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Nonadiabatic dynamics simulations complement time-resolved experiments by revealing ultrafast excited-state mechanistic information in photochemical reactions. Understanding the relaxation mechanisms of photoexcited molecules finds application in energy, material, and medicinal research. However, with substantial computational costs, the nonadiabatic dynamics simulations have been restricted to ultrafast timescales, typically less than a few picoseconds, thus neglecting a wide range of photoactivated processes occurring in much longer timescales. Before developing new methodologies, we must ask: How well do the popular nonadiabatic dynamics methods perform in a long timescale simulation? In this study, we employ the multiconfiguration time-dependent Hartree (MCTDH) and its multilayer variants (ML-MCTDH), ab initio multiple spawning (AIMS), and fewest-switches surface hopping (FSSH) methodologies to simulate the excited-states dynamics of a weakly coupled multidimensional Spin-Boson model Hamiltonian designed for a long timescale decay behavior. Our study assures that despite having very different theoretical backgrounds, all the above methods deliver qualitatively similar results. While quantum dynamics would be very costly for long timescale simulations, the trajectory-based approaches are paving the way for future advancements.

Introduction: Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model., Method: A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement., Results: A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge., Conclusion: Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed., Competing Interests: A.D-C. reports support from ARAIRLOR for the present manuscript; a contract with the French Public Agency ANSES as an expert in allergy and pediatric; consulting fees for expertise in pediatric allergy for Stallergens, Aimmune Therapeutics and ALK; and support for attending meetings from Mead Johnson, Nutricia, Aimmune Therapeutics and Novartis Pharma SAS. F.M. reports a grant from the French public agency ANSES and participation on a Data Safety Monitoring Board for the clinical “Propila-Rifax”. All other authors have no conflict of interest in relation to this work., (Copyright: © 2023 Divaret-Chauveau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Newton-X is an open-source computational platform to perform nonadiabatic molecular dynamics based on surface hopping and spectrum simulations using the nuclear ensemble approach. Both are among the most common methodologies in computational chemistry for photophysical and photochemical investigations. This paper describes the main features of these methods and how they are implemented in Newton-X. It emphasizes the newest developments, including zero-point-energy leakage correction, dynamics on complex-valued potential energy surfaces, dynamics induced by incoherent light, dynamics based on machine-learning potentials, exciton dynamics of multiple chromophores, and supervised and unsupervised machine learning techniques. Newton-X is interfaced with several third-party quantum-chemistry programs, spanning a broad spectrum of electronic structure methods.

We present the implementation of trajectory surface-hopping nonadiabatic dynamics for a polarizable embedding QM/MM formulation. Time-dependent density functional theory was used at the quantum mechanical level of theory, whereas the molecular mechanics description involved the polarizable AMOEBA force field. This implementation has been obtained by integrating the surface-hopping program Newton-X NS with an interface between the Gaussian 16 and the Tinker suites of codes to calculate QM/AMOEBA energies and forces. The implementation has been tested on a photoinduced electron-driven proton-transfer reaction involving pyrimidine and a hydrogen-bonded water surrounded by a small cluster of water molecules and within a large water droplet.

Nonadiabatic dynamics simulations in the long timescale (much longer than 10 ps) are the next challenge in computational photochemistry. This paper delimits the scope of what we expect from methods to run such simulations: they should work in full nuclear dimensionality, be general enough to tackle any type of molecule and not require unrealistic computational resources. We examine the main methodological challenges we should venture to advance the field, including the computational costs of the electronic structure calculations, stability of the integration methods, accuracy of the nonadiabatic dynamics algorithms and software optimization. Based on simulations designed to shed light on each of these issues, we show how machine learning may be a crucial element for long time-scale dynamics, either as a surrogate for electronic structure calculations or aiding the parameterization of model Hamiltonians. We show that conventional methods for integrating classical equations should be adequate to extended simulations up to 1 ns and that surface hopping agrees semiquantitatively with wave packet propagation in the weak-coupling regime. We also describe our optimization of the Newton-X program to reduce computational overheads in data processing and storage. This article is part of the theme issue 'Chemistry without the Born-Oppenheimer approximation'.

A large variety of disposable face masks have been produced since the onset of the COVID-19 pandemic. Decreased resistance to inspiration improves adherence to the use of the mask; the so called breathability is usually estimated by the measurement of air flow across a section of the tissue under a given pressure difference. We hypothesized that the mask pressure-flow relationship studied in conditions that mimic tidal breathing could allow a more comprehensive characterization of airflow resistance, a major determinant of mask comfort. A physical analog was made of a plaster cast dummy head connected through a pneumotachograph to a series of bellows inflated/deflated by a respirator. Pressure was measured at the mock airway opening over which the mask was carefully secured. The precision of the measurement equipment was quantified using two estimates of measurement error: repeatability coefficient (RC) and within-mask coefficient of variation (CV wm ). The airflow resistance of 10 surgical masks was tested on 4 different days. Resistance means did not differ significantly among four repeated measures (0.34 hPa.s.L -1 ; 0.37 hPa.s.L -1 ; 0.37 hPa.s.L -1 ; and 0.37 hPa.s.L -1 ; p  = 0.08), the estimated RC was 0.08 hPa.s.L -1 [95%CI: 0.06-0.10 hPa.s.L -1 ], and CV wm was 8.7% [95%CI: 1.5-12.2%]. Multiple comparisons suggest the presence of a learning effect by which the operator reduced the error over the course of repetitive resistance measurements. Measurement precision improved considerably when the first set of measures was not taken into account [RC ~ 0.05 hPa.s.L -1 (95%CI: 0.03-0.06 hPa.s.L -1 ); CV wm ~4.5% (95%CI: 1.9-6.1%)]. The testing of the face mask resistance (R) appears simple and highly repeatable in conditions that resemble tidal breathing, once operator training was assured. The procedure adds further to the current standard assessment of breathability and allows estimating the maximal added respiratory load, about 10-20% of the respiratory resistance reported in heathy adult subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Demoulin, Duvivier, Marchal and Demoulin-Alexikova.)

Introduction: Cough is a major lower airway defense mechanism that can be triggered by exercise in asthma patients. Studies on cough reflex in experimental animal models revealed a decrease of cough reflex sensitivity during exercise in healthy animals, but a lack of desensitization in ovalbumin-sensitized rabbits. The aim of our study is to evaluate the impact of inhaled corticosteroids on cough reflex during artificial limb exercise in an animal model of eosinophilic airway inflammation., Materials and Methods: Sixteen adult ovalbumin-sensitized rabbits were randomly divided into two groups. The "OVA-Corticoid" group ( n = 8) received inhaled corticosteroids (budesonide; 1 mg/day during 2 consecutive days) while the "OVA-Control" ( n = 8) group was exposed to saline nebulization. The sensitivity of defensive reflexes induced by direct mechanical stimulation of the trachea was studied in anesthetized animals, at rest and during artificial limb exercise. Cell count was performed on bronchoalveolar lavage fluid and middle lobe tissue sections to assess the level of eosinophilic inflammation., Results: All rabbits were significantly sensitized but there was no difference in eosinophilic inflammation on bronchoalveolar lavage or tissue sections between the two groups. Artificial limb exercise resulted in a significant ( p = 0.002) increase in minute ventilation by 30% (+ 209 mL.min -1 , ± 102 mL/min -1 ), with no difference between the two groups. 322 mechanical tracheal stimulations were performed, 131 during exercise (40.7%) and 191 at rest (59.3%). Cough reflex was the main response encountered (46.9%), with a significant increase in cough reflex threshold during artificial limb exercise in the "OVA-Corticoid" group ( p = 0.039). Cough reflex threshold remained unchanged in the "OVA-Control" group ( p = 0.109)., Conclusion: Inhaled corticosteroids are able to restore desensitization of the cough reflex during artificial limb exercise in an animal model of airway eosinophilic inflammation. Airway inflammation thus appears to be involved in the physiopathology of exercise-induced cough in this ovalbumin sensitized rabbit model. Inhaled anti-inflammatory treatments could have potential benefit for the management of exercise-induced cough in asthma patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Basin, Valentin, Demoulin-Alexikova, Demoulin, Foucaud, Gérard, Pouget, Allado, Chenuel and Poussel.)

Artificial biomimetic chromophore-protein complexes inspired by natural visual pigments can feature color tunability across the full visible spectrum. However, control of excited state dynamics of the retinal chromophore, which is of paramount importance for technological applications, is lacking due to its complex and subtle photophysics/photochemistry. Here, ultrafast transient absorption spectroscopy and quantum mechanics/molecular mechanics simulations are combined for the study of highly tunable rhodopsin mimics, as compared to retinal chromophores in solution. Conical intersections and transient fluorescent intermediates are identified with atomistic resolution, providing unambiguous assignment of their ultrafast excited state absorption features. The results point out that the electrostatic environment of the chromophore, modified by protein point mutations, affects its excited state properties allowing control of its photophysics with same power of chemical modifications of the chromophore. The complex nature of such fine control is a fundamental knowledge for the design of bio-mimetic opto-electronic and photonic devices., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

The numerous existing publications on benchmarking quantum chemistry methods for excited states rarely include Charge Transfer (CT) states, although many interesting phenomena in, e.g., biochemistry and material physics involve the transfer of electrons between fragments of the system. Therefore, it is timely to test the accuracy of quantum chemical methods for CT states, as well. In this study we first propose a new benchmark set consisting of dimers having low-energy CT states. On this set, the vertical excitation energy has been calculated with Coupled Cluster methods including triple excitations (CC3, CCSDT-3, CCSD(T)(a)*), as well as with methods including full or approximate doubles (CCSD, STEOM-CCSD, CC2, ADC(2), EOM-CCSD(2)). The results show that the popular CC2 and ADC(2) methods are much less accurate for CT states than for valence states. On the other hand, EOM-CCSD seems to have similar systematic overestimation of the excitation energies for both types of states. Among the triples methods the novel EOM-CCSD(T)(a)* method including noniterative triple excitations is found to stand out with its consistently good performance for all types of states, delivering essentially EOM-CCSDT quality results.

Introduction: Cough is a major symptom frequently experienced during exercise, mainly in asthmatic patients. Inhaled glucocorticoids represent the keystone treatment in the management of asthma, but little is known about interactions between cough and exercise, especially in controlled patients. During exercise, cough reflex (CR) appears downregulated in healthy animal models whereas a lack of desensitization of CR has been shown in ovalbumin-sensitized animal models, mimicking asthmatic disease., Aims and Objectives: The goal of our study was to clarify the potential modulation of the CR induced by inhaled corticosteroids (CS) in ovalbumin (OVA) sensitized rabbits during artificial limb exercise., Materials and Methods: Seventeen OVA sensitized rabbits were studied. Among them, 9 were treated with CS delivered intravenously (OVA-Corticoids). The ventilatory response to direct tracheal stimulation, performed at rest and during exercise, was determined to assess the incidence and the sensitivity of the CR. Broncho-alveolar lavage (BAL) and cell counts were performed to determine the level of airway inflammation. Exercise was mimicked by electrically induced hindlimb muscular contractions (EMC)., Results: Compared to rest values, EMC increased minute ventilation by 28% without any decrease in respiratory resistance (Rsr). Among 322 tracheal stimulations, 172 (53%) were performed at rest and 150 (47%) during exercise. The sensitivity of CR decreased during artificial limb exercise compared to baseline in OVA-Corticoids rabbits ( p = 0.0313) while it remained unchanged in OVA rabbits ( p = NS)., Conclusion: Corticosteroids appear to restore the desensitization of the CR in OVA sensitized rabbits during artificial limb exercise, suggesting the potential role of airway inflammation in the pathophysiology of cough during exercise in asthmatics., (Copyright © 2020 Valentin, Chenuel, Demoulin-Alexikova, Demoulin, Gérard, Foucaud and Poussel.)

Chronic irritating cough in patients with allergic disorders may reflect behavioral or reflex response that is inappropriately matched to the stimulus present in the respiratory tract. Such dysregulated response is likely caused by sensory nerve damage driven by allergic mediators leading to cough hypersensitivity. Some indirect findings suggest that even acid-sensitive, capsaicin-insensitive A-δ fibers called "cough receptors" that are likely responsible for protective reflex cough may be modulated through immune driven inflammation. The aim of this study was to find out whether protective reflex cough is altered during acute allergic airway inflammation in rabbits sensitized to ovalbumin. In order to evaluate the effect of such inflammation exclusively on protective reflex cough, C-fiber mediated cough was silenced using general anesthesia. Cough provocation using citric acid inhalation and mechanical stimulation of trachea was realized in 16 ovalbumin (OVA) sensitized, anesthetized and tracheotomised rabbits 24h after OVA (OVA group, n = 9) or saline challenge (control group, n = 7). Number of coughs provoked by citric acid inhalation did not differ between OVA and control group (12,2 ±6,1 vs. 17,9 ± 6,9; p = 0.5). Allergic airway inflammation induced significant modulation of cough threshold (CT) to mechanical stimulus. Mechanically induced cough reflex in OVA group was either up-regulated (subgroup named "responders" CT: 50 msec (50-50); n = 5 p = 0.003) or down-regulated (subgroup named "non responders", CT: 1200 msec (1200-1200); n = 4 p = 0.001) when compared to control group (CT: 150 msec (75-525)). These results advocate that allergen may induce longer lasting changes of reflex cough pathway, leading to its up- or down-regulation. These findings may be of interest as they suggest that effective therapies for chronic cough in allergic patients should target sensitized component of both, reflex and behavioral cough., Competing Interests: The authors have declared that no competing interests exist.

This work describes a domain-based local pair natural orbital (DLPNO) implementation of the equation of motion coupled cluster method for the computation of electron affinities (EAs) including single and double excitations. Similar to our earlier work on ionization potentials (IPs), the method reported in this study uses the ground state DLPNO framework and extends it to the electron attachment problem. While full linear scaling could not be achieved as in the IP case, leaving the Fock/Koopmans' contributions in the canonical basis and using a tighter threshold for singles PNOs allows us to compute accurate EAs and retain most of the efficiency of the DLPNO technique. Thus as in the IP case, the ground state truncation parameters are sufficient to control the accuracy of the computed EA values, although a new set of integrals for singles PNOs must be generated at the DLPNO integral transformation step. Using standard settings, our method reproduces the canonical results with a maximum absolute deviation of 49 meV for bound states of a test set of 24 molecules. Using the same settings, a calculation involving more than 4500 basis functions, including diffuse functions, takes four days on four cores, with only 48 min spent in the EA module itself.

We present a multilayer implementation of the EOM-CCSD for the computation of ionization potentials of atoms and molecules in the presence of their environment. The method uses local orbitals to partition the system into a number of hypothetical fragments and treat different fragments of the system at different levels of theory. This approach significantly reduces the computational cost with a systematically controllable accuracy and is equally applicable to describe the environmental effect of both bonded and nonbonded nature. An accurate description of the interfragment interaction has been found to be crucial in determining the accuracy of the calculated IP values.

Chimeric Antigen Receptor (CAR) T cells expressing the fusion of the NKG2D protein with CD3ζ (NKG2D-CAR T Cells) acquire a specificity for stress-induced ligands expressed on hematological and solid cancers. However, these stress ligands are also transiently expressed by activated T cells implying that NKG2D-based T cells may undergo self-killing (fratricide) during cell manufacturing or during the freeze thaw cycle prior to infusion in patients. To avoid target-driven fratricide and enable the production of NKG2D-CAR T cells for clinical application, two distinct approaches were investigated. The first focused upon the inclusion of a Phosphoinositol-3-Kinase inhibitor (LY294002) into the production process. A second strategy involved the inclusion of antibody blockade of NKG2D itself. Both processes impacted T cell fratricide, albeit at different levels with the antibody process being the most effective in terms of cell yield. While both approaches generated comparable NKG2D-CAR T cells, there were subtle differences, for example in differentiation status, that were fine-tuned through the phasing of the inhibitor and antibody during culture in order to generate a highly potent NKG2D-CAR T cell product. By means of targeted inhibition of NKG2D expression or generic inhibition of enzyme function, target-driven CAR T fratricide can be overcome. These strategies have been incorporated into on-going clinical trials to enable a highly efficient and reproducible manufacturing process for NKG2D-CAR T cells.

Lung hyperinflation may alter the pattern of ventilatory reflexes in chronic respiratory disorders. The aim of the study was to test the effect of continuous positive airway pressure (CPAP) on ventilatory responses to mechanical stimulation of the trachea., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Multi-center studies in specific airway resistance have shown significant inter laboratory variability. Comparison of plethysmographic equipment using a lung model easily transportable from one site to another should be of help to international normative studies. A resistor made of parallel capillary tubes - insuring adequate linearity within 1 L/sec - was connected to a glass bottle. Thermal time constants were measured while the bottle was empty and while stuffed with steel wool. In the latter, isothermal condition was estimated to occur only at very low frequency (around 0.01 Hz) and gas compression was polytropic up to 0.6 Hz. With the empty analog, adiabatic gas compression was estimated to occur at frequencies ≥0.2 Hz, and more accurate volume estimation was obtained. The empty analog volume and specific resistance measured in a body plethysmograph on different days indicated within 5% accuracy as well as intersession repeatability. It is concluded that a physical analog built out of simple material provides accurate measurements of specific resistance. The apparatus should be of help to compare plethysmographic equipments from different laboratories.

Some of the 12 criminal trials and sentences in France for HIV transmission in 1998-2011 attracted substantial public attention, with a possible negative impact on people living with HIV (PLWH) through reinforced stigma and discrimination. This analysis aimed to characterize PLWH enrolled in the representative ANRS-VESPA2 survey, aware of and concerned about convictions for HIV transmission. Being a migrant from Sub-Saharan Africa, having difficult socio-economic conditions, having unprotected sex with one's main partner and concealing one's HIV status were all factors statistically associated with concern about the sentences. Participants tempted to press charges against someone for infecting them were more likely to be younger, women, not living in a couple, unemployed, and to report a major depressive disorder. Concern about HIV-related criminal proceedings among the most vulnerable PLWH do not reflect the actual risk of prosecution they are exposed to.

Single methylation at position C 10 of the all-trans retinal protonated Schiff base switches its excited-state decay in methanol from a slower picosecond into an ultrafast, protein-like subpicosecond process. QM/MM modeling in conjunction with on-the-fly excited-state dynamics provides fundamental understanding of the fine-tuning mechanics that "catalyzes" the photoinduced decay of solvated retinals. Methylation alters the interplay between the ionic S 1 and covalent S 2 states, reducing the excited-state lifetime by favoring the formation of a S 1 transient fluorescent state with fully inverted bond lengths that accounts for the recorded transient spectroscopy and from which a space-saving conical intersection seam is quickly (<1 ps) reached. Minimal and apparently innocent chemical modifications thus affect the characteristic intramolecular charge-transfer of the S 1 state as well as the interaction with the covalent S 2 excited state, eventually providing the high tunability of retinal photophysics and photochemistry and delivering a new concept for the rational design of retinal-based photoactive molecular devices.

Chimeric antigen receptors (CARs) are genetically engineered proteins that combine an extracellular antigen-specific recognition domain with one or several intracellular T-cell signaling domains. When expressed in T cells, these CARs specifically trigger T-cell activation upon antigen recognition. While the clinical proof of principle of CAR T-cell therapy has been established in hematological cancers, CAR T cells are only at the early stages of being explored to tackle solid cancers. This special report discusses the concept of exploiting natural killer cell receptors as an approach that could broaden the specificity of CAR T cells and potentially enhance the efficacy of this therapy against solid tumors. New data demonstrating feasibility of this approach in humans and supporting the ongoing clinical trial are also presented.

Context: Twenty years after the advent of combined antiretroviral therapies (ARTs), there is a growing need for up-to-date information about the daily experience of people living with HIV (PLWH)., Objectives: This study aimed to investigate the relationship between socioepidemiological groups and the types of bothersome symptoms reported by PLWH participating in a national survey in France., Methods: We analyzed self-reported bothersome symptoms in a representative sample of PLWH (ANRS-VESPA2 survey), most of whom were receiving ART treatment. PLWH (N = 2505) were grouped into three clusters according to the number of bothersome symptoms reported: Cluster A (low number, n = 1848), Cluster B (moderate number, n = 271), and Cluster C (high number, n = 386)., Results: Individuals in Cluster A (low number of bothersome symptoms) were less likely to report all the symptom types investigated. Psychological, sexual, and general symptoms were more likely to be reported in Cluster B (moderate number), whereas gastric-, pain-, and appearance-related symptoms were more likely in Cluster C (high number). In multivariate analyses, women not natives of Sub-Saharan Africa and former/active female injecting drug users were more likely to report a medium or high number of symptoms, and lower adherence to ART., Conclusion: Combining new biomedical strategies with coping mechanisms and providing better support to socially vulnerable PLWH may improve this population's quality of health and daily life., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Cough is typically associated with physical activity in children with asthma, but the characteristics of the relationship between cough and exercise has not been established under physiological conditions. The aim of the study was to describe the effect of exercise on the reflex cough response elicited by a single breath of capsaicin in non-asthmatic children. A group of non-asthmatic adults was studied as reference. Thirty children and 29 adults were recruited. The cough reflex sensitivity to capsaicin was first determined to establish the dose that provokes 5 cough efforts (C5). The number of coughs elicited by C5 (NC5) was then compared at baseline and during a standardized submaximal treadmill exercise. Data are expressed as median (interquartile range). Children and adults showed a significant decrease in NC5 (respectively from 5.0 (4.0-6.0) to 2.5 (2.0-4.0), p < 0.0005 and from 6.0 (5.0-7.0) to 2.0 (0.0-3.0, p < 0.0005). During exercise, NC5 was observed to decrease in all adult subjects, but in only 24/30 children (80%, p = 0.02). A trend for a higher incidence of personal and familial atopy was observed in children that lacked cough down-regulation during exercise compared with other children. It is concluded that the cough reflex response to capsaicin is down regulated by exercise in both children and adults. The effect however is less consistently observed in the former. The difference may reflect maturation of descending inhibitory pathways of the cough reflex, but may also be associated to atopy. The data stress the importance of assessing the time relationship of cough and exercise in questionnaire studies of asthma.

Purpose: The two life-threatening signs of anaphylactic shock (AS) are severe arterial hypotension and bronchospasm. Guidelines recommend epinephrine as first-line treatment. Arginine vasopressin (AVP) has been proposed as an alternative if epinephrine does not correct arterial hypotension. These two drugs may have beneficial, neutral or deleterious effects on airflow either directly or by modifying factors that regulate vasodilatation and/or edema in the bronchial wall., Aim of the Study: To compare the effects of epinephrine and AVP on airflow and airway leakage in a rat model of AS., Materials and Methods: Thirty-two ovalbumin-sensitized rats were randomized into four groups: control (CON), AS without treatment (OVA), AS treated with epinephrine (EPI), and AS treated with AVP (AVP). Mean arterial pressure (MAP), respiratory resistance and elastance and microvascular leakage in the airways were measured., Results: All OVA rats died within 20 minutes following ovalbumin injection. Ovalbumin induced severe arterial hypotension and airway obstruction (221 ± 36 hPa.s.L -1 vs. vehicle 52 ± 8 hPa.s.L -1 ; p < 0.0001) associated with microvascular leakage distributed throughout the trachea, bronchi and intra-pulmonary airways. EPI and AVP extended survival time; EPI restored a higher level of MAP than AVP. Airway obstruction was attenuated by epinephrine (146 ± 19 hPa.s.L -1 ; p < 0.0001), but not by AVP (235 ± 58 hPa.s.L -1 ; p = 0.42)., Conclusions: Epinephrine was superior to AVP for alleviating the airway response in a rat model of AS. When bronchospasm and severe arterial hypotension are present during AS, epinephrine should be the drug of choice.

Introduction: Cough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation., Materials & Methods: Ten ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR. Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC)., Results: Among 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits., Conclusion: The desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Cough and expiration reflex are major lower airway defense mechanisms that have not been studied throughout development in relation with the feeding behavior. Aim: To describe airway defense reflexes evoked by mechanical stimulation of the trachea in developing rabbit pups. Material and Methods: Sixty one pups were allocated to 3 groups according to their feeding behavior: suckling ( n = 22), weanling ( n = 21) and weaning ( n = 18) group. The incidence and sensitivity of defense reflexes triggered by mechanical tracheal stimulation were studied in anesthetized and tracheotomized animals. Data are expressed as median (25th to 75th percentile). Results: The overall incidence of defensive responses (cough and/or expiration reflex) was found to be significantly higher in suckling [100% (50-100%); p = 0.01] and weanling [75% (40-100%); p = 0.05] animals when compared to weaning ones [37.5% (0-75%)]. However, cough motor pattern accounted for only 29% (0-62%) of all defensive responses in suckling rabbits and its frequency was significantly lower in this group when compared with weanling [100%(50-100%); p = 0.006] or weaning group [62%(50-100%), p = 0.05]. In other word the expiration reflex was the dominant response in suckling animals. Conclusion: Incidence and motor pattern of defensive responses were found to be linked to the pup feeding behavior and the expiration reflex was the major response triggered in suckling pups. The results suggest that this reflex is especially fitted to occur during the coordinated swallowing - breathing fast activities of sucking.

Introduction: People living with HIV (PLHIV) on antiretroviral therapy (ART), with sustained undetectable viral load (sUVL) and no history of sexually transmitted infections for at least six months, are considered to have a low risk of HIV transmission (LRT). We aimed to characterize, in a representative sample of French PLHIV, the sexual behaviour of LRT PLHIV compared with non-LRT PLHIV., Methods: The cross-sectional ANRS-VESPA2 survey was conducted on adult PLHIV attending French hospitals in 2011. The LRT PLHIV group included participants with sUVL and no sexually transmitted infection for at least 12 months. Socio-behavioural and medical data were collected. Chi-square tests helped compare sexual risk indicators between LRT and non-LRT PLHIV. The survey's retrospective nature allowed us to perform complementary category-based analyses of LRT PLHIV according to whether they had sUVL for at least 18, 24 or 36 months in three socio-epidemiological groups: men who have sex with men (MSM), other men and women., Results: Analysis included 2638 PLHIV diagnosed > 12 months with available viral load data. The proportion of LRT PLHIV varied from 58% (≥ 12 months sUVL) to 38% (≥ 36 months sUVL). Irrespective of sUVL duration, we found the following: 1) LRT men (MSM and other men) were more likely to report having no sexual partner than their non-LRT counterparts. Among men having sexual partners in the previous 12 months, no significant difference was seen between LRT and non-LRT men in the number of sexual partners. LRT women were less likely to report having more than one sexual partner than non-LRT women; 2) LRT MSM were more likely to report being in sexually inactive couples than their non-LRT counterparts; 3) among sexually active participants, no difference was observed between LRT and non-LRT PLHIV concerning condom use with their serodiscordant steady partner or with their most recent casual sexual partners., Conclusions: LRT PLHIV with sUVL ≥ 12 months did not report more sexual risk behaviours than their non-LRT counterparts. Because the same result was obtained for those having a sUVL ≥ 36 months, the hypothesis of increased sexual risk behaviour over time in PLHIV meeting non-transmission biomedical criteria is not supported.

The double-blind phase of the randomized ANRS IPERGAY trial, evaluating sexual activity-based oral HIV pre-exposure prophylaxis (PrEP), was conducted among high-risk men who have sex with men (MSM). Results showed an 86% (95% CI: 40-98) relative reduction in HIV incidence among participants with tenofovir disoproxil fumarate-emtricitabine vs. placebo. The present pooled analysis aimed to analyze (i) participants' adherence to the prescribed treatment and/or condom use during sexual intercourse and (ii) sexual behavior during the double-blind phase of the study. Four hundred MSM were enrolled in the trial. Every 2 months they completed online questionnaires collecting sexual behavior and PrEP adherence data regarding their most recent sexual intercourse. A total of 2232 questionnaires (M0-M24) were analyzed. Changes over time were evaluated using a mixed model accounting for multiple measures. Irrespective of sexual partner and practice type, on average, 42.6% (min: 32.1-max: 45.8%) reported PrEP use only during their most recent episode of sexual intercourse; 29% (22.9-35.6%) reported both PrEP and condom use; 11.7% (7.2-18.9%) reported condom-use only, and 16.7% (10.8-29.6%) reported no PrEP or condom use with no significant change during the study. Scheduled (i.e., correct) PrEP use was reported on average by 59.0% (47.2-68.5%) of those reporting PrEP use during their most recent sexual intercourse. Overall, 70.3% (65.3-79.4%) and 69.3% (58.3-75.4%) of participants reported, respectively, condomless anal and condomless receptive anal intercourse during their most recent sexual encounter without significant change during follow-up. Overall, on average 83.3% (min: 70.4-max: 89.2%) of participants protected themselves by PrEP intake or condom use or both during the trial, and no increase in at-risk sexual practices was observed. None of these indicators showed significant trend during the follow-up, although we found a tendency toward decrease (p = .19) of the median number of sexual partners strengthening the absence of behavioral disinhibition. On-demand PrEP within a comprehensive HIV prevention package could improve prevention in MSM.

Aims: To study the effectiveness of an educational intervention on risks associated with drug injection, comparing primary [unsafe HIV-hepatitis C virus (HCV) practices] and secondary (local complications at injecting site) end-points in harm reduction (HR) programmes offering this intervention versus HR programmes not offering it., Design: This non-random clustered intervention study was conducted in nine intervention groups (programmes offering the intervention) and eight control groups (programmes not offering it). Each participant was followed-up through a telephone interview at enrolment and at 6 and 12 months., Setting: The study took place in 17 cities throughout France., Participants: Of the 271 participants, 144 were enrolled into the intervention group and 127 in the control group. Of the latter, 113 received at least one educational session., Intervention: A series of participant-centred face-to-face educational sessions. Each session included direct observation by trained non-governmental organization (NGO) staff or volunteers of participants' self-injecting the psychoactive product they used habitually; analysis by the trained NGO staff or volunteers of the participant's injecting practices, identification of injection-related risks and explanation of safer injecting practices; and an educational exchange on the individual participant's injection practices and the questions he or she asked., Measurements: Primary and secondary outcomes were 'at least one unsafe HIV-HCV practice' and at least one injection-related complication (derived from a checklist)., Findings: The proportion of participants with at least one unsafe HIV-HCV practice in the intervention group decreased significantly, from 44% at M0 to 25% at M6, as well as complications at the injection site (from 66 to 39% at M12), while in the control group it remained mainly stable. Multivariate probit analyses showed that the intervention group experienced a significant reduction in unsafe HIV-HCV practices at M6 [coefficient, 95% confidence interval (CI) = -0.73 (-1.47 to 0.01)] and in injection-related complications at M12 [coefficient, 95% CI = -1.01 (-1.77 to -0.24)], compared with the control group., Conclusions: An inexpensive and easily implemented educational intervention on risks associated with drug injection reduces significantly unsafe HIV-HCV transmission practices and injection-related complications., (© 2015 Society for the Study of Addiction.)

Background: The forced oscillation technique (FOT) may be affected by the upper airway artifact in children with airway obstruction. The aim was to test the impact of the artifact on FOT ability to diagnose asthma in children as recommended by current guidelines., Methods: The FOT was performed in 58 asthmatics and 27 controls before and after salbutamol. Respiratory resistance (Rrs) was measured at 8 Hz with a standard generator (SG), and a head generator (HG) that minimizes the upper airway artifact. The response to salbutamol was computed as change in respiratory resistance (Δ%Rrs) and admittance (Δ%Ars) that almost cancels the effect of the upper airway artifact., Results: Rrs and Δ%Rrs were significantly larger in patients than controls by HG (respectively P < 0.001 and P = 0.002) but not SG, while Δ%Ars was larger in asthma than control by both (P < 0.04). Best discriminators between patients and controls were Rrs or Δ%Rrs by HG and Δ%Ars by SG., Conclusion: In asthmatic children, the upper airway artifact significantly impacts FOT measurements. The diagnostic value may be improved by minimization of the shunt, such as the computation of Δ%Ars., (© 2014 Wiley Periodicals, Inc.)

Panting majors turbulent flow and contribution of larger airways to the measurement of specific airway resistance (sRaw). The hypothesis was tested that the difference between asthmatic and healthy children is enhanced by narrowing the flow interval to compute sRaw. sRaw was measured during panting in 40 asthmatic and 25 healthy children and computed using all data points (full scale flow) and limited to the flow intervals ± 1L/sec and ± 0.5 L/sec. sRaw was not different between asthmatics (0.87 ± 0.20 kPa.s) and controls (0.80 ± 0.25 kPa.s) when computed full scale, while it was significantly larger in asthmatics than controls within ± 1L/sec (0.77 ± 0.16 kPa.s vs 0.65 ± 0.15 kPa.s, P < 0.004) or ± 0.5 L/sec (0.77 ± 0.21 kPa.s vs 0.61 ± 0.17 kPa.s, P < 0.002). On the other hand, the within subject coefficient of variation was significantly larger when sRaw was computed within ± 1L/sec (13.7 ± 7.2%) or ± 0.5 L/sec (28.3 ± 18.1%) than full scale (11.0 ± 6.7%), respectively P < 0.002 and P < 0.0001. It is concluded that narrowing the flow interval to compute sRaw is associated with better discrimination between asthma and health in children, although the short term variability of sRaw is increased., (© 2014 Wiley Periodicals, Inc.)

Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol synthesized by various plants such as grape vine. Resveratrol (RSV) is a widely studied molecule, largely for its chemopreventive effect in different mouse cancer models. We propose a mechanism underlying the cytotoxic activity of RSV on colon cancer cells. Our data show that resveratrol induces apoptosis, as observed by the cleavage of PARP-1 and chromatin condensation. We show that the tumor suppressor p53 is activated in response to RSV and participates to the apoptotic process. Additionally, we show that HCT-116 p53 wt colon carcinoma cells are significantly more sensitive than HCT-116 p53-/- cells to RSV. RSV induces DNA damage including double strand breaks, as evidenced by the presence of multiple γ-H2AX foci in 50% of cells after a 24 h treatment with 25 μM RSV. The formation of DNA damage does not appear to rely on a pro-oxidant effect of the molecule, inhibition of topoisomerase I, or DNA intercalation. Rather, we show that DNA damage is the consequence of type II topoisomerase poisoning. Exposure of HCT-116 cells to RSV leads to activation of the Ataxia Telangiectasia Mutated (ATM) kinase, and ATM is required to activate p53., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In healthy Vietnamese children the respiratory resistance has been suggested to be similar at 110 cm height but larger at 130 cm when compared with data in Caucasians from the literature, suggesting smaller airways in older Vietnamese children (Vu et al., 2008). The hypothesis tested here is whether the difference in airway resistance remains consistent throughout growth, and if it is larger in adult Vietnamese than in Caucasians. Airway resistance and Functional Residual Capacity were measured in healthy young Caucasian and Vietnamese adults in their respective native country using identical equipment and protocols. Ninety five subjects in Vietnam (60 males) and 101 in France (41 males) were recruited. Airway resistance was significantly larger in Vietnamese than in Caucasians and in females than in males, consistent with difference in body dimensions. Specific airway resistance however was not different by ethnicity or gender. The findings do not support the hypothesis that airway size at adult age - once normalized for lung volume - differs between Vietnamese and Caucasians., (Copyright © 2015 Elsevier B.V. All rights reserved.)