Search

The aim of this study was to compare the prognostic significance of microvascular obstruction (MO) and persistent microvascular obstruction (PMO) as assessed by cardiac magnetic resonance (CMR) in patients with acute myocardial infarction (AMI). CMR was performed in 184 patients within the week following successfully reperfused first AMI. First-pass images were performed to evaluate extent of MO and late gadolinium-enhanced images to assess PMO and infarct size (IS). Major adverse cardiac events (MACE) were collected at 1-year follow-up. MO and PMO were found in 127 (69%) and 87 (47%) patients, respectively. By using univariate logistic regression analysis, high Global Registry of Acute Coronary Events (GRACE) risk score (odds ratio [OR] 95% confidence interval [CI]: 3.6 [1.8-7.4], p < 0.001), IS greater than 10% (OR [95% CI]: 2.7 [1.1-6.9], p = 0.036), left ventricular ejection fraction less than 40% (OR [95% CI]: 2.4 [1.1-5.2], p = 0.027), presence of MO (OR [95% CI]: 3.1 [1.3-7.3], p = 0.004) and presence of PMO (OR [95% CI]:10 [4.1-23.9], p < 0.001) were shown to be significantly associated with the outcome. By using multivariate analysis, presence of MO (OR [95% CI]: 2.5 [1.0-6.2], p = 0.045) or of PMO (OR [95% CI]: 8.7 [3.6-21.1], p < 0.001), associated with GRACE score, were predictors of MACE. Presence of microvascular obstruction and persistent microvascular obstruction is very common in AMI patients even after successful reperfusion and is associated with a dramatically higher risk of subsequent cardiovascular events, beyond established prognostic markers. Moreover, our data suggest that the prognostic impact of PMO might be superior to MO. [ABSTRACT FROM AUTHOR]

Hyperglycemia has been shown to be a powerful predictor of worse outcome after ST-segment-elevation myocardial infarction (STEMI), which could be related to impaired myocardial reperfusion. This study investigated the association between hyperglycemia and ST-segment resolution (STR) after thrombolysis. From the French regional Observatoire des Infarctus de Côte-d'Or survey, admission glucose in 371 patients with STEMIs who were treated by lysis<12 hours was analyzed. The single worst lead electrocardiogram before and 90 minutes after lysis was analyzed, and patients were divided into 3 groups according to the degree of STR: none (<30%), partial (30% to 70%), or complete (>or=70%). Of the 371 patients, 101 (27.2%) had no STR, 124 (33.4%) had partial STR, and 146 (39.4%) had complete STR. STR decreased with increasing glycemia (p=0.029), and patients with hyperglycemia (glycemia>or=11 mmol/L) were more likely to have no STR. Moreover, hyperglycemia was an independent predictor of incomplete STR even after adjustment for potential confounders (odds ratio 2.348, 95% confidence interval 1.212 to 4.547). In conclusion, the present study suggests a strong association between hyperglycemia and electrocardiographic signs of reperfusion in patients with STEMIs after lysis and suggests the usefulness of evaluating early glycemic control in the setting of reperfusion for acute myocardial infarction. [ABSTRACT FROM AUTHOR]

A variety of commercial platforms are available for the simultaneous detection of multiple cytokines and associated proteins, often employing Ab pairs to capture and detect target proteins. In this study, we comprehensively evaluated the performance of three distinct platforms: the fluorescent bead-based Luminex assay, the proximity extension-based Olink assay, and a novel proximity ligation assay platform known as Alamar NULISAseq. These assessments were conducted on human serum samples from the National Institutes of Health IMPACC study, with a focus on three essential performance metrics: detectability, correlation, and differential expression. Our results reveal several key findings. First, the Alamar platform demonstrated the highest overall detectability, followed by Olink and then Luminex. Second, the correlation of protein measurements between the Alamar and Olink platforms tended to be stronger than the correlation of either of these platforms with Luminex. Third, we observed that detectability differences across the platforms often translated to differences in differential expression findings, although high detectability did not guarantee the ability to identify meaningful biological differences. Our study provides valuable insights into the comparative performance of these assays, enhancing our understanding of their strengths and limitations when assessing complex biological samples, as exemplified by the sera from this COVID-19 cohort., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The blood proteome holds great promise for precision medicine but poses substantial challenges due to the low abundance of most plasma proteins and the vast dynamic range of the plasma proteome. Here we address these challenges with NUcleic acid Linked Immuno-Sandwich Assay (NULISA™), which improves the sensitivity of traditional proximity ligation assays by ~10,000-fold to attomolar level, by suppressing assay background via a dual capture and release mechanism built into oligonucleotide-conjugated antibodies. Highly multiplexed quantification of both low- and high-abundance proteins spanning a wide dynamic range is achieved by attenuating signals from abundant targets with unconjugated antibodies and next-generation sequencing of barcoded reporter DNA. A 200-plex NULISA containing 124 cytokines and chemokines and other proteins demonstrates superior sensitivity to a proximity extension assay in detecting biologically important low-abundance biomarkers in patients with autoimmune diseases and COVID-19. Fully automated NULISA makes broad and in-depth proteomic analysis easily accessible for research and diagnostic applications., (© 2023. The Author(s).)

Objectives: This study aimed to understand the cost implications of managing people living with type 1 diabetes mellitus in the South African public healthcare system., Methods: A multicenter, noninterventional retrospective chart review study was performed. Data on healthcare resource consumption, demographics, risk factors, clinical history, and acute events were collected. Direct medical costs were collected over a 1-year period, stratified by controlled versus uncontrolled patients. In addition, the costs in people with controlled (glycated hemoglobin < 7%) versus uncontrolled glycated hemoglobin (≥ 7%) at time horizons of 1, 5, 10, and 25 years were modeled using the IQVIA Core Diabetes Model., Results: The costs based on the retrospective chart review were $630 versus $1012 (controlled versus uncontrolled population). The modeled costs at various time horizons were as follows: at 1 year, $900 versus $1331; at 5 years, $4163 versus $6423; at 10 years, $7759 versus $16 481; and at 25 years, $16 969 versus $66 268. The largest cost in the controlled population was severe hypoglycemia requiring nonmedical assistance, severe hypoglycemia requiring medical assistance, and treatment costs. In the uncontrolled population, the largest cost was the cost of diabetic ketoacidosis, severe hypoglycemia requiring nonmedical assistance, severe hypoglycemia requiring medical assistance, and foot complications., Conclusions: Strict glycemic control reduces healthcare resource use overall. Patients in the controlled group still experienced high resource use related to hypoglycemic events. The introduction of a structured patient education program and analog insulins may result in less episodes of hypoglycemia and potential cost savings., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Childhood mild traumatic brain injury (mTBI) is associated with elevated risk of developing social problems, which may be underpinned by changes in the structural developmental trajectory of the social brain, a network of cortical regions supporting social cognition and behavior. However, limited sample sizes and cross-sectional designs generally used in neuroimaging studies of pediatric TBI have prevented explorations of this hypothesis. This longitudinal retrospective study examined the development of parent-reported social problems and cortical thickness in social brain regions following childhood mTBI using data from the large population-based Adolescent Brain Cognitive Development (ABCD) Study. Two-group latent change score models revealed different developmental trajectories from ages 10-12 years in the level of social problems between children with (n = 345) and without (n = 7,089) mTBI. Children with mTBI showed higher, but non-clinical, levels of social problems than controls at age 10. Then, social problems decreased over 2 years, but still remained higher, but non-clinical, than in controls in which they stayed stable. Both groups showed similar decreases in social brain cortical thickness between ages 10 and 12 years. Further studies providing detailed information on the injury mechanism and acute symptoms are needed to better understand individual differences in social functioning and brain development in pediatric TBI., Competing Interests: Declaration of competing interest IKK receives grant funding from the National Institutes of Health, The European Research Council, and the German Ministry for Research and Education. She receives funding for a collaborative project and serves as a paid scientific advisor for Abbott. She receives royalties for scientific book chapters. Her spouse is an employee at Siemens AG. The other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Depression is a common and debilitating disorder in the elderly. Late-life depression (LLD) has been associated with inflammation and elevated levels of proinflammatory cytokines including interleukin (IL)-1β, tumor necrosis factor-alpha, and IL-6, but often depressed individuals have comorbid medical conditions that are associated with immune dysregulation. To determine whether depression has an association with inflammation independent of medical illness, 1120 adults were screened to identify individuals who had clinically significant depression but not medical conditions associated with systemic inflammation. In total, 66 patients with LLD screened to exclude medical conditions associated with inflammation were studied in detail along with 26 age-matched controls (HC). At baseline, circulating cytokines were low and similar in LLD and HC individuals. Furthermore, cytokines did not change significantly after treatment with either an antidepressant (escitalopram 20 mg/day) or an antidepressant plus a COX-2 inhibitor or placebo, even though depression scores improved in the non-placebo treatment arms. An analysis of cerebrospinal fluid in a subset of individuals for IL-1β using an ultrasensitive digital enzyme-linked immunosorbent assay revealed low levels in both LLD and HC at baseline. Our results indicate that depression by itself does not result in systemic or intrathecal elevations in cytokines and that celecoxib does not appear to have an adjunctive antidepressant role in older patients who do not have medical reasons for having inflammation. The negative finding for increased inflammation and the lack of a treatment effect for celecoxib in this carefully screened depressed population taken together with multiple positive results for inflammation in previous studies that did not screen out physical illness support a precision medicine approach to the treatment of depression that takes the medical causes for inflammation into account., (© 2022. The Author(s).)

To acquire larger samples for answering complex questions in neuroscience, researchers have increasingly turned to multi-site neuroimaging studies. However, these studies are hindered by differences in images acquired across multiple sites. These effects have been shown to bias comparison between sites, mask biologically meaningful associations, and even introduce spurious associations. To address this, the field has focused on harmonizing data by removing site-related effects in the mean and variance of measurements. Contemporaneously with the increase in popularity of multi-center imaging, the use of machine learning (ML) in neuroimaging has also become commonplace. These approaches have been shown to provide improved sensitivity, specificity, and power due to their modeling the joint relationship across measurements in the brain. In this work, we demonstrate that methods for removing site effects in mean and variance may not be sufficient for ML. This stems from the fact that such methods fail to address how correlations between measurements can vary across sites. Data from the Alzheimer's Disease Neuroimaging Initiative is used to show that considerable differences in covariance exist across sites and that popular harmonization techniques do not address this issue. We then propose a novel harmonization method called Correcting Covariance Batch Effects (CovBat) that removes site effects in mean, variance, and covariance. We apply CovBat and show that within-site correlation matrices are successfully harmonized. Furthermore, we find that ML methods are unable to distinguish scanner manufacturer after our proposed harmonization is applied, and that the CovBat-harmonized data retain accurate prediction of disease group., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Resting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ΔMADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact., (© 2021. The Author(s).)

Objective: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ 42 ) levels., Rationale: Serotonin signaling suppresses Aβ 42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram., Methods: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ 42 was used as the primary outcome in subsequent analyses., Results: An overall 9.4% greater reduction in CSF Aβ 42 was found in escitalopram-treated compared with placebo-treated groups ( p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ 42 levels <250 pg/mL) was associated with smaller Aβ 42 reduction ( p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ 42 levels >250 pg/mL)., Conclusions: Short-term longitudinal doses of escitalopram decreased CSF Aβ 42 in cognitively normal older adults, the target group for AD prevention., Clinicaltrialsgov Identifier: NCT02161458., Classification of Evidence: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ 42 ., (© 2020 American Academy of Neurology.)

Introduction: Depression commonly accompanies Alzheimer's disease, but the nature of this association remains uncertain., Methods: Longitudinal data from the COSMIC consortium were harmonized for eight population-based cohorts from four continents. Incident dementia was diagnosed in 646 participants, with a median follow-up time of 5.6 years to diagnosis. The association between years to dementia diagnosis and successive depressive states was assessed using a mixed effect logistic regression model. A generic inverse variance method was used to group study results, construct forest plots, and generate heterogeneity statistics., Results: A common trajectory was observed showing an increase in the incidence of depression as the time to dementia diagnosis decreased despite cross-national variability in depression rates., Discussion: The results support the hypothesis that depression occurring in the preclinical phases of dementia is more likely to be attributable to dementia-related brain changes than environment or reverse causality., (© 2020 the Alzheimer's Association.)

While aggregation of neuroimaging datasets from multiple sites and scanners can yield increased statistical power, it also presents challenges due to systematic scanner effects. This unwanted technical variability can introduce noise and bias into estimation of biological variability of interest. We propose a method for harmonizing longitudinal multi-scanner imaging data based on ComBat, a method originally developed for genomics and later adapted to cross-sectional neuroimaging data. Using longitudinal cortical thickness measurements from 663 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, we demonstrate the presence of additive and multiplicative scanner effects in various brain regions. We compare estimates of the association between diagnosis and change in cortical thickness over time using three versions of the ADNI data: unharmonized data, data harmonized using cross-sectional ComBat, and data harmonized using longitudinal ComBat. In simulation studies, we show that longitudinal ComBat is more powerful for detecting longitudinal change than cross-sectional ComBat and controls the type I error rate better than unharmonized data with scanner included as a covariate. The proposed method would be useful for other types of longitudinal data requiring harmonization, such as genomic data, or neuroimaging studies of neurodevelopment, psychiatric disorders, or other neurological diseases., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that better cognitive functioning is associated with better mobility in older age. It is unknown whether older adults with better cognitive function are more resilient to mobility decline after a fall., Methods: Participants from the Monongahela Youghiogheny Healthy Aging Team (MYHAT) study were followed annually for up to 9 years for incident falls. We examined one-year (mean 1.0 year, SD 0.1) change in mobility pre- to post-fall using the Timed Up and Go (TUG) in relation to pre-fall cognition (executive function, attention, memory, and visuospatial function) among incident fallers (n = 598, mean age 79.1, SD = 7.0). Linear regression models tested the association of cognition with change in TUG. Interaction terms were tested to explore if age, sex, body mass index, physical activity, depressive symptoms, or visual acuity modified the associations of cognition and mobility among fallers. The association between cognition and one-year change in TUG was also tested in a comparison sample of non-fallers (n = 442, mean age 76.3, SD = 7.2)., Results: Overall, mobility decline was greater in fallers compared to non-fallers. In fully-adjusted models, higher executive function, but not attention, memory, or visuospatial function, was associated with less decline in mobility among incident fallers. The effect was significantly stronger for those who were older, sedentary, and had lower body mass index. Higher scores in memory tests, but not in other domains, was associated with less mobility decline among non-fallers., Conclusions: Higher executive function may offer resilience to mobility decline after a fall, especially among older adults with other risk factors for mobility decline. Future studies should assess whether executive function may be a helpful risk index of fall-related physical functional decline in geriatric settings., Competing Interests: Declaration of competing interest The authors have no conflicts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. The lack of effective treatments, coupled with its etiology, has resulted in more than 400,000 deaths at the time of writing. The SARS-CoV-2 genome is highly homologous to that of SARS-CoV, the causative agent behind the 2003 SARS outbreak. Based on prior reports, clinicians have pursued the off-label use of several antiviral drugs, while the scientific community has responded by seeking agents against traditional targets, especially viral proteases. However, several avenues remain unexplored, including disrupting E and M protein oligomerization, outcompeting host glycan-virus interactions, interfering with the heparan sulfate proteoglycans-virus interaction, and others. In this review, we highlight some of these opportunities while summarizing the drugs currently in use against coronavirus 2019 (COVID-19)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Acute infection is a frequent trigger of myocardial infarction (MI). However, whether percutaneous coronary intervention (PCI) improves post-infectious MI prognosis is a major but unsolved issue. In this prospective multicenter study from coronary care units, we performed propensity score-matched analysis to compare outcomes in patients with and without PCI for post-infectious MI with angiography-proven significant coronary stenosis (>50%). Among 4573 consecutive MI patients, 476 patients (10%) had a concurrent diagnosis of acute infection at admission, of whom 375 underwent coronary angiography and 321 patients had significant stenosis. Among the 321 patients, 195 underwent PCI. Before the matching procedure, patients without PCI had a similar age and sex ratio but a higher rate of risk factors (hypertension, diabetes, chronic renal failure, and prior coronary artery disease), pneumonia, and SYNTAX score than patients without PCI. After propensity score matching, neither in-hospital mortality (13% with PCI vs. 8% without PCI; p = 0.4) nor one-year mortality (24% with PCI vs. 19% without PCI, p = 0.5) significantly differed between the two groups. In this first prospective cohort of post-infectious MI in coronary care units, PCI might not improve short- and long-term prognosis in patients with angiography-proven significant coronary stenosis. If confirmed, these results do not argue for systematic invasive procedures after post-infectious MI.

Background/objectives: To investigate potential mechanisms underlying the well-established relationship of diabetes and obesity with cognitive decline, among older adults participating in a population-based study., Design/setting: Ten-year population-based cohort study., Participants: A total of 478 individuals aged 65 years and older., Measurements: We assayed fasting blood for markers of glycemia (glucose and hemoglobin A1c [HbA1c]), insulin resistance (IR) (insulin and homeostatic model assessment of IR), obesity (resistin, adiponectin, and glucagon-like peptide-1), and inflammation (C-reactive protein). We modeled these indices as predictors of the slope of decline in global cognition, adjusting for age, sex, education, APOE*4 genotype, depressive symptoms, waist-hip ratio (WHR), and systolic blood pressure, in multivariable regression analyses of the entire sample and stratified by sex-specific median WHR. We then conducted WHR-stratified machine-learning (Classification and Regression Tree [CART]) analyses of the same variables., Results: In multivariable regression analyses, in the entire sample, HbA1c was significantly associated with cognitive decline. After stratifying by median WHR, HbA1c remained associated with cognitive decline in those with higher WHR. No metabolic indices were associated with cognitive decline in those with lower WHR. Cross-validated WHR-stratified CART analyses selected no predictors in participants older than 87 to 88 years. Faster cognitive decline was associated, in lower WHR participants younger than 87 years, with adiponectin of 11 or greater; and in higher WHR participants younger than 88 years, with HbA1c of 6.2% or greater., Conclusions: Our population-based data suggest that, in individuals younger than 88 years with central obesity, even modest degrees of hyperglycemia might independently predispose to faster cognitive decline. In contrast, among those younger than 87 years without central obesity, adiponectin may be a novel independent risk factor for cognitive decline. J Am Geriatr Soc 68:991-998, 2020., (© 2020 The American Geriatrics Society.)

Background Optimal blood pressure in elderly patients after acute myocardial infarction is still a matter of debate. In a prospective observational study, we aimed to identify optimal systolic blood pressure during the 48 first hours after admission for acute myocardial infarction and its prognostic value for cardiovascular mortality. Methods and Results From the Observatoire des Infarctus de Côte d'Or survey, all consecutive patients aged >75 years admitted for an acute myocardial infarction in a coronary care unit from 2012 to 2015 and discharged alive were included (n=814). Exclusion criteria were in-hospital death, cardiogenic shock, and end-stage renal disease. Average systolic blood pressure (aSBP) values over the first 48 hours after admission were recorded, and the population was dichotomized into 2 groups: low aSBP group (<125 mm Hg) and control group (aSBP ≥125 mm Hg). When compared with patients without cardiovascular death at 1-year follow-up, patients who died from a cardiovascular cause had higher rate of cardiovascular risks factors, including age, diabetes mellitus, comorbidities, and cardiovascular history. They had higher rates of low body mass index (<21 kg/m 2 ) and more elevated Global Registry of Acute Coronary Events risk score. Patients with aSBP <125 mm Hg had a 2-fold risk of 1-year cardiovascular death (47 [12.0%] versus 28 [6.6%]; P =0.008). By multivariable logistic regression analysis, low aSBP (odds ratio [95% CI], 1.91 [1.07-3.41]) remained a strong and independent predictor of 1-year cardiovascular mortality. Conclusions In our large population-based study in elderly patients with acute myocardial infarction, low aSBP was an independent and powerful predictor of 1-year cardiovascular mortality. Early aSBP measurement could help to improve risk stratification. Moreover, our results may suggest an optimal blood pressure target in elderly patients.

Purpose: Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD + ) concentration may provide insights on its roles in normal and pathological aging. In the present study, we report a 1 H MRS pulse sequence for the in vivo, localized 1 H MRS detection of NAD + from the human brain., Methods: Studies were carried out on a 7T Siemens MRI scanner using a 32-channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E-BURP-1 90° pulse. PRESS localization was achieved using optimized Shinnar-Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD + quantification was measured in 11 healthy volunteers. The association of cerebral NAD + with age was assessed in 16 healthy subjects 26-78 years old., Results: Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H 2 , H 4 , and H 6 protons of the nicotinamide moiety of NAD + between 8.9-9.35 ppm. The mean ± SD within-session and between-session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age-dependent decline of the NAD + levels in the brain was also observed (β = -1.24 μM/y, SE = 0.21, P < 0.001)., Conclusion: We demonstrated the feasibility and robustness of a newly developed 1 H MRS technique to measure localized cerebral NAD + at 7T MRI using a commercially available RF head coil. This technique may be further applied to detect and quantify NAD + from different regions of the brain as well as from other tissues., (© 2019 International Society for Magnetic Resonance in Medicine.)

Streptococcus pneumoniae (pneumococcus) remains an important cause of morbidity and mortality. Pneumococcal vaccination is part of the South African pediatric public immunization program but the potential cost-effectiveness of such an intervention for adults is unknown. This study aimed to compare the cost-effectiveness of two widely used pneumococcal vaccines: pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23) in South African adults, 18 years and older. Four analyses were carried out in a) both the private and public health care sectors; and b) for the HIV-infected population alone and for the total mixed population (all HIV-infected and -uninfected people). A previously published global pharmacoeconomic model was adapted and populated to represent the South African adult population. The model utilized a Markov-type process to depict the lifetime clinical and economic outcomes of patients who acquire pneumococcal disease in 2015, from a societal perspective. Costs were sourced in South African rand and converted to US dollar (USD). The incremental cost divided by the incremental effectiveness (expressed as quality-adjusted life years gained) represented the incremental cost-effectiveness ratio for PCV13 compared to PPSV23. Results indicated that the use of PCV13 compared to PPSV23 is highly cost-effective in the public sector cohorts with incremental cost-effectiveness ratios of $771 (R11,106)/quality-adjusted life year and $956 (R13,773)/quality-adjusted life year for the HIV-infected and mixed populations, respectively. The private sector cohort showed similar highly cost-effective results for the mixed population (incremental cost-effectiveness ratio $626 (R9,013)/quality-adjusted life year) and the HIV-infected cohort (dominant). In sensitivity analysis, the model was sensitive to vaccine price and effectiveness. Probabilistic sensitivity analyses found predominantly cost-effective ICERs. From a societal perspective, these findings provide some guidance to policy makers for consideration and implementation of an immunization strategy for both the public and private sector and amongst different adult patient pools in South Africa., Competing Interests: Charles Feldman: Charles Feldman acts on the advisory board and speaker’s bureau for Pfizer and received an honorarium for attendance of the Delphi panel meeting. Sipho Dlamini: Sipho Dlamini has received payment for lectures from the following companies Pfizer-South Africa, MSD-South Africa and Janssen Pharmaceutica. He has participated on an advisory board for MSD-South Africa and Pfizer-South Africa. He received an honorarium for attendance of the Delphi panel meeting. Shabir Madhi: Shabir Madhi has received institutional grants from BMGF, Pfizer, GSK and Novartis. He received an honorarium for attendance of the Delphi panel meeting. Susan Meiring: Susan Meiring has received travel funding only (flights and accommodation) to present at three meetings presented by Pfizer: AfMe Value Summit in 2016 and 2017 and the African Regional Pneumococcal Disease Scientific Meeting in 2016. She received an honorarium for attendance of the Delphi panel meeting. Anne von Gottberg: Anne von Gottberg received research funds to institution from Pfizer and Sanofi, and expenses reimbursed for educational travel by Pfizer, Sanofi and Novartis. Margreet de Necker: The pharmacoeconomic study performed by TCD Outcomes Research was funded by Pfizer. Margreet de Necker has consulted to other pharmaceutical companies in the past. Janetta Catharina de Beer: The pharmacoeconomic study performed by TCD Outcomes Research was funded by Pfizer. Janetta Catharina de Beer has consulted to other pharmaceutical companies in the past. Tienie Stander: The pharmacoeconomic study performed by TCD Outcomes Research was funded by Pfizer. Tienie Stander has consulted to Pfizer and other pharmaceutical companies in the past. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: High blood pressure is one of the main modifiable risk factors for dementia. However, there is conflicting evidence regarding the best antihypertensive class for optimizing cognition. Our objective was to determine whether any particular antihypertensive class was associated with a reduced risk of cognitive decline or dementia using comprehensive meta-analysis including reanalysis of original participant data., Methods: To identify suitable studies, MEDLINE, Embase, and PsycINFO and preexisting study consortia were searched from inception to December 2017. Authors of prospective longitudinal human studies or trials of antihypertensives were contacted for data sharing and collaboration. Outcome measures were incident dementia or incident cognitive decline (classified using the reliable change index method). Data were separated into mid and late-life (>65 years) and each antihypertensive class was compared to no treatment and to treatment with other antihypertensives. Meta-analysis was used to synthesize data., Results: Over 50,000 participants from 27 studies were included. Among those aged >65 years, with the exception of diuretics, we found no relationship by class with incident cognitive decline or dementia. Diuretic use was suggestive of benefit in some analyses but results were not consistent across follow-up time, comparator group, and outcome. Limited data precluded meaningful analyses in those ≤65 years of age., Conclusion: Our findings, drawn from the current evidence base, support clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals., Clinical Trials Registration: The review was registered with the international prospective register of systematic reviews (PROSPERO), registration number CRD42016045454., (© 2019 American Academy of Neurology.)

To identify novel loci that affect cognitive decline in older adults free of dementia, we conducted genome-wide and gene-based meta-analyses on longitudinal slopes of 5 cognitive domains (memory, executive function, language, attention/processing speed, and visuospatial ability) derived from 2 population-based cohorts. For decline over time in each cognitive domain, we normalized intraindividual slopes within each cohort, accounting for baseline age, sex, and years of education. Normalized slope for each domain was used in cohort-specific genome-wide analyses after including top principal components as covariates followed by genome-wide and gene-based meta-analyses. Both analyses revealed a novel WDFY2 locus at genome-wide (p = 3.37E-08) and gene-wide (p = 7.10E-07) significance levels for the attention/processing speed domain. In the GTEx eQTL analysis, genome-wide significant single-nucleotide polymorphism was associated with RNA expression levels of WDFY2 in several brain regions: cerebellar hemisphere (p = 1.07E-04), cerebellum (p = 6.92E-04), hippocampus (p = 2.18E-03) and cortex (p = 2.29E-02), and in whole blood (p = 4.41E-05). Our results suggest that WDFY2 genetic variation may affect individual differences in decline over time on tests of attention/processing speed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Predicting clinical variables from whole-brain neuroimages is a high-dimensional problem that can potentially benefit from feature selection or extraction. Penalized regression is a popular embedded feature selection method for high-dimensional data. For neuroimaging applications, spatial regularization using the ℓ 1 or ℓ 2 norm of the image gradient has shown good performance, yielding smooth solutions in spatially contiguous brain regions. Enormous resources have been devoted to establishing structural and functional brain connectivity networks that can be used to define spatially distributed yet related groups of voxels. We propose using the fused sparse group lasso (FSGL) penalty to encourage structured, sparse, and interpretable solutions by incorporating prior information about spatial and group structure among voxels. We present optimization steps for FSGL penalized regression using the alternating direction method of multipliers algorithm. With simulation studies and in application to real functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange, we demonstrate conditions under which fusion and group penalty terms together outperform either of them alone., (© 2019 The International Biometric Society.)

Background: Individuals with heterozygous familial hypercholesterolemia (FH) are at high risk of early myocardial infarction (MI). However, coronary artery disease (CAD) burden of FH remains not well described, especially for French patients., Objective: The objective of this study was to assess the prevalence of FH and severity of CAD from a large database of a French regional registry of acute MI., Methods: All consecutive patients hospitalized for an acute MI in a multicenter database from 2001 to 2017 were considered. FH was diagnosed using an algorithm adapted from the Dutch Lipid Clinic Network criteria. The prevalence and clinical features of FH and the severity of CAD were assessed., Results: Among the 11,624 patients included in the study, the proportion of "probable/definite", "possible", and "unlikely" FH in patients with MI was 2.1% (n = 249), 20.7% (n = 2405), and 77.2% (n = 8970), respectively. When compared with patients with "unlikely" FH, patients with "probable/definite" FH were 20 years younger (51 vs 71, P < .001), with a lower rate of diabetes (17% vs 25%, P = .007) and a higher prevalence of personal and familial history of CAD. Chronic statin treatment was only used in 48% of FH patients and ezetimibe in 8%. After adjustment for age, sex, and diabetes, patients with FH were characterized by increased extent of CAD (SYNTAX score 11 vs 7, P < .001) and multivessel disease (55% vs 40%, P < .001)., Conclusions: In this large cohort of French individuals, FH was common in patients with MI, associated with markedly early age of MI and severity of CAD burden and limited use of preventive lipid-lowering therapy., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Kenya has the world's 4th largest HIV burden. Various strategies to control the epidemic have been implemented, including the implementation of viral load (VL) testing to monitor HIV patients on ARVs. Like many resource limited settings, Kenya's healthcare system faces serious challenges in effectively providing quality health services to its population. Increased investments to strengthen the country's capacity to diagnose, monitor and treat diseases, particularly HIV and TB, continue to be made but are still inadequate in the face of global health goals like the UNAIDS 90:90:90 which require scaling up of VL tests amid existing constraints. In Kenya, there is an increase in the demand for VL tests amidst these existing constraints. The GeneXpert system is a diagnostic point-of-care technology that can quantify, amongst others, HIV VL. Currently, GeneXpert technology is widely distributed in Kenya for testing of tuberculosis. This study aimed to determine the economic and public health impact of incorporating VL test modules on the existing GeneXpert infrastructure. Markov models were constructed for different populations (non-pregnant adults, pregnant women and children). The scenarios analysed were 100% centralized VL testing compared to 50% GeneXpert plus 50% centralized VL testing, with time horizons of 5 years for the adult and child populations, and 31 months for the pregnant population. Incremental effectiveness was measured in terms of the number of HIV transmissions or opportunistic infections avoided when implementing the GeneXpert scenario compared to a 100% centralized scenario. The model indicated that, for all three populations combined, the GeneXpert scenario resulted in 117 less HIV transmissions and 393 less opportunistic infections. The cost decreased by $21,978,755 for the non-pregnant and pregnant adults and $22,808,533 for non-pregnant adults, pregnant adults and children. The model showed that GeneXpert would cost less and be more effective in terms of total cost per HIV transmission avoided and the total cost per opportunistic infection avoided, except for the pregnant population, when considered separately., Competing Interests: The authors’ affiliation with TCD Outcomes Research does not alter our adherence to PLOS ONE policies on sharing data and materials.

An extraordinary binding site generated in heparan sulfate (HS) structures, during its biosynthesis, provides a unique opportunity to interact with multiple protein ligands including viral proteins, and therefore adds tremendous value to this master molecule. An example of such a moiety is the sulfation at the C3 position of glucosamine residues in HS chain via 3- O sulfotransferase (3- O ST) enzymes, which generates a unique virus-cell fusion receptor during herpes simplex virus (HSV) entry and spread. Emerging evidence now suggests that the unique patterns in HS sulfation assist multiple viruses in invading host cells at various steps of their life cycles. In addition, sulfated-HS structures are known to assist in invading host defense mechanisms and initiating multiple inflammatory processes; a critical event in the disease development. All these processes are detrimental for the host and therefore raise the question of how HS-sulfation is regulated. Epigenetic modulations have been shown to be implicated in these reactions during HSV infection as well as in HS modifying enzyme sulfotransferases, and therefore pose a critical component in answering it. Interestingly, heparanase (HPSE) activity is shown to be upregulated during virus infection and multiple other diseases assisting in virus replication to promote cell and tissue damage. These phenomena suggest that sulfotransferases and HPSE serve as key players in extracellular matrix remodeling and possibly generating unique signatures in a given disease. Therefore, identifying the epigenetic regulation of O ST genes, and HPSE resulting in altered yet specific sulfation patterns in HS chain during virus infection, will be a significant a step toward developing potential diagnostic markers and designing novel therapies.

ABSTRACTBackground:Evidence suggests that semantic interference may be a sensitive indicator of early dementia. We examined the utility of the Semantic Interference Test (SIT), a cognitive stress memory paradigm which taps proactive and retroactive semantic interference, for predicting progression from mild cognitive impairment (MCI) to dementia in both a clinical and a population-based sample., Methods: Participants with MCI in the clinical (n = 184) and population-based (n = 435) samples were followed for up to four years. We employed receiver operating characteristic (ROC) methods to establish optimal thresholds for four different SIT indices. Threshold performance was compared in the two samples using logistic and Cox proportional hazard regression models., Results: Within four years, 42 (22.8%) MCI individuals in the clinical sample and 45 (10.3%) individuals in the population-based sample progressed to dementia. Overall classification accuracy of SIT thresholds ranged from 61.4% to 84.8%. Different subtests of the SIT had slightly different performance characteristics in the two samples. However, regression models showed that thresholds established in the clinical sample performed similarly in the population sample before and after adjusting for demographics and other baseline neuropsychological test scores., Conclusions: Despite differences in demographic composition and progression rates, baseline SIT scores predicted progression from MCI to dementia similarly in both samples. Thresholds that best predicted progression were slightly below thresholds established for distinguishing between amnestic MCI and cognitively normal subjects in clinical practice. This confirms the utility of the SIT in both clinical and population-based samples and establishes thresholds most predictive of progression of individuals with MCI.

Aims: To derive and validate a readily useable risk score to identify patients at high-risk of in-hospital ST-segment elevation myocardial infarction (STEMI)-related cardiogenic shock (CS)., Methods and Results: In all, 6838 patients without CS on admission and treated by primary percutaneous coronary intervention (pPCI), included in the Observatoire Régional Breton sur l'Infarctus (ORBI), served as a derivation cohort, and 2208 patients included in the obseRvatoire des Infarctus de Côte-d'Or (RICO) constituted the external validation cohort. Stepwise multivariable logistic regression was used to build the score. Eleven variables were independently associated with the development of in-hospital CS: age >70 years, prior stroke/transient ischaemic attack, cardiac arrest upon admission, anterior STEMI, first medical contact-to-pPCI delay >90 min, Killip class, heart rate >90/min, a combination of systolic blood pressure <125 mmHg and pulse pressure <45 mmHg, glycaemia >10 mmol/L, culprit lesion of the left main coronary artery, and post-pPCI thrombolysis in myocardial infarction flow grade <3. The score derived from these variables allowed the classification of patients into four risk categories: low (0-7), low-to-intermediate (8-10), intermediate-to-high (11-12), and high (≥13). Observed in-hospital CS rates were 1.3%, 6.6%, 11.7%, and 31.8%, across the four risk categories, respectively. Validation in the RICO cohort demonstrated in-hospital CS rates of 3.1% (score 0-7), 10.6% (score 8-10), 18.1% (score 11-12), and 34.1% (score ≥13). The score demonstrated high discrimination (c-statistic of 0.84 in the derivation cohort, 0.80 in the validation cohort) and adequate calibration in both cohorts., Conclusion: The ORBI risk score provides a readily useable and efficient tool to identify patients at high-risk of developing CS during hospitalization following STEMI, which may aid in further risk-stratification and thus potentially facilitate pre-emptive clinical decision making.

Background: Red blood cell transfusion benefit during acute myocardial infarction remains unclear in the elderly. We aimed to assess the transfusion impact on 1-year mortality in acute myocardial infarction patients aged ≥65 years, according to their age and hemoglobin nadir., Methods: We included 3316 consecutive patients with acute myocardial infarction aged ≥65 years from the "obseRvatoire des Infarctus de Côte d'Or" (RICO) survey. They were categorized according to their hemoglobin nadir (≤8, >8 to ≤10, and >10 g/dL) and age (<80 or ≥80 years)., Results: A total of 1906 patients (57%) were 65-79 years old, and 1410 (43%) were aged ≥80 years, of whom 103 (5%) and 145 (10%) patients received red blood cell transfusion, respectively (P < .001). In Cox regression analysis, transfusion was associated with increased 1-year mortality for hemoglobin nadir >10 g/dL but no significant effect for hemoglobin nadir between 8 and 10 g/dL. When hemoglobin nadir was ≤8 g/dL, transfusion did not influence 1-year mortality for younger patients (65-79 years). However, for older patients (≥80 years), transfusion was associated with lower mortality (hazard ratio 0.43 [95% confidence interval, 0.22-0.86], P = .016)., Conclusion: Among older patients with acute myocardial infarction, the effect of transfusion was largely dependent on hemoglobin threshold and age. Transfusion was associated with increased 1-year mortality when hemoglobin nadir was >10 g/dL. However, in patients aged ≥80 years with hemoglobin nadir <8 g/dL, transfusion was associated with a 50% reduction in 1-year mortality., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: The primary objective of this study was to evaluate 1- and 2-year survival rates and durable remissions in pretreated patients with advanced (unresectable or metastatic) malignant melanoma treated with ipilimumab in a South African expanded-access program (SA-EAP)., Patients and Methods: This multicenter, retrospective study obtained data from pretreated patients with advanced malignant melanoma who were eligible for the ipilimumab SA-EAP. Ipilimumab was administered at a dose of 3 mg/kg intravenously every 3 weeks for four cycles to adults with advanced melanoma for whom at least one line of treatment for metastatic disease had failed. Data from the medical records of 108 patients treated within the SA-EAP were collected and statistically analyzed to determine overall (OS) and progression-free survival (PFS) at 1 and 2 years., Results: In the population of 108 patients, a median OS of 8.98 months (95% CI, 7.47 to 10.79 months) was observed. One-year OS was 36% (95% CI, 26% to 45%), and 2-year survival was observed as 20% (95% CI, 12% to 27%). The median survival without progression (ie, PFS) was 3.44 months (95% CI, 2.98 to 4.16 months), and 1- and 2-year PFS were 22% (95% CI, 14% to 29%) and 14% (95% CI, 8% to 21%), respectively. The longest recorded survival was 3.4 years. No independent prognostic variables were identified to predict for OS by multivariate Cox proportional hazards model., Conclusion: In this multicenter South African setting, ipilimumab at a dose of 3 mg/kg was an effective treatment with long-term OS in a subset of patients with pretreated advanced malignant melanoma., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Bernardo L. RapoportHonoraria: Tesaro, Merck, Bristol-Myers Squibb Consulting or Advisory Role: Tesaro, Merck, Bristol-Myers Squibb Speakers’ Bureau: Tesaro, Merck, Bristol-Myers Squibb Research Funding: Tesaro, Merck, Bristol-Myers Squibb Travel, Accommodations, Expenses: Tesaro, Merck, Bristol-Myers SquibbDaniel A. VorobiofConsulting or Advisory Role: Amgen, Roche, Bristol-Myers SquibbLydia M. DreostiHonoraria: Roche, Janssen Pharmaceuticals Consulting or Advisory Role: Roche, Janssen Pharmaceuticals, Novartis Speakers’ Bureau: Janssen Pharmaceuticals Travel, Accommodations, Expenses: Roche, Janssen Pharmaceuticals, Merck SeronoAdam NosworthySpeakers’ Bureau: Key Oncologics Travel, Accommodations, Expenses: Bristol-Myers Squibb, Janssen OncologyGeorgina McAdamNo relationship to discloseJohan P. JordaanSpeakers’ Bureau: Merck Serono Research Funding: Roche, PAREXEL International, Ipsen, Quintiles, Novartis Travel, Accommodations, Expenses: RocheHelen Miller-JansönConsulting or Advisory Role: HEXOR (Inst) Research Funding: HEXOR (Inst)Margreet de NeckerConsulting or Advisory Role: HEXOR (Inst) Research Funding: HEXOR (Inst)Janetta C. de BeerConsulting or Advisory Role: HEXOR (Inst) Research Funding: HEXOR (Inst)Hennie DuvenhageEmployment: Bristol-Myers Squibb Research Funding: Bristol-Myers Squibb

Depression is a common psychiatric disorder and can be costly, having a significant impact on the individual and employers. The South African Depression and Anxiety Group (SADAG) in partnership with HEXOR, with the support of Lundbeck, undertook research into depression in the workplace, because South African information is not available on this topic. It provides insight into the prevalence of depression within the workplace in South Africa, as well as the impact of depression on the employees and employers in terms of sick leave and levels of productivity, especially when the symptoms include cognitive impairment. It is apparent that stigma plays a pivotal role in the reasons for non-disclosure to employers. It further highlights the magnitude of awareness, early detection and the provision of a holistic support system within the work environment, free from bias, to ensure that optimum benefit can be achieved for both employer and employee., Competing Interests: The authors declare that the study was funded by a research grant from Lundbeck.

Objective: To examine the relationships over time between dual trajectories of depressive symptoms and several cognitive domains., Methods: In a 5-year longitudinal study, 1,978 randomly selected individuals aged 65+ years at recruitment were assessed annually. Repeated measures were of depressive symptoms on the modified Center for Epidemiologic Studies Depression Scale and composite scores in the cognitive domains of attention, executive function, memory, language, and visuospatial function. Latent class trajectories were identified for depression and for each cognitive domain and their associations investigated using dual trajectory modeling. Cognitive trajectories with z scores below -1 were designated as persistently low., Results: Five depressive symptom trajectories were observed: rarely depressed (60.5%); low-grade, decreasing symptoms (18.5%); low-grade, increasing symptoms (9.6%); moderate-grade symptoms (7.4%); and consistent higher-grade symptoms (4.0%). For each cognitive domain six trajectories were observed. The rarely depressed and low-grade decreasing symptom groups were the least likely to have persistently low cognition. The symptom trajectory most strongly associated with persistently low functioning in each domain was not the higher-grade group but rather the low-grade increasing group in the case of attention and the moderate-grade trajectory in the other four domains., Conclusion: Consistently higher-grade depressive symptoms are less strongly associated with poor cognitive functioning than with either moderate- or low-grade increasing depressive symptom trajectories, over time and across different domains. Examining both depression and cognition longitudinally allows heterogeneity of both to be addressed, revealing latent groups with potential diagnostic and prognostic implications., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most frequent heart rhythm disorder in the general population and contributes not only to a major deterioration in quality of life but also to an increase in cardiovascular morbimortality. The onset of AF in the acute phase of myocardial infarction (MI) is a major event that can jeopardize the prognosis of patients in the short-, medium- and long-term, and is a powerful predictor of a poor prognosis after MI. The suspected mechanism underlying the excess mortality is the drop in coronary flow linked to the acceleration and arrhythmic nature of the left ventricular contractions, which reduce the left ventricular ejection fraction. The principal causes of AF-associated death after MI are linked to heart failure. Moreover, the excess risk of death in these heart failure patients has also been associated with the onset of sudden death. Whatever its form, AF has a major negative effect on patient prognosis. In recent studies, symptomatic AF was associated with inhospital mortality of 17.8%, to which can be added mortality at 1year of 18.8%. Surprisingly, silent AF also has a negative effect on the prognosis, as it is associated with an inhospital mortality rate of 10.4%, which remains high at 5.7% at 1year. Moreover, both forms of AF are independent predictors of mortality beyond traditional risk factors. The frequency and seriousness of silent AF in the short- and long-term, which were until recently rarely studied, raises the question of systematically screening for it in the acute phase of MI. Consequently, the use of continuous ECG monitoring could be a simple, effective and inexpensive solution to improve screening for AF, even though studies are still necessary to validate this strategy. Finally, complementary studies also effect of oxidative stress and endothelial dysfunction, which seem to play a major role in triggering this rhythm disorder., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: In secondary prevention (SP) of coronary artery disease (CAD), in particular after an acute myocardial infarction (MI), a better knowledge and self-management by the patient may have various supports. The Log book (LB) for CAD patients in Côte d'Or, was created in 2010 by a multidisciplinary team of healthcare professionals of Côte d'Or, from a regional care network. This pilot study evaluated LB as novel support for SP after acute MI., Methods: A prospective study on 183 patients hospitalised for an acute MI in the region of Côte d'Or from 1st May to 30th October 2010. Patients were randomized in 91 patients who received an LB at the time of their hospitalisation (LB+ group), and 92 patients who were not given an LB (LB- group). The follow up (FU) was performed at 4 months and 1 year., Results: Baseline characteristics were similar in the 2 groups, except for smoking, which was more frequent in the LB-group than in the LB+ group. At FU, LB was usually well accepted by both patients and their general practitioners (GP). At 4 months FU, the patients LB+ were more prone to see their general practitioners than patients LB- (100% vs 85% in the LB- group, P=0.007). Moreover, in LB+ group, there was a trend towards a more frequent physical activity, including exercise bike (P=0.009) and an increase in HDL-cholesterol (HDL-c) (P=0.165). At 1 year FU, body mass index from LB+ was more reduced than in patients LB- (P=0.029). Finally, there was a trend towards lower morbi-mortality (hospitalisation for cardiovascular cause or death) in the LB+ group than in the LB- group (11 vs 22%, P=0.083)., Conclusion: This pilot study showed the feasibility of LB as a support for SP and its interest in post MI management in a local care network setting. In addition, our study provides encouraging data on the potential benefits of this pioneer tool for SP., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Atrial fibrillation (AF), whether silent or symptomatic, is a frequent and severe complication of acute myocardial infarction (AMI). Asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor, is a risk factor for endothelial dysfunction. We addressed the relationship between ADMA plasma levels and AF occurrence in AMI., Methods: 273 patients hospitalized for AMI were included. Continuous electrocardiographic monitoring (CEM) ≥48 hours was recorded and ADMA was measured by High Performance Liquid Chromatography on admission blood sample., Results: The incidence of silent and symptomatic AF was 39(14%) and 29 (11%), respectively. AF patients were markedly older than patients without AF (≈ 20 y). There was a trend towards higher ADMA levels in patients with symptomatic AF than in patients with silent AF or no AF (0.53 vs 0.49 and 0.49 μmol/L, respectively, p = 0.18,). After matching on age, we found that patients with symptomatic AF had a higher heart rate on admission and a higher rate of patients with LV dysfunction (28% vs. 3%, p = 0.025). Patients who developed symptomatic AF had a higher ADMA level than patients without AF (0.53 vs. 0.43 μmol/L; p = 0.001). Multivariate logistic regression analysis to estimate symptomatic AF occurrence showed that ADMA was independently associated with symptomatic AF (OR: 2.46 [1.21-5.00], p = 0.013) beyond history of AF, LVEF<40% and elevated HR., Conclusion: We show that high ADMA level is associated with the occurrence of AF. Although no causative role can be concluded from our observational study, our work further supports the hypothesis that endothelial dysfunction is involved in the pathogenesis of AF in AMI.

Background: Silent atrial fibrillation (AF), assessed by continuous ECG monitoring (CEM), has recently been shown to be common in acute myocardial infarction (AMI), and associated with higher hospital mortality. However, the long-term prognosis is still unknown. We aimed to assess 1-year prognosis in patients experiencing silent AF in AMI., Methods: All consecutive patients with AMI who were prospectively analysed by CEM during the first 48 h after admission and who survived at hospital discharge were included. Silent AF was defined as asymptomatic episodes lasting at least 30 s. Patients were followed up at 1 year for cardiovascular (CV) outcomes., Results: Among the 737 patients analysed, 106 (14%) developed silent AF and 32 (4%) symptomatic AF. Compared with the no-AF group, patients with silent AF were markedly older (79 vs 62 years, p<0.001), more frequently hypertensive (71% vs 49%, p<0.001) and less likely to be smokers (23% vs 37%, p<0.001). Also, they were more likely to have impaired LVEF (50% vs 55%, p<0.001). Risk factors in patients with silent AF were similar to those in patients with symptomatic AF. However, a history of stroke or AF was less frequent in silent AF than in symptomatic-AF patients (10% vs 25% and 10% vs 38%, respectively). At 1 year, CV events including hospitalisation for heart failure (HF) and CV mortality were markedly higher in silent-AF patients than in no-AF patients (6.6% vs 1.3% and 5.7% vs 2.0%, p<0.001, respectively)., Conclusions: Our large prospective study showed for the first time that silent AF is associated with worse 1-year prognosis after AMI. Systematic screening and specific management should be investigated in order to improve outcomes of patients after AMI., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Silent atrial fibrillation (AF) has been suggested to be frequent after acute myocardial infarction (MI). Continuous ECG monitoring (CEM) has been shown to improve AF screening in patients at risk of stroke., Objectives: We aimed to assess the incidence and prognosis of silent AF in patients with acute MI., Methods: All the consecutive patients with acute MI were prospectively analyzed by CEM ≥ 48 h after admission. Silent AF was defined as asymptomatic episodes lasting at least 30s. The population was divided into three groups: no-AF, silent AF and symptomatic AF., Results: Among the 849 patients, 135 (16%) developed silent AF and 45 (5%) symptomatic AF. Compared with the no-AF group, patients with silent AF were markedly older (80 vs. 62 y, p<0.001), more frequently women (43% vs. 30%, p=0.006) and less likely to be smokers (20% vs. 36%, p<0.001). They had impaired left ventricular ejection fraction (LVEF) and left atrial (LA) enlargement. By multivariate analysis, age, history of AF, indexed LA area and LVEF were identified as independent predictors of silent AF. In-hospital heart failure and death rates were markedly higher in silent AF group when compared with no-AF patients (41.8% vs 21.0% and 10.4% vs. 1.3%, respectively)., Conclusion: Our large prospective study showed for the first time that silent AF is more frequent than symptomatic AF after MI. Our work suggests that indexed LA area could help to predict the risk of developing silent AF. Moreover, the onset of silent AF is associated with worse hospital prognosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The risks for several cancer types are increased in people with diabetes. Hyperglycaemia, hyperinsulinaemia, inflammation and altered hormonal concentrations are common characteristics between the two diseases and can all be linked to hyperglycaemia., Methods: Here, we use glycated haemoglobin (HbA1c) as a biomarker for chronic hyperglycaemia. We explore whether cancer risk increases with HbA1c, independent of diabetes, and, therefore, if risk is already increased below the diabetic HbA1c range, by analysing data from current studies linking HbA1c to risk of several cancer types., Results: The data reveal that chronic hyperglycaemia correlates with increased cancer risk for a number of cancers, except prostate cancer. Evidence is also provided that risk is already increased in the pre-diabetic and normal ranges for several cancers., Conclusions: These results merit urgent investigation into the risks and advantages of updating recommendations for stricter glycaemic control in diabetic and non-diabetic subjects, as this could help reduce the risk of cancer incidence and mortality.

Objective: The aim of this study was to analyze the impact of diverting off-hour calls to Emergency Medical Dispatch Centers (EMDC) on time delays and revascularization procedures for patients with ST-segment elevation myocardial infarction (STEMI) in a French region., Methods: A total of 3376 consecutive patients admitted for acute STEMI were included from the RICO survey (a French regional survey for acute myocardial infarction). Patients were retrospectively classified into two groups: before (2001-2004) and after EMDC (2005-2008) implementation and followed up for mortality as primary outcomes. In addition, we examined the impact of the diversion on the delay to definitive care., Results: During the study, 1781 (53%) patients were evaluated before and 1595 (47%) after the EMDC implementation. Access to healthcare facilities was similar for the two groups. The rate of off-hour calls remained stable over time. The median delay from first medical intervention to hospital admission decreased from 75 to 60 min. The off-hour median interval from door to primary percutaneous coronary intervention dropped from 152 to 98 min. The multivariate analyses showed that EMDC implementing reduced preadmission delays even when adjusting for potential confounders. Moreover, EMDC implementing was associated with a fall in 30-day mortality by 60% in patients admitted during off hours and undergoing primary percutaneous coronary intervention (10 vs. 4%)., Conclusion: In a real world setting, improving the quality of prehospital organization was effective not only on reducing delays but also on improving access to revascularization. Our results showed the beneficial impact of EMDC implementing on management of STEMI.

Background: Myocardial infarction with ST-segment elevation (STEMI) is a medical emergency requiring specific management, with the main aim of achieving reperfusion as quickly as possible. Guidelines from medical societies have defined optimal management, with proven efficacy on morbi-mortality., Aims: Our study aimed to evaluate trends in practices between 2002 and 2010 in the emergency management of STEMI in a single French department, namely Cote d'Or., Methods: All patients admitted with a first STEMI to one of the six participating coronary care units (private or public) in Cote d'Or since January 2001 were included in a prospective registry (obseRvatoire des Infarctus de Côte d'Or [RICO]). Based on these data, we analysed trends in prehospital times between 2002 and 2010., Results: A total of 4114 patients were included in this analysis. Between 2002 and 2010, there was an increase in the proportion of patients who contacted the emergency services (by dialling 15) as first medical contact; however, the time from onset of symptoms to first medical contact remained stable over the study period. Overall, there was little change in prehospital management times but we noted a slight reduction in time to reperfusion., Conclusion: Despite some improvement in prehospital management practices between 2002 and 2010 in Cote d'Or, there is still significant room for improvement to achieve earlier reperfusion in STEMI patients., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: The presence of pre-infarction angina (PIA) has been shown to confer cardioprotection after ST-segment elevation myocardial infarction (STEMI). However, the clinical impact of PIA in non-ST-segment elevation myocardial infarction (NSTEMI) remains to be determined., Methods and Results: From the obseRvatoire des Infarctus de Côte d'Or (RICO) survey, 1541 consecutive patients admitted in intensive care unit with a first NSTEMI were included. Patients who experienced chest pain <7 days before the episode leading to admission were defined as having PIA and were compared with patients without PIA. Incidence of in-hospital ventricular arrhythmias (VAs), heart failure and 30-day mortality were collected. Among the 1541 patients included in the study, 693 (45%) patients presented PIA. PIA was associated with a lower creatine kinase peak, as a reflection of infarct size (231(109-520) vs. 322(148-844) IU/L, p<0.001) when compared with the group without PIA. Patients with PIA developed fewer VAs, by 3 fold (1.6% vs. 4.0%, p = 0.008) and heart failure (18.0% vs. 22.4%, p = 0.040) during the hospital stay. Overall, there was a decrease in early CV events by 26% in patients with PIA (19.2% vs. 25.9%, p = 0.002). By multivariate analysis, PIA remained independently associated with less VAs., Conclusion: From this large contemporary prospective study, our work showed that PIA is very frequent in patients admitted for a first NSTEMI, and is associated with a better prognosis, including reduced infarct size and in hospital VAs. Accordingly, protecting the myocardium by ischemic or pharmacological conditioning not only in STEMI, but in all type of MI merits further attention.

Objective: To examine the influence of obesity on the predictive value of the pro-B-type natriuretic peptide (NT-proBNP) assay in acute myocardial infarction., Design: Prospective observational study., Setting: All intensive care units in one region of France. Patients 2217 consecutive patients admitted for an acute myocardial infarction matched with respect to age, gender, Killip class and renal function., Main Outcome Measure: Cardiovascular death at one year., Results: There were three groups (according to body mass index (BMI): obese, overweight and normal) of 739 matched patients. Median levels of NT-proBNP were considerably lower in high BMI patients, by about 20% in overweight and by 60% in obese patients, compared with normal BMI patients. An inverse relationship between the propeptide values and BMI was found in the overall study population (r = -0.20, p < 0.0001), and for both genders. In multivariate linear regression, BMI as a continuous variable was a predictor of the log NT-proBNP level, even when adjusted for potential confounders. CV mortality at 1-year follow-up was similar for the three BMI groups (p = 0.691). In multivariate logistic regression analysis, log NT-proBNP predicted mortality in normal (OR (95% CI) 3.48 (2.00 to 6.12)) and overweight (OR (95% CI) 3.96 (1.95 to 8.06)) patients, even when adjusted for confounders (GRACE risk score, left ventricular ejection fraction). However, in obese patients, propeptide levels failed to retain their independent prognostic value (OR (95% CI) 1.34 (0.86 to 2.08))., Conclusions: In this large population of patients with myocardial infarction, circulating NT-proBNP levels were considerably lower in obese patients; the significance of the propeptide level as an independent prognostic factor is severely compromised.