Flux footprint models are often used for interpretation of flux tower measurements, to estimate position and size of surface source areas, and the relative contribution of passive scalar sources to ...measured fluxes. Accurate knowledge of footprints is of crucial importance for any upscaling exercises from single site flux measurements to local or regional scale. Hence, footprint models are ultimately also of considerable importance for improved greenhouse gas budgeting. With increasing numbers of flux towers within large monitoring networks such as FluxNet, ICOS (Integrated Carbon Observation System), NEON (National Ecological Observatory Network), or AmeriFlux, and with increasing temporal range of observations from such towers (of the order of decades) and availability of airborne flux measurements, there has been an increasing demand for reliable footprint estimation. Even though several sophisticated footprint models have been developed in recent years, most are still not suitable for application to long time series, due to their high computational demands. Existing fast footprint models, on the other hand, are based on surface layer theory and hence are of restricted validity for real-case applications. To remedy such shortcomings, we present the two-dimensional parameterisation for Flux Footprint Prediction (FFP), based on a novel scaling approach for the crosswind distribution of the flux footprint and on an improved version of the footprint parameterisation of Kljun et al. (2004b). Compared to the latter, FFP now provides not only the extent but also the width and shape of footprint estimates, and explicit consideration of the effects of the surface roughness length. The footprint parameterisation has been developed and evaluated using simulations of the backward Lagrangian stochastic particle dispersion model LPDM-B (Kljun et al., 2002). Like LPDM-B, the parameterisation is valid for a broad range of boundary layer conditions and measurement heights over the entire planetary boundary layer. Thus, it can provide footprint estimates for a wide range of real-case applications. The new footprint parameterisation requires input that can be easily determined from, for example, flux tower measurements or airborne flux data. FFP can be applied to data of long-term monitoring programmes as well as be used for quick footprint estimates in the field, or for designing new sites.
We consider the nonlinear optimisation of the mixing of a passive scalar, initially arranged in two layers, in a two-dimensional plane Poiseuille flow at finite Reynolds and Péclet numbers, below the ...linear instability threshold. We use a nonlinear-adjoint-looping approach to identify optimal perturbations leading to maximum time-averaged energy as well as maximum mixing in a freely evolving flow, measured through the minimisation of either the passive scalar variance or the so-called mix-norm, as defined by Mathew, Mezić & Petzold (Physica D, vol. 211, 2005, pp. 23–46). We show that energy optimisation appears to lead to very weak mixing of the scalar field whereas the optimal mixing initial perturbations, despite being less energetic, are able to homogenise the scalar field very effectively. For sufficiently long time horizons, minimising the mix-norm identifies optimal initial perturbations which are very similar to those which minimise scalar variance, demonstrating that minimisation of the mix-norm is an excellent proxy for effective mixing in this finite-Péclet-number bounded flow. By analysing the time evolution from initial perturbations of several optimal mixing solutions, we demonstrate that our optimisation method can identify the dominant underlying mixing mechanism, which appears to be classical Taylor dispersion, i.e. shear-augmented diffusion. The optimal mixing proceeds in three stages. First, the optimal mixing perturbation, energised through transient amplitude growth, transports the scalar field across the channel width. In a second stage, the mean flow shear acts to disperse the scalar distribution leading to enhanced diffusion. In a final third stage, linear relaxation diffusion is observed. We also demonstrate the usefulness of the developed variational framework in a more realistic control case: mixing optimisation by prescribed streamwise velocity boundary conditions.
As conventional electronics approaches its limits
, nanoscience has urgently sought methods of fast control of electrons at the fundamental quantum level
. Lightwave electronics
-the foundation of ...attosecond science
-uses the oscillating carrier wave of intense light pulses to control the translational motion of the electron's charge faster than a single cycle of light
. Despite being particularly promising information carriers, the internal quantum attributes of spin
and valley pseudospin
have not been switchable on the subcycle scale. Here we demonstrate lightwave-driven changes of the valley pseudospin and introduce distinct signatures in the optical readout. Photogenerated electron-hole pairs in a monolayer of tungsten diselenide are accelerated and collided by a strong lightwave. The emergence of high-odd-order sidebands and anomalous changes in their polarization direction directly attest to the ultrafast pseudospin dynamics. Quantitative computations combining density functional theory with a non-perturbative quantum many-body approach assign the polarization of the sidebands to a lightwave-induced change of the valley pseudospin and confirm that the process is coherent and adiabatic. Our work opens the door to systematic valleytronic logic at optical clock rates.
The linear amplification of axisymmetric external forcing in incompressible jet flows is investigated within a fully non-parallel framework. Experimental and numerical studies have shown that ...isothermal jets preferably amplify external perturbations for Strouhal numbers in the range
$0. 25\leq {\mathit{St}}_{D} \leq 0. 5$
, depending on the operating conditions. In the present study, the optimal forcing of an incompressible jet is computed as a function of the excitation frequency. This analysis characterizes the preferred amplification as a pseudo-resonance with a dominant Strouhal number of around
$0. 45$
. The flow response at this frequency takes the form of a vortical wavepacket that peaks inside the potential core. Its global structure is characterized by the cooperation of local shear-layer and jet-column modes.
Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II ...KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC.
Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival.
All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9–31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9–34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0–2.2), and median overall survival was 18.0 months (95% CI 12.9–23.0).
Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC.
ClinicalTrials.gov, NCT02447003.
This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus‐based guideline, taking available ...evidence from other guidelines, systematic reviews and published studies into account. This first part of the guideline covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy, whereas the second part covers antimicrobial therapy, systemic treatment, allergen‐specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions. Management of AE must consider the individual clinical variability of the disease; highly standardized treatment rules are not recommended. Basic therapy is focused on treatment of disturbed barrier function by hydrating and lubricating topical treatment, besides further avoidance of specific and unspecific provocation factors. Topical anti‐inflammatory treatment based on glucocorticosteroids and calcineurin inhibitors is used for flare management and for proactive therapy for long‐term control. Topical corticosteroids remain the mainstay of therapy, whereas tacrolimus and pimecrolimus are preferred in sensitive skin areas and for long‐term use. Topical phosphodiesterase inhibitors may be a treatment alternative when available. Adjuvant therapy includes UV irradiation, preferably with UVB 311 nm or UVA1. Pruritus is targeted with the majority of the recommended therapies, but some patients may need additional antipruritic therapy. Antimicrobial therapy, systemic anti‐inflammatory treatment, immunotherapy, complementary medicine and educational intervention will be addressed in part II of the guideline.
Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as second or later ...line of treatment for patients with mTNBC.
Eligible patients had centrally confirmed mTNBC, ≥1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary end points were objective response rate in the total and PD-L1–positive populations, and safety. Secondary end points included duration of response, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), progression-free survival, and overall survival.
All enrolled patients (N = 170) were women, 61.8% had PD-L1–positive tumors, and 43.5% had received ≥3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7–9.9) in the total and 5.7% (2.4–12.2) in the PD-L1–positive populations. Disease control rate (95% CI) was 7.6% (4.4–12.7) and 9.5% (5.1–16.8), respectively. Median duration of response was not reached in the total (range, 1.2+–21.5+) and in the PD-L1–positive (range, 6.3–21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9–2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.6–11.2), and the 6-month rate was 69.1%. Treatment-related adverse events occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs.
Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile.
ClinicalTrials.gov, NCT02447003
Future information technology demands ever-faster, low-loss quantum control. Intense light fields have facilitated milestones along this way, including the induction of novel states of matter
, ...ballistic acceleration of electrons
and coherent flipping of the valley pseudospin
. These dynamics leave unique 'fingerprints', such as characteristic bandgaps or high-order harmonic radiation. The fastest and least dissipative way of switching the technologically most important quantum attribute-the spin-between two states separated by a potential barrier is to trigger an all-coherent precession. Experimental and theoretical studies with picosecond electric and magnetic fields have suggested this possibility
, yet observing the actual spin dynamics has remained out of reach. Here we show that terahertz electromagnetic pulses allow coherent steering of spins over a potential barrier, and we report the corresponding temporal and spectral fingerprints. This goal is achieved by coupling spins in antiferromagnetic TmFeO
(thulium orthoferrite) with the locally enhanced terahertz electric field of custom-tailored antennas. Within their duration of one picosecond, the intense terahertz pulses abruptly change the magnetic anisotropy and trigger a large-amplitude ballistic spin motion. A characteristic phase flip, an asymmetric splitting of the collective spin resonance and a long-lived offset of the Faraday signal are hallmarks of coherent spin switching into adjacent potential minima, in agreement with numerical simulations. The switchable states can be selected by an external magnetic bias. The low dissipation and the antenna's subwavelength spatial definition could facilitate scalable spin devices operating at terahertz rates.
This guideline was developed as a joint interdisciplinary European project, including physicians from all relevant disciplines as well as patients. It is a consensus‐based guideline, taking available ...evidence from other guidelines, systematic reviews and published studies into account. This second part of the guideline covers antimicrobial therapy, systemic treatment, allergen‐specific immunotherapy, complementary medicine, psychosomatic counselling and educational interventions, whereas the first part covers methods, patient perspective, general measures and avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy. Management of AE must consider the individual clinical variability of the disease. Systemic immunosuppressive treatment with cyclosporine, methotrexate, azathioprine and mycophenolic acid is established option for severe refractory cases, and widely available. Biologicals targeting the T helper 2 pathway such as dupilumab may be a safe and effective, disease‐modifying alternative when available. Oral drugs such as JAK inhibitors and histamine 4 receptor antagonists are in development. Microbial colonization and superinfection may cause disease exacerbation and can require additional antimicrobial treatment. Allergen‐specific immunotherapy with aeroallergens may be considered in selected cases. Psychosomatic counselling is recommended especially in stress‐induced exacerbations. Therapeutic patient education (‘Eczema school’) is recommended for children and adult patients. General measures, basic emollient treatment, bathing, dietary intervention, topical anti‐inflammatory therapy, phototherapy and antipruritic therapy have been addressed in the first part of the guideline.
Harnessing the carrier wave of light as an alternating-current bias may enable electronics at optical clock rates
. Lightwave-driven currents have been assumed to be essential for high-harmonic ...generation in solids
, charge transport in nanostructures
, attosecond-streaking experiments
and atomic-resolution ultrafast microscopy
. However, in conventional semiconductors and dielectrics, the finite effective mass and ultrafast scattering of electrons limit their ballistic excursion and velocity. The Dirac-like, quasi-relativistic band structure of topological insulators
may allow these constraints to be lifted and may thus open a new era of lightwave electronics. To understand the associated, complex motion of electrons, comprehensive experimental access to carrier-wave-driven currents is crucial. Here we report angle-resolved photoemission spectroscopy with subcycle time resolution that enables us to observe directly how the carrier wave of a terahertz light pulse accelerates Dirac fermions in the band structure of the topological surface state of Bi
Te
. While terahertz streaking of photoemitted electrons traces the electromagnetic field at the surface, the acceleration of Dirac states leads to a strong redistribution of electrons in momentum space. The inertia-free surface currents are protected by spin-momentum locking and reach peak densities as large as two amps per centimetre, with ballistic mean free paths of several hundreds of nanometres, opening up a realistic parameter space for all-coherent lightwave-driven electronic devices. Furthermore, our subcycle-resolution analysis of the band structure may greatly improve our understanding of electron dynamics and strong-field interaction in solids.
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