Sex differences in the association between insulin resistance and non-fatal myocardial infarction across glycaemic states.

BACKGROUND: Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index - VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. METHODS: IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. RESULTS: Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1-3.4 respectively). CONCLUSIONS: These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

Does Periodontitis Increase the Risk for Future Cardiovascular Events? Long-Term Follow-Up of the PAROKRANK Study.

BACKGROUND AND AIM: The study 'Periodontitis and Its Relation to Coronary Artery Disease' (PAROKRANK) reported an association between periodontitis (PD) and the first myocardial infarction (MI). This follow-up study aims to test the hypothesis that those with PD-compared to periodontally healthy individuals-are at increased risk for cardiovascular (CV) events and death. METHODS: A total of 1587 participants (age <75 years; females 19%) had a dental examination including panoramic radiographs between 2010 and 2014. PD was categorized as healthy (≥80% alveolar bone height), mild/moderate (79%-66%) or severe (<66%). A composite CV event (first of all-cause death, non-fatal MI or stroke and hospitalization following to heart failure) was investigated during a mean follow-up period of 9.9 years (range 0.2-12.5 years). Participants were divided into two groups: those with and without PD. The primary event rate, stratified by periodontal status at baseline, was calculated using the Kaplan-Meier method and Cox regression. RESULTS: The number of events was 187 in the 985 periodontally healthy participants (19%) and 174 in the 602 participants with PD (29%; p < 0.0001). Those with PD had a higher likelihood for a future event (hazard ratio [HR] = 1.26; 95% CI: 1.01-1.57; p = 0.038), following adjustment for age, smoking and diabetes. CONCLUSION: The PAROKRANK follow-up revealed that CV events were more common among participants with PD, which supports the assumption that there might be a direct relation between PD and CV disease.

Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia : Experiences from the randomized, controlled SOCOGAMI trial.

BACKGROUND: Empagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and ß-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM. METHODS: Forty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and ß-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit. RESULTS: After 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and ß-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline. CONCLUSIONS: Empagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia. TRIAL REGISTRATION NUMBER: EudraCT number 2015-004571-73.

Plasma mannose as a novel marker of myocardial infarction across different glycaemic states: a case control study.

BACKGROUND: Plasma mannose, an emerging novel biomarker of insulin resistance, is associated with both diabetes mellitus and coronary atherosclerosis, but the relationship between mannose concentrations and myocardial infarction (MI) across different glycaemic states remains to be elucidated. The aim of this study was to investigate the independent association between mannose and a first MI in a group of subjects characterized according to their glycaemic state. METHODS: Fasting plasma mannose concentrations were analysed in 777 patients 6-10 weeks after a first myocardial infarction and in 770 matched controls by means of high-performance liquid chromatography coupled to tandem mass spectrometry. Participants without known diabetes mellitus were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT, n = 1045), impaired glucose tolerance (IGT, n = 246) or newly detected type 2 diabetes (T2DM, n = 112). The association between mannose and MI was investigated across these glycaemic states by logistic regression. RESULTS: Mannose levels increased across the glycaemic states (p < 0.0001) and were significantly associated with a first MI in the whole study population (odds ratio, OR: 2.2; 95% CI 1.4 to - 3.5). Considering the different subgroups separately, the association persisted only in subjects with NGT (adjusted OR: 2.0; 95% CI 1.2-3.6), but not in subgroups with glucose perturbations (adjusted OR: 1.8, 95% CI 0.8-3.7). CONCLUSIONS: Mannose concentrations increased across worsening levels of glucose perturbations but were independently associated with a first MI only in NGT individuals. Thus, mannose might be a novel, independent risk marker for MI, possibly targeted for the early management of previously unidentified patients at high cardiovascular risk.

Mannose-binding lectin does not explain the dismal prognosis after an acute coronary event in dysglycaemic patients. A report from the GAMI cohort.

BACKGROUND: Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events. METHODS: MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes. RESULTS: At hospital discharge patients had higher MBL levels (median 1246 µg/L) than three months later (median 575 µg/L; p < 0.01), the latter did not significantly differ from those in the controls (801 µg/L; p = 0.47). MBL levels were not affected by dysglycaemia either in patients or controls. Independent of glycaemic state, increasing MBL levels did not predict any of the studied outcomes in patients. In unadjusted analyses increasing MBL levels predicted cardiovascular events (hazard ratio HR: 1.67, 95% confidence interval CI 1.06-2.64) and total mortality (HR 1.53, 95% CI 1.12-2.10) in the control group. However, this did not remain in adjusted analyses. CONCLUSIONS: Patients had higher MBL levels than controls during the hospital phase of AMI, supporting the assumption that elevated MBL reflects acute stress. MBL was not found to be independently associated with cardiovascular prognosis in patients with AMI regardless of glucose state.

Long-term prognosis after a first myocardial infarction: eight years follow up of the case-control study PAROKRANK.

Objective. To explore long-term cardiovascular outcomes and mortality in patients after a first myocardial infarction (MI) compared with matched controls in a contemporary setting. Methods. During 2010-2014 the Swedish study PAROKRANK recruited 805 patients <75 years with a first MI and 805 age-, gender-, and area-matched controls. All study participants were followed until 31 December 2018, through linkage with the National Patient Registry and the Cause of Death Registry. The primary endpoint was the first of a composite of all-cause death, non-fatal MI, non-fatal stroke, and heart failure hospitalization. Event rates in cases and controls were calculated using a Cox regression model, subsequently adjusted for baseline smoking, education level, and marital status. Kaplan-Meier curves were computed and compared by log-rank test. Results. A total of 804 patients and 800 controls (mean age 62 years; women 19%) were followed for a mean of 6.2 (0.2-8.5) years. The total number of primary events was 211. Patients had a higher event rate than controls (log-rank test p < .0001). Adjusted hazard ratio (HR) for the primary outcome was 2.04 (95% CI 1.52-2.73). Mortality did not differ between patients (n = 38; 4.7%) and controls (n = 35; 4.4%). A total of 82.5% patients and 91.3% controls were event-free during the follow up. Conclusions. In this long-term follow up of a contemporary, case-control study, the risk for cardiovascular events was higher in patients with a previous first MI compared with their matched controls, while mortality did not differ. The access to high quality of care and cardiac rehabilitation might partly explain the low rates of adverse outcomes.

Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke: Results From EFFECTS, a Randomized Controlled Trial.

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine­a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76­1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75­100) versus 93 (interquartile range, 82­100); P=0.0021 and communication 93 (interquartile range, 82­100) versus 96 (interquartile range, 86­100); P=0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02683213.

Copeptin is associated with mortality in elderly people.

BACKGROUND: Elevated copeptin, a marker for vasopressin release, has been associated with impaired prognosis in acute myocardial infarction (MI). The aim was to investigate whether this association extends beyond the acute phase and whether it is related to markers of stress (cortisol) and heart failure (NTproBNP). METHODS: Copeptin, cortisol and NTproBNP were measured in 926 participants (age: 76.0; male: 48.5%) in the ICELAND MI study whereof 246 had a previous MI (91 recognizable (RMI) and 155 previously unrecognizable (UMI) detected by cardiac magnetic resonance imaging). The primary endpoint was cardiovascular events (CVEs), and secondary endpoints were total mortality, heart failure and MI (median follow-up was 9.1 years). The relation between copeptin and prognosis was assessed with the Cox proportional hazard regression (unadjusted, adjusted for cortisol and NTproBNP, respectively, and a multiple model: copeptin, cortisol, NTproBNP, age, sex, serum creatinine, heart failure). RESULTS: Copeptin was higher in participants with MI (8.9 vs. 6.4 pmol/L; P < .01), with no difference between RMI vs. UMI. Increased copeptin correlated with evening cortisol (r = .11; P < .01) and NTproBNP (r = .07; P = .04). Copeptin was associated with CVE and total mortality after adjusting for cortisol and NTproBNP separately, and remained significantly associated with total mortality in the multiple model. CONCLUSIONS: Copeptin was higher in subjects with previous MI regardless whether previously recognized or not. Copeptin correlated weakly with cortisol and NTproBNP, and was independently associated with total mortality. This indicates that the prognostic implications of copeptin are not only mediated by heart failure or stress, supporting the assumption that copeptin is a marker of general vulnerability.

Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model's applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.

Outcome and characteristics of non-measurable myeloma: A cohort study with population-based data from the Swedish Myeloma Registry.

OBJECTIVE: We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM. METHODS: Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. RESULTS: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015). CONCLUSION: In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease.

Validation of the Simplified Modified Rankin Scale Questionnaire.

INTRODUCTION: The modified Rankin scale (mRS) is the most common assessment tool for measuring overall functional outcome in stroke studies. The traditional way of using mRS face-to-face is time- and cost-consuming. The aim of this study was to test the validity of the Swedish translation of the simplified modified Rankin scale questionnaire (smRSq) as compared with the mRS assessed face-to-face 6 months after a stroke. METHODS: Within the ongoing EFFECTS trial, smRSq was sent out to 108 consecutive stroke patients 6 months after a stroke. The majority, 90% (97/108), of the patients answered the questionnaire; for the remaining 10%, it was answered by the next of kin. The patients were assessed by face-to-face mRS by 7 certified healthcare professionals at 4 Swedish stroke centres. The primary outcome was assessed by Cohen's kappa and weighted kappa. RESULTS: There was good agreement between postal smRSq, answered by the patients, and the mRS face-to-face; Cohen's kappa was 0.43 (CI 95% 0.31-0.55), weighted kappa was 0.64 (CI 95% 0.55-0.73), and Spearman rank correlation was 0.82 (p < 0.0001). In 55% (59/108), there was full agreement, and of the 49 patients not showing exact agreement, 44 patients differed by 1 grade and 5 patients had a difference of 2 grades. DISCUSSION/CONCLUSION: Our results show good validity of the postal smRSq, answered by the patients, compared with the mRS carried out face-to-face at 6 months after a stroke. This result could help trialists in the future simplify study design and make multicentre trials and quality registers with a large number of patients more feasible and time-saving.

Limited value of NT-proBNP as a prognostic marker of all-cause mortality in patients with heart failure with preserved and mid-range ejection fraction in primary care: A report from the swedish heart failure register.

Aim: The prognostic value of natriuretic peptides in the management of heart failure (HF) patients with ejection fraction (EF) <40% is well established, but is less known for those with EF ≥40% managed in primary care (PC). Therefore, the aim of this study is to describe the prognostic significance of plasma NT-proBNP in such patients managed in PC.Subjects: We included 924 HF patients (48% women) with EF ≥40% and NT-proBNP registered in the Swedish Heart Failure Registry. Follow-up was 1100 ± 687 days.Results: One-, three- and five-year mortality rates were 8.1%, 23.9% and 44.7% in patients with EF 40-50% (HFmrEF) and 7.3%, 23.6% and 37.2% in patients with EF ≥50% (HFpEF) (p = 0.26). Patients with the highest mean values of NT-proBNP had the highest all-cause mortality but wide standard deviations (SDs). In univariate regression analysis, there was an association only between NT-proBNP quartiles and all-cause mortality. In HFmrEF patients, hazard ratio (HR) was 1.96 (95% CI 1.60-2.39) p < 0.0001) and in HFpEF patients, HR was 1.72 (95% CI 1.49-1.98) p < 0.0001). In a multivariate Cox proportional hazard regression analysis, adjusted for age, NYHA class, atrial fibrillation and GFR class, this association remained regarding NT-proBNP quartiles [HR 1.83 (95% CI 1.38-2.44), p < 0.0001] and [HR 1.48 (95% CI 1.16-1.90), p = 0.0001], HFmrEF and HFpEF, respectively.Conclusion: NT-proBNP has a prognostic value in patients with HF and EF ≥40% managed in PC. However, its clinical utility is limited due to high SDs and the fact that it is not independent in this population which is characterized by high age and much comorbidity.Key pointsIt is uncertain whether NT-proBNP predicts risk in heart failure with preserved ejection fraction (EF > 40%, HFpEF) managed in primary care.We show that high NT-proBNP predicts increased all-cause mortality in HFpEF-patients managed in primary care.The clinical use is however limited due to large standard deviations, many co-morbidities and high age.Many of these co-morbidities contribute to all-cause mortality and management of these patients should also focus on these co-morbidities.

A Systems-Based Risk Assessment Framework for Intentional Electromagnetic Interference (IEMI) on Critical Infrastructures.

Modern infrastructures are becoming increasingly dependent on electronic systems, leaving them more vulnerable to electrical surges or electromagnetic interference. Electromagnetic disturbances appear in nature, e.g., lightning and solar wind; however, they may also be generated by man-made technology to maliciously damage or disturb electronic equipment. This article presents a systematic risk assessment framework for identifying possible, consequential, and plausible intentional electromagnetic interference (IEMI) attacks on an arbitrary distribution network infrastructure. In the absence of available data on IEMI occurrences, we find that a systems-based risk assessment is more useful than a probabilistic approach. We therefore modify the often applied definition of risk, i.e., a set of triplets containing scenario, probability, and consequence, to a set of quadruplets: scenario, resource requirements, plausibility, and consequence. Probability is "replaced" by resource requirements and plausibility, where the former is the minimum amount and type of equipment necessary to successfully carry out an attack scenario and the latter is a subjective assessment of the extent of the existence of attackers who possess the motivation, knowledge, and resources necessary to carry out the scenario. We apply the concept of intrusion areas and classify electromagnetic source technology according to key attributes. Worst-case scenarios are identified for different quantities of attacker resources. The most plausible and consequential of these are deemed the most important scenarios and should provide useful decision support in a countermeasures effort. Finally, an example of the proposed risk assessment framework, based on notional data, is provided on a hypothetical water distribution network.

Periodontitis Increases the Risk of a First Myocardial Infarction: A Report From the PAROKRANK Study.

BACKGROUND: The relationship between periodontitis (PD) and cardiovascular disease is debated. PD is common in patients with cardiovascular disease. It has been postulated that PD could be causally related to the risk for cardiovascular disease, a hypothesis tested in the Periodontitis and Its Relation to Coronary Artery Disease (PAROKRANK) study. METHODS AND RESULTS: Eight hundred five patients (<75 years of age) with a first myocardial infarction (MI) and 805 age- (mean 62±8), sex- (male 81%), and area-matched controls without MI underwent standardized dental examination including panoramic x-ray. The periodontal status was defined as healthy (≥80% remaining bone) or as mild-moderate (from 79% to 66%) or severe PD (<66%). Great efforts were made to collect information on possibly related confounders (≈100 variables). Statistical comparisons included the Student pairwise t test and the McNemar test in 2×2 contingency tables. Contingency tables exceeding 2×2 with ranked alternatives were tested by Wilcoxon signed rank test. Odds ratios (95% confidence intervals) were calculated by conditional logistic regression. PD was more common (43%) in patients than in controls (33%; P<0.001). There was an increased risk for MI among those with PD (odds ratio, 1.49; 95% confidence interval, 1.21-1.83), which remained significant (odds ratio, 1.28; 95% confidence interval, 1.03-1.60) after adjusting for variables that differed between patients and controls (smoking habits, diabetes mellitus, years of education, and marital status). CONCLUSIONS: In this large case-control study of PD, verified by radiographic bone loss and with a careful consideration of potential confounders, the risk of a first MI was significantly increased in patients with PD even after adjustment for confounding factors. These findings strengthen the possibility of an independent relationship between PD and MI.

Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

Lipid-lowering treatment and inflammatory mediators in diabetes and chronic kidney disease.

BACKGROUND: Inflammation may contribute to the high cardiovascular risk in diabetes mellitus (DM) and chronic kidney disease (CKD). Monocyte chemoattractant protein-1 (MCP-1) facilitates the recruitment of monocytes into atherosclerotic lesions and is involved in diabetic nephropathy. Interferon gamma (IFNγ) is important in atherosclerosis and increases the synthesis of chemokines including MCP-1. Lipid-lowering treatment (LLT) with statins may have anti-inflammatory effects, and ezetimibe cotreatment provides additional cholesterol lowering. METHODS: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S+E) were compared in a randomized, double-blind, cross-over study on inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min × 1·73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR > 75 mL/min (DM only) were included. RESULTS: At baseline, monocyte chemoattractant protein 1 (MCP-1) (P = 0·03), IFNγ (P = 0·02), tumour necrosis factor-α (TNFα) (P < 0·01) and soluble vascular adhesion molecule (sVCAM) (P = 0·001) levels were elevated in DM-CKD compared with DM-only patients. LLT with S and S+E reduced MCP-1 levels (P < 0·01 by anova) and IFNγ levels (P < 0·01) in DM-CKD patients but not in DM-only patients. Reductions were most pronounced with the combination treatment. CONCLUSIONS: DM patients with CKD stages 3-4 had increased inflammatory activity compared with DM patients with normal GFR. Lipid-lowering treatment decreased the levels of MCP-1 and IFNγ in DM patients with concomitant CKD, which may be beneficial with regard to the progression of both atherosclerosis and diabetic nephropathy.

High Mannose Correlates With Surrogate Indexes of Insulin Resistance and Is Associated With an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors.

OBJECTIVE: To explore the associations among mannose, indexes of insulin resistance (IR) and secretion, and long-term cardiovascular outcomes. RESEARCH DESIGN AND METHODS: Fasting mannose was assayed in 1,403 participants, one-half of which had a first myocardial infarction (MI) with either normal glucose tolerance (n = 1,045) or newly detected dysglycemia (i.e., impaired glucose tolerance or type 2 diabetes; n = 358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between high (higher quartile) versus low (lower three quartiles) mannose and major adverse cardiac events (MACE) (n = 163) during the 10-year follow-up. RESULTS: Mannose was independently associated with IR indexes (all P ≤ 0.001). High versus low mannose was independently associated with MACE (hazard ratio 1.54, 95% CI 1.07-2.20) in the overall population. CONCLUSIONS: Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations independently of glycemic state.

Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke.

BACKGROUND: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data. METHODS: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. FINDINGS: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results. INTERPRETATION: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months.

Risk prediction in stable angina pectoris.

BACKGROUND: Although stable angina pectoris often carries a favourable prognosis, it remains important to identify patients with an increased risk of cardiovascular (CV) complications. Many new markers of disease activity and prognosis have been described. We evaluated whether common and easily accessible markers in everyday care provide sufficient prognostic information. MATERIALS AND METHODS: The Angina Pectoris Prognosis Study in Stockholm treated 809 patients (248 women) with stable angina pectoris with metoprolol or verapamil double blind during a median follow-up of 3·4 years, with a registry-based extended follow-up after 9·1 years. Clinical and mechanistic variables, including lipids and glucose, renal function, ambulatory and exercise-induced ischaemia, heart rate variability, cardiac and vascular ultrasonography, and psychosocial variables were included in an integrated analysis. Main outcome measures were nonfatal myocardial infarction (MI) and CV death combined. RESULTS: In all, 139 patients (18 women) suffered a main outcome. Independent predictive variables were (odds ratio [95% confidence intervals]), age (1·04 per year [1·00;1·08], P = 0·041), female sex (0·33 [0·16;0·69], P = 0·001), fasting blood glucose (1.29 per mM [1.14; 1.46], P < 0·001), serum creatinine (1·02 per µM [1·00;1·03], P < 0·001) and leucocyte counts (1·21 per 10(6)  cells/L [1·06;1·40], P = 0·008). Smoking habits, lipids and hypertension or a previous MI provided limited additional information. Impaired fasting glucose was as predictive as manifest diabetes and interacted adversely with serum creatinine. Sexual problems were predictive among men. CONCLUSIONS: Easily accessible clinical and demographic variables provide a good risk prediction in stable angina pectoris. Impaired glucose tolerance and an elevated serum creatinine are particularly important.