Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

[Flap harvest training on a new ultrarealistic simulation model: In-training operator feedback about a pulsating reperfused and reventilated cadaver Simlife®]. / Prélèvement des lambeaux sur sujet anatomique et nouveau modèle de simulation ultra-réaliste : retour d'expérience d'un opérateur en formation sur corps reperfusé pulsatile et reventilé Simlife®.

INTRODUCTION: The anatomical subject is still a key element to learn complex procedures in plastic surgery. We present here the evaluation of an in-training operator on a SIMLIFE® model, hyper realistic model consisting in human bodies donated to science equipped with pulsating recirculation and reventilation device. MATERIAL AND METHODS: From February 2019 to October 2019, 8 forearm flaps with radial proximal pedicle were harvested by the learner on a SIMLIFE® model. Conditions were as close as possible to the operating room : asepsy, sterile draping, assistant and instrumentation including electrocoagulation. RESULTS: The procedure was decomposed in 13 distinct steps. Mean total surgery time was 90,5±11,62minutes. There was only one case of arterial pedicle lesion resulting in major blood leak. Bleeding was measured by fake blood loss from the SIMLIFE® console. Mean intraoperatoy bleeding was 171±108 milliliters. We review pros and cons of this new technology particulary suited for complex plastic and reconstructive surgery training. CONCLUSION: Using SIMLIFE® technology we have a new mean to train for complex procedures in plastic and reconstructive surgery. This new technology could be applied to numerous other surgical procedures. Broader applications are still limited by cost and cadaver use legislation.

[Male to female sex reassignment surgery with a new surgical simulation device using a human perfused cadaver SIMLIFE®: New paradigm in transsexual surgery education ?] / Aïdoïopoïèse sur modèle cadavérique humain revascularisé pulsatile et ventilé SIMLIFE® : cas isolé ou futur changement de paradigme en chirurgie de réassignation génitale ?

INTRODUCTION: In 2015, we reported our experience with the learning curve in genital reassignment surgery and highlighted a four-step learning concept. CLINICAL CASE: In this article, we present our first vaginoplasty performed on a humanoid model SIMLIFE®, a human body associated with a pulsating circulation device and a ventilation device. RESULTS: The surgical technique included 14 steps. The total surgical time was 182minutes. There was no intraoperative complication, and there was no damage to the urethra or rectum. The intraoperative bleeding measured by the loss of operative fluid was 280mL. We discuss the advantages of this technology perfectly adapted to transsexual surgery. CONCLUSION: We demonstrated the feasibility of vaginoplasty performed on a humanoid model SIMLIFE® and highlighted improvement of the surgical skills with this model. This technology could find many other surgical applications. However, it faces cost constraints and legislation on corpses.

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome.

OBJECTIVES: Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. MATERIAL & METHODS: We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. RESULTS: Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. CONCLUSION: Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Relativistic Acceleration of Electrons Injected by a Plasma Mirror into a Radially Polarized Laser Beam.

We propose a method to generate femtosecond, relativistic, and high-charge electron bunches using few-cycle and tightly focused radially polarized laser pulses. In this scheme, the incident laser pulse reflects off an overdense plasma that injects electrons into the reflected pulse. Particle-in-cell simulations show that the plasma injects electrons ideally, resulting in a dramatic increase of charge and energy of the accelerated electron bunch in comparison to previous methods. This method can be used to generate femtosecond pC bunches with energies in the 1-10 MeV range using realistic laser parameters corresponding to current kHz laser systems.

SIM Life: a new surgical simulation device using a human perfused cadaver.

PURPOSE: In primary and continuing medical education, simulation is becoming a mandatory technique. In surgery, simulation spreading is slowed down by the distance which exists between the devices currently available on the market and the reality, in particular anatomical, of an operating room. We propose a new model for surgical simulation with the use of cadavers in a circulation model mimicking pulse and artificial respiration available for both open and laparoscopic surgery. METHODS: The model was a task trainer designed by four experts in our simulation laboratory combining plastic, electronic, and biologic material. The cost of supplies needed for the construction was evaluated. The model was used and tested over 24 months on 35 participants, of whom 20 were surveyed regarding the realism of the model. RESULTS: The model involved a cadaver, connected to a specific device that permits beating circulation and artificial respiration. The demonstration contributed to teaching small groups of up to four participants and was reproducible over 24 months of courses. Anatomic correlation, realism, and learning experience were highly rated by users CONCLUSION: This model for surgical simulation in both open and laparoscopic surgery was found to be realistic, available to assessed objectively performance in a pedagogic program.

Limitations in ionization-induced compression of femtosecond laser pulses due to spatio-temporal couplings.

It was recently proposed that ionization-induced self-compression could be used as an effective method to further compress femtosecond laser pulses propagating freely in a gas jet [He et al., Phys. Rev. Lett. 113, 263904 2014]. Here, we address the question of the homogeneity of the self-compression process and show experimentally that homogeneous self-compression down to 12fs can be obtained by finding the appropriate focusing geometry for the laser pulse. Simulations are used to reproduce the experimental results and give insight into the self-compression process and its limitations. Simulations suggest that the ionization process induces spatio-temporal couplings which lengthen the pulse duration at focus, possibly making this method ineffective for increasing the laser peak intensity.

Appropriate dosing of sugammadex to reverse deep rocuronium-induced neuromuscular blockade in morbidly obese patients.

In morbidly obese patients, the speed of reversal of neuromuscular blockade with sugammadex based on ideal body weight is still matter of debate. In this single-center, randomised, double-blinded study, neuromuscular blockade was monitored in 50 patients using acceleromyography at the adductor pollicis. At the end of surgery with deep rocuronium-induced neuromuscular blockade, patients randomly received sugammadex 4 mg.kg(-1) (high dose group), 2 mg.kg(-1) (middle dose group), or 1 mg.kg(-1) (low dose group) of ideal body weight. After administration of the first dose of sugammadex, the mean (SD) recovery time (censored at 600 s) from deep neuromuscular blockade was significantly shorter (p < 0.001) in the high-dose group (n = 14; 255 (63) s) vs the middle-dose group (n = 13; 429 (102) s), or low-dose group (n = 4; 581 (154) s). Success rate from neuromuscular blockade reversal defined by a train-of-four ≥ 0.9 within 10 min after sugammadex administration, were 93%, 77% and 22% for these high, middle and low-dose groups respectively (p < 0.05 vs low-dose group). In morbidly obese patients, 4 mg.kg(-1) of ideal body weight of sugammadex allows suitable reversal of deep rocuronium-induced neuromuscular blockade. Monitoring remains essential to detect residual curarisation or recurarisation.

From anatomy to laparoscopic surgery, or how to reconcile surgeons to embryology.

PURPOSE: With the development of laparoscopy, new surgical techniques for colon resection were required. New anatomic plans of dissection were described for laparoscopic technique (medial to lateral approach) and the surgeons had to learn a complete different anatomy known as "laparoscopic anatomy". To help the surgeon through the milestones of laparoscopic colon resection, we propose an embryological and anatomical analysis of the changes of the colon and peritoneum during the foetal period to highlight the laparoscopic approach and surgical landmarks. METHODS: Seventeen human foetuses, age ranged from 7½ to 33 weeks were studied by dissections and histology. Three adult cadavers underwent laparoscopic colon surgery. RESULTS: Photographic representations of surgical views are displayed, and detailed descriptions applicable to anatomical structures are presented. CONCLUSION: Understanding the changes in the colon and peritoneum morphology leads to a clarification of the surgical technique for laparoscopic colon surgery.

High-energy acceleration phenomena in extreme-radiation-plasma interactions.

We simulate, using a particle-in-cell code, the chain of acceleration processes at work during the Compton-based interaction of a dilute electron-ion plasma with an extreme-intensity, incoherent γ-ray flux with a photon density several orders of magnitude above the particle density. The plasma electrons are initially accelerated in the radiative flux direction through Compton scattering. In turn, the charge-separation field from the induced current drives forward the plasma ions to near-relativistic speed and accelerates backwards the nonscattered electrons to energies easily exceeding those of the driving photons. The dynamics of those energized electrons is determined by the interplay of electrostatic acceleration, bulk plasma motion, inverse Compton scattering and deflections off the mobile magnetic fluctuations generated by a Weibel-type instability. The latter Fermi-like effect notably gives rise to a forward-directed suprathermal electron tail. We provide simple analytical descriptions for most of those phenomena and examine numerically their sensitivity to the parameters of the problem.

Peroral endoscopic myotomy: a two-center retrospective study of practice and adverse events.

Background and study aims: Peroral endoscopic myotomy (POEM) is the preferred technique for the treatment of esophageal motility disorders and is less invasive than surgery. This study was performed to compare two university centers in the practice of POEM, in terms of efficacy and adverse events, for the treatment of esophageal motility disorder. Patients and methods: Retrospective comparative study of patients undergoing a POEM between September 2020 and December 2022 from the University Hospital of Liège (Belgium) and Besançon (France). The clinical success was defined by an Eckardt score ≤ 3 after the procedure. Results: Fifty-five patients were included. In both centers, 87,3% of the patients had achalasia (mostly type II), and 12,7% had another esophageal motility disorder. The use of antibiotic prophylaxis was systematic in Liège center but not in Besançon center (100% and 9.1% respectively). The mean value of the post-operative Eckardt score was 1.55± 2.48 in both center with 93.2% of patients with a score ≤ 3 (92% in Besançon and 94.74% in Liège). The rate of adverse event was generally low. There were two minor adverse events more frequent in Liège, clinical capnomediastinum and pain at day one, but they were managed with conservative treatment. Only 7.3% of the total patients had an infectious phenomenon that did not correlate with the use of antibiotic prophylaxis. Conclusion: The post-operative Eckardt score and the adverse event rate were comparable between the university centers. This study confirmed that POEM is a safe and effective technique. It also showed that using an antibiotic prophylaxis does not influence the development of infectious adverse events.

Laser temperature programmed desorption: A flexible technique to study ion-surface interaction.

Understanding the physical-chemical processes ruling the interaction of particles (atoms, molecules, and ions) with surfaces is fundamental in several research fields, such as heterogeneous catalysis, astrochemistry, and nuclear fusion. In particular, the interaction of hydrogen isotopes with plasma facing materials represents a high-priority research task in the fusion community. Such studies are essential to ensure the successful operation of experimental fusion reactors, such as the tokamak ITER. In this work, we present a surface science apparatus developed to study ion-surface interaction in fusion relevant systems. It combines laser-based techniques with contaminant-free ion/molecular beams, mass spectrometry, and surface science tools such as low-energy electron diffraction and Auger electron spectroscopy. It allows to cover a wide range of sample temperatures, from 130 to 2300 K, by changing the heating rate of samples from 0.1 to 135 K/s and maintaining the linearity of the heating ramps, a powerful feature to gain insight on adsorption, absorption, and desorption mechanisms. Experimental calibration and performance are presented in detail. Moreover, to provide a factual overview of the experimental capabilities, we focus on two different applications: the protocol used to clean a W(110) single crystal sample and the development of laser temperature programmed desorption to study helium retention in tungsten.

Experimental measurements of electron-bunch trains in a laser-plasma accelerator.

Spectral measurements of visible coherent transition radiation produced by a laser-plasma-accelerated electron beam are reported. The significant periodic modulations that are observed in the spectrum result from the interference of transition radiation produced by multiple bunches of electrons. A Fourier analysis of the spectral interference fringes reveals that electrons are injected and accelerated in multiple plasma wave periods, up to at least 10 periods behind the laser pulse. The bunch separation scales with the plasma wavelength when the plasma density is changed over a wide range. An analysis of the spectral fringe visibility indicates that the first bunch contains most of the charge.

Circular dichroism and superdiffusive transport at the surface of BiTeI.

We investigate the electronic states of BiTeI after the optical pumping with circularly polarized photons. Our data show that photoexcited electrons reach an internal thermalization within 300 fs of the arrival of the pump pulse. Instead, the dichroic contrast generated by the circularly polarized light relaxes on a time scale shorter than 80 fs. This result implies that orbital and spin polarization created by the circular pump pulse rapidly decays via manybody interaction. The persistent dichroism at longer delay times is due to the helicity dependence of superdiffussive transport. We ascribe it to the lack of inversion symmetry in an electronic system far from equilibrium conditions.

Giant anisotropy of spin-orbit splitting at the bismuth surface.

We investigate the bismuth (111) surface by means of time and angle resolved photoelectron spectroscopy. The parallel detection of the surface states below and above the Fermi level reveals a giant anisotropy of the spin-orbit spitting. These strong deviations from the Rashba-like coupling cannot be treated in k·p perturbation theory. Instead, first principles calculations could accurately reproduce the experimental dispersion of the electronic states. Our analysis shows that the giant anisotropy of the spin-orbit splitting is due to a large out-of plane buckling of the spin and orbital texture.

Coherent phonon coupling to individual Bloch states in photoexcited bismuth.

We investigate the temporal evolution of the electronic states at the bismuth (111) surface by means of time- and angle-resolved photoelectron spectroscopy. The binding energy of bulklike bands oscillates with the frequency of the A(1g) phonon mode, whereas surface states are insensitive to the coherent displacement of the lattice. A strong dependence of the oscillation amplitude on the electronic wave vector is correctly reproduced by ab initio calculations of electron-phonon coupling. Besides these oscillations, all the electronic states also display a photoinduced shift towards higher binding energy whose dynamics follows the evolution of the electronic temperature.

Comparison of measured with calculated dose distribution from a 120-MeV electron beam from a laser-plasma accelerator.

PURPOSE: To evaluate the dose distribution of a 120-MeV laser-plasma accelerated electron beam which may be of potential interest for high-energy electron radiation therapy. METHODS: In the interaction between an intense laser pulse and a helium gas jet, a well collimated electron beam with very high energy is produced. A secondary laser beam is used to optically control and to tune the electron beam energy and charge. The potential use of this beam for radiation treatment is evaluated experimentally by measurements of dose deposition in a polystyrene phantom. The results are compared to Monte Carlo simulations using the geant4 code. RESULTS: It has been shown that the laser-plasma accelerated electron beam can deliver a peak dose of more than 1 Gy at the entrance of the phantom in a single laser shot by direct irradiation, without the use of intermediate magnetic transport or focusing. The dose distribution is peaked on axis, with narrow lateral penumbra. Monte Carlo simulations of electron beam propagation and dose deposition indicate that the propagation of the intense electron beam (with large self-fields) can be described by standard models that exclude collective effects in the response of the material. CONCLUSIONS: The measurements show that the high-energy electron beams produced by an optically injected laser-plasma accelerator can deliver high enough dose at penetration depths of interest for electron beam radiotherapy of deep-seated tumors. Many engineering issues must be resolved before laser-accelerated electrons can be used for cancer therapy, but they also represent exciting challenges for future research.

Controlled injection and acceleration of electrons in plasma wakefields by colliding laser pulses.

In laser-plasma-based accelerators, an intense laser pulse drives a large electric field (the wakefield) which accelerates particles to high energies in distances much shorter than in conventional accelerators. These high acceleration gradients, of a few hundreds of gigavolts per metre, hold the promise of compact high-energy particle accelerators. Recently, several experiments have shown that laser-plasma accelerators can produce high-quality electron beams, with quasi-monoenergetic energy distributions at the 100 MeV level. However, these beams do not have the stability and reproducibility that are required for applications. This is because the mechanism responsible for injecting electrons into the wakefield is based on highly nonlinear phenomena, and is therefore hard to control. Here we demonstrate that the injection and subsequent acceleration of electrons can be controlled by using a second laser pulse. The collision of the two laser pulses provides a pre-acceleration stage which provokes the injection of electrons into the wakefield. The experimental results show that the electron beams obtained in this manner are collimated (5 mrad divergence), monoenergetic (with energy spread <10 per cent), tuneable (between 15 and 250 MeV) and, most importantly, stable. In addition, the experimental observations are compatible with electron bunch durations shorter than 10 fs. We anticipate that this stable and compact electron source will have a strong impact on applications requiring short bunches, such as the femtolysis of water, or high stability, such as radiotherapy with high-energy electrons or radiography for materials science.