Low-grade inflammation as a risk factor for cardiovascular events and all-cause mortality in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes is a condition associated with a state of low-grade inflammation caused by adipose tissue dysfunction and insulin resistance. High sensitive-CRP (hs-CRP) is a marker for systemic low-grade inflammation and higher plasma levels have been associated with cardiovascular events in various populations. The aim of the current study is to evaluate the relation between hs-CRP and incident cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients. METHODS: Prospective cohort study of 1679 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART). Cox proportional hazard models were used to evaluate the risk of hs-CRP on cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. Hs-CRP was log-transformed for continuous analyses. Findings were adjusted for age, sex, BMI, current smoking and alcohol use, non-HDL-cholesterol and micro-albuminuria. RESULTS: 307 new cardiovascular events and 343 deaths occurred during a median follow-up of 7.8 years (IQR 4.2-11.1). A one unit increase in log(hs-CRP) was related to an increased vascular- and all-cause mortality risk (HR 1.21, 95% CI 1.01-1.46 and HR 1.26, 95% CI 1.10-1.45 respectively). No relation was found between log(hs-CRP) and myocardial infarction or stroke. The relations were similar in patients with and without previous vascular disease. CONCLUSION: Low grade inflammation, as measured by hs-CRP, is an independent risk factor for vascular- and all-cause mortality but not for cardiovascular events in high-risk type 2 diabetes patients. Chronic low-grade inflammation may be a treatment target to lower residual cardiovascular risk in type 2 diabetes patients.

Predicting 10-year risk of recurrent cardiovascular events andcardiovascular interventions in patients with established cardiovascular disease: results from UCC-SMART and REACH.

BACKGROUND: Existing cardiovascular risk scores for patients with established cardiovascular disease (CVD) estimate residual risk of recurrent major cardiovascular events (MACE). The aim of the current study is to develop and externally validate a prediction model to estimate the 10-year combined risk of recurrent MACE and cardiovascular interventions (MACE+) in patients with established CVD. METHODS: Data of patients with established CVD from the UCC-SMART cohort (N = 8421) were used for model development, and patient data from REACH Western Europe (N = 14,528) and REACH North America (N = 19,495) for model validation. Predictors were selected based on the existing SMART risk score. A Fine and Gray competing risk-adjusted 10-year risk model was developed for the combined outcome MACE+. The model was validated in all patients and in strata of coronary heart disease (CHD), cerebrovascular disease (CeVD), peripheral artery disease (PAD). RESULTS: External calibration for 2-year risk in REACH Western Europe and REACH North America was good, c-statistics were moderate: 0.60 and 0.58, respectively. In strata of CVD at baseline good external calibration was observed in patients with CHD and CeVD, however, poor calibration was seen in patients with PAD. C-statistics for patients with CHD were 0.60 and 0.57, for patients with CeVD 0.62 and 0.61, and for patients with PAD 0.53 and 0.54 in REACH Western Europe and REACH North America, respectively. CONCLUSIONS: The 10-year combined risk of recurrent MACE and cardiovascular interventions can be estimated in patients with established CHD or CeVD. However, cardiovascular interventions in patients with PAD could not be predicted reliably.

The relation between healthy lifestyle changes and decrease in systemic inflammation in patients with stable cardiovascular disease.

BACKGROUND AND AIMS: Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease. METHODS: In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4-10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses. RESULTS: Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (ß-coefficient -0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (ß-coefficients -0.25; 95%CI -0.33,-0.16 and -0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (ß-coefficient -0.17; 95%CI -0.26,-0.07). CONCLUSIONS: Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease.

Limited benefit of haemoglobin glycation index as risk factor for cardiovascular disease in type 2 diabetes patients.

BACKGROUND: The haemoglobin glycation index (HGI) has been proposed as a marker of interindividual differences in haemoglobin glycosylation. Previous studies have shown a relationship between high HGI and risk of cardiovascular disease (CVD) in patients with diabetes. However, no studies have investigated the role of previous CVD in this association. METHODS: The study cohort comprised patients with type 2 diabetes mellitus (T2DM; n=1910) included in the Second Manifestations of Arterial Disease (SMART) study. The relationship between either HGI or HbA1c and a composite of cardiovascular events as the primary outcome, and mortality, cardiovascular mortality, myocardial infarction and stroke as secondary outcomes, was investigated using Cox proportional-hazards models. Similar analyses were performed after stratification according to previous CVD. RESULTS: A 1-unit higher HGI was associated with a 29% greater risk of a composite of cardiovascular events (HR: 1.29, 95% CI: 1.06-1.57) in patients without previous CVD, whereas no such relationship was seen in patients with previous CVD (HR: 0.96, 95% CI: 0.86-1.08). The direction and magnitude of the hazard ratios (HRs) of HGI and HbA1c in relation to outcomes were similar. Additional adjustment for HbA1c in the association between HGI and outcomes lowered the HRs. CONCLUSION: Similar to HbA1c, higher HGI is related to higher risk of cardiovascular events in patients with T2DM without CVD. As HbA1c has proved to be a comparable risk factor, and obtaining and interpreting the HGI is complicated, any additional benefit of applying the HGI in clinical settings is likely to be limited.

Thyroid-stimulating hormone levels in the normal range and incident type 2 diabetes mellitus.

AIM: To evaluate the relationship between thyroid-stimulating hormone (TSH) levels within the normal range and the risk of type 2 diabetes mellitus (T2DM) in a cohort of patients at high cardiovascular risk, and to perform a systematic review and meta-analysis of previous studies. METHODS: We included 5542 patients without T2DM from the prospective Secondary Manifestations of ARTerial disease study with TSH levels between 0.35 and 5.0 mIU/L without anti-thyroid medication or thyroid-hormone replacement therapy. Cox regression was used to investigate the relationship between baseline plasma TSH levels and incident T2DM. MEDLINE, EMBASE, and Cochrane were searched for prospective cohorts assessing TSH and incident T2DM. Hazard ratios (HR) from included prospective cohort studies were pooled using a random-effects model. RESULTS: In patients at high cardiovascular risk, higher plasma TSH levels in the normal range were not associated [HR 1.07 per mIU/L increase in TSH (95% confidence interval (95% CI) 0.95-1.22)] with an increased risk of T2DM, adjusted for age, sex, smoking, total and HDL cholesterol, and triglycerides. In the meta-analysis involving three prospective cohort studies, including the present study, including 29,791 participants with 1930 incident events, there was no relation between plasma TSH levels in the normal range and incident T2DM [pooled HR 1.06 (95% CI 0.99-1.14)]. CONCLUSION: There is no apparent relation between plasma TSH levels in the normal range and incident T2DM in patients at high cardiovascular risk.

Relation between adiposity and vascular events, malignancy and mortality in patients with stable cerebrovascular disease.

BACKGROUND: Abdominal adiposity is associated with various risk factors including hypertension, and is therefore particularly relevant in patients with stable cerebrovascular disease (CeVD). A U-shaped relation between body mass index (BMI, kg m-2) and cardiovascular events is often described. Whether this U-shape persists for abdominal adiposity, and consequently which reference values should guide clinical practice, is unclear. We described the relation between multiple adiposity measurements and risk of vascular events, vascular mortality, malignancy and all-cause mortality in patients with clinically stable CeVD. METHODS: During a median follow-up time of 6.8 years, 1767 patients were prospectively followed. Relations were assessed using multivariable adjusted Cox proportional hazards models. Adiposity was assessed with BMI, waist circumference (stratified by gender) and the contribution of visceral fat to total abdominal fat (VAT%) measured using ultrasound. Relations were nonlinear if the χ2-statistic of the nonlinear term was significant (P-value<0.05). Nadirs were reported for nonlinear and hazard ratios (HRs) for linear relations. RESULTS: The relations between BMI and outcomes were nonlinear with nadirs ranging between 27.1 (95% confidence interval (CI) 21.9-29.3) kg m2 for vascular mortality and 28.1 (95% CI, 19.0-38.2)) kg m-2 for malignancy. The relation between waist circumference and all-cause mortality was nonlinear with a nadir of 84.0 (95% CI, 18.7-134.8) cm for females and 94.8 (95% CI, 80.3-100.1) cm for males. No nonlinearity was detected for VAT%. A 1-s.d. (9.8%) increase in VAT% was related to both vascular (HR, 1.23, 95% CI 1.00-1.51) and all-cause mortality (HR, 1.22, 95% CI 1.05-1.42). CONCLUSIONS: In patients with CeVD, a BMI around 27-28 kg m-2 relates to the lowest risk of vascular events, vascular mortality, malignancy and all-cause mortality. However, increasing abdominal adiposity confers a higher risk of all-cause mortality. Thus, whereas traditional BMI cutoffs may be re-evaluated in this population, striving for low abdominal obesity should remain a goal.

Hippocampal volume and the course of depressive symptoms over eight years of follow-up.

OBJECTIVE: To estimate the association between hippocampal and total brain volume and the course of depressive symptoms over eight years of follow-up in patients with a history of vascular disease. METHOD: Within the SMART-Medea study, 636 participants (62 ± 10 years) had a 1.5-tesla brain MRI obtaining hippocampal and total brain volumes. Depressive symptoms were assessed with the Patient Health Questionnaire-9 biannually during eight-year follow-up. Generalized estimating equation models with robust standard errors were used to assess the associations of hippocampal and total brain volumes with depressive symptoms during follow-up adjusting for age, sex, education, and intracranial volume. An interaction term between volume and time (6-month intervals) was included to examine whether the course of depressive symptoms differed according to hippocampal and total brain volume. RESULTS: The mean PHQ-9 score was 2.8 ± 3.5. Smaller hippocampal volumes were associated with an increasing course of depressive symptom levels, while larger volumes were associated with decreasing levels (P-value interaction = 0.07). Smaller total brain volume was associated with consistently higher levels of depressive symptoms, but not with change in course of depressive symptoms (P-value interaction = 0.45). CONCLUSION: Smaller hippocampal volume but not total brain volume is associated with poorer course of depressive symptoms over eight years of follow-up.

Individualized prediction of the effect of angiotensin receptor blockade on renal and cardiovascular outcomes in patients with diabetic nephropathy.

AIMS: To predict individualized treatment effects of angiotensin receptor blockers (ARBs) on cardiovascular and renal complications in order to help clinicians and patients assess the benefit of treatment (or adherence) and estimate remaining disease risk. MATERIALS AND METHODS: In patients with diabetic nephropathy, the 3-year treatment effect of ARBs was predicted in terms of absolute risk reduction (ARR) for end-stage renal disease (ESRD) and cardiovascular disease (CVD; i.e. myocardial infarction, stroke, hospitalization for heart failure) and all-cause mortality. Competing-risk-adjusted proportional hazard models were developed based on the Irbesartan Diabetic Nephropathy Trial (IDNT) and externally validated in the Reduction of Endpoints NIDDM with Angiotensin II Antagonist Losartan (RENAAL) trial. RESULTS: Predictors included in the model were age, sex, smoking sex, systolic blood pressure, urinary albumin/creatinine ratio, estimated glomerular filtration rate, albumin and phosphorus. The median predicted 3-year risk without treatment was 6.0% for ESRD and 28.0% for CVD and mortality. The median [interquartile range (IQR)] predicted 3-year ARR was 1.2 (0.4-3.1)% for ESRD and 2.2 (1.8-2.6)% for CVD and mortality, resulting in a combined ARR of 3.4 (2.4-5.5)%. The remaining disease risk was 4.7 (IQR 1.7-12.8)% for ESRD and 25.8% (IQR 20.3-31.9)% for CVD and mortality. CONCLUSIONS: The combined effects of ARBs on ESRD and CVD and mortality in patients with diabetic nephropathy vary considerably between patients. A substantial proportion of patients remain at high risk for both outcomes despite ARB treatment.

Pemetrexed plus carboplatin versus pemetrexed in pretreated patients with advanced non-squamous non-small-cell lung cancer: treating the right patients based on individualized treatment effect prediction.

BACKGROUND: Translating results from randomized clinical trials (RCTs) to individual patients in clinical practice is challenging, as treatment effects can vary substantially among individuals. Data from RCTs can be used for individualized treatment effect prediction, to identify patients who benefit from specific treatments. In this study, we developed and validated a prediction model for estimating absolute treatment effect of pemetrexed plus carboplatin versus single-agent pemetrexed in the second-line treatment of non-squamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Using data of relapsed patients with advanced non-squamous NSCLC from the NVALT-7 trial, a Weibull model for prediction of gain in median progression-free survival (PFS) by pemetrexed-carboplatin was derived based on patient and tumor characteristics. The model was externally validated in the GOIRC 02-2006 trial. The applicability of the model for guiding clinical decision-making was evaluated using decision curve analysis. RESULTS: A wide distribution of predicted gain in median PFS by pemetrexed-carboplatin over pemetrexed was found, with a median of 0.7 months (interquartile range: -0.1 to 1.5 months). Patients who benefited most included women, those with stage IV, high body mass index and/or adenocarcinoma. External validation showed satisfactory calibration and moderate discrimination (C-index: 0.61, 95% confidence interval 0.56-0.67). Decision curve analysis confirmed that the model adequately identified patients who benefit from pemetrexed-carboplatin, as prediction-based treatment led to improvement in net benefit with regard to PFS and overall survival when assuming a treatment threshold of 0-5 months gain in PFS, compared with other treatment strategies. CONCLUSIONS: The effects of pemetrexed-carboplatin can be predicted for individual patients based on routinely available patient and tumor characteristics. There is important heterogeneity in the effects on PFS of pemetrexed-carboplatin versus pemetrexed in pretreated patients with advanced non-squamous NSCLC. Individualized prediction of treatment effect could be used to guide shared decision-making by discriminating patients who benefit most, to improve clinical outcome. CLINICAL TRIAL NUMBERS: NVALT-7: ISRCTN38269072 (ISRCTN registry), GOIRC 02-2006: NCT00786331 (clinicaltrials.gov).

Imaging Findings Associated with Space-Occupying Edema in Patients with Large Middle Cerebral Artery Infarcts.

BACKGROUND AND PURPOSE: Prominent space-occupying cerebral edema is a devastating complication occurring in some but not all patients with large MCA infarcts. It is unclear why differences in the extent of edema exist. Better knowledge of factors related to prominent edema formation could aid treatment strategies. This study aimed to identify variables associated with the development of prominent edema in patients with large MCA infarcts. MATERIALS AND METHODS: From the Dutch Acute Stroke Study (DUST), 137 patients were selected with large MCA infarcts on follow-up NCCT (3 ± 2 days after stroke onset), defined as ASPECTS ≤4. Prominent edema was defined as a midline shift of ≥5 mm on follow-up. Admission patient and treatment characteristics were collected. Admission CT parameters used were ASPECTS on NCCT and CBV and MTT maps, and occlusion site, clot burden, and collaterals on CTA. Permeability on admission CTP, and day 3 recanalization and reperfusion statuses were obtained if available. Unadjusted and adjusted (age and NIHSS) odds ratios were calculated for all variables in relation to prominent edema. RESULTS: Prominent edema developed in 51 patients (37%). Adjusted odds ratios for prominent edema were higher with lower ASPECTS on NCCT (adjusted odds ratio, 1.32; 95% CI, 1.13-1.55) and CBV (adjusted odds ratio, 1.26; 95% CI, 1.07-1.49), higher permeability (adjusted odds ratio, 2.35; 95% CI, 1.30-4.24), more proximal thrombus location (adjusted odds ratio, 3.40; 95% CI, 1.57-7.37), higher clot burden (adjusted odds ratio, 2.88; 95% CI, 1.11-7.45), and poor collaterals (adjusted odds ratio, 3.93; 95% CI, 1.78-8.69). CONCLUSIONS: Extensive proximal occlusion, poor collaterals, and larger ischemic deficits with higher permeability play a role in the development of prominent edema in large MCA infarcts.

Obesity and risk of bleeding: the SMART study.

UNLABELLED: Essentials Whether obesity protects against clinically relevant bleeding is unclear. We investigated the risk of bleeding according to various measures of obesity in a cohort of 9736 patients. Obesity was not associated with a lower risk of bleeding. The procoagulant profile in obese subjects may not be enough to protect against clinically relevant bleeding. SUMMARY: Background Obesity is associated with increased levels of procoagulant factors and decreased fibrinolytic activity. Whether this hemostatic profile protects against clinically relevant bleeding has been scarcely investigated. Objectives To assess the impact of measures of obesity on the risk of bleeding in a large cohort of patients at increased atherothrombotic risk. Methods The Second Manifestation of ARTerial disease (SMART) study included 9736 patients aged 18-79 years, followed for a median of 5.9 years. Body mass index (BMI), waist circumference and hip circumference were measured at inclusion. All incident fatal or non-fatal hemorrhagic events were recorded. Results During follow-up, 359 first bleeding events occurred. In quintile-based analyses, the risk of bleeding was highest in the lowest quintile (Q) of BMI (age and sex-adjusted HR Q2 vs. Q1, 0.68; 95% CI, 0.50-0.94), but there was a threshold effect at low BMI levels (men, < 23.84 kg m(-2) ; women, < 22.49 kg m(-2) ), and the risk estimates for bleeding did not further change across the remaining quintiles (HR Q3 0.81 and Q5 0.75). For waist circumference the relationship appeared to be U-shaped, with the lowest risk of bleeding in quintile 3 (HR Q3 vs. Q1, 0.69; 95% CI, 0.46-1.04). Adjustments for hypertension, hemoglobin level, renal failure, diabetes and use of oral anticoagulants or platelet inhibitors did not affect the results. Conclusion Obesity was not associated with lower risk of bleeding. Our findings suggest that presumed protection against bleeding due to an apparently efficient hemostatic system may be counterbalanced by other factors in obese subjects.

Childhood maltreatment modifies the relationship of depression with hippocampal volume.

BACKGROUND: Childhood maltreatment (CM) may modify the relationship between major depressive disorder (MDD) and hippocampal volume reduction. To disentangle the impact of MDD and CM on hippocampal volume we investigated the association between MDD and hippocampal volume in persons with and without a history of CM in two independent cohorts. METHOD: We used data of 262 participants from the Netherlands Study of Depression and Anxiety (NESDA) (mean age 37 years, 32% male) and 636 participants from the SMART-Medea study (mean age 61 years, 81% male). In both studies a 12-month diagnosis of MDD and CM were assessed using a diagnostic interview. Hippocampal volume was measured in NESDA using FreeSurfer software on 3-T magnetic resonance (MR) images and in SMART it was manually outlined on 1.5-T MR images. With analysis of covariance adjusted for intracranial volume, age, gender and lifestyle factors we estimated the effects of MDD and CM on hippocampal volume. RESULTS: In both cohorts CM was not significantly associated with hippocampal volume. After pooling the data MDD was associated with smaller hippocampal volume (B = -138.90 mm(3), p = 0.05) and the interaction between MDD and CM reached significance (p = 0.04); in participants with CM, MDD was related to smaller hippocampal volume (NESDA: B = -316.8 mm(3), p = 0.02; SMART: B = -407.6, p = 0.046), but not in participants without CM (p > 0.05). CONCLUSIONS: Our study shows that in two independent cohorts, particularly in individuals with CM, a diagnosis of MDD is related to smaller hippocampal volume. Prospective studies are needed to further determine through which mechanism CM may amplify the relationship between MDD and hippocampal volume.

Risk Chart for Future Mortality and Ischaemic Events Following Peripheral Bypass Surgery.

OBJECTIVES: A prediction model to identify determinants and quantify the risk of future ischaemic events in patients with peripheral arterial disease (PAD) provides a personal risk profile to offer individualized patient care. A risk chart was derived and validated in patients who received infrainguinal bypass surgery. METHODS: The Bypass Oral anticoagulants or Aspirin Risk Chart (BOA-RC2) was based on a pre-defined subgroup of the Dutch BOA trial (N = 482), the derivation cohort. The primary outcome event for BOA-RC2 was the composite of all cause death, non-fatal myocardial infarction, or non-fatal ischaemic stroke during a 10 year follow up. Determinants and long-term risk were identified with multivariate Cox regression analyses. Validation of the BOA-RC2 was performed in the remaining patients of the complete BOA trial cohort (N = 2,650 - 482 = 2,168), the validation cohort. RESULTS: The primary outcome event occurred in 67% (321/454) of the derivation cohort and in 66% (1,371/2,083) of the validation cohort during a median follow up of 6.6 years. The BOA-RC2 included the following determinants: age, critical limb ischaemia, diabetes, and a prior vascular intervention. The performance of the BOA-RC2 was good with a Brier score of 0.19, an area under the curve of 0.73, and a Hosmer-Lemeshow statistic of p = .9. CONCLUSIONS: The BOA-RC2 proves to be fit for the prediction of mortality and major ischaemic events in patients after peripheral bypass surgery. The BOA-RC2 can be used to adequately inform the patient about his/her risk of future events in an illustrative manner and stress the necessity of preventative measures, such as lifestyle adjustments, screening for risk factors, and drug treatments. In the future, the BOA-RC2 may be of interest to identify patients at high risk of mortality and ischaemic events for clinical research on new therapeutic options.

Cost-effectiveness of a nurse-led internet-based vascular risk factor management programme: economic evaluation alongside a randomised controlled clinical trial.

OBJECTIVE: To assess the cost-effectiveness of an internet-based, nurse-led vascular risk factor management programme in addition to usual care compared with usual care alone in patients with a clinical manifestation of a vascular disease. DESIGN: Cost-effectiveness analysis alongside a randomised controlled trial (the Internet-based vascular Risk factor Intervention and Self-management (IRIS) study). SETTING: Multicentre trial in a secondary and tertiary healthcare setting. PARTICIPANTS: 330 patients with a recent clinical manifestation of atherosclerosis in the coronary, cerebral, or peripheral arteries and with ≥2 treatable vascular risk factors not at goal. INTERVENTION: The intervention consisted of a personalised website with an overview and actual status of patients' vascular risk factors, and mail communication with a nurse practitioner via the website for 12 months. The intervention combined self-management support, monitoring of disease control and pharmacotherapy. MAIN OUTCOME MEASURES: Societal costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness. RESULTS: Patients experienced equal health benefits, that is, 0.86 vs 0.85 QALY (intervention vs usual care) at 1 year. Adjusting for baseline differences, the incremental QALY difference was -0.014 (95% CI -0.034 to 0.007). The intervention was associated with lower total costs (€4859 vs €5078, difference €219, 95% CI -€2301 to €1825). The probability that the intervention is cost-effective at a threshold value of €20,000/QALY, is 65%. At mean annual cost of €220 per patient, the intervention is relatively cheap. CONCLUSIONS: An internet-based, nurse-led intervention in addition to usual care to improve vascular risk factors in patients with a clinical manifestation of a vascular disease does not result in a QALY gain at 1 year, but has a small effect on vascular risk factors and is associated with lower costs. TRIAL REGISTRATION NUMBER: NCT00785031.

Predictors of reperfusion in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Ischemic stroke studies emphasize a difference between reperfusion and recanalization, but predictors of reperfusion have not been elucidated. The aim of this study was to evaluate the relationship between reperfusion and recanalization and identify predictors of reperfusion. MATERIALS AND METHODS: From the Dutch Acute Stroke Study, 178 patients were selected with an MCA territory deficit on admission CTP and day 3 follow-up CTP and CTA. Reperfusion was evaluated on CTP, and recanalization on CTA, follow-up imaging. Reperfusion percentages were calculated in patients with and without recanalization. Patient admission and treatment characteristics and admission CT imaging parameters were collected. Their association with complete reperfusion was analyzed by using univariate and multivariate logistic regression. RESULTS: Sixty percent of patients with complete recanalization showed complete reperfusion (relative risk, 2.60; 95% CI, 1.63-4.13). Approximately one-third of patients showed some discrepancy between recanalization and reperfusion status. Lower NIHSS score (OR, 1.06; 95% CI, 1.01-1.11), smaller infarct core size (OR, 3.11; 95% CI, 1.46-6.66; and OR, 2.40; 95% CI, 1.14-5.02), smaller total ischemic area (OR, 4.20; 95% CI, 1.91-9.22; and OR, 2.35; 95% CI, 1.12-4.91), lower clot burden (OR, 1.35; 95% CI, 1.14-1.58), distal thrombus location (OR, 3.02; 95% CI, 1.76-5.20), and good collateral score (OR, 2.84; 95% CI, 1.34-6.02) significantly increased the odds of complete reperfusion. In multivariate analysis, only total ischemic area (OR, 6.12; 95% CI, 2.69-13.93; and OR, 1.91; 95% CI, 0.91-4.02) was an independent predictor of complete reperfusion. CONCLUSIONS: Recanalization and reperfusion are strongly associated but not always equivalent in ischemic stroke. A smaller total ischemic area is the only independent predictor of complete reperfusion.

Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 tesla MRI: the PREDICT-MR study.

INTRODUCTION: Smaller hippocampal volumes have been associated with major depressive disorder (MDD). The hippocampus consists of several subfields that may be differentially related to MDD. We investigated the association of occurrence of major depressive episodes (MDEs), assessed five times over seven years, with hippocampal subfield and entorhinal cortex volumes at 7 tesla MRI. METHODS: In this prospective study of randomly selected general practice attendees, MDEs according to DSM-IV-R criteria were assessed at baseline and after 6, 12, 39 and 84 months follow-up. At the last follow-up, a T2 (0.7 mm(3)) 7 tesla MRI scan was obtained in 47 participants (60±10 years). The subiculum, cornu ammonis (CA) 1 to 3, dentate gyrus&CA4 and entorhinal cortex volumes were manually segmented according a published protocol. RESULTS: Of the 47 participants, 13 had one MDE and 5 had multiple MDEs. ANCOVAs, adjusted for age, sex, education and intracranial volume, revealed no significant differences in hippocampal subfield or entorhinal cortex volumes between participants with and without an MDE in the preceding 84 months. Multiple episodes were associated with smaller subiculum volumes (B=-0.03 mL/episode; 95% CI -0.06; -0.003), but not with the other hippocampal subfield volumes, entorhinal cortex, or total hippocampal volume. LIMITATIONS: A limitation of this study is the small sample size which makes replication necessary. CONCLUSIONS: In this exploratory study, we found that an increasing number of major depressive episodes was associated with smaller subiculum volumes in middle-aged and older persons, but not with smaller volumes in other hippocampal subfields or the entorhinal cortex.

Paternal or maternal history of cardiovascular disease and the risk of cardiovascular disease in offspring. A systematic review and meta-analysis.

BACKGROUND: Parental history of cardiovascular disease (CVD) is an established risk factor for the development of CVD in offspring. Several studies have suggested that a maternal transmission of CVD is more important for the development of CVD than paternal transmission. METHODS: A systematic search and meta-analysis were conducted, using the Medline and Embase databases. Included were cohort, case-control and cross-sectional studies (n=26) focusing on the relation between paternal and maternal histories of cardiovascular disease and offspring CVD (myocardial infarction, stroke or cardiovascular mortality). The pooled estimates were calculated using a random-effects model. RESULTS: The pooled OR of CVD in offspring having a positive paternal history of CVD compared to not having a positive parental history was 1.91 (95% CI 1.56-2.34; I(2)53%), the RR1.54 (95% CI 1.33-1.77; I(2)96%). The OR of a maternal history was 2.16 (95% CI 1.71-2.74; I(2)50%), RR1.59 (95% CI 1.38-1.84; I(2)90%). Regarding different age limits, a maternal history <50 years (3.15, 95% CI 2.18-4.55) and paternal history <55 years (2.82, 95% CI 2.25-3.54) were associated with the highest cardiovascular risk. Additional analyses for sons demonstrated an estimate for a positive paternal history of 1.55 (95% CI 1.39-1.71; I(2)74%) and 1.56 (95% CI 1.46-1.67; I(2)16%) for maternal history. For daughters, the estimate for paternal history was 1.48 (95% CI 1.26-1.74; I(2)73%) and 1.79 (95% CI 1.50-2.13; I(2)68%) for maternal history . CONCLUSIONS: The conferred risk of CVD in offspring was not substantially different between positive paternal and maternal histories of CVD, the highest risk was observed for maternal history <50years. Since a positive parental history of CVD involves an increased cardiovascular risk, parental history inquiry is useful in clinical practice. No distinction has to be made whether the affected parent is the mother or the father.

The validation of cardiovascular risk scores for patients with type 2 diabetes mellitus.

OBJECTIVE: Various cardiovascular prediction models have been developed for patients with type 2 diabetes. Their predictive performance in new patients is mostly not investigated. This study aims to quantify the predictive performance of all cardiovascular prediction models developed specifically for diabetes patients. DESIGN AND METHODS: Follow-up data of 453, 1174 and 584 type 2 diabetes patients without pre-existing cardiovascular disease (CVD) in the EPIC-NL, EPIC-Potsdam and Secondary Manifestations of ARTerial disease cohorts, respectively, were used to validate 10 prediction models to estimate risk of CVD or coronary heart disease (CHD). Discrimination was assessed by the c-statistic for time-to-event data. Calibration was assessed by calibration plots, the Hosmer-Lemeshow goodness-of-fit statistic and expected to observed ratios. RESULTS: There was a large variation in performance of CVD and CHD scores between different cohorts. Discrimination was moderate for all 10 prediction models, with c-statistics ranging from 0.54 (95% CI 0.46 to 0.63) to 0.76 (95% CI 0.67 to 0.84). Calibration of the original models was poor. After simple recalibration to the disease incidence of the target populations, predicted and observed risks were close. Expected to observed ratios of the recalibrated models ranged from 1.06 (95% CI 0.81 to 1.40) to 1.55 (95% CI 0.95 to 2.54), mainly driven by an overestimation of risk in high-risk patients. CONCLUSIONS: All 10 evaluated models had a comparable and moderate discriminative ability. The recalibrated, but not the original, prediction models provided accurate risk estimates. These models can assist clinicians in identifying type 2 diabetes patients who are at low or high risk of developing CVD.

Osteoporosis markers on low-dose lung cancer screening chest computed tomography scans predict all-cause mortality.

OBJECTIVES: Further survival benefits may be gained from low-dose chest computed tomography (CT) by assessing vertebral fractures and bone density. We sought to assess the association between CT-measured vertebral fractures and bone density with all-cause mortality in lung cancer screening participants. METHODS: Following a case-cohort design, lung cancer screening trial participants (N = 3,673) who died (N = 196) during a median follow-up of 6 years (inter-quartile range: 5.7-6.3) were identified and added to a random sample of N = 383 from the trial. We assessed vertebral fractures using Genant's semiquantative method on sagittal reconstructions and measured bone density (Hounsfield Units (HU)) in vertebrae. Cox proportional hazards modelling was used to determine if vertebral fractures or bone density were independently predictive of mortality. RESULTS: The prevalence of vertebral fractures was 35% (95% confidence interval 30-40%) among survivors and 51% (44-58%) amongst cases. After adjusting for age, gender, smoking status, pack years smoked, coronary and aortic calcium volume and pulmonary emphysema, the adjusted hazard ratio (HR) for vertebral fracture was 2.04 (1.43-2.92). For each 10 HU decline in trabecular bone density, the adjusted HR was 1.08 (1.02-1.15). CONCLUSIONS: Vertebral fractures and bone density are independently associated with all-cause mortality. KEY POINTS: • Lung cancer screening chest computed tomography contains additional, potentially useful information. • Vertebral fractures and bone density are independently predictive of mortality. • This finding has implications for screening and management decisions.