted HR for DM as risk factor for TF was 2.0 (95% CI: 1.5-2.6, pConclusionThis longitudinal study showed that DM is an important risk factor for developing TF. When adjusting for sex, age, BMI, manual work, statin use, smoking and alcohol consumption, DM remained the main risk factor for TF.

This study sought to identify homogenous echocardiographic phenotypes in community-based cohorts and assess their association with outcomes.Asymptomatic cardiac dysfunction leads to a high risk of long-term cardiovascular morbidity and mortality; however, better echocardiographic classification of asymptomatic individuals remains a challenge.Echocardiographic phenotypes were identified using K-means clustering in the first generation of the STANISLAS (Yearly non-invasive follow-up of Health status of Lorraine insured inhabitants) cohort (N = 827; mean age: 60 ± 5 years; men: 48%), and their associations with vascular function and circulating biomarkers were also assessed. These phenotypes were externally validated in the Malmö Preventive Project cohort (N = 1,394; mean age: 67 ± 6 years; men: 70%), and their associations with the composite of cardiovascular mortality (CVM) or heart failure hospitalization (HFH) were assessed as well.Three echocardiographic phenotypes were identified as "mostly normal (MN)" (n = 334), "diastolic changes (D)" (n = 323), and "diastolic changes with structural remodeling (D/S)" (n = 170). The D and D/S phenotypes had similar ages, body mass indices, cardiovascular risk factors, vascular impairments, and diastolic function changes. The D phenotype consisted mainly of women and featured increased levels of inflammatory biomarkers, whereas the D/S phenotype, consisted predominantly of men, displayed the highest values of left ventricular mass, volume, and remodeling biomarkers. The phenotypes were predicted based on a simple algorithm including e', left ventricular mass and volume (e'VM algorithm). In the Malmö cohort, subgroups derived from e'VM algorithm were significantly associated with a higher risk of CVM and HFH (adjusted HR in the D phenotype = 1.87; 95% CI: 1.04 to 3.37; adjusted HR in the D/S phenotype = 3.02; 95% CI: 1.71 to 5.34).Among asymptomatic, middle-aged individuals, echocardiographic data-driven classification based on the simple e'VM algorithm identified profiles with different long-term HF risk. (4th Visit at 17 Years of Cohort STANISLAS-Stanislas Ancillary Study ESCIF [STANISLASV4]; NCT01391442).

Summary Background Increased blood pressure is the biggest contributor to the global burden of disease and mortality. Data suggest that less than half of the population with hypertension is aware of it. May Measurement Month was initiated to raise awareness of the importance of blood pressure and as a pragmatic interim solution to the shortfall in screening programmes. Methods This cross-sectional survey included volunteer adults (≥18 years) who ideally had not had their blood pressures measured in the past year. Each participant had their blood pressure measured three times and received a a questionnaire about demographic, lifestyle, and environmental factors. The primary objective was to raise awareness of blood pressure, measured by number of countries involved, number of people screened, and number of people who have untreated or inadequately treated hypertension (defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, or on the basis of receiving antihypertensive medication). Multiple imputation was used to estimate the mean of the second and third blood pressure readings if these were not recorded. Measures of association were analysed using linear mixed models. Findings Data were collected from 1 201 570 individuals in 80 countries. After imputation, of the 1 128 635 individuals for whom a mean of the second and third readings was available, 393 924 (34·9%) individuals had hypertension. 153 905 (17·3%) of 888 616 individuals who were not receiving antihypertensive treatment were hypertensive, and 105 456 (46·3%) of the 227 721 individuals receiving treatment did not have controlled blood pressure. Significant differences in adjusted blood pressures and hypertension prevalence were apparent between regions. Adjusted blood pressure was higher in association with antihypertensive medication, diabetes, cerebrovascular disease, smoking, and alcohol consumption. Blood pressure was higher when measured on the right arm than on the left arm, and blood pressure was highest on Saturdays. Interpretation Inexpensive global screening of blood pressure is achievable using volunteers and convenience sampling. Pending the set-up of systematic surveillance systems worldwide, MMM will be repeated annually to raise awareness of blood pressure. Funding International Society of Hypertension, Centers for Disease Control and Prevention, Servier Pharmaceutical Co.

BackgroundPresently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine.MethodsWe analyzed 2,140 patients with established diabetes from the DOLCE study (n= 887 with new-onset diabetes andn= 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration.ResultsSevere autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in theTCF7L2gene as compared to all other clusters, cumulatively and individually (p= 0.0001).ConclusionThe novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve β-cell function. Long-term diabetes cases with preserved β-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR).METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945.RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05).CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications. (Less)

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias., Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

Aims/hypothesis Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Background: Genome-wide association studies (GWAS) have identified >50 single nucleotide polymorphisms (SNP) in association with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) but little is known about whether the combination of these SNPs may aid in prediction of future incidence of CKD in the population. Methods: We included 2301 participants with baseline eGFR ≥60 mL/min per 1.73 m2 from the Malmö Diet and Cancer Study–Cardiovascular Cohort. The eGFR was estimated during baseline (1991–1996) and after a mean follow-up of 16.6 years using the CKD–Epidemiology Collaboration 2009 creatinine equation. We combined 53 SNPs into a genetic risk score weighted by the effect size (wGRSCKD), and examined its association with incidence of CKD stage 3A (eGFR ≤60 mL/min per 1.73 m2). Results: At follow-up, 453 study participants were defined as having CKD stage 3A. We observed a strong association between wGRSCKD and eGFR at baseline (P = 6.5 × 10−8) and at the follow-up reexamination (P = 5.0 × 10−10). The odds ratio (OR) for incidence of CKD stage 3A was 1.25 per 1 SD increment in the wGRSCKD (95% confidence interval [CI]: 1.12–1.39) adjusting for potential confounders (sex, age, body mass index [BMI], baseline eGFR, fasting glucose, systolic blood pressure (SBP), antihypertensive treatment, smoking, follow-up time). Adding wGRSCKD on the top of traditional risk factors did not improve the C-statistics (P = 0.12), but the Net Reclassification-Improvement-Index was significantly improved (cNRI = 21.3%; 95% CI: 21.2–21.4; P < 0.0001). Conclusion: wGRSCKD was associated with a 25% increased incidence of CKD per 1 SD increment. Although the wGRSCKD did not improve the prediction model beyond clinical risk factors per se, the information of genetic predisposition may aid in reclassification of individuals into correct risk direction. Keywords: CKD, eGFR, GRS, renal function

Background Epidemiological data indicate decreased risk for development and growth of abdominal aortic aneurysm (AAA) among patients with diabetes mellitus (DM), but DM also goes with increased cardiovascular (CV) morbidity and mortality. We evaluated the effects of DM on mortality and CV morbidity after elective open AAA repair. Methods This is a nationwide observational cohort study of patients registered in the Swedish Vascular Registry and the Swedish National Diabetes Register. Comparison of mortality and CV morbidity after elective open AAA repair in 397 patients with and 1709 without DM with propensity score–adjusted analysis, during median 4.51 years of follow-up for patients with DM and 4.59 years for those without. Results In adjusted analysis, diabetic patients showed higher rates of acute myocardial infarction (AMI) (relative risk [RR] 1.57, 95% confidence interval [CI] 1.04–2.36; P = 0.03) and major adverse cardiovascular events (MACEs, RR 1.28, CI 1.04–1.58; P = 0.02) during follow-up, whereas there were no differences in total (RR 0.98, CI 0.75–1.29; P = 0.91) or CV (RR 0.30, CI 0.07–1.26; P = 0.10) mortality or stroke (RR 1.06, CI 0.67–1.67; P = 0.80). Among diabetic patients, higher HbA1c was related to a higher risk for AMI during follow-up (RR 1.04, CI 1.01–1.08; P = 0.02). Conclusions Patients with DM had higher rates of AMI and MACE after elective open AAA repair than those without DM, whereas neither total nor CV mortality differed between groups. Putative beneficial effects of DM on the aortic wall might not be relevant after open surgery including thrombus removal and aneurysmorrhaphy.

Objective— RAGE (receptor for advanced glycation end products) and EMMPRIN (extracellular matrix metalloproteinase inducer) are immune receptors for proinflammatory mediators. These receptors can also be found in a soluble form in the circulation. Soluble RAGE (sRAGE) has shown atheroprotective properties in animal studies, possibly by acting as a decoy receptor for its ligands. Whether sEMMPRIN (soluble EMMPRIN) has similar roles is unknown. We hypothesized that sRAGE and sEMMPRIN might be associated with vascular disease progression, incident coronary events, and mortality. Approach and Results— We measured baseline sRAGE and sEMMPRIN in 4612 cardiovascular disease-free individuals from the population-based Malmö Diet and Cancer cohort. Measurements of intima-media thickness in the common carotid artery were performed at inclusion and after a median of 16.5 years. sRAGE was negatively correlated with carotid intima-media thickness progression, independently of traditional cardiovascular risk factors, kidney function, and hsCRP (high sensitive C-reactive protein). Additionally, sRAGE was associated with decreased risk for major adverse coronary events (hazard ratio=0.90 [0.82–0.97]; P =0.009) and mortality (hazard ratio=0.93 [0.88–0.99]; P =0.011) during a follow-up period of 21 years. The relationship with mortality was independent of all considered potential confounders. We found no correlations between EMMPRIN, intima-media thickness progression, or prognosis. Conclusions— Individuals with high levels of circulating sRAGE have a slower rate of carotid artery disease progression and a better prognosis. Although its predictive value was too weak to promote sRAGE as a useful clinical biomarker in the population, the findings support further research into the potential anti-inflammatory and atheroprotective properties of this soluble receptor.

BACKGROUND AND AIM: Progression to fibrosis in non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of liver-related events, overall mortality and possibly metabolic comorbidities. Our aim was to determine if non-invasive fibrosis scoring systems can predict the future risk of diabetes mellitus, cardiovascular disease (CVD), chronic kidney disease (CKD), liver-related events and overall mortality.METHODS: Patients with biopsy-proven NAFLD 1978 to 2006 were identified from a computerised register in Malmo, Sweden. Medical records were scrutinised in detail to collect data from inclusion to endpoint (death or end of 2016). Non-invasive fibrosis scoring systems (FIB-4-index, NAFLD fibrosis score (NFS), APRI and BARD score) were calculated and the scores classified into three risk categories (low, intermediate and high risk for advanced fibrosis). Chronic kidney disease was evaluated using the CKD-EPI equation.RESULTS: One hundred and forty-four patients with biopsy-proven NAFLD were included, with a mean age of 53.2 years and a mean follow-up time of 18.8 years. At inclusion, 18% had advanced fibrosis. NFS was the only score that could predict the future risk of all included outcomes with fairly good accuracy (Area-under-ROC curve). Multivariate-adjusted hazard ratios revealed that both the intermediate and high-risk category of FIB-4-index and NFS could significantly predict metabolic outcomes. All four scoring systems significantly predicted overall mortality in the high-risk category.CONCLUSIONS: Non-invasive fibrosis scoring systems, especially NFS and FIB-4-index, can be used to identify patients at risk of future liver-related events, overall mortality, metabolic comorbidities and CKD. (Less)

OBJECTIVES: Elevated plasma levels of the vasodilating hormone adrenomedullin (ADM) predict cardiovascular disease and have been associated with hypertension and obesity. We aimed to examine the independent relationship between ADM and the progression of major cardiometabolic risk factors during long-term follow-up. METHODS: We studied midregional pro-ADM (MR-proADM) in fasting plasma in 3298 participants from the population-based Malmo Diet and Cancer Study - Cardiovascular Cohort, re-examined after 17 years of follow-up and related baseline MR-proADM to cardiometabolic risk factors cross-sectionally and longitudinally. RESULTS: At baseline, after full adjustment, each SD increment of MR-proADM was independently related to (beta ± standard error, P value) higher SBP (0.956 ± 0.319 mmHg, P = 0.003), BMI (0.912 ± 0.061 kg/m, P = 1.42 × 10), waist (2.28 ± 0.158 cm, P = 8.46 × 10) and fasting blood glucose (0.046 ± 0.018 mmol/l, P = 0.01). After full adjustment, including the baseline level of the risk factor whose degree of progression was studied, each SD increment of MR-proADM predicted significantly reduced progression of SBP (-1.170 ± 0.337 mmHg, P = 0.001) and fasting blood glucose (-0.055 ± 0.023 mmol/l, P = 0.015), but greater increase of BMI (0.101 ± 0.051 kg/m, P = 0.047) and waist (0.600 ± 0.144 cm, P = 3.1 × 10). CONCLUSION: Despite cross-sectional associations with higher levels of blood pressure and glucose, high levels of MR-proADM predict a slower progression of blood pressure and glycemia during long-term follow-up. Conversely, the cross-sectional associations with higher levels of MR-proADM and obesity were paralleled by a faster progression of obesity markers over time. These results may be important for assessment of long-term effects of therapies modulating levels of ADM. (Less)

With older and aging populations, patients experience multiple chronic diseases at the same time. Individual chronic disease guidelines often recommend pharmacological therapies as a key intervention, resulting in patients being prescribed multiple regular medications for their different diseases. Although the term "polypharmacy" has been applied to the use of multiple medications, there is no consistent definition, and this term is now being used all inclusively. To improve both scientific rigor and optimal patient care, it is crucial that a standard terminology is used, which reclassifies the term "polypharmacy" into distinct phenotypes relating to the index chronic disease, additional conditions to the index (comorbidity), or the experience of multiple chronic conditions at the same time (multimorbidity). Using three exemplar index conditions; heart failure, type 2 diabetes, and breast cancer, we propose the reclassification of the term "polypharmacy" into three distinct phenotypes. First, index drug or multi-index drug therapy, where each index condition creates multiple drug use for that condition; second, codrug therapy, where addition of other comorbid conditions increases the multiple drug use and may influence the management of the index disease and third, multidrug therapy, where adult population with multimorbidity may be on many drugs. This article reviews guidelines for the individual exemplars to develop the basis for the new terms and then develops the pharmacoepidemiology of multiple drug use further by reviewing the evidence on the relationship between the phenotypic classification and important outcomes. The importance of standardizing "polypharmacy" terminology for the scientific agenda and clinical practice is that it relates to an index condition or disease safety outcomes including drug interactions, adverse side effects in hospital admissions, and related "polypill" concept.

Background The kidney injury molecule-1 (KIM-1) has previously been associated with kidney function in rodents and humans. Yet its role as a predictive marker for future decline in kidney function has remained less clear. Methods At baseline (1991–1994), fasting plasma KIM-1 (p-KIM-1) was measured in 4739 participants of the population-based Malmö Diet and Cancer Study. Creatinine and cystatin C were used to calculate estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration 2012 creatinine–cystatin C equation at baseline and follow-up examination (2007–2012). Incident CKD was defined as an eGFR Results During a mean follow-up time of 16.6 years, high p-KIM-1 levels were associated with a greater decline in eGFR (quartile 1 −1.36 versus quartile 4 −1.54 mL/min/1.73 m2; P Conclusion Our results show that p-KIM-1 predicts the future decline of eGFR and risk of CKD in healthy middle-aged participants. Whether p-KIM-1 can be used to prioritize preventive action that needs to be further investigated.

Multiplex proteomic platforms provide excellent tools for investigating associations between multiple proteins and disease (e.g., diabetes) with possible prognostic, diagnostic, and therapeutic implications. In this study our aim was to explore novel pathophysiological pathways by examining 92 proteins and their association with incident diabetes in a population-based cohort (146 cases of diabetes versus 880 controls) followed over 8 years. After adjusting for traditional risk factors, we identified seven proteins associated with incident diabetes. Four proteins (Scavenger receptor cysteine rich type 1 protein M130, Fatty acid binding protein 4, Plasminogen activator inhibitor 1 and Insulin-like growth factor-binding protein 2) with a previously established association with incident diabetes and 3 proteins (Cathepsin D, Galectin-4, Paraoxonase type 3) with a novel association with incident diabetes. Galectin-4, with an increased risk of diabetes, and Paraoxonase type 3, with a decreased risk of diabetes, remained significantly associated with incident diabetes after adjusting for plasma glucose, implying a glucose independent association with diabetes.

Objectives: Endometriosis has been associated with a wide range of factors. The disease share immunological features with autoimmune diseases, and the prevalence of both hypo- and hyperthyroidism has been reported to be increased. However, the associations have to be confirmed and the mechanisms explored. The aim of this observational study was to investigate socioeconomic factors, lifestyle habits, and somatic and mental comorbidities in endometriosis compared to the general population. Study design: In all, 172 women with endometriosis completed a study questionnaire and were interviewed regarding socioeconomic factors, lifestyle habits, psychological well-being, and medical history. Bowel symptoms were measured by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS). Serum was analyzed for IgG levels of TSH receptor antibodies (TRAb) and anti-thyroid peroxidase (TPO) antibodies. Women from the general population served as controls. Differences were calculated by logistic regression, adjusted for confounders. Results: Alcohol intake, leisure time physical activity, body mass index and asthma were inversely, whereas IBS was positively associated with endometriosis. Hypothyroidism and anti-TPO antibodies did not associate, but elevated TRAb antibody titers were associated with endometriosis (odds ratio (OR): 539.26; 95% confidence interval (CI): 114.29–2544.32 for highest versus lowest tertile; p for trend < 0.001). Impaired psychological well-being (p for trend = 0.003) and current intake of antidepressant medication (OR: 3.54; 95% CI: 1.22–10.28; p = 0.020) associated with endometriosis, and impaired psychological well-being correlated with all gastrointestinal symptoms measured (all p < 0.001). Conclusions: Lifestyle habits and asthma are inversely associated, and IBS and impaired psychological well-being are positively associated with endometriosis. TRAb titers are associated with endometriosis, supporting a link between endometriosis, autoimmunity and thyroid pathophysiology, although overt thyroid diseases do not associate. (Less)

Background Diabetes is a risk factor for cognitive impairment, but whether there is also a link between pre-diabetes and cognitive dysfunction is not yet fully established. The aim of this observational study was to investigate associations between pre-diabetes/diabetes and cognitive test results, and also between glucose levels measured during the Oral Glucose Tolerance Test (OGTT) and cognitive outcomes. Methods During 2007–2012, in all 2994 people (mean age 72 years), residing in Malmö, Sweden, underwent a clinical examination including the OGTT, cardiovascular measurements including carotid-femoral pulse wave velocity (c-f PWV) and two cognitive tests, the Mini Mental State Examination (MMSE), measuring global cognitive function, and A Quick Test of Cognitive Speed (AQT), measuring processing speed and executive functioning. Regression analyses were performed to investigate associations between: (a) categories of normal or impaired glucose metabolism, and (b) OGTT measurements, respectively, as exposure variables and cognitive test results as outcomes. Adjustments were made for demographics, lifestyle factors and cardiovascular risk factors. Results Participants with pre-diabetes and diabetes scored slightly worse cognitive test results compared to the control group. Results of participants with a long disease duration of diabetes since the baseline examination 13 years earlier were poorer (mean AQT test time 17.8 s slower than controls, p Funding Agencies|Research Council of Sweden [K2011-65X-20752-04-6]; Anders Palsson Foundation; Ernhold Lundstrom Foundation; Skane County Council; Swedish Alzheimers Foundation; Region Skane; Lund University

Low-grade inflammation and arterial stiffness are key factors in the development of vascular aging. However, the interplay between arterial stiffness and inflammation for cardiovascular (CV) disease is unclear. Aortic pulse wave velocity (aPWV) and the inflammatory markers, high-sensitivity C-reactive protein (CRP) and orosomucoid, were measured in 2710 participants (median age: 72 years). These participants were followed up for a mean of 7.6 years for a composite CV disease end point. Per 1 interquartile range increment of CRP and orosomucoid, respectively, aPWV increased by 0.19 m/s (95% CI: 0.07-0.32) and 0.19 m/s (0.11-0.27), after multifactorial adjustment. Mediation analysis showed that aPWV, after multifactorial adjustment, mediated 8% (−4, 20) of the CV disease risk associated with CRP and 8% (−4, 18) of orosomucoid risk. The associated risk increased with combinations of high aPWV and high CRP or orosomucoid. We found no evidence that arterial PWV acted as an important mediator of the relationship between systemic inflammation and CV disease risk in this elderly population. The results instead indicate an additive effect. Our study supports the view that arterial stiffness and chronic inflammation affects CV risk mainly through separate causal pathways.

Background and Aims The “Shrunken pore syndrome” is characterized by a difference in renal filtration between cystatin C and creatinine resulting in a low eGFRcystatinC/eGFRcreatinine-ratio, and studies have demonstrated a high risk for cardiovascular morbidity and mortality for patients with shrunken pore syndrome. In this observational study, we explored associations between shrunken pore syndrome and proteins implicated in cardiovascular disease and inflammation in patients with heart failure. Method Plasma samples from 300 individuals HARVEST-Malmö trial hospitalized for the diagnosis of heart failure (mean age 75 years; 30% female), were analyzed with a proximity extension assay consisting of 92 proteins, to identify proteins associated with shrunken pore syndrome. Shrunken pore syndrome was defined as eGFRcystatinC ≤60% of eGFRcreatinine. Proteins associated with shrunken pore syndrome in the initial age and sex-adjusted analyses (Bonferroni-corrected p≤ 5.4x10-4) were further adjusted for relevant covariates. Results In multivariate analyses, Shrunken pore syndrome was associated with elevated levels of six proteins; scavenger receptor cysteine-rich type 1 protein M130, tumor necrosis factor receptor 1, tumor necrosis factor receptor 2, osteoprotegerin, interleukin-2 receptor subunit alpha, and tyrosine-protein kinase receptor UFO (p Conclusion In heart failure patients, shrunken pore syndrome was independently associated with proteins linked to atherosclerosis and cell proliferation.

Background and Aims The cardiorenal syndrome was studied in heart failure (HF) patients with respect to the “Shrunken pore syndrome” (SPS) that is characterized by a difference in renal filtration between cystatin C and creatinine, resulting in a low eGFRcystatin C/eGFRcreatinine-ratio. Method 373 patients hospitalized for HF were retrieved from the HeARt and brain failure inVESTigation trial (HARVEST-Malmö). We used CKD-EPI formulas for estimated glomerular filtration rate (eGFR). Presence of SPS was defined as eGFRcystatinC ≤60% of eGFRcreatinine. In Cox regression multivariate models, associations between SPS, risk of death and risk of 30-day re-hospitalization were studied. Associations between SPS and impaired quality of life (QoL) were studied using multivariate logistic regressions. Results SPS was associated with all-cause mortality (124 events; hazard ratio (HR) 2.35; confidence interval (CI95%) 1.17-4.71; p=0.016 and with 30-day re-hospitalization (70 events; HR 1.82; CI95% 1.04-3.18; p=0.036). Analyses of QoL, based on a Kansas City Cardiomyopathy Questionnaire overall score Conclusion The results of this observational study show for the first time an association between SPS and poor prognosis in HF. Further studies are needed to confirm the results in HF cohorts and experimental settings to identify pathophysiological mechanisms.

Background It has been shown that individuals with obesity have a higher risk for chronic kidney disease (CKD). However, it is unclear which measure of obesity is most useful for prediction of CKD in the general population. The aim of this large prospective study was to explore the association between several anthropometric measures of obesity, i. e., body mass index (BMI), waist circumference (WC), waist circumference to height ratio (WHtR), waist-to-hip ratio (WHR), percentage of body fat (BF%), weight, height and incidence of hospitalizations due to CKD, in a population-based cohort study. Methods The ‘Malmö Diet and Cancer Study (MDCS)’ cohort in Sweden was examined during 1991 to 1996. A total of 28,449 subjects underwent measurement of anthropometric measures and blood pressure and filled out a questionnaire. Incidence of in- and outpatient hospital visits for CKD was monitored from the baseline examination over a mean follow-up of 18 years. Cox proportional hazards regression was used to explore the association between anthropometric measures and incidence of CKD, with adjustments for risk factors. Results The final study population included 26,723 subjects, 45-73 years old at baseline. Higher values of BMI, WC, WHR, WHtR and weight were associated with an increased risk of developing CKD in both men and women. Only in women, higher values of BF% was associated with higher risk of CKD. Comparing the 4th vs 1st quartile of the obesity measure, the highest hazard ratio (HR) for CKD in men was observed for BMI, HR 1.51 (95% CI: 1.18-1.94) and weight (HR 1.52 (95% CI: 1.19-1.94). For women the highest HR for CKD was observed for BF%, HR 2.01 (95% CI: 1.45-2.78). Conclusions In this large prospective study, all anthropometric measures of obesity were associated with a substantially increased incidence of CKD, except for BF% in men. Some measures were slightly more predictive for the risk of CKD than others such as BMI and weight in men and BF% in women. In clinical daily practice use of all anthropometric measures of obesity might be equally useful to assess the risk of developing CKD. This study supports the strong evidence for an association between obesity and CKD.

Background: Arterial ageing is characterised by degradation of elastic fibres and increased stiffness of elastic arteries. Although low lung function and arterial stiffness are strongly related to age, the association between lung function and arterial ageing has not been widely explored. We used a large population-based study of 50-64 year olds to assess the association between lung function (measured by spirometry and CO diffusing capacity (D-LCO)) and arterial stiffness (measured by carotid-femoral pulse-wave velocity (c-f PWV)). Methods: Participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort with information on spirometry (n = 8941) and D-LCO (n = 8616) were included. General linear models (lung function quartiles) and linear regression was used to determine the association between lung function and c-f PWV. Results: FEV1 (L), FVC (L), D-LCO (mmol/(min kPa)) and D-LCO/V-A (mmol/(min kPa L)) were significantly and inversely associated with c-f PWV after adjustments; mean PWV (m/s) in Q1 (highest lung function) vs Q4: FEV1; 8.45 vs 8.60, p-value 0.001; FVC; 8.45 vs 8.57, p-value 0.018; D-LCO; 8.46 vs 8.60, p-value 0.002; and D-LCO/V-A; 8.47 vs 8.58, p-value 0.001. In sex-stratified analyses, significant findings were reflected for FEV1 and D-LCO in men only. The results remained significant for D-LCO in all never smokers and in all participants without COPD or airflow limitation on spirometry. Conclusions: A reduction in spirometry and D-LCO is associated with elevated arterial stiffness in middle-aged men. A reduction in D-LCO is associated with higher c-f PWV even in never smokers and in those without COPD or airflow limitation on spirometry. Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2014-0047]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [822-2013-2000, 2019-01236]; VINNOVA (Swedens Innovation agency)Vinnova [2012-04476]; Linoping University and University Hospital; Lund University; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation [2020-0173]; Skane University Hospital; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation