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Contact investigations following the diagnosis of active tuberculosis (TB) are paramount for the control of the disease. Epidemiological data are very powerful for contact tracing but might be delayed and/or difficult to integrate, especially in the setting of multiple contact-tracing investigations. The aim of this study was to address the added-value of whole-genome sequencing (WGS) to routine local TB surveillance systems. From November 2016 to July 2017, the local TB surveillance system identified three clusters that could constitute a unique larger outbreak. Epidemiological and clinical information were integrated with WGS genotyping data of Mycobacterium tuberculosis strains obtained using a simple DNA extraction method coupled with sequencing using an Illumina MiSeq platform and an in-house bioinformatics pipeline for single nucleotide polymorphism (SNP) analysis. Epidemiological investigations identified three putative TB clusters potentially interrelated including eight patients with active TB. Seven M. tuberculosis isolates were available and analysed by WGS. Using a 5-SNP threshold to define recent transmission, WGS-based genotyping supported the occurrence of the three clusters as well as a link between clusters 1 and 2 (SNP ≤1), constituting a larger outbreak. This outbreak was clearly delineated by refuting a potential link with the third cluster (SNP >500). Genotyping data did not support the belonging of patient 7 to any studied cluster. This study illustrates the usefulness of WGS genotyping for routine TB surveillance systems in local communities to rapidly confirm or disprove epidemiological hypotheses and delineate TB clusters, especially in the context of multiple contact-tracing investigations. Keywords: Contact investigation, genotyping outbreak, molecular epidemiology, Mycobacterium tuberculosis, whole-genome sequencing

Background and aim: Magnetic resonance imaging (MRI) provides excellent anatomical coverage for local and regional indices of aortic function and structure. However, blood pressure (BP) assessments is usually necessary for the calculation of these functional MRI parameters. Unfortunately, most pressure devices are not safe in high magnetic field. The aim of our study was to evaluate the use of the new SphygmoCor XCEL device (AtCor Medical, Australia) with a 6m hose to estimate central BP. Methods and results: A SphygmoCor XCEL device with a 2m hose and a 2nd device with a 6m hose were fitted simultaneously on both arms of 38 subjects (63% men, median age:36.8years (28.5–58.4)). After 5 minutes rest supine, BP was recorded and then cables were changed (cuffs unchanged). Brachial, central BP, augmentation pressure (AP) and augmentation index (Aix) were recorded. Brachial SBP, DBP, PP, central SBP, DBP PP, AP and Aix from the 2m and 6m device were strongly correlated (R2=0.96, 0.91, 0.78, 0.97, 0.85, 0.95, 0,96 respectively, p

Background: Whether angiotensin receptor blockers can dose-dependently remodel the arterial wall during long-term treatment has only been rarely studied. Olmesartan (OM) has previously shown a favourable pharmacodynamic profile for such an action. Methods: In this phase 3, multi-centre, double-blind, randomized, parallel-group study, 133 subjects with hypertension and metabolic syndrome were assigned to three treatment groups and received either OM 20 mg (n=44), OM 40 mg (n=42), or OM 80 mg (n=47) once a day according to a force-titration design during a 1 year period. Office blood pressure (BP), 24hABPM, aortic stiffness (carotid-femoral pulse wave velocity-PWV) and carotid parameters (diameter, intima-media thickness, and stiffness) were measured at baseline, 24 weeks (W24) and 52 weeks (W52). A mixed-model was used for statistical analysis. Results: PWV significantly decreased (P

Background. Inflammatory bowel disease (IBD) is associated with an increased cardiovascular risk that is not explained by traditional cardiovascular risk factors, as well as an increased arterial stiffness. In this study, we investigated the relationship between inflammation and arterial stiffening and tested the hypothesis that aortic stiffening is reduced by immunomodulatory therapy in IBD. Methods. Pulse wave velocity (PWV) was measured in 80 IBD patients and 80 matched controls. Both acute and chronic inflammatory measures were determined. The effect of therapy on PWV was measured at 0 and 3.3 ± 0.3 years in 13 IBD patients treated with immunomodulating drugs (steroids, anti TNF-α or azathioprine) and in 10 IBD patients treated only with salicylates. Results. IBD patients, compared with controls, have higher carotid-femoral PWV (7.9 ± 1.6 vs. 7.0 ± 1.1 m/s, respectively; P < 0.001) and carotid-radial PWV (8.8 ± 1.3 vs. 7.2 ± 0.9 m/s, respectively; P < 0.001). Age was a determinant of carotid-femoral PWV in both groups and of carotid-radial PWV in IBD patients. In fully adjusted models performed on IBD subjects, carotid-femoral PWV was positively associated with disease duration, and carotid-radial PWV was positively associated with a history of IBD reactivation and high-sensitivity C-reactive protein. For a comparable value at baseline, the variation of carotid-femoral PWV during follow-up was significantly reduced in subjects treated with immunomodulating drugs compared with those treated only with salicylates (+0.03 ± 0.22 vs. +0.23 ± 0.19 m/s/year of follow-up, respectively; P < 0.05; Fig. 1). Conclusions. IBD is associated with increased arterial stiffness, which correlates with markers of chronic and acute inflammation. Aortic stiffening is reduced by immunomodulating drugs.

Objective: Carotid-femoral PWV (cfPWV) is a regional marker of vascular ageing: our aim was to take advantage of Magnetic Resonance (MRI) and High resolution Echotracking (HRE) in order to non-invasively investigate the effect of age and blood pressure (BP) on different segments of large arteries. Methods: Regional stiffness was measured as cfPWV using Sphygmocor and as aortic arch PWV using MRI (ArchPWV). Local stiffness was measured at the carotid artery site using HRE (carPWV), and at the ascending and descending thoracic aorta sites using MRI (As and DsAoPWV). Local PWVs were calculated using Bramwell-Hill equation and all velocities were expressed in m/s. We included 72 normotensive non diabetic subjects (56.7% men), free from overt cardiovascular disease. Results: In these 42±15 yrs-old subjects, having SBP/DBP 119±11/66±8 mmHg, PWV increased from proximal to distal segments: AsAoPWV=5.37±2.07 m/s; ArchPWV= 5.47±2.07 m/s; DsAoPWV=5.45±1.40 m/s; carPWV=5.79±1.5 m/s; and cfPWV=7.65±1.58 m/s. In univariate analysis, all PWVs strongly increased with age (r2 ranging from 0.36 for ArchPWV to 0.54 for AsAoPWV; p

Background: Finger-toe pathway could represent a good alternative to assess the arterial stiffness conveniently. The aim of this study is to evaluate the accuracy of the pOpmètre which measures finger-toe pulse wave velocity (ft-PWV). Methods: The pOpmètre® has 2 photodiodes sensors, positioned on the finger and on the toe, next to the pulp artery, and a cardiac activity electrode. Pulse waves were recorded continuously for 20 sec, and the difference (Dtf) between the toe pulse wave transit times (PWtt) and the finger PWtt was calculated relative to R-ECG. The travel distance was based on subject’s height. Study 1 compared the ft-PWV to the carotid-femoral PWV (cf-PWV) obtained by the reference method SphygmoCor in 86 subjects (53±20 yrs) including 69 patients with various pathologies and 9 healthy normotensives. Study 2 compared the changes of ft-PWV and cf-PWV during a dynamic test in 10 healthy subjects. Results: ft-PWV correlated significantly with cf-PWV (r2 = 0.43, p

This paper presents the design of an MMIC oscillator operating at a 38 GHz frequency. This circuit was fabricated by the III–V Lab with the new InP/GaAsSb Double Heterojunction Bipolar Transistor (DHBT) submicronic technology (We=700 nm). The transistor used in the circuit has a 15 μm long two-finger emitter. This paper describes the complete nonlinear modeling of this DHBT, including the cyclostationary modeling of its low frequency (LF) noise sources. The specific interest of the methodology used to design this oscillator resides in being able to choose a nonlinear operating condition of the transistor from an analysis in amplifier mode. The oscillator simulation and measurement results are compared. A 38 GHz oscillation frequency with 8.6 dBm output power and a phase noise of −80 dBc/Hz at 100 KHz offset from carrier have been measured.

CTLA-4 is the major nefative regulator of T cell response. We have analyzed the expression of CTLA-4 in human monocytes and monocyte-derived DCs and the effects of its engagement on cytokine production and T cell stimulatory activity by mature DCs (mDCs). We found the CTLA-4 was highly expressed on freshly isolated monocytes, then down-modulated on the immature DCs (iDCs) and upregulated on mDCs. Treatment of mDCS with an agonistic anti-CTLA-4 m Ab enhanced secretion of IL-10 but reduced secretion of IL-8 and IL-12, as well as autologous CD4* T-cell proliferation in response to simulation with PPD recall antigenloaded-DCs. Neutralization of IL-10 with an anti-IL-10 antibody partially restored the ability of anti-CTLA-4-treated mDCs to stimulate T cell proliferation in response to PPD. Our data provide the first evidence that CTLA-4 receptor is expressed by human mDCs and exerts immune modulatory effects in these cells.

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare severe genetic disease which results from mutations in the gene encoding type III procollagen (COL3A1), characterized by vascular and/or hollow organic ruptures. No treatment is yet validated. We tested the ability of celiprolol, a beta1-adrenoceptor antagonist with a beta2-adrenoceptor agonist action, for preventing the complications of vEDS in a prospective, randomized, open, blinded endpoints trial. Methods: Fifty three previously untreated vEDS patients were randomized to a 5-year treatment with either celiprolol (n=25) or no treatment (n=28). The two groups were matched for demographic, medical historic and clinical characteristics. Celiprolol was up-titrated from 100 to 400mg by steps of 100mg every 6 months. The primary end-point was an arterial event (rupture or dissection, fatal or not) occurring during follow-up. Secondary endpoints were intestinal or uterine rupture or major clinical events, related to vEDS, judged by the event committee. Results: Mean duration of follow-up was 47 (± 15) months. The study was ended prematurely by the safety monitoring board since significant differences were reached between two groups. The primary endpoint was reached by 5 patients (20%) in the celiprolol group and by 14 patients (50%) in the control group (hazard ratio, 0.36; 95% CI, 0.15 to 0.88; P=0.04). Primary plus secondary endpoints occurred in 6 patients (24%) in the celiprolol group and in 17 patient (61%) in the control group (hazard ratio, 0.31; 95% CI, 0.14 to 0.71; P=0.0097). Conclusions: Celiprolol effectively reduced both vascular complications and organic ruptures in vEDS patients.

Arterial baroreflex sensitivity (BS) is dependent on distension rate of baroreceptors, itself dependent on arterial stiffness. Differences in BS between younger and older subjects, and normotensive and hypertensive patients may be explained by differences in arterial stiffness. The objective was to demonstrate that increased carotid stiffness is a determinant of reduced baroreflex sensitivity. Methods: 312 subjects were randomly selected from the EPP3 study (10000), a general population based cohort. We obtained intima-media thickness, internal-diameter and distensibility of the common carotid artery thanks to the Artlab ® echotracking device. Cross spectral analysis between distension rate and RR interval on 5min recordings was used for BS, estimated through the gain in the low frequency range (LF). Sympathetic activation (LF distension rate) Baroreflex sensitivity (LF gain) IMT R2=0.01, p

Purpose: Fabry disease is a deficiency of lysosomal enzyme α-galactosidase A leading to accumulation of glycosphyngolipids in cardiac and vascular tissues. After long-term enzyme replacement treatment, we described a continuous vascular hypertrophy whereas the aortic stiffness was paradoxically decreasing. Preliminary results reported aorta dilatation in treated patients. The objective of this study was to determine the prevalence of aortic dilatation, and the relationship between aorta dilatation, aortic stiffness and arterial remodeling in treated Fabry patients. Methods: Case-control study in 34 Fabry males patients (38±12 yrs) receiving enzyme infusions every other week (3.5±1.5 yrs), age-matched with 34 controls. All patients and subjects had arterial measurements of a) carotid IMT and diameter, pulse pressure (PP) and stiffness obtained with echotracking; b) aortic stiffness obtained through carotid-femoral PWV and c) aorta diameters (sinus, ascending and descending tubule, arch aortic) assessed by MRI examinations. Results: Aorta root dilatation (>40mm at sinus) was observed in 13 FD patients (35%), but not at others segments. In controls, sinus diameter was positively correlated with age, aortic and carotid stiffness in univariate analysis (R=0.59, P0.0001 respectively) and with both age and CPP in multivariate analysis (R=0.59, P

Epidemiologic studies have clearly demonstrated that cardiovascular risk is not only determined by conventional risk factors of importance in adult life, but also by early life events resulting of re-settings of key physiological functions. In our model of rats exposed in utero to maternal diabetes, we previously identified a specific gene expression profile of the thoracic aorta at a pre-hypertensive stage (3 months) in favour of vasoconstriction, which could explain the development of hypertension in the adult offsprings. We found an increase of CYP4f2 (however we failed to confirm its up-regulation at the protein level), and a decrease by 50 percent of the prostacyclin (IP) receptor at messenger and protein levels in aorta of rats exposed to maternal diabetes (DMO) compared to rats from control mothers (CMO). We demonstrated the functional implication of this down-expression of the IP receptor in a pharmacological study using a prostacyclin analogue: Iloprost (iv, 4 ng/kg/ml). Indeed, we showed that, even before the onset of hypertension, SBP reduction in response to Iloprost was attenuated in DMO rats (−10.7% vs −21.3% in CMO, p

Purpose: A decrease in aortic stiffness could theoretically occur after several years of treatment but reduction has never been unequivocally demonstrated in clinical practice. Association with changes in blood pressure remained unclear. Methods: This longitudinal observational study was conducted in 97 patients (63±1 yrs, 47 women) with treated essential hypertension attending the outpatient hypertension clinic at Pompidou Hospital. Aortic stiffness and carotid pulse pressure (CPP) were determined through carotid-femoral PWV and applanation tonometry. The first measurement of PWV was performed when brachial SBP was lowered below 140 mmHg under treatment. 66 patients had 3 PWV measurements, and 31 patients had 2 measurements during an extended follow-up (5.3±1.2 yrs). Results: The reduction in PWV (from 14.2±4.2 to 11.1±2.4m/s, linear mixed model, P

Background: We previously described longitudinal strain gradient named bending strain (BS), along the common carotid artery (CCA) with two distinct patterns (Paini, Stroke 2007, Beaussier, Hypertension 2008): Pattern A (larger radial strain at the plaque level than at adjacent CCA) and its opposite, Pattern B. Aim: To assess the role of change in CCA thickness (IMT) and medial diameter (D) during the cardiac cycle at the level of plaques according to functional patterns of BS. Method: 45 CCA were analysed at the level of the plaque in 26 patients. Mechanical parameters were measured at 128 sites on a 4 cm long CCA segment by an echotracking system (ArtLab®). Plaque composition was determined by magnetic resonance imaging (MRI). For each plaque, systolo(s)-diastolic(d) variation of IMT and D were calculated. We obtained ΔIMT ((IMTs - IMTd)/IMTd), ΔDiameter ((Ds - Dd)/Dd) and ratio R (ΔIMT/ΔD). Results: R did not significantly differ according to remodeling pattern neither to plaque composition. Plaques exhibiting Pattern B (n=25) were characterized by an R 73 % higher than plaques exhibiting Pattern A (n=20) (5.9 ± 3.0 versus 3.4 ± 1.6, p