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Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Abstract Background An ageing population leads up to increasing multi-morbidity and polypharmacy. This demands a comprehensive and interprofessional approach in meeting patients’ complex needs. This study describes graduate students’ experiences of working practice based in interprofessional teams with complex patients’ care needs in nursing homes. Method Students from advanced geriatric nursing, clinical nutrition, dentistry, medicine and pharmacy at the University of Oslo in Norway were assigned to groups to examine and develop a care plan for a nursing home patient during a course. Focus groups were used, 21 graduate students participating in four groups. Data were collected during spring 2018, were inductively analysed according to a thematic analysis method (Systematic Text Condensation). An analytical framework of co-ordination practices was applied to get an in-depth understanding of the data. Results Three themes were identified: 1) Complex patients as learning opportunities- an eye-opener for future interprofessional collaboration 2) A cobweb of relations, and 3) Structural facilitators for new collective knowledge. Graduate university students experienced interprofessional education (IPE) on complex patients in nursing homes as a comprehensive learning arena. Overall, different co-ordination practices for work organization among the students were identified. Conclusions IPE in nursing homes facilitated the students’ scope from a fragmented approach of the patients towards a relational and collaborative practice that can improve patient care and strengthen understanding of IPE. The study also demonstrated the need for preparatory teamwork training to gain maximum benefit from the experience. Something that can be organized by the education institutions in the form of a stepwise learning module and as an online pre-training course in interprofessional teamwork. Further, focusing on the need for well thought through processes of the activity by the institutions and the timing the practice component in students’ curricula. This could ensure that IPE is experienced more efficient by the students.

Nanostructured and microstructured thin foils have been fabricated and used experimentally as targets to manipulate the spatial profile of proton bunches accelerated through the interaction with high intensity laser pulses (6×10^{19} W/cm^{2}). Monolayers of polystyrene nanospheres were placed on the rear surfaces of thin plastic targets to improve the spatial homogeneity of the accelerated proton beams. Moreover, thin targets with grating structures of various configurations on their rear sides were used to modify the proton beam divergence. Experimental results are presented, discussed, and supported by 3D particle-in-cell numerical simulations.

The properties of laser wakefield accelerated electrons in supersonic gas flows of hydrogen and helium are investigated. At identical backing pressure, we find that electron beams emerging from helium show large variations in their spectral and spatial distributions, whereas electron beams accelerated in hydrogen plasmas show a higher degree of reproducibility. In an experimental investigation of the relation between neutral gas density and backing pressure, it is found that the resulting number density for helium is ∼30% higher than for hydrogen at the same backing pressure. The observed differences in electron beam properties between the two gases can thus be explained by differences in plasma electron density. This interpretation is verified by repeating the laser wakefield acceleration experiment using similar plasma electron densities for the two gases, which then yielded electron beams with similar properties.

We report on a study on controlled injection of electrons into the accelerating phase of a plasma wakefield accelerator by tailoring the target density distribution using two independent sources of gas. The tailored density distribution is achieved experimentally by inserting a narrow nozzle, with an orifice diameter of only 400 μm, into a jet of gas supplied from a 2 mm diameter nozzle. The combination of these two nozzles is used to create two regions of different density connected by a density gradient. Using this setup we show independent control of the charge and energy distribution of the bunches of accelerated electron as well as decreased shot-to-shot fluctuations in these quantities compared to self-injection in a single gas jet. Although the energy spectra are broad after injection, simulations show that further acceleration acts to compress the energy distribution and to yield peaked energy spectra.

The dynamics of electron acceleration driven by laser wakefield inside a 30.5 mm long dielectric capillary tube is analyzed using radiation emitted in the x-ray range. 3D particle-in-cell simulations, performed with parameters close to the experimental ones, show that in long plasmas, the accelerated electrons catch up and finally overrun the driving laser owing to a higher velocity of the electrons in the plasma. The electrons are then transversely scattered by the laser pulse, and penetrate the capillary wall where they generate bremsstrahlung radiation, modeled using geant4 simulations. The signature of bremsstrahlung radiation is detected using an x-ray camera, together with the betatron radiation emitted during electron acceleration in the plasma bubble. The reflection of betatron radiation from the inner capillary surface also accounts for a fraction of the observed signal on the x-ray camera. The simulation results are in agreement with the experimental ones and provide a detailed description of the electron and radiation properties, useful for the design of laser wakefield accelerators or radiation sources using long plasma media.

A novel approach to implement and control electron injection into the accelerating phase of a laser wakefield accelerator is presented. It utilizes a wire, which is introduced into the flow of a supersonic gas jet creating shock waves and three regions of differing plasma electron density. If tailored appropriately, the laser plasma interaction takes place in three stages: Laser self-compression, electron injection, and acceleration in the second plasma wave period. Compared to self-injection by wave breaking of a nonlinear plasma wave in a constant density plasma, this scheme increases beam charge by up to 1 order of magnitude in the quasimonoenergetic regime. Electron acceleration in the second plasma wave period reduces electron beam divergence by ≈25%, and the localized injection at the density downramps results in spectra with less than a few percent relative spread.

A laser pulse traveling through a plasma can excite large amplitude plasma waves that can be used to accelerate relativistic electron beams in a very short distance—a technique called laser wakefield acceleration. Many wakefield acceleration experiments rely on the process of wave breaking, or self-injection, to inject electrons into the wave, while other injection techniques rely on operation without self-injection. We present an experimental study into the parameters, including the pulse energy, focal spot quality, and pulse power, that determine whether or not a wakefield accelerator will self-inject. By taking into account the processes of self-focusing and pulse compression we are able to extend a previously described theoretical model, where the minimum bubble size k_{p}r_{b} required for trapping is not constant but varies slowly with density and find excellent agreement with this model.

In the assessment of the safety of a new drug, a large battery of toxicological studies is performed. In toxicological studies it is common practice to analyse the data from the sexes separately. We argue that this is not best practice and that much is to be gained from combining data from both sexes when evaluating studies. The main benefits and arguments in favour of combining the data are: (i) Improved efficiency, allowing fewer test animals and/or better precision. (ii) Other phases of drug development, clinical trials in particular, combine sexes. (iii) Most substances act similarly on both sexes and most drugs are prescribed without sex differentiation. (iv) If sex differences are of interest, combined data facilitates the quantification of the difference. (v) Reduced number of false positive and false negative findings. Although there might be some grounds to analysing the sexes separately, we argue that these are comparatively minor. We do not promote simply pooling the data and neglecting the existence of two sexes when comparing treatment groups. Rather, the analysis of combined data should allow for sex differences, for instance by using stratified procedures or by including a sex factor in a statistical model. We illustrate from real study data where the approach we propose has substantial benefits over traditional methods. A theoretical illustration is provided to quantify mathematically the potential gains and the corresponding sample size reduction, i.e. a reduction of animal use of ca. 50%, that would be possible without impairing the precision of studies., (Copyright 2005 John Wiley & Sons, Ltd.)

In this study possible mechanisms underlying the vaso- and bronchoconstriction caused by the tricyclic antidepressant drug amitriptyline in isolated rat lungs were investigated. Some features here are similar to those apparent in adult respiratory distress syndrome and acute lung injury. Amitriptyline exposure (50 and 100 microM) caused a dose-related, pronounced, and rapid vaso- (50 microM, 30 min, p < 0.001 and 100 microM, 30 min, p < 0.001) and bronchoconstriction (50 microM, 30 min, p = 0.01 and 100 microM, 30 min, p < 0.001). The maximal noted decrease in perfusion flow was 28 +/- 2.9% at 25 min and 80 +/- 4.5% at 30 min for 50 and 100 microM amitriptyline, respectively. The maximal noted decrease in airway conductance was 29 +/- 4.7% at 25 min and 68 +/- 5.0% at 30 min. To investigate mechanisms thought to be involved in amitriptyline-induced lung function impairment, lungs were treated with several different substances including antiinflammatory agents, antioxidants, inhibitors of enzymes involved in the arachidonic acid cascade, physiological antagonists, and neurogenic antagonists. A significant reduction of amitriptyline-induced vasoconstriction was observed when lungs were treated with the protein kinase inhibitor staurosporine (3 microM, 30 min, p < 0.001), the NO-donor S-nitrosoglutathione (100 microM, 30 min, p < 0.001) and the combined endothelin A/endothelin B receptor antagonist PD 145065. This latter inhibitor caused a significant attenuation of late vasoconstriction (1 microM, 60 min, p = 0.03). The amitriptyline-induced bronchoconstriction was attenuated by the beta(2)-agonist salbutamol (1 microM, 30 min, p = 0.03) and the platelet-activating factor antagonist WEB2086 (10 microM, 30 min, p = 0.03). Staurosporine had an initial protective effect on bronchoconstriction (3 microM, 5 min, p = 0.003), while PD145065 significantly decreased bronchoconstriction 60 min after start of amitriptyline exposure (1 microM, 30 min, p = 0.003). This indicates that endothelin as well as platelet activating factor and protein kinase activation are important in mediating amitriptyline-induced lung function impairment in our experimental model and perhaps also in acute lung injury., (c)2001 Elsevier Science.)