Epidemiological transition in morbidity: 10-year data from emergency consultations in Dakar, Senegal.

BACKGROUND: It is thought that low-income countries are undergoing an epidemiological transition from infectious to non-communicable diseases; however, this phenomenon is yet to be examined with long-term data on morbidity. METHODS: We performed a prospective evaluation of all emergency medical consultations at a major emergency service provider in Dakar, Senegal from 2005 to 2014. Using standardised definitions, the primary diagnosis for each consultation was classified using the International Classification of Diseases-10 and then broadly categorised as 'infectious', 'non-communicable' and 'other' diseases. Morbidity rates for each year in the 10-year observation period were plotted to depict the epidemiological transition over time. To quantify the yearly rate ratios of non-communicable over infectious diagnosis, we used a generalised Poisson mixed model. RESULTS: Complete data were obtained from 49 702 visits by African patients. The mean age was 36.5±23.2 and 34.8±24.3 years for women and men, respectively. Overall, infections accounted for 46.3% and 42.9% and non-communicable conditions 32.2% and 40.1% of consultations in women and men, respectively. Consultation for non-communicable compared with infectious conditions increased by 7% every year (95% CI: 5% to 9%; p<0.0001) over the 10 years. Consultations for non-communicable condition were more likely in women compared with men (RR=1.29, 95% CI: 1.18, 1.40) and at older ages (RR=1.27; 95% CI 1.25, 1.29 for 10-year increase in age). CONCLUSION: Using high-quality disease morbidity data over a decade, we provide novel data showing the epidemiological transition of diseases as manifested in emergency service consultations in a large Sub-Saharan African city. These results can help reorientation of healthcare policy in Sub-Saharan Africa.

Is von Willebrand factor associated with stroke and death at mid-term in patients with non-valvular atrial fibrillation?

BACKGROUND: Heart failure and atrial fibrillation share common mechanisms that may contribute to hypercoagulability and thrombotic risk. Elevated von Willebrand factor (vWF) concentration has been associated with increased risk of thromboembolism and cardiovascular events. AIM: To investigate whether increased vWF plasma concentration predicts occurrence of a composite endpoint (all-cause death and stroke) in patients with non-valvular atrial fibrillation (NVAF). METHODS: We prospectively studied 122 patients (mean age 70±14years; 46% men) hospitalized with NVAF, and followed over a median (interquartile range) of 5.4 (2.3-9.0)years. Cox proportional models were used to estimate the association of vWF concentration with time to stroke and death. RESULTS: Forty-three patients (35%) had at least a stroke or died during the 5-year follow-up. Kaplan-Meier curves using vWF plasma concentration tertiles (≤191IU/dL;>191 to≤295IU/dL;>295IU/dL) showed that vWF plasma concentrations discriminated groups of patients with higher cardiovascular event rates (log-rank P=0.01). In the multivariable analysis, higher vWF concentrations (middle tertile hazard ratio [HR] 4.59, 95% confidence interval [CI] 1.55-13.50 [P=0.006]; upper tertile HR 4.10, 95% CI 1.43-11.75 [P=0.009]), age≥75years (HR 5.02, 95% CI 1.53-16.49; P=0.008), heart failure (HR 2.05, 1.01-4.19; P=0.048), C-reactive protein, log2 per unit increase (HR 1.29, 95% CI 1.04-1.61; P=0.021), no warfarin at discharge (HR 4.96, 95% CI 2.02-12.20; P<0.0001) and no aspirin at discharge (HR 4.41, 95% CI 1.71-11.97; P=0.002) were independently associated with an increased risk of stroke and all-cause death, whereas female sex was a protective factor (HR 0.35, 0.16-0.78; P=0.01). CONCLUSIONS: High vWF plasma concentrations may discriminate patients with NVAF at greater risk of stroke or all-cause death.

Left ventricular diastolic dysfunction in obstructive sleep apnoea syndrome by an echocardiographic standardized approach: An observational study.

BACKGROUND: The association between obstructive sleep apnoea syndrome (OSAS), left ventricular (LV) diastolic dysfunction and LV geometry remains controversial because of coexisting disorders. AIMS: To evaluate LV diastolic dysfunction and its independent predictors in a real-life cohort of OSAS patients, by a standardized approach. METHODS: We consecutively included 188 OSAS patients after an overnight polysomnography to undergo clinical evaluation, ambulatory blood pressure measurement and complete echocardiography, combining M-mode, two-dimensional Doppler and tissue Doppler imaging modes. Correlations between OSAS severity and clinical and echocardiographical variables were assessed, and logistic regression models were used to identify possible determining factors of LV diastolic dysfunction. RESULTS: Most patients were hypertensive (n=148, 78.7%) and already receiving treatment by continuous positive airway pressure (n=158, 84.5%). The prevalence of LV hypertrophy, defined by LV mass index (LVMi) normalized by height (2.7), was 12.4%, with a significant correlation with hypertension (P=0.004). The apnoea-hypopnoea index was correlated with body mass index (P<0.0001), 24-hour systolic blood pressure (P=0.01) and LVMi normalized by height (2.7) (P=0.03). Diastolic function assessed by a global approach was impaired for 70 patients (37.2%) and none of the OSAS severity variables was a determining factor after multivariable analysis with adjustment for age and sex. CONCLUSION: Diastolic dysfunction assessed by a standardized approach is common in OSAS and should be routinely evaluated; it is independently predicted by none of the respiratory severity variables.

An education program for risk factor management after an acute coronary syndrome: a randomized clinical trial.

IMPORTANCE: Lifestyle improvements after an acute coronary syndrome reduce cardiovascular risk but are difficult to achieve. OBJECTIVE: To determine whether a nurse-led or dietician-led cardiovascular risk factor education program would improve risk factor reduction over the long term after an acute coronary syndrome. DESIGN, SETTING, AND PARTICIPANTS: The Réseau Insuffisance Cardiaque (RESICARD) PREVENTION: study was a 2-arm, parallel-group, multicenter, randomized clinical trial at 6 tertiary care hospitals in France. Patients hospitalized in a cardiac intensive care unit for an acute coronary syndrome with at least 1 lifestyle risk factor (current smoking, sedentary lifestyle, or overweight or obesity) were randomized according to a computer-generated list with sequentially numbered, sealed envelopes. INTERVENTION: Patients underwent an education program in a unique non-hospital setting (a House of Education) or were treated according to physicians' usual standard of care. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite that included at least 1 of the following: smoking cessation, at least 3 hours per week of physical activity, at least 5% reduction in weight, and at least 4% reduction in waist circumference. Patients were followed up for 1 year. An intent-to-treat analysis was performed. RESULTS From June 21, 2006, to July 30, 2008, a total of 251 patients were randomized to the House of Education and 251 to conventional care. The 2 groups did not differ significantly at 12 months in the primary composite outcome (51.8% vs 49.8% success rate; adjusted relative risk [aRR], 1.11; 95% CI, 0.90-1.37) or with correction of all risk factors (aRR, 1.22; 95% CI, 0.89-1.66). Similarly, the 2 groups did not differ by physical activity (aRR, 1.05; 95% CI, 0.92-1.21), smoking cessation (aRR, 0.99; 95% CI, 0.87-1.13), and weight or waist reduction (aRR, 1.07; 95% CI, 0.84-1.36). CONCLUSIONS AND RELEVANCE: Compared with conventional care, the House of Education did not result in superior improvement in lifestyle-related cardiovascular risk factors after an acute coronary syndrome. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00337480.

C-reactive protein and transesophageal echocardiographic markers of thromboembolism in patients with atrial fibrillation.

BACKGROUND: To determine whether C-reactive protein (CRP) in combination with a stroke risk stratification scheme can help in identifying transesophageal echocardiographic (TEE) markers of thromboembolism such as left atrial (LA)/left atrial appendage (LAA) thrombus, severe LA/LAA spontaneous echocardiographic contrast (SEC), and aortic plaque ≥ 4 mm. METHODS: Transthoracic echocardiography, TEE, and CRP measurement were performed at admission in 178 patients with non-valvular atrial fibrillation not receiving oral anticoagulant therapy. Patients were classified as at low, moderate, or high risk of thromboembolism based on seven clinical risk stratification schemes (SPAF, CHADS(2), Framingham, Birmingham/NICE, ACC/AHA/ESC 2006 guidelines, ACCP 2008, CHA(2)DS(2)VASc). RESULTS: Severe LA/LAA SEC, LA/LAA thrombus, and aortic plaque ≥ 4 mm were present in 6.2%, 6.7%, and 10.1% of patients, respectively. The combination of CRP with a cut-off value of 3.4 mg/L with the Birmingham/Nice or ACC/AHA/ESC 2006 risk score, led to a negative predictive value of 100% in low-risk patients and 91% in moderate-risk patients. For the detection of severe LA/LAA SEC or thrombus, a good discrimination (area under curve ≥ 0.70) using only clinical risk markers was observed for all classifications except for the Framingham and CHADS(2) risk scores. The addition of CRP did not improve the detection of LA/LAA SEC or thrombus, or of severe LA/LAA SEC, thrombus, or aortic plaque. CONCLUSION: The combination of clinical risk markers and CRP can help to exclude the presence of the TEE markers LA/LAA SEC or LA/LAA thrombus, particularly in patients classified at low or moderate risk of stroke.

Should all patients with non-valvular atrial fibrillation be anticoagulated?

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. The prevalence and incidence of AF are rising, as confirmed in several European and American registries. Guidelines published in 2008 from the European Society of Cardiology/American Heart Association and from the American College of Chest Physicians, clarified the strategy of antithrombotic treatment in AF, which is based on the presence of risk factors for thromboembolism. This approach allows physicians to classify patients as at low, moderate or high risk, according to their individual risk characteristics, which are relatively similar in both sets of recommendations. Patients at moderate risk, however, who might justify anticoagulant or antiplatelet treatment, could be better characterized using morphological (echocardiographic) and/or biological factors or risk markers. Recent data have shown that the existence of a thrombogenic milieu in the left atrium (e.g., dilatation of the left atrial appendage and/or thrombus and/or spontaneous echocontrast and/or reduced emptying/filling flow velocity) indicates a higher risk of embolism and mortality. Furthermore, high-sensitivity C-reactive protein and haemostasis markers of coagulation are associated with thromboembolic risk and excess mortality in AF. Although current recommendations for the management of AF are not based on such markers, both could help physicians choose the optimal antithrombotic treatment (either vitamin K antagonists or antiplatelet drugs) according to the patient's specific risk profile. Nowadays, registries confirm under-prescription of vitamin K antagonist treatment in the 'real world,' even in patients at high thromboembolic risk, and over-prescription for at least one-third of low-risk patients. It is crucially important to realize that the risk of bleeding in patients with risk factors (e.g., older age, hypertension) is close to the risk of thromboembolism, which can have devastating outcomes in patients in AF. Alternative and efficient strategies (new oral anticoagulants, non-surgical closure of the left atrial appendage using percutaneous devices) are currently under investigation. Therefore reducing the risk of thromboembolism should be physicians' primary aim, particularly with the advent of alternative treatments and the development of new antithrombotic drugs such as oral thrombin and factor Xa inhibitors, which are currently being evaluated in clinical trials.

Is the aortic root dilated in obstructive sleep apnoea syndrome?

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) is associated with an increased risk of arterial hypertension (AH), coronary artery disease, atrial arrhythmias, heart failure, stroke and death. Whether OSAS influences aortic root size has not been fully investigated. The aim of our study was to investigate aortic root diameter and aortic stiffness in OSAS. METHODS: Using transthoracic Doppler echocardiography, we evaluated 76 patients with OSAS (mean age 52.7 +/- 9.5 years, 70 men [92%]) with no overt cardiovascular disease. The following parameters were measured offline: aortic diameter at Valsalva sinuses, aortic regurgitation (AR) grade, left ventricular (LV) mass, LV ejection fraction (LVEF, Simpson rule), systolic pulmonary artery pressure (sPAP). Aortic stiffness (carotid-femoral pulse wave velocity, PWV) was measured non-invasively using SphygmoCor technology. RESULTS: Mean duration of OSAS was four years and 84% of patients were being treated with continuous positive airway pressure. AH was documented in 39 (51%) patients. The mean aortic root diameter was 35.3 +/- 3.8 mm (26.9-44.6 mm) and the prevalence of aortic root dilatation was 3.9% (3 of 76 patients). On univariate analysis, age and sex were significant predictors of aortic root dilatation whereas arterial hypertension was not. CONCLUSIONS: The prevalence of aortic root enlargement was not increased in OSAS. Only age and sex and not arterial hypertension, were associated with aortic dilatation.

A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex.

The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated 6-(4-hydroxyphenyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells.

Two-step activation of ATM by DNA and the Mre11-Rad50-Nbs1 complex.

DNA double-strand breaks (DSBs) trigger activation of the ATM protein kinase, which coordinates cell-cycle arrest, DNA repair and apoptosis. We propose that ATM activation by DSBs occurs in two steps. First, dimeric ATM is recruited to damaged DNA and dissociates into monomers. The Mre11-Rad50-Nbs1 complex (MRN) facilitates this process by tethering DNA, thereby increasing the local concentration of damaged DNA. Notably, increasing the concentration of damaged DNA bypasses the requirement for MRN, and ATM monomers generated in the absence of MRN are not phosphorylated on Ser1981. Second, the ATM-binding domain of Nbs1 is required and sufficient to convert unphosphorylated ATM monomers into enzymatically active monomers in the absence of DNA. This model clarifies the mechanism of ATM activation in normal cells and explains the phenotype of cells from patients with ataxia telangiectasia-like disorder and Nijmegen breakage syndrome.

Synthesis and anti-HIV-1 activity of 4-[4-(4,6-bisphenylamino-triazin-2-ylamino)-5-methoxy-2-methylphenylazo]-5-hydroxynaphthalene-2,7-disulfonic acid and its derivatives.

A structure-based design approach has been used to optimize a lead HIV-1 entry inhibitor targeted to the envelope glycoprotein gp41. The docking study on this lead compound revealed important structural requirements that need to be preserved as well as structural non-requirements that could be eliminated to substantially reduce the molecular size of the lead compound. Based on the results from docking study, a limited number of analogues were designed and synthesized. This approach yielded a new analogue (compound 4) that retained the anti-HIV-1 activity with reduced molecular size approaching towards more drug-like character.

Rapid and automated fluorescence-linked immunosorbent assay for high-throughput screening of HIV-1 fusion inhibitors targeting gp41.

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 plays an important role in the virus entry. During the process of fusion between the viral and target cell membranes, the N- and C-terminal heptad repeat (HR) regions of the gp41 extracellular domain associate to form a 6-helical bundle, corresponding to the fusion-active gp41 core. Any compound that blocks the gp41 6-helix bundle formation between the N- and C-peptides, which are derived from the N- and C-terminal HR regions, respectively, may inhibit HIV-1 mediated membrane fusion. Based on this principle, we previously established a sandwich enzyme-linked immunosorbent assay (ELISA) for drug screening by using the N-peptide N36 and the C-peptide C34 and a monoclonal antibody (NC-1) which specifically recognizes the gp41 6-helix bundle. In the present study, a fluorescence-linked immunosorbent assay (FLISA) was developed by using fluorescein isothiocyanate (FITC)-conjugated C34 to replace C34 and by directly detecting fluorescence intensity instead of more complicated enzymatic reaction. Compared with the sandwich ELISA, this FLISA has similar sensitivity and specificity, but it is much more rapid, economic and convenient. Using an Integrated Robotic Sample Processing System, this assay has been applied for high-throughput screening of organic compounds on a large scale for HIV-1 fusion inhibitors targeting gp41.