Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine administered concomitantly with other paediatric vaccines in toddlers: a phase III randomised study.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) vs. a licensed quadrivalent meningococcal tetanus toxoid-conjugate vaccine in meningococcal vaccine-naïve and meningococcal C conjugate vaccine-primed toddlers: a phase III randomised study.

Vaccination remains the best strategy to reduce invasive meningococcal disease. This study evaluated an investigational tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT) vs. a licensed tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MCV4-TT) (NCT02955797). Healthy toddlers aged 12-23 months were included if they were either meningococcal vaccine-naïve or MenC conjugate (MCC) vaccine-primed (≥1 dose of MCC prior to 12 months of age). Vaccine-naïve participants were randomised 1:1 to either MenACYW-TT (n = 306) or MCV4-TT (n = 306). MCC-primed participants were randomised 2:1 to MenACYW-TT (n = 203) or MCV4-TT (n = 103). Antibody titres against each of the four meningococcal serogroups were measured by serum bactericidal antibody assay using the human complement. The co-primary objectives of this study were to demonstrate the non-inferiority of MenACYW-TT to MCV4-TT in terms of seroprotection (titres ≥1:8) at Day 30 in both vaccine-naïve and all participants (vaccine-naïve and MCC-primed groups pooled). The immune response for all four serogroups to MenACYW-TT was non-inferior to MCV4-TT in vaccine-naïve participants (seroprotection: range 83.6-99.3% and 81.4-91.6%, respectively) and all participants (seroprotection: range 83.6-99.3% and 81.4-98.0%, respectively). The safety profiles of both vaccines were comparable. MenACYW-TT was well-tolerated and demonstrated non-inferior immunogenicity when administered to MCC vaccine-primed and vaccine-naïve toddlers.

Association between breast milk fatty acids and HIV-1 transmission through breastfeeding.

A residual mother-to-child transmission of HIV through breastfeeding persists despite prophylaxis. We identified breast milk fatty acids (FA) associated with postnatal HIV transmission through breastfeeding in a case-control study. Cases (n=23) were HIV-infected women with an infant who acquired HIV after 6 weeks of age. Controls (n=23) were matched on infant׳s age at sample collection. Adjusting for maternal antenatal plasma CD4 T cell count, cis-vaccenic acid (18:1n-7) and eicosatrienoic acid (20:3n-3) were associated with HIV transmission in opposite dose-response manner: OR (tertile 3 versus tertile 1): 10.8 and 0.16, p for trend=0.02 and 0.03, respectively. These fatty acids correlated with HIV RNA load, T helper-1 related cytokines, IL15, IP10, and ß2 microglobulin, positively for cis-vaccenic acid, negatively for eicosatrienoic acid. These results suggested a change in FA synthesis by mammary gland cells leading to increased cis-vaccenic acid in milk of mothers who transmitted HIV to their infant during breastfeeding.

Students perceived stress in academic programs: consequences for its management.

BACKGROUND: Academic stress contributes to the deterioration of the students' quality of life. Psychological determinants involved in the stress process, trait anxiety and coping, have been neglected when assessing the role of academic programs in stress. This study aimed at determining whether academic programs are associated with a high level of perceived stress above and beyond potential personal and environmental risk factors, as well as coping strategies. METHODS: A cross-sectional survey was conducted in 2009 among third-year medical (total n=170, participants 88%), dental (n=63, 94%), psychology (n=331, 61%) and sports sciences (n=312, 55%) students in Montpellier (France). The stress level experienced during the last 2months, trait anxiety and coping strategies were appraised. Substance use, psychological care, and stress triggers were also collected using a self-administered questionnaire. RESULTS: Compared with medicine and after adjusting for gender and age, only the sports program was associated with a lower perceived stress risk: adjusted odds ratio: 0.54 [95% Confidence interval: 0.30; 0.99]. Substantial reductions in perceived stress risks were observed in science students after additional adjustments for non-academic stress triggers, substance use, psychological care (adjusted odds ratio: 0.20 [95% Confidence interval: 0.09; 0.41]), and also for trait anxiety and coping strategies (adjusted odds ratio: 0.23 [95% Confidence interval: 0.10; 0.54]). Compared with medicine and after these additional adjustments, psychology had a significantly lower perceived stress risk (0.34 [0.18; 0.64]; 0.40 [0.19; 0.86], respectively), dentistry had a similar risk (0.82 [0.35; 1.91]; 0.53 [0.20; 1.43], respectively). CONCLUSION: Sports and psychology programs had a lower perceived stress risk compared with medicine. Personal and environmental risk factors and coping strategies modified the association between academic program and perceived stress. Developing efficient coping strategies in students and improving academic environment could contribute to prevent the potential deleterious consequences of stress.

[Medicoeconomic assessment of epilepsy surgery in adults with medically intractable partial epilepsy. Three-year outcomes from a multicenter French cohort]. / Evaluation médicoéconomique de la chirurgie des épilepsies partielles pharmacorésistantes de l'adulte. Résultats à trois ans d'une étude prospective multicentrique française.

PURPOSE: To compare resective surgery and medical therapy in a cost-effectiveness analysis in a multicenter cohort of adult patients with partial intractable epilepsy. POPULATION AND METHODS: Adult patients with partial, medically intractable, potentially operable epilepsy were eligible and followed every year over five years. Effectiveness was defined as one year without seizure. The long-term costs and effectiveness were extrapolated over the patients' lifetime with a Markov model. Productivity (indirect costs) and quality of life (QOLIE-31, SEALS) were also assessed. Changes before and after surgery were compared between the two groups. RESULTS: Two hundred and eighty-nine patients were included (119 with surgery, 161 medically treated, six not eligible, three lost to follow-up). One year after surgery, 81% of the patients were seizure-free; at two and three years, this rate was 78%. In the medical group, these rates were 10, 18, and 15%, respectively. The cost of the explorations was euro 8464; including surgery, it was euro 19,700. In the medical group, the average annual direct costs were between 3500 and euro 6000. At two years after surgery, the annual direct cost decreased to euro 2768, at three years, it was euro 1233, predominately antiepileptic drug costs. Surgery became cost-effective between seven and eight years. In the surgical group, all the quality-of-life scores improved at one year after surgery and were stable during the second and third years. CONCLUSION: Surgical therapy was cost-effective at the middle term even though indirect costs were not considered.

Measuring agreement for ordered ratings in 3 x 3 tables.

OBJECTIVES: When two raters consider a qualitative variable ordered according to three categories, the qualitative agreement is commonly assessed with a symmetrically weighted kappa statistic. However, these statistics can present paradoxes, since they may be insensitive to variations of either complete agreements or disagreements. METHODS: Agreement may be summarized by the relative amounts of complete agreements, partial and maximal disagreements beyond chance. Fixing the marginal totals and the trace, we computed symmetrically weighted kappa statistics and we developed a new statistic for qualitative agreements. Data sets from the literature were used to illustrate the methods. RESULTS: We show that agreement may be better assessed with the unweighted kappa index, kappa(c), and a new statistic zeta, which assesses the excess of maximal disagreements with respect to the partial ones, and does not depend on a particular weighting system. When zeta is equal to zero, maximal and partial disagreements beyond chance are equal. With its estimated large sample variance, we compared the values of two contingency tables. CONCLUSIONS: The (kappa(c), zeta) pair is sensitive to variations in agreements and/or disagreements and enables locating the difference between two qualitative agreements. The qualitative agreement is better with increasing values of kappa(c) and zeta.

[Cost-effectiveness of epilepsy surgery in a cohort of patients with medically intractable partial epilepsy--preliminary results]. / Evaluation médico-économique de la chirurgie des épilepsies partielles pharmaco-résistantes de l'adulte. Etude coût-efficacité--résultats préliminaires.

OBJECTIVE: Patients with medically intractable epilepsy are potential candidates for surgery if the epileptogenic tissue is localized and resectable. Surgical therapy can eliminate seizures but is very expensive. We followed a prospective adult cohort of intractable epileptic patients in order to perform a cost-effectiveness analysis. POPULATION AND METHODS: Adult patients with a suspected partial medically intractable and operable epilepsy were eligible for evaluation, explorations and/or surgery. Clinical and economical data were collected at the inclusion and every 6 months over at least two years. Two patient groups were analyzed: some underwent a surgery, others did not. Clinical data were compared between both groups. As the data collection was not yet complete, we compared the surgery to a continuation of the preoperative medical management in a cost-effectiveness analysis. Direct medical and nonmedical costs were evaluated according to a societal perspective. The effectiveness was defined as one year without seizure. We assessed the incremental cost-effectiveness ratio (ICER) for the first two years after the surgery. We also modeled long-term costs and effectiveness and extrapolated the results over the patients' lifetime with a Markov model. We computed the ICER and performed a sensitivity analysis. Indirect costs were measured in physical units and intangible costs were assessed with quality-of-life measures (QOLIE-31, SEALS). Data were compared before and after surgery. RESULTS: Among the 286 patients included, 119 did not enter in the analysis: 7 were not eligible, 44 not operable, 31 did not present a follow-up, 37 still underwent exams. Finally, 89 underwent a surgical treatment, and 78 were medically treated. Disease was more severe in surgical patients than in medical patients: seizures frequency, depressive disorders and cognitive impairment were greater. One year after the surgery, 83% patients were seizure free. During the year before inclusion and the year after surgery, direct costs were mainly due to hospitalization. During the second year after surgery, the cost of antiepileptic drugs predominated. One additional year without seizure costs 23 531 euro one year after surgery and 9533 euro two years after surgery. In a long-term perspective, the surgery became cost-effective between 7 and 8 years after the surgery. CONCLUSION: Surgical therapy is a cost-effective treatment in a middle-term even without indirect costs consideration.

Can endobronchial biopsy analysis be recommended to discriminate between asthma and COPD in routine practice?

BACKGROUND: International guidelines stress the importance of accurately discriminating between asthma and chronic obstructive pulmonary disease (COPD). Although characteristic pathological features have been described for both conditions, their discriminatory power has never been systematically assessed. METHODS: Endobronchial biopsy (EBB) specimens from patients with a clear clinical diagnosis of asthma and COPD (50 per group) were examined by three pathologists in a double blind manner. They were asked to propose a pathological diagnosis of either asthma or COPD and to analyse qualitatively the most frequent abnormalities reported in the literature. RESULTS: The sensitivity and specificity of EBB ranged from 36% to 48% and from 56% to 79%, respectively. Eosinophils strongly biased the pathological diagnoses in favour of asthma, whereas their estimated prevalence was similar (11-37% in asthma and 13-41% in COPD). Metaplasia (11-39% in COPD, 1-18% in asthma) and epithelial inflammation (28-61% in COPD, 11-38% in asthma) tended to be specific to COPD, whereas epithelial desquamation (80-98% in asthma, 61-88% in COPD) and basement membrane thickening (71-94% in asthma, 53-88% in COPD) tended to be associated with asthma. There was acceptable intra- and inter-observer agreement only for metaplasia and epithelial eosinophils. CONCLUSIONS: Specific histopathological features of asthma and COPD probably exist, but current routine analysis procedures to assess EBB specimens are not sufficiently discriminatory. This might be rectified by improving pathological definitions.

Long-lasting potentiation and depression without presynaptic activity.

1. Long-term potentiation (LTP) and long-term depression (LTD) require a rise in intracellular Ca2+ concentration ([Ca2+]i) in the postsynaptic CA1 pyramidal neuron to activate Ca-dependent biochemical processes. This rise in [Ca2+]i is a necessary trigger for the induction of LTP and LTD, but it is unclear if concurrent presynaptic activity is required for their induction or expression. 2. We used photolysis of the caged-Ca2+ compound nitr-5 to elevate postsynaptic [Ca2+]i. Long-lasting potentiation (LLP) and long-lasting depression (LLD) were obtained in the absence of presynaptic activity. 3. Because LLP and LLD share common features with LTP and LTD induced by presynaptic stimulation these results show that a rise in [Ca2+]i in the postsynaptic CA1 pyramidal neurons is necessary and sufficient for the induction and expression of LTP and LTD, and that concurrent presynaptic activity is not required.

Postsynaptic levels of [Ca2+]i needed to trigger LTD and LTP.

Long-term potentiation (LTP) and long-term depression (LTD) in CA1 pyramidal neurons are both triggered by a postsynaptic rise in intracellular Ca2+ concentration ([Ca2+]i). We used photolysis of postsynaptic caged Ca2+ compounds to search for differential thresholds for activation of these processes. Long-lasting potentiation (LLP) resembling LTP, and long-lasting depression (LLD) resembling LTD, were evoked by [Ca2+]i elevations of comparable magnitude and duration in different cells. No distinctions in threshold for these processes were detectable. LLP was occluded by tetanically induced LTP and blocked by calmodulin inhibition, and LLD was occluded by electrically induced LTD and blocked by phosphatase inhibition.

Differential beta-adrenergic regulation and phenotypic modulation of voltage-gated calcium currents in rat aortic myocytes.

1. We studied the beta-adrenergic regulation of voltage-gated Ca2+ channel currents using the whole-cell patch-clamp technique (18-22 degrees C) in freshly isolated and in cultured (1-20 days) rat aortic vascular smooth muscle cells (VSMCs). These currents include a transient low-voltage-activated (LVA) current and two L-type-related high-voltage-activated currents (HVA1 and HVA2, respectively). 2. At 10 microM, the beta-adrenergic agonist, isoprenaline, increased the HVA2 current (65 +/- 30%, n = 10) but had no effect on LVA and HVA1 currents. This potentiation was dose dependent in the range 0.01-10 microM, developed with a slow time course and was mimicked by elevating intracellular cyclic AMP using the permeant analogue dibutyryl cyclic AMP (100 microM). 3. In the well-differentiated freshly isolated myocytes, only the HVA1 current was recorded. In cultured cells, a predominant frequency of occurrence of LVA and HVA1 currents was observed in modulated and differentiated myocytes, respectively. The occurrence of the HVA2 current was stable during culture but this current disappeared when the cells were confluent. It was retrieved when the confluent cells were dispersed and subcultured. 4. In conclusion, we present evidence for a differential beta-adrenergic regulation of three types of Ca2+ channel current in adult rat aortic VSMCs. The differential expression of these currents, associated with marked changes in cell phenotypes in vitro, suggests that they serve distinct physiological functions.

Two high-voltage-activated, dihydropyridine-sensitive Ca2+ channel currents with distinct electrophysiological and pharmacological properties in cultured rat aortic myocytes.

In smooth muscle cells, essentially two distinct types of voltage-gated Ca2+ channels have been shown, on the basis of their distinct electrophysiological and pharmacological properties, to coexist. Here we report that, in addition to a dihydropyridine (DHP)-sensitive, low-voltage-activated Ba2+ current (IBa,LVA), two types of high-voltage-activated Ba2+ currents with distinct waveforms were recorded in whole-cell clamped aortic myocytes; these were referred to as IBa,HVA1 and IBa,HVA2. They were investigated in cells where no IBa,LVA was detectable. IBa,HVA1 had a slow, monoexponential decay. In contrast, the decay of IBa,HVA2 was much faster and biexponential. In addition, IBa,HVA2 had more negative ranges of activation and steady-state inactivation than IBa,HVA1 and was more sensitive to the DHP antagonist nicardipine (concentrations for half maximum inhibition 0.2 microM and 2 microM, respectively). When using the physiological ion Ca2+ as the charge carrier, the decay of HVA1 currents was not altered, whereas both time constants of HVA2 current decay were accelerated five-fold. Moreover, permeability ratios (ICa/IBa) were also significantly different (0.2 and 0.6 for HVA1 and HVA2 respectively). IBa,HVA1 and IBa,HVA2 are consistent either with the existence and activation of two functionally distinct subtypes of the so-called "DHP-sensitive L-type" Ca2+ channel or with different gating behaviours of a single type of channel. Potentially, they may serve distinct biological functions and constitute distinct targets for neurotransmitters and drugs.

Differential expression of voltage-gated Ca(2+)-currents in cultivated aortic myocytes.

The expression of different types of Ca(2+)-channels was studied using the whole-cell patch-clamp technique in cultured rat aortic smooth-muscle myocytes. Ca(2+)-currents were identified as either low- or high voltage-activated (ICa,LVA or ICa,HVA, respectively) based on their distinct voltage-dependences of activation and inactivation, decay kinetics using Ba2+ as the charge carrier and sensitivity to dihydropyridines. The heterogeneity in the functional expression of the two types of Ca(2+)-channels in the cultured myocytes delineated four distinct phenotypes; (i), cells exhibiting only LVA currents; (ii), cells exhibiting only HVA currents; (iii), cells exhibiting both LVA and HVA currents and (iv), cells exhibiting no current. The myocytes exclusively expressed HVA currents both during the first five days in primary culture and after the cells had reached confluence (> 15 days). In contrast, LVA currents were expressed transiently between 5 and 15 days, during which time the cells were proliferating and had transient loss of contractility. Thus, both LVA and HVA Ca(2+)-current types contribute to Ca(2+)-signalling in cultured rat aortic myocytes. However, the differential expression of the two Ca2+ current types associated with differences in contractile and proliferative phenotypes suggest that they serve distinct cellular functions. Our results are consistent with the idea that LVA current expression is important for cell proliferation.

[Effect of a buzepide metiodide-haloperidol combination in treating functional intestinal disorders. Randomized double-blind controlled versus placebo study]. / Effet de l'association métiodure de buzépide-halopéridol dans le traitement des troubles fonctionnels intestinaux. Etude randomisée en double-aveugle contrôlée contre placebo.

The efficacy and safety of a combination of buzepide metiodide and haloperidol was assessed in a placebo-controlled double-blind trial during 2 months in 224 patients (154 women, 79 men) with the irritable bowel syndrome. The 2 groups were comparable at inclusion. The efficacy was assessed at days 15, 30 and 60. Inclusion and assessment criteria were clinical, abdominal pain being considered as the main assessment criterion. The combination proved statistically better than placebo on the frequency of symptoms at all visits and on the intensity of the most frequent symptoms (abdominal pain and distension) at the final visit. A previously defined global assessment score was found significantly better in favor of the treated group at day 15 and day 30. At the final visit, the score of a visual scale assessing the patient's global impression was also found significantly better on the combination, There was no serious side-effect. In conclusion, this study demonstrates the efficacy and safety of a combination of buzepide metiodide and haloperidol in patients with the irritable bowel syndrome.

[Sarcoidosis and portal and pulmonary arterial hypertension: a case report (author's transl)]. / Sarcoïdose avec hypertension portale et hypertension artérielle pulmonarie: une observation.

A 27-year-old patient, originally from Martinique, presented with a progressive hepatic granulomatosis with hepatomegaly, splenomegaly, and non-icteric cholestasis, associated with bronchial granulomatosis lesions. The sarcoidosis regressed rapidly after high doses (60 mg/day) of prednisone. Portal hypertension developed later and provoked a severe hematemesis from rupture of esophageal varices. Signs of pulmonary arterial hypertension were then observed, and the diagnosis confirmed by pressure tests after catheterization, and angiography. A portocaval shunt caused the esophageal varices to subside, but the pulmonary arterial hypertension, resistant to corticotherapy, was rapidly fatal. In the case reported, the pulmonary arterial hypertension, independent of any parenchymatous lesion, was attributed to fibrosis of the arterial walls. The association of portal and pulmonary arterial hypertension with sarcoidosis is a very rare occurrence, and the pathogenesis of this association remains a debatable subject.

[Local immune response in mouse experimental airborne influenza: immunoglobulin concentrations, antibody levels of immunoglobulin classes and anamnestic response in bronchial washings (author's transl)]. / La réponse immunitaire locale au cours de la grippe expérimentale de la souris: immunoglobulines, anticorps spécifiques et réponse anammestique des sécrétions bronchiques

Sera and bronchial washings from normal mice and from mice previously infected with influenza virus were analyzed for their concentration of four immunoglobulin (Ig) classes by the method of single radial immunodiffusion and for their content of specific antibody of these Ig classes by the immunofluorescent method. IgA were not detected in bronchial washings from normal mice. The IgA/IgG ratio was not higher than 0.33 in infected mice. The IgA level increased briefly in infected bronchial washings, but the levels of IgG2 and particularly of IgG1 exhibited a longer and higher increase. The maximal increase of these three Ig classes occurred by the seventh day and might have derived from transsudated serum. IgM was not identified in normal bronchial washings, but immunofluorescence detected IgM in infected washings, which also showed specific antibody in each of the four Ig classes. IgG2 and IgM contained antibody in greatest, IgA in lower concentration. Our results indicate that the most part of bronchial antibody was produced locally, since the ratio of Ig concentration to antibody titre of each Ig class was consistently higher for bronchial washings than for sera. An anamnestic secretory antibody response could not be demonstrated in bronchial washings.