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Background Urinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal. Methods and findings After clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6–9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group. Conclusions While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials. Trial registration ClinicalTrials.gov NCT 00870649, Author summary Vaccines represent an attractive tool in the fight against schistosomiasis. Pre-clinical immunization studies with the schistosome enzyme 28 kDa glutathione S-transferase (28GST) have shown a significant reduction of schistosome egg production and subsequent pathology. The objective of the present phase 3 trial was to assess the efficacy and safety of vaccination with the recombinant 28GST of Schistosoma haematobium (rSh28GST) named Bilhvax, in infected school children. After Praziquantel treatment before inclusion and three administrations of rSh28GST at one month interval as primo-vaccination, subjects received a boost injection one year after the first administration. The efficacy was evaluated as a delay of recurrence of urinary schistosomiasis. While immunological analysis showed that Bilhvax induced a consistent immune response characterized by antibodies able to inhibit 28GST enzymatic activity, the efficacy endpoint was not reached. This lack of significant effect may be due to the negative conjunction of a too challenging recurrence criterion associated with safety measures ensuring repeated PZQ treatment. The control of these main factors will be essential for the subsequent trials and must provide evidence of the Bilhvax efficacy as a safe vaccine against uro-genital schistosomiasis.

Introduction Lateral tenodesis (LT) is performed to limit the risk of iterative tear following anterior cruciate ligament (ACL) reconstruction in at-risk patients. By adding an extra procedure to isolated ACL graft, LT reconstruction increases operating time and may complicate postoperative course. The objective of the present study was to evaluate the rate of early complications. The study hypothesis was that associating ALL reconstruction to ACL reconstruction does not increase the complications rate found with isolated ACL reconstruction. Material and methods A prospective multicenter study included 392 patients: 70% male; mean age, 29.9 years; treated by associated ACL and LT reconstruction. All adverse events were inventoried. Results Mean hospital stay was 2 days, with 46% day-surgery. Walking was resumed at a mean 27 days, with an advantage for patients treated by the hamstring technique. The early postoperative complications rate was 12%, with 1.7% specifically implicating LT reconstruction: pain, hematoma, stiffness in flexion and extension, and infection. There was a 5% rate of surgical revision during the first year, predominantly comprising arthrolysis for extension deficit. The 1-year recurrence rate was 2.8%. Discussion The complications rate for combined intra- and extra-articular reconstruction was no higher than for isolated intra-articular ACL reconstruction, with no increase in infection or stiffness rates. The rate of complications specific to ALL reconstruction was low, at 1.7%, and mainly involved fixation error causing lateral soft-tissue impingement. Level of evidence IV, prospective multicenter study.

To test the hypothesis that cycling exercise modulates heart rate variability (HRV), we applied a short-time Fourier transform on the electrocardiogram of subjects performing a maximal graded cycling test. A pedaling frequency component (PFC) in HRV was continuously observed over the time course of the exercise test and extracted from R-R interval series obtained from 15 healthy subjects with a heterogeneous physical fitness, exercising at three different pedaling frequency ( n = 5): 70, 80, and 90 rpm. From 30 to 50% of the maximal power output (Pmax), in the 90 rpm group, spectral aliasing caused PFC to overlap with the respiratory sinus arrhythmia (RSA) band, significantly overestimating the PFC amplitude ( APFC). In the meantime, APFC did not increase significantly from its minimal values in the 70 rpm (∼1.26 ms) and 80 rpm (∼1.20 ms) groups. Then, from 60 to 100% maximal power output (Pmax), workload increase caused a significant ∼2.8-, ∼3.3-, and ∼3.4-fold increase in APFC in the 70, 80, and 90 rpm groups, respectively, with no significant difference between groups. At peak exercise, APFC accounted for ∼43, ∼39, and ∼49% of the total HRV in the 70, 80, and 90 rpm groups, respectively. Our findings indicate that cycling continuously modulates the cardiac chronotropic response to exercise, inducing a new component in HRV, and that workload increase during intense exercise further accentuates this cardiolocomotor coupling. Moreover, because PFC and RSA overlapped at low workloads, methodological care should be taken in future studies aiming to quantify RSA as an index of parasympathetic activity.

International audience; To perform their specific functional role, B and T lymphocytes, cells of the adaptive immune system of jawed vertebrates, need to express one (and, preferably, only one) form of antigen receptor, i.e. the immunoglobulin or T-cell receptor (TCR), respectively. This end goal depends initially on a series of DNA cis-rearrangement events between randomly chosen units from separate clusters of V, D (at some immunoglobulin and TCR loci) and J gene segments, a biomolecular process collectively referred to as V(D)J recombination. V(D)J recombination takes place in immature T and B cells and relies on the so-called RAG nuclease, a site-specific DNA cleavage apparatus that corresponds to the lymphoid-specific moiety of the VDJ recombinase. At the genome level, this recombinase's mission presents substantial biochemical challenges. These relate to the huge distance between (some of) the gene segments that it eventually rearranges and the need to achieve cell-lineage-restricted and developmentally ordered routines with at times, mono-allelic versus bi-allelic discrimination. The entire process must be completed without any recombination errors, instigators of chromosome instability, translocation and, potentially, tumorigenesis. As expected, such a precisely choreographed and yet potentially risky process demands sophisticated controls; epigenetics demonstrates what is possible when calling upon its many facets. In this vignette, we will recall the evidence that almost from the start appeared to link the two topics, V(D)J recombination and epigenetics, before reviewing the latest advances in our knowledge of this joint venture.

International audience; We present a novel analysis tool for time delay estimation in electrocardiographic signal processing. This tool enhances PR interval estimation (index of the atrioventricular conduction time) by limiting the distortion effect of the T wave overlapping the P wave at high heart rates. Our approach consists of modeling the T wave, cancelling its influence, and finally estimating the PR intervals during exercise and recovery with the proposed generalized Woody method. Different models of the T wave are presented and compared in a statistical summary that quantitatively justifies the improvements introduced by this study. Among the different models tested, we found that a piecewise linear function significantly reduces the T wave-induced bias in the estimation process. Combining this modeling with the proposed time delay estimation method leads to accurate PR interval estimation. Using this method on real ECGs recorded during exercise and its recovery, we found: 1) that the slopes of PR interval series in the early recovery phase are dependent on the subjects' training status (average of the slopes for sedentary men = 0.11 ms/s, and for athlete men = 0.28 ms/s), and 2) an hysteresis phenomenon exists in the relation PR/RR intervals when data from exercise and recovery are compared.

International audience; It has been shown that a pedaling frequency component can be extracted from the heart rate variability (HRV) signal using a time-varying filter. It is shown that this filter can be implemented directly in the time-frequency plane with different approaches. The need of resampling the data is also discussed with regard to the artifacts produced when the shanon condition is not fulfilled. In order to interpret the similar amplitude profiles of the pedaling component for untrained and trained subjects, an attempt for the model parameters setting is proposed. Consistent results on a large data set illustrate the feasibility of such processing.

International audience; During exercise, analysis of the spectral components of the heart rate variability (i.e. R-R interval series variability; HRV) points out a new high frequency component related to the pedalling frequency. This component is independent of the classical low and high frequency bands related to the autonomic nervous system modulation of the heart period. It is not related to ECG distortion or artifacts, and could be linked to the mechanical influence of the muscle pump on venous return. To assess this new component, we develop and propose a method based on a time-varying filter, designed in the time-frequency plane, as well as a new model to link the potential input of the modulation (the muscle pump) to the pedalling frequency component of HRV.

International audience; The analysis of heart period series is a difficult task especially under graded exercise conditions. From all the information present in these series, we are the most interested in the coupling between respiratory and cardiac systems, known as respiratory sinus arrythmia. In this paper, we show that precise patterns concerning the respiratory frequency can be extracted from the heart period series. An evolutive model is introduced in order to achieve tracking of the main respiratory-related frequencies and their time-varying amplitudes. Since respiration acts to modulate the sinus rhythm, we relate the frequencies and amplitudes to this modulation by analyzing in detail its nonlinear transformation giving the heart period signal. This analysis is performed assuming stationary conditions but also in the realistic case where the mean heart period, the amplitude, and the frequency of the respiration are time-varying. Since this paper is devoted to the theoretical and complete presentation of the method used in a physiological study published elsewhere, the capabilities of our method will be illustrated in a realistic simulated case.

International audience; OBJECTIVE: To test whether ventilatory thresholds, measured during an exercise test, could be assessed using time varying analysis of respiratory sinus arrhythmia frequency (f(RSA)). METHODS: Fourteen sedentary subjects and 12 endurance athletes performed a graded and maximal exercise test on a cycle ergometer: initial load 75 W (sedentary subjects) and 150 W (athletes), increments 37.5 W/2 min. f(RSA) was extracted from heart period series using an evolutive model. First (T(V1)) and second (T(V2)) ventilatory thresholds were determined from the time course curves of ventilation and ventilatory equivalents for O(2) and CO(2). RESULTS: f(RSA) was accurately extracted from all recordings and positively correlated to respiratory frequency (r = 0.96 (0.03), p

Persistence of respiratory sinus arrhythmia (RSA) has been described in humans during intense exercise and attributed to an increase in ventilation. However, the direct influence of ventilation on RSA has never been assessed. The dynamic evolution of RSA and its links to ventilation were investigated during exercise in 14 healthy men using an original modeling approach. An evolutive model was estimated from the detrended and high-pass-filtered heart period series. The instantaneous RSA frequency ( FRSA, in Hz) and amplitude ( ARSA, in ms) were then extracted from all recordings. ARSA was calculated with short-time Fourier transform. First, measurements of FRSA and ARSA were performed from data obtained during a graded and maximal exercise test. Influences of different ventilation regimens [changes in tidal volume (VT) and respiratory frequency ( FR)] on ARSA were then tested during submaximal [70% peak O2 consumption (V̇o2peak)] rectangular exercise bouts. Under graded and maximal exercise conditions, ARSA decreased from the beginning of exercise to 61.9 ± 3.8% V̇o2peak and then increased up to peak exercise. During the paced breathing protocol, normoventilation (69.4 ± 8.8 l/min), hyperventilation (81.8 ± 8.3 l/min), and hypoventilation (56.4 ± 6.2 l/min) led to significantly ( P < 0.01) different ARSA values (3.8 ± 0.5, 4.6 ± 0.8, and 2.9 ± 0.5 ms, respectively). In addition, no statistical difference was found in ARSA when ventilation was kept constant, whatever the FR-VT combinations. Those results indicate that RSA persists for all exercise intensities and increases during the highest intensities. Its persistence and increase are strongly linked to both the frequency and degree of lung inflation, suggesting a mechanical influence of breathing on RSA.

International audience; Electrocortical effects of long duration exercise on cognitive function were investigated by analyzing P300 amplitude and latency changes during a 3-h cycling exercise. P300 components were measured in 12 well-trained cyclists and blood glucose, cortisol, insulin, glycerol, and free fatty acids (FFAs) epinephrine and norepinephrine were analyzed. Results indicated that P300 components were affected by exercise with a temporary increase in amplitude between the 1st and the 2nd hour and an increase in latency after 2 h of exercise concomitant with some hormonal changes, including an increase in cortisol and epinephrine and a decrease in blood glucose. These findings suggest a combined effect of arousal and central fatigue on electrocortical indices of cognitive function during acute physical exercise.

International audience; Transversal studies have shown a strong correlation between specific evoked potential (EP) values and specific physical activities, as well as between EP values and the amount of training. Prior to longitudinal studies investigating the effect of training in EPs, it is mandatory to determine whether a recent training session could interfere with regular EP recording. Exercise-induced hyperthermia is known to modify EP values. The purpose of the study was to determine whether an acute exercise can induce EP modification persisting after body temperature recovery. We measured two sets of visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) in 16 males (8 cyclists and 8 sedentary peers), one before and the other after a maximal cycloergometric graded exercise test. The second test was performed immediately after body temperature recovery. We chose to test cyclists, as their specific training corresponded to the exercise test we performed on a cycloergometer. The repeated measures before and after the exercise test showed no significant differences, neither in VEPs nor in BAEPs, for any subject of the study. Recording VEPs and BAEPs in cyclists, we observed no difference related to this particular sport training. This study showed that VEP and BAEP values were similar to those measured before a maximal exercise when body temperature returned to pre-exercise value. This original work demonstrated that VEP and BAEP recordings can be reliably performed after a recent training session, provided body temperature has returned to basal level.

The analysis of the heart period series is a difficult task especially under graded exercise conditions. Having a good tool to characterize the P-R and R-R intervals, i.e. a good method of time delay estimation, would carry out a better knowledge of the neural activity during exercise and recovery in the field of pacemaker's design. Unfortunately, for the P-R intervals, the problem of estimation has been rarely addressed. In this paper, we propose a new method for estimating the P-R intervals based on an iterative Maximum-Likelihood approach. The main contribution is to take into account the overlapping T wave on ECG recorded during exercise. The goal of this study is to compute a model of the T wave which overlaps the P wave and then to cancel this influence before the determination of the P-R intervals.