A Deep Neural Network-Based Decision Support Tool for the Detection of Lymph Node Metastases in Colorectal Cancer Specimens.

The identification of lymph node metastases in colorectal cancer (CRC) specimens is crucial for the planning of postoperative treatment and can be a time-consuming task for pathologists. In this study, we developed a deep neural network (DNN) algorithm for the detection of metastatic CRC in digitized histologic sections of lymph nodes and evaluated its performance as a diagnostic support tool. First, the DNN algorithm was trained using pixel-level annotations of cancerous areas on 758 whole slide images (360 with cancerous areas). The algorithm's performance was evaluated on 74 whole slide images (43 with cancerous areas). Second, the algorithm was evaluated as a decision support tool on 288 whole slide images covering 1517 lymph node sections, randomized in 16 batches. Two senior pathologists (C.K. and C.O.) assessed each batch with and without the help of the algorithm in a 2 × 2 crossover design, with a washout period of 1 month in between. The time needed for the evaluation of each node section was recorded. The DNN algorithm achieved a median pixel-level accuracy of 0.952 on slides with cancerous areas and 0.996 on slides with benign samples. N+ disease (metastases, micrometastases, or tumor deposits) was present in 103 of the 1517 sections. The algorithm highlighted cancerous areas in 102 of these sections, with a sensitivity of 0.990. Assisted by the algorithm, the median time needed for evaluation was significantly shortened for both pathologists (median time for pathologist 1, 26 vs 14 seconds; P < .001; 95% CI, 11.0-12.0; median time for pathologist 2, 25 vs 23 seconds; P < .001; 95% CI, 2.0-4.0). Our DNN showed high accuracy for detecting metastatic CRC in digitized histologic sections of lymph nodes. This decision support tool has the potential to improve the diagnostic workflow by shortening the time needed for the evaluation of lymph nodes in CRC specimens without impairing diagnostic accuracy.

Higher age and obesity limit atelectasis formation during anaesthesia: an analysis of computed tomography data in 243 subjects.

BACKGROUND: General anaesthesia is increasingly common in elderly and obese patients. Greater age and body mass index (BMI) worsen gas exchange. We assessed whether this is related to increasing atelectasis during general anaesthesia. METHODS: This primary analysis included pooled data from previously published studies of 243 subjects aged 18-78 yr, with BMI of 18-52 kg m-2. The subjects had no clinical signs of cardiopulmonary disease, and they underwent computed tomography (CT) awake and during anaesthesia before surgery after preoxygenation with an inspired oxygen fraction (FIO2) of >0.8, followed by mechanical ventilation with FIO2 of 0.3 or higher with no PEEP. Atelectasis was assessed by CT. RESULTS: Atelectasis area of up to 39 cm2 in a transverse scan near the diaphragm was seen in 90% of the subjects during anaesthesia. The log of atelectasis area was related to a quadratic function of (age+age2) with the most atelectasis at ∼50 yr (r2=0.08; P<0.001). Log atelectasis area was also related to a broken-line function of the BMI with the knee at 30 kg m-2 (r2=0.06; P<0.001). Greater atelectasis was seen in the subjects receiving FIO2 of 1.0 than FIO2 of 0.3-0.5 (12.8 vs 8.1 cm2; P<0.001). A multiple regression analysis, including a quadratic function of age, a broken-line function of the BMI, and dichotomised FIO2 (0.3-0.5/1.0) adjusting for ventilatory frequency, strengthened the association (r2=0.23; P<0.001). PaO2 decreased with both age and BMI. CONCLUSIONS: Atelectasis during general anaesthesia increased with age up to 50 yr and decreased beyond that. Atelectasis increased with BMI in normal and overweight patients, but showed no further increase in obese subjects (BMI ≥30 kg m-2). Therefore, greater age and obesity appear to limit atelectasis formation during general anaesthesia.

Oxygenation Impairment during Anesthesia: Influence of Age and Body Weight.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: During anesthesia oxygenation is impaired, especially in the elderly or obese, but the mechanisms are uncertain. WHAT THIS ARTICLE TELLS US THAT IS NEW: Pooled data were examined from 80 patients studied with multiple inert gas elimination technique and computed tomography. Oxygenation was impaired by anesthesia, more so with greater age or body mass index. The key contributors were low ventilation/perfusion ratio (likely airway closure) in the elderly and shunt (atelectasis) in the obese. BACKGROUND: Anesthesia is increasingly common in elderly and overweight patients and prompted the current study to explore mechanisms of age- and weight-dependent worsening of arterial oxygen tension (PaO2). METHODS: This is a primary analysis of pooled data in patients with (1) American Society of Anesthesiologists (ASA) classification of 1; (2) normal forced vital capacity; (3) preoxygenation with an inspired oxygen fraction (FIO2) more than 0.8 and ventilated with FIO2 0.3 to 0.4; (4) measurements done during anesthesia before surgery. Eighty patients (21 women and 59 men, aged 19 to 69 yr, body mass index up to 30 kg/m2) were studied with multiple inert gas elimination technique to assess shunt and perfusion of poorly ventilated regions (low ventilation/perfusion ratio [(Equation is included in full-text article.)]) and computed tomography to assess atelectasis. RESULTS: PaO2/FIO2 was lower during anesthesia than awake (368; 291 to 470 [median; quartiles] vs. 441; 397 to 462 mm Hg; P = 0.003) and fell with increasing age and body mass index. Log shunt was best related to a quadratic function of age with largest shunt at 45 yr (r2 =0.17, P = 0.001). Log shunt was linearly related to body mass index (r2 = 0.15, P < 0.001). A multiple regression analysis including age, age2, and body mass index strengthened the association further (r2 = 0.27). Shunt was highly associated to atelectasis (r2 = 0.58, P < 0.001). Log low (Equation is included in full-text article.)showed a linear relation to age (r2 = 0.14, P = 0.001). CONCLUSIONS: PaO2/FIO2 ratio was impaired during anesthesia, and the impairment increased with age and body mass index. Shunt was related to atelectasis and was a more important cause of oxygenation impairment in middle-aged patients, whereas low(Equation is included in full-text article.), likely caused by airway closure, was more important in elderly patients. Shunt but not low(Equation is included in full-text article.)increased with increasing body mass index. Thus, increasing age and body mass index impaired gas exchange by different mechanisms during anesthesia.

Self-perceived ability to cope with stress and depressive mood without smoking predicts successful smoking cessation 12 months later in a quitline setting: a secondary analysis of a randomized trial.

BACKGROUND: Telephone-based smoking cessation services ('quitlines') are both effective and cost-effective. Knowledge of modifiable baseline factors in real-life settings with heterogeneous participants is essential for the development and improvement of treatment protocols to assist in telephone-based smoking cessation. The aim was to assess if self-perceived abilities to cope measured at baseline, would predict abstinence at the 12-month follow-up at the Swedish National Tobacco Quitline (SNTQ). METHODS: The data were retrieved from a previous randomized controlled trial comparing the effectiveness of proactive and reactive service at the SNTQ. Included were 612 clients calling the SNTQ between February 2009 and September 2010. Outcome measures were self-reported point prevalence and 6-month continuous abstinence at the 12-month follow-up. Plausible predictors of smoking cessation were assessed at the first call and in a baseline questionnaire. Self-perceived abilities at baseline were measured by two questions: (1) How likely is it that you will be smoke-free in one year? and (2) How likely are you to be able to handle stress and depressive mood without smoking? The associations between potential predictors and outcome (smoke-free at 12-month follow-up) were assessed by logistic regression analysis. RESULTS: Of the two potential predictors for abstinence at 12-month follow-up, only the perceived ability to handle stress and depressive mood without smoking remained significant in the adjusted analyses (Odds Ratio, OR 1.13, 95% CI 1.00-1.27 for point prevalence and OR 1.16, 95% CI 1.01-1.33 for 6-month continuous abstinence according to intention-to-treat). The overall strongest predictor in the adjusted analyses was smoking status in the week before baseline (OR 3.30, 95% CI 1.79-6.09 for point prevalence and OR 3.97, 95% CI 2.01-7.83 for 6-month continuous abstinence). CONCLUSIONS: The perceived ability to handle stress and depressive mood without smoking at baseline predicted the subjects' abstinence at the 12-month follow-up. An assessment of/adjustment for stress and depressive mood coping skills may be appropriate in future smoking cessation treatment and research. The treatment protocol can be tailored to individual differences and needs for optimal support. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02085616 . Registered March 10, 2014, 'retrospectively registered'.

Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors.

BACKGROUND: The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment. METHODS AND RESULTS: Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30-2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12-1.95). CONCLUSIONS: Serum PCSK9 concentration is associated with future risk of CVD even after adjustments for established CVD risk factors. Further studies are needed to confirm this observation.

Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with high risk for cardiovascular disease.

IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA=0.11, P=6.73E(-5) and chromosome 14, rs4902762, BETA=0.12, P=5.76E(-6)) and one for eosinophil count (rs72797327, BETA=-0.10, P=1.41E(-6)). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA=0.04, P=0.2763, I(2)=24, I(2)-P=0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2=0.93 with rs56183820) BETA=-0.10, P=8.64E(-6) and rs11739623 (r2=0.96 with rs72797327) BETA=-0.23, P=1.74E(-29), respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels.

Association between parental depressive symptoms and impaired bonding with the infant.

Impaired bonding with the infant is associated with maternal postpartum depression but has not been investigated extensively in fathers. The primary study aim was to evaluate associations between maternal and paternal depressive symptoms and impaired bonding with their infant. A secondary aim was to determine the associations between parents' marital problems and impaired bonding with the infant. The study is part of a population-based cohort project (UPPSAT) in Uppsala, Sweden. The Edinburgh Postnatal Depression Scale (EPDS) at 6 weeks and 6 months postpartum and the Postpartum Bonding Questionnaire at 6 months postpartum were completed by 727 couples. The prevalence of impaired bonding was highest among couples in which both spouses had depressive symptoms. Impaired bonding was associated with higher EPDS scores in both mothers and fathers, as well as with experiencing a deteriorated marital relationship. The association between maternal and paternal impaired bonding and the mothers' and fathers' EPDS scores remained significant even after adjustment for relevant confounding factors. Depressive symptoms at 6 weeks postpartum are associated with impaired bonding with the infant at 6 months postpartum for both mothers and fathers. It is critical to screen for and prevent depressive symptoms in both parents during early parenthood.

Associations among pain, disability and psychosocial factors and the predictive value of expectations on returning to work in patients who undergo lumbar disc surgery.

PURPOSE: The aim of this study was to describe the associations among pain, disability and psychosocial factors preoperatively as well as 3 and 24 months later for patients who undergo first time discectomy and to analyse the predictive value of psychosocial factors on the outcome 24 months after surgery. METHODS: Fifty-nine patients, 41 % women, with a mean age of 40 years and without comorbidities were included, of whom 56 responded to the 24-month follow-up; at that point, they were divided into patients with complaints (C, n = 36) and patients without complaints (NC, n = 20). Correlations among the pain intensity, disability and psychosocial factors were analysed preoperatively, 3 and 24 months after discectomy, and regression analyses of psychosocial factors on the outcome at 24 months were performed. RESULTS: Psychosocial variables were weakly correlated with the pain intensity and disability preoperatively. High expectations on the return to work were predictive of both pain intensity (ß = 8.0, p = 0.03) and disability (ß = 9.1, p < 0.001) at 24 months. Associations between psychosocial variables and outcome variables were strengthened at the 3-month follow-up in the C group, and this association remained 24 months after surgery. Fear of movement was most strongly correlated with leg pain intensity (r (s) 0.64, p < 0.001) and the ability to decrease pain was the most correlated with disability (r (s) 0.78, p < 0.001). CONCLUSION: Having high expectations on the return to work after surgery was the strongest predictor for a favourable outcome. Therefore, low preoperative expectations on return to work convey an important prognostic signal.

A serum 25-hydroxyvitamin D concentration-associated genetic variant in DHCR7 interacts with type 2 diabetes status to influence subclinical atherosclerosis (measured by carotid intima-media thickness).

AIMS/HYPOTHESIS: The findings of studies investigating whether or not low serum 25-hydroxyvitamin D [25(OH)D] concentration promotes development of atherosclerosis have been contradictory. The present study employed a Mendelian randomisation approach and carotid artery intima-media thickness (cIMT), a surrogate marker of coronary artery disease, to address this question. METHODS: The multicentre, longitudinal Carotid Intima-Media Thickness and IMT-Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE) cohort study, which enrolled individuals with at least three cardiovascular risk factors and no history or symptoms of cardiovascular disease, was used for the present investigation. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30. Six single nucleotide polymorphisms (SNPs) associated with serum 25(OH)D concentration in genome-wide association studies were identified and genotyped in 3,418 individuals, of whom 929 had type 2 diabetes. RESULTS: SNPs in the genes encoding vitamin D binding protein (GC; rs2282679 and rs7041) and 7-dehydrocholesterol reductase/NAD synthetase-1 (DHCR7; rs12785878 and rs3829251) were negatively associated with 25(OH)D levels. Effect sizes and significance of associations between SNPs and 25(OH)D levels differed between individuals with and without type 2 diabetes, although no significant interactions were observed. A SNP in DHCR7 interacted with type 2 diabetes to significantly influence progression of cIMT measures independent of 25(OH)D levels and established risk factors. Expression analysis demonstrated that this SNP modulates DHCR7 mRNA levels in aortic adventitia. CONCLUSIONS/INTERPRETATION: SNPs in GC and DHCR7 were associated with serum levels of 25(OH)D, but only rs3829251 (DHCR7) influenced progression of subclinical atherosclerosis, as measured by cIMT, in a manner dependent on type 2 diabetes status but independent of 25(OH)D levels.

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis.

OBJECTIVE: Vitamin D deficiency has been implicated in cardiovascular disease and is associated with multiple cardiovascular risk factors. We investigated the serum 25-hydroxyvitamin D (25(OH)D) concentration in relation to latitude, baseline carotid intima-media thickness (IMT), and IMT progression, the carotid IMT measures being surrogate markers of subclinical atherosclerosis and cardiovascular disease risk. APPROACH AND RESULTS: Serum 25(OH)D concentration was related to high-resolution carotid IMT measures in 3430 middle-aged and elderly subjects with high cardiovascular risk but no prevalent disease, who were recruited at 7 centers in Finland, Sweden, The Netherlands, France, and Italy. Participants underwent carotid ultrasound examination at baseline and at months 15 and 30 after entry into the study, whereas blood samples, clinical data, and information about lifestyle were collected at baseline. Serum 25(OH)D levels were positively associated with latitude (Jonckheere-Terpstra χ=166.643; P<0.001) and, as previously reported, associated with a range of cardiovascular risk factors. There were no independent relationships between 25(OH)D and segment-specific or composite IMT measures in the entire cohort. In analyses stratified by sex, diabetes mellitus, and statin treatment, weak associations with some baseline and progression measures of carotid IMT were observed in males, diabetics, and nonstatin-treated individuals. CONCLUSIONS: Levels of 25(OH)D differed across Europe, were highest in the North, showed multiple associations with established and emerging cardiovascular risk factors but were not consistently, independently related to measures of carotid IMT. This argues against a protective role of vitamin D against subclinical atherosclerosis in high-risk individuals.

Occurrence of metabolic syndrome in midlife in relation to cardiovascular morbidity and all-cause mortality-lessons from a population-based matched cohort study with 27 years follow-up.

OBJECTIVES: We examined how asymptomatic metabolic syndrome (MetS) in midlife affects cardiovascular (CV) morbidity and all-cause mortality later in life and studied difference in time to event and from the individual components related to MetS. DESIGN: Population-based matched cohort study including data from a screening programme for identification of CV risk factors. SETTING: Primary care, County of Västmanland, Sweden. PARTICIPANTS: All inhabitants turning 40 or 50 years between 1990 and 1999 were invited to a health screening. Total 34 269 (60.1%) individuals completed the health examination. Participants that met a modified definition of MetS were individually matched to two controls without MetS with regard to age, sex and date of health examination. INTERVENTIONS: None. MAIN OUTCOME MEASURES: CV events and all-cause mortality from the index examination to June 2022. RESULTS: All 5084 participants with MetS were matched to two controls. There were 1645 (32.4%) CV events in the MetS group and 2321 (22.8%) CV events for controls. 1317 (25.9%) MetS and 1904 (18.7%) control subjects died. The adjusted HRs (aHR) for CV event and death were significantly higher when MetS was present (aHR) 1.39*** (95% CI 1.28 to 1.50) and 1.27*** (95% CI 1.16 to 1.40) respectively. The factor analysis identified three dominating factors: blood pressure, cholesterol and blood glucose. Mean time for first CV event and death was 2.6 years and 1.5 years shorter respectively for participants within the highest quartile compared with participants with lower mean arterial blood pressure (MAP). The aHR for each 10 mm Hg increased MAP were 1.19*** (95% CI 1.15 to 1.23) for CV event and 1.16*** (95% CI 1.11 to 1.21) for death. CONCLUSION: The risk of a CV event and premature death is significantly increased when MetS is present. Early detection of metabolic risk factors, especially, high blood pressure, opens a window of opportunity to introduce preventive treatment to reduce CV morbidity and all-cause mortality.

Long-term follow-up of a high- and a low-intensity smoking cessation intervention in a dental setting--a randomized trial.

BACKGROUND: Achieving lifelong tobacco abstinence is an important public health goal. Most studies use 1-year follow-ups, but little is known about how good these are as proxies for long-term and life-long abstinence. Also, intervention intensity is an important issue for development of efficient and cost-effective cessation treatment protocols.The study aims were to assess the long-term effectiveness of a high- and a low-intensity treatment (HIT and LIT) for smoking cessation and to analyze to what extent 12-month abstinence predicted long-term abstinence. METHODS: 300 smokers attending dental or general health care were randomly assigned to HIT or LIT at the public dental clinic. Main outcome measures were self-reported point prevalence, continuous abstinence (≥6 months), and sustained abstinence. The study was a follow-up after 5-8 years of a previously performed 12-month follow-up, both by postal questionnaires. RESULTS: Response rate was 85% (n=241) of those still alive and living in Sweden. Abstinence rates were 8% higher in both programs at the long-term than at the 12-month follow-up. The difference of 7% between HIT and LIT had not change, being 31% vs. 24% for point prevalence and 26% vs. 19% for 6-month continuous abstinence, respectively. Significantly more participants in HIT (12%) than in LIT (5%) had been sustained abstinent (p=0.03). Logistic regression analyses showed that abstinence at 12-month follow-up was a strong predictor for abstinence at long-term follow-up. CONCLUSIONS: Abstinence at 12-month follow-up is a good predictor for long-term abstinence. The difference in outcome between HIT and LIT for smoking cessation remains at least 5-8 years after the intervention. TRIAL REGISTRATION NUMBER: NCT00670514.

Enigma of the cholesterol paradox in acute myocardial infarction: lessons from an 8-year follow-up of all-cause mortality in an age-matched and sex-matched case-control study with controls from the patients' recruitment area.

OBJECTIVE: To assess the impact of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) on long-term all-cause mortality (ACM) in patients with acute myocardial infarction (AMI) and controls. DESIGN: Matched case-control study with 8-year follow-up. SETTING: Vastmanland County Hospital, Vasteras, Sweden. PARTICIPANTS: Consecutive patients with AMI admitted to the coronary care unit from March 2005 to May 2010 and age-matched and sex-matched controls from the general population. OUTCOME MEASURES: ACM. RESULTS: Person-year at risk among patients with AMI and controls was 11 667 (cases: 5780 and controls: 5887). During follow-up, 199 patients and 84 controls died, implying 3.4 deaths among patients and 1.4 among controls per 100 person-years at risk. Unadjusted Cox analyses showed significantly increasing mortality by decreasing TC and LDL-C levels in both patients (HR=0.70, 95% CI 0.62 to 0.79, p<0.001, and HR=0.64, 95% CI 0.56 to 0.74, p<0.001) and controls (HR=0.73, 95% CI 0.60 to 0.89, p=0.002, and HR=0.74, 95% CI 0.59 to 0.93, p=0.010). After adjusting for clinical variables, the results for the patients remained significant. Cox analyses of the relations between mortality and TC and LDL-C below and above their respective medians revealed the following pattern. PATIENTS: below medians were TC and LDL-C levels significantly inversely related to mortality; above medians there were no relations with mortality. CONTROLS: below medians were TC and LDL-C levels significantly inversely related to mortality; above medians were LDL-C levels significantly positively related to mortality. Mean LDL-C level in patients with blood sampled >12 hours after symptom onset was 0.41 mmol/L lower than that in patients with blood sampled ≤12 hours (p=0.030). This LDL-C decrease was reasonably caused by ongoing AMI and reflects the difference in LDL-C levels between patients and controls. CONCLUSIONS: In patients with AMI, lower TC and LDL-C levels independently predict higher ACM. In their controls, LDL-C levels above the median independently predict higher ACM. This study adds to the body of evidence supporting the existence of a cholesterol paradox.

Resting heart rate in patients with stable coronary artery disease and diabetes: a report from the euro heart survey on diabetes and the heart.

AIMS: epidemiological studies suggest that resting heart rate (RHR) is an independent predictor of cardiovascular and all-cause mortality. Still, this parameter has never been specifically assessed in patients with diabetes mellitus (DM). This study describes the association between RHR and cardiovascular events (CVE) in patients with coronary artery disease (CAD) with and without DM. METHODS AND RESULTS: the Euro Heart Survey on Diabetes and the Heart enroled 2608 patients with stable CAD, of these 780 (30%) had known DM. Resting heart rate was registered in 2507 (96%) patients: 1756 (96%) without and 751 (96%) with DM. Patients were followed with respect to CVE (all-cause mortality, non-fatal myocardial infarction, and stroke) for 1 year. Overall, median RHR was 70 (62-78) b.p.m. The RHR quartile stratification was significantly associated with outcome in the overall population (P = 0.002 and P = 0.021 for survival and CVE, respectively), whereas it was not in patients without DM. In patients with DM, the RHR quartiles correlated with survival (P = 0.032). In an adjusted regression model performed in patients without DM, RHR associated with neither survival [hazard ratio (HR): 0.97, 95% confidence interval (CI): 0.74-1.27; P = 0.804] nor CVE (HR: 0.85, 95% CI: 0.71-1.01, P = 0.068). In contrast, a 10-b.p.m. increase in RHR was independently associated with survival (HR: 1.34, 95% CI: 1.06-1.69, P = 0.015), but not with CVE (HR: 0.99, 95% CI: 0.84-1.18; P = 0.359) in patients with DM. CONCLUSION: the present report, based on patients with stable CAD, is the first to reveal that the association between RHR and CVE seems to subsist in those with DM, however, not in those without DM.

Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population.

AIMS: Prospective studies indicate that apolipoprotein measurements predict coronary heart disease (CHD) risk; however, evidence is conflicting, especially in the US. Our aim was to assess whether measurements of apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) can improve the ability to predict CHD death beyond what is possible based on traditional cardiovascular (CV) risk factors and clinical routine lipid measurements. METHODS AND RESULTS: We analysed prospectively associations of apolipoprotein measurements, traditional CV risk factors, and clinical routine lipid measurements with CHD mortality in a multi-ethnic representative subset of 7594 US adults (mean age 45 years; 3881 men and 3713 women, median follow-up 124 person-months) from the Third National Health and Nutrition Examination Survey mortality study. Multiple Cox-proportional hazards regression was applied. There were 673 CV deaths of which 432 were from CHD. Concentrations of apoB [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.09-3.61], apoA-I (HR 0.48, 95% CI 0.27-0.85) and total cholesterol (TC) (HR 1.17, 95% CI 1.02-1.34) were significantly related to CHD death, whereas high density lipoprotein cholesterol (HDL-C) (HR 0.68, 95% CI 0.45-1.05) was borderline significant. Both the apoB/apoA-I ratio (HR 2.14, 95% CI 1.11-4.10) and the TC/HDL-C ratio (HR 1.10, 95% CI 1.04-1.16) were related to CHD death. Only apoB (HR 2.01, 95% CI 1.05-3.86) and the apoB/apoA-I ratio (HR 2.09, 95% CI 1.04-4.19) remained significantly associated with CHD death after adjusting for CV risk factors. CONCLUSION: In the US population, apolipoprotein measurements significantly predict CHD death, independently of conventional lipids and other CV risk factors (smoking, dyslipidaemia, hypertension, obesity, diabetes and C-reactive protein). Furthermore, the predictive ability of apoB alone to detect CHD death was better than any of the routine clinical lipid measurements. Inclusion of apolipoprotein measurements in future clinical guidelines should not be discarded.

Controlled 3-year follow-up of a multidisciplinary pain rehabilitation program in primary health care.

PURPOSE: The high prevalence of musculoskeletal pain generates significant costs for primary health care and the whole of society. The development of appropriate interventions is therefore necessary. The aim of this effectiveness study was to assess the long-term effects of a primary health care multidisciplinary rehabilitation program in Sweden. METHODS: An experimental group comprising 89 patients from two primary health care units received individualised treatment interventions after a multidisciplinary investigation. A control group of 69 patients with the same inclusion criteria from four other primary health care units were treated according to routine. All participants completed questionnaires measuring pain, sick leave, quality of life, health care utilisation, drug consumption and psychosocial factors at baseline and at 3-year follow-up. RESULTS: After 3 years, utilisation of primary health care was significantly lower in the experimental group and work capacity was slightly but not significantly higher. The control group showed a trend of having a higher risk of high consumption after 3 years compared to the intervention group. There was no significant difference between the two groups concerning remaining variables such as function, catastrophising and pain. CONCLUSION: Both groups demonstrated considerable improvement over the course of 3 years. The experimental group had lower health care utilisation and a reduced risk of using large amounts of medication at the 3-year follow-up, indicating that compared with participants in the control group they were coping in a better way with pain.

A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study.

AIMS: Myocardial diastolic dysfunction (MDD) and impaired coronary flow reserve (CFR) are early signs of myocardial involvement in patients with diabetes. The important question of whether this may be reversed by glucose normalization has not been tested in a controlled clinical trial. We hypothesized that strict glycaemic control, particularly if insulin based, will improve MDD and CFR. METHODS AND RESULTS: Thirty-nine type 2 diabetes patients (mean age 61.0 +/- 7 years) with signs of diastolic dysfunction were randomly assigned to strict metabolic control by insulin (I-group; n = 21) or oral glucose lowering agents (O-group; n = 18). MDD and CFR were studied with Doppler-echocardiography including Tissue Doppler Imaging and myocardial contrast enhanced echocardiography. Fasting glucose (I-group = -2.2 +/- 2.1; O-group -1.5 +/- 0.8 mmol/L) and HbA(1c) were normalized (-0.6 +/- 0.4 and -0.7 +/- 0.4%, respectively) in both groups, but this did not significantly improve MDD in either of the groups (P = 0.65). There was no difference in CFR before and after improved glycaemic control. CONCLUSION: The hypothesis that strict glycaemic control would reverse early signs of MDD and improve CFR in patients with type 2 diabetes could not be confirmed, despite achieved normalization. Whether it is possible to influence a more pronounced diastolic dysfunction, particularly in less well-controlled diabetic patients, remains to be established.

Rationale and design of the Karolinska-Rennes (KaRen) prospective study of dyssynchrony in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFPEF) is common but not well understood. Electrical dyssynchrony in systolic heart failure is harmful. Little is known about the prevalence and the prognostic impact of dyssynchrony in HFPEF. METHODS AND RESULTS: We have designed a prospective, multicenter, international, observational study to characterize HFPEF and to determine whether electrical or mechanical dyssynchrony affects prognosis. Patients presenting with acute heart failure (HF) will be screened so as to identify 400 patients with HFPEF. Inclusion criteria will be: acute presentation with Framingham criteria for HF, left ventricular ejection fraction>or=45%, brain natriuretic peptide (BNP)>100 pg/mL or NT-proBNP>300 pg/mL. Once stabilized, 4-8 weeks after the index presentation, patients will return and undergo questionnaires, serology, ECG, and Doppler echocardiography. Thereafter, patients will be followed for mortality and HF hospitalization every 6 months for at least 18 months. Sub-studies will focus on echocardiographic changes from the acute presentation to the stable condition and on exercise echocardiography, cardiopulmonary exercise testing, and serological markers. CONCLUSION: KaRen aims to characterize electrical and mechanical dyssynchrony and to assess its prognostic impact in HFPEF. The results might improve our understanding of HFPEF and generate answers to the question whether dyssynchrony could be a target for therapy in HFPEF.

High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction.

AIMS: We examined whether antibodies against peptides 45 and 210 of apoB-100 are related to myocardial infarction (MI) and severity of coronary atherosclerosis. METHODS AND RESULTS: Three hundred and eighty-seven survivors of a first MI (aged <60 years) and 387 sex- and age-matched controls were characterized in detail. IgG and IgM autoantibodies against native and malondialdehyde (MDA)-modified peptides 45 and 210 of apoB-100 (amino acids 661-680 and 3136-3155) were quantified in plasma and quantitative coronary angiography was performed in 243 patients. Post-infarction patients had significantly lower IgG against the native peptide 210 (IgG-p210(nat)) and higher IgM against the MDA-modified peptide 210 (IgM-p210(MDA)) compared with controls, whereas no differences were found for other antibodies. Plasma concentrations of IgG-p210(nat), but not IgM-p210(MDA), were independently and inversely related to the degree of coronary atherosclerosis in patients. In multiple logistic regression analysis (including established risk indicators), MI risk was 0.55 (95%CI: 0.37-0.81) for individuals in the IgG-p210(nat) upper quartile compared with the remaining individuals. CONCLUSION: Circulating IgG antibodies against the native peptide 210 of apoB-100 are inversely related to the severity of coronary atherosclerosis and associated with lower risk of MI. Epitope 210 of apoB-100 emerges as a target for immunization against atherosclerosis in humans.