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Bedload transport can fluctuate considerably over relatively short periods of time and for a given quasi‐constant flow rate. What are the implications of replacing the fluctuating signal with a smoothed signal when calculating bedload transport using averaged values, as is common practice? This question was investigated with the BedloadR code, which allows 1D bedload calculation as well as Monte Carlo simulations using a new data set collected in the Severaisse River (French Ecrins massif). Four bedload equations (Camenen & Larson, 2005, https://doi.org/10.1016/j.ecss.2004.10.019; Meyer‐Peter & Mueller, 1948; Parker, 1990, https://doi.org/10.1080/00221689009499058; Recking, 2013a, https://doi.org/10.1061/(asce)hy.1943‐7900.0000653) were selected for their performance relative to the measured bedload (except for and Meyer‐Peter and Mueller) and because each equation has a different mathematical form and degree of nonlinearity. They were used in a Monte Carlo approach, with input probability distributions fitted to the measured river width, slope, bed grain‐size distribution, and to the associated (computed) Shields stress. The results show that accounting for natural variability in the calculation reproduces bedload fluctuations well. But overall, when calculating the bedload volume transported by a flow event, accounting for variability systematically leads to higher estimated volumes (of the order of 20%) than those obtained with a deterministic approach using average input parameters. This is a direct consequence of the nonlinearity of the equations. Plain Language Summary: Transport of bedload in a river, that is, sediment in motion that stays close to the riverbed, fluctuates a lot over relatively short time periods for a given near‐constant discharge. In this paper, we try to reproduce this natural process. To do this, we use a protocol that involves running a bedload equation several thousand times, slightly and randomly modifying the input data with each run. The results show that by taking into account the natural variability of sediment size or channel geometry, we obtain realistic modeling of bedload transport fluctuations. Key Points: A new field data set is used for computing bedload in a Monte Carlo approachBedload modeling accounting for input variability reproduces bedload fluctuation wellBecause of non‐linearity, volumes computed with input variability are 20% higher [ABSTRACT FROM AUTHOR]

Bedload Self-Generated Noise (SGN) measurements consist in deploying an underwater microphone (i.e. a hydrophone) in the water course and to record the ambient noise of a river. The use of hydrophones is of interest as it can be easily deployed and can provide a continuous monitoring of bedload transport. However, developments are still required to fully understand how bedload characteristics (e.g. specific flux or granulometry) are related to bedload SGN parameters (e.g. acoustic power and spectrum). Laboratory experiments have shown that central and peak frequencies of bedload noise decrease as the particle size increases, just like in string instruments where the tone frequency decreases from a narrow string to a broader string. In this paper, we propose to test a new inverse method enabling the estimation of bedload grain size distributions from SGN measurements. The inverse method is based on a theoretical modelling of the noise generated by a bedload mixture. SGN and physical sampling measurements have been made in 5 French alpine rivers having several transport conditions (bedload D50 from 1 to 40 mm) and varying slopes (0.05 to 1%). Measurements were made for specific bedload flux varying from 10 to 150 g.m-1s-1. The proposed inverse method was used to estimate the bedload grain size distributions. SGN results are compared to bedload samples and are found to largely overestimate sampled granulometries. Finally, it is observed that the spectral characteristics of bedload SGN are not related to bedload GSD but rather to the roughness of the river bed, acting as a source of attenuation and shaping bedload SGN spectra.

Bedload Self-Generated Noise (SGN) measurements consist in deploying an underwater microphone (i.e. a hydrophone) in the river and to record the ambient noise. The use of hydrophones to measure bedload characteristics (flux, spatial distribution, granulometry) could be of interest as it can be more easily and rapidly deployed than physical samplers in rivers. Several measurement campaigns where conducted during spring and summer 2017 in 5 alpine rivers with contrasted transport conditions (bedload D50 between 1 and 40 mm) and varying slopes (0.05 to 1 %). Physical sampling measurements were done from a bridge along the river cross section for specific bedload flux varying between 10 and 150 g.m-1s-1. Bedload SGN measurements were obtained with a small board equipped with a hydrophone and deriving downstream the bridge within a 10 to 50 m long river section. For 2 of the 5 rivers, acoustic Doppler current profilers (ADCP) were also deployed along the river cross-section to provide a surrogate measurement of apparent bedload velocity. As a result, we have been able to draw an acoustic 1D-map of the river bottom, derived from the SGN sub-surface measurements obtained with the deriving board. The results show a coherent relation between the riverbed acoustic maps and the physical samplings for 3 rivers over 5. Bedload profile were less consistent with SGN measurements when bedload transport was localized in a narrow channel. The apparent bedload velocities obtained with ADCP for 2 rivers are consitent with the physical samplings (bedload location and flux distribution) but a slight bias was observed and is attributed to grain-size sorting effects along the cross-section. Finally, when plotting together 4 over 5 rivers, an almost linear relation can be established between bedload discharge (computed with physical samplings data) and the average acoustic response (i.e acoustic power averaged over the cross-section). This result suggests that a generalized calibration curve could exist between bedload SGN and bedload discharge. The existence of an outsider is interpreted as a problem related to propagation effects. Further researches should therefore concentrate their effort on deconvoluting SGN signals from propagation effects to give a better confident proxy for bedload discharge measurement in different rivers types.

Expanded access (EA) to investigational medicines offers a potential lifeline for patients suffering from a serious or life-threatening disease, who have exhausted other comparable or satisfactory alternative therapeutic options and are not eligible to enter a clinical trial. The 21st Century Cures Act requires that a company developing new medicines shall make a policy regarding EA public. Bionical Emas have developed a patient centric decision-making framework for EA starting from a position of "yes, EA will be provided if specific conditions are met". This framework takes the burden away from patients and families by allowing pharmaceutical companies to work through internal and external barriers backwards to provide reasoning, transparent rationale, and reflection on whether to provide EA to eligible patients. We present a case study in which we applied this framework to Duchenne muscular dystrophy (DMD) and consider disease specific challenges. There are licensed drugs available however, as these therapies are mutation specific, there remains an unmet need for the majority of the DMD population. There is no cure for DMD and most treatment options available are to help manage symptoms and improve the quality of life. As a result, EA programs are considered by DMD patients, families and physicians as a possible route to access potentially effective treatments. There are novel therapies in the pipeline which may be able to address the unmet need however, the pharmaceutical company must assess factors including benefit: risk ratio, the impact on clinical development activities, supply and manufacturing constraints, commercial sustainability, and the needs of the patient community through engagement with Patient Advocacy Groups and Key Opinion Leaders. This decision-making framework enables a pharmaceutical company to assess EA through a clear patient centric approach which is especially crucial for debilitating and life-threatening conditions such as DMD. [ABSTRACT FROM AUTHOR]

Objective: To determine the long-term safety and efficacy of repeated intrathecal (IT) administration of autologous mesenchymal stem cell-derived neural progenitors (MSC-NPs) in patients with progressive MS by evaluating subjects 2 years after treatment., Methods: Twenty subjects were enrolled as part of a phase I, open-label single-arm study of 3 IT injections of MSC-NPs spaced 3 months apart. Subjects were evaluated for adverse events and disability outcomes including the Expanded Disability Status Scale (EDSS) and the timed 25-foot walk (T25FW). Long-term evaluation was conducted 2 years after the third treatment. CSF was collected before and 3 months after treatment., Results: Eighteen of the 20 study participants completed the full 2-year follow-up protocol. There were no long-term adverse events associated with repeated IT-MSC-NP treatment. Seven subjects showed sustained improvement in EDSS after 2 years, although the degree of improvement was not maintained in 5 of the subjects. Three of the 10 ambulatory subjects showed sustained improvement in the T25FW after 2 years. CSF biomarker analysis revealed a decrease in C-C motif chemokine ligand 2 (CCL2) and an increase in interleukin 8, hepatocyte growth factor, and C-X-C motif chemokine ligand 12 (CXCL12) after treatment., Conclusions: Safety and efficacy of repeated IT-MSC-NP treatment was sustained for 2 years; however, the degree of disability reversal was not sustained in a subset of patients. CSF biomarkers altered in response to IT-MSC-NP treatment may reflect specific immunoregulatory and trophic mechanisms of therapeutic response in MS., Classification of Evidence: This study provides Class IV evidence that for patients with progressive MS, IT administration of MSC-NPs is safe and effective. The study is rated Class IV because of the absence of a non-IT-MSC-NP-treated control group., Clinicaltrialsgov Identifier: NCT01933802., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

One of the most important application areas of molecular quantum chemistry is the study and prediction of chemical reactivity. Large-scale, fully error-tolerant quantum computers could provide exact or near-exact solutions to the underlying electronic structure problem with exponentially less effort than a classical computer thus enabling highly accurate predictions for comparably large molecular systems. In the nearer future, however, only "noisy" devices with a limited number of qubits that are subject to decoherence will be available. For such near-term quantum computers the hybrid quantum-classical variational quantum eigensolver algorithm in combination with the unitary coupled-cluster ansatz (UCCSD-VQE) [ Peruzzo et al. Nat. Commun. 2014 , 5 , 4213 and McClean et al. New J. Phys. 2016 , 18 , 023023 ] has become an intensively discussed approach that could provide accurate results before the dawn of error-tolerant quantum computing. In this work we present an implementation of UCCSD-VQE that allows for the first time to treat both open- and closed-shell molecules. We study the accuracy of the obtained energies for nine small molecular systems as well as for four exemplary chemical reactions by comparing to well-established electronic structure methods like (nonunitary) coupled-cluster and density functional theory. Finally, we roughly estimate the required quantum hardware resources to obtain "useful" results for practical purposes.

We study an analog quantum simulator coupled to a reservoir with a known spectral density. The reservoir perturbs the quantum simulation by causing decoherence. The simulator is used to measure an operator average, which cannot be calculated using any classical means. Since we cannot predict the result, it is difficult to estimate the effect of the environment. Especially, it is difficult to resolve whether the perturbation is small or if the actual result of the simulation is in fact very different from the ideal system we intend to study. Here, we show that in specific systems a measurement of additional correlators can be used to verify the reliability of the quantum simulation. The procedure only requires additional measurements on the quantum simulator itself. We demonstrate the method theoretically in the case of a single spin connected to a bosonic environment.

Background: Second-generation laryngeal masks with gastric access are increasingly used in daily practice and expand the indications for laryngeal masks in the OR. Only limited data exist comparing different types of laryngeal masks. We investigated the second-generation laryngeal masks LMA Supreme™ and Ambu® AuraGain™ in a clinical setting. We hypothesized that the two devices would be comparable in terms of success rate and airway complications., Methods: After approval from the local ethics committee, data were collected in a prospective trial. Endpoints were success rate, time to insertion and airway morbidity. Anesthesiologists used either the Supreme (Teleflex Medical GmbH) or Gain (Ambu GmbH) laryngeal mask. Patients <18 years and those with a possible risk of regurgitation were excluded., Results: Data from 351 adult patients were documented (Supreme N.=177; Gain N.=174). Success rate for first attempt was 80% (Supreme) and 72% (Gain; P=0.08). Overall success rate was 89% and 92%, respectively (P=0.38). Providers with minimal experience were more successful at first attempt using Supreme (95%), compared to Gain (67%; P=0.01). The median insertion time was shorter in Supreme at 18 s [interquartile range (IQR), 14-25 s] compared to 30 s for Gain [18-41s] (P<0.0001). A higher incidence of airway complications was observed after device removal for Gain (P=0.009)., Conclusions: Supreme was superior to Gain in terms of insertion time and airway morbidity. Novices were more successful at first attempt using Supreme. These differences between supraglottic airway devices might be due to the different shapes and materials of the masks.

Recent progress with microfabricated quantum devices has revealed that an ubiquitous source of noise originates in tunneling material defects that give rise to a sparse bath of parasitic two-level systems (TLSs). For superconducting qubits, TLSs residing on electrode surfaces and in tunnel junctions account for a major part of decoherence and thus pose a serious roadblock to the realization of solid-state quantum processors. Here, we utilize a superconducting qubit to explore the quantum state evolution of coherently operated TLSs in order to shed new light on their individual properties and environmental interactions. We identify a frequency-dependence of TLS energy relaxation rates that can be explained by a coupling to phononic modes rather than by anticipated mutual TLS interactions. Most investigated TLSs are found to be free of pure dephasing at their energy degeneracy points, around which their Ramsey and spin-echo dephasing rates scale linearly and quadratically with asymmetry energy, respectively. We provide an explanation based on the standard tunneling model, and identify interaction with incoherent low-frequency (thermal) TLSs as the major mechanism of the pure dephasing in coherent high-frequency TLS.

The market for veterinary vaccines is spread across species but it is limited in size and the development of vaccines is becoming more complex and expensive. Vaccines are amongst the most effective means of preventing disease in both animals and humans. In many cases, diseases have been eradicated or their impact on animal health and welfare greatly reduced. It is an ethical responsibility to ensure the availability of a wide range of vaccines even where the market needs to be financially supported, as in the case of less common animal species and those with less common conditions (commonly referred to by the acronym MUMS: Minor Use and Minor Species). Mass slaughter is becoming unacceptable to society and we must move to a 'vaccinate to live' policy wherever possible. We need to use vaccines to avoid the high costs of disease and to enhance food safety. In developing vaccines, we need to minimise animal testing. In addition, we need to ensure that the public acceptthe use of vaccines in food-producing animals as a means of protecting the health and welfare of all animals. As we look to the future, vaccines will be vital to ensure our ability to provide more food to a growing global population. The European Technology Platform for Global Animal Health has a key role to play in identifying key research priorities.

Objectives: This study evaluated the safety, tolerability, and efficacy of natalizumab, a humanized monoclonal immunoglobulin-G4 antibody to [alpha]4 integrin, in adolescent patients with moderately to severely active Crohn disease (CD)., Patients and Methods: In a single-arm study, 38 adolescent patients (ages 12-17 y) with active CD (Pediatric Crohn Disease Activity Index [PCDAI] >30) received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks. The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs. Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed. Efficacy outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of C-reactive protein and serum albumin., Results: Thirty-one patients (82%) received 3 natalizumab infusions. The most common adverse events were headache (26%), pyrexia (21%) and CD exacerbation (24%). Clinical response (> or =15-point decrease from baseline PCDAI) and remission (PCDAI < or =10) rates were greatest at week 10 (55% and 29%, respectively). Three patients (8%) tested positive for anti-natalizumab antibodies. The peak level (61.0 and 66.3 microg/mL) and half-life (92.3 and 96.3 h) of natalizumab were comparable after the first and third infusions. Mean [alpha]4 integrin receptor saturation was 93% at 2 hours and <40% at 4 weeks after the first and third infusions. Increase from baseline in circulating lymphocytes ranged from 106% to 122% at 2 weeks and 45% to 65% at 4 weeks after each infusion., Conclusion: Natalizumab (3 mg/kg) was well tolerated in these adolescent patients with active CD, with a safety and efficacy profile similar to that of adult natalizumab-treated CD patients. Future studies should evaluate long-term safety and efficacy.

The efficacy of a vaccinia-rabies recombinant virus (10(8) TCID50) contained in a machine-made baiting system has been tested in 22 captive young foxes which were divided into three experimental groups of six and a control group of four foxes. Each fox in groups 1, 2 and 3 were fed one, two and three vaccine-baits, respectively, on successive days. The four unvaccinated foxes were housed separately. As shown by the incorporation of a tetracycline biomarker into their bones, all the baited foxes ingested at least one bait. Thirty days after baiting seroconversion to rabies was observed in 15 (83 per cent) of the foxes and seroconversion to vaccinia in 14 (78 per cent). Sixteen of the 18 (89 per cent) baited foxes resisted a rabies challenge 30 days after baiting. One cub was protected against rabies despite the absence of detectable anti-rabies antibody. The results demonstrate that the bait-sachet system permits a good release of the virus suspension into the mouth.