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Antoni Sicras-Mainar,1 Francisco J de Abajo,2,3 José Luis Izquierdo-Alonso4,5 1Health Economics & Outcomes Research, Atrys Health, Barcelona, Spain; 2Unidad de Farmacología Clínica, Hospital Universitario Príncipe de Asturias, Madrid, Spain; 3Departamento de Ciencias Biomédicas, Universidad de Alcalá (IRYCIS), Madrid, Spain; 4Departamento de Medicina y Especialidades, Universidad de Alcalá, Madrid, Spain; 5Servicio de Neumología, Hospital Universitario de Guadalajara, Guadalajara, SpainCorrespondence: Antoni Sicras-MainarAtrys Health SA, C/Provença 392, bajos, Barcelona 08025 SpainTel +34 934 581 561Email ansicras@atryshealth.comObjective: To determine the clinical and economic consequences of inhaled corticosteroid doses and particle size in patients on triple-inhalation therapy for COPD.Methods: Patients aged ≥ 40 years who initiated treatment with multi-inhaler triple-inhaled therapy between 1 January 2015 and 31 March were included and followed for 1 year. Patients were grouped according to inhaled corticosteroid (ICS) dose (low/medium/high) and particle size device (extrafine/non-extrafine particles). Outcome variables were moderate and severe exacerbations, pneumonia and healthcare resource use (HCRU) costs. A multivariate analysis was performed for model correction (p< 0.05).Results: A total of 2185 patients (mean age 72.3 years, 82.9% male) were analysed. Of these, 849 (38.9%) patients received low-dose ICS, 612 medium-dose ICS (28.0%) and 724 (33.1%) high-dose ICS. Exacerbations occurred more frequently with increasing IC dose (low: 26.4%, medium: 28.7% and high: 30.4%; p=0.047), as did the proportion of pneumonia (3.4%, 4.2% and 6.9%, respectively (p=0.041)). The annual mean cost/unit was € 2383 for low dose, € 2401 for medium dose and € 2625 for high dose (p=0.024). Four hundred and sixty-two (31.6%) patients used an extrafine particle device and 999 (68.4%) a non-extrafine particle device: the proportion of exacerbations was 24.0% vs 30.4% (p=0.012), and the annual mean cost/unit was € 2090 vs € 2513, respectively (p< 0.001). The number of exacerbations was directly correlated with FEV1 (β= − 0.157), age (β=0.071), Charlson index (β=0.050) and device type (extrafine: β=0.049) (p< 0.02).Conclusion: In patients with COPD receiving multi-inhaler triple therapy, higher ICS doses were not associated with a further reduction in exacerbations, whereas we found an increased risk of pneumonia. The use of inhaler devices delivering extrafine ICS particle was associated with a lower rate of exacerbations, resulting in lower overall HCRU costs.Keywords: COPD, triple-therapy, extrafine particle, exacerbations, pneumonia, health costs

Background: Post-launch drug safety monitoring is essential for the detection of adverse drug signals that may be missed during preclinical trials. Traditional methods of postmarketing surveillance such as spontaneous reporting have intrinsic limitations, many of which can be overcome by the additional application of structured pharmacoepidemiological approaches. However, further improvement in drug safety monitoring requires a shift towards more proactive pharmacoepidemiological methods that can detect adverse drug signals as they occur in the population.Objective: To assess the feasibility of using proactive monitoring of an electronic medical record system, in combination with an independent endpoint adjudication committee, to detect adverse events among users of selected drugs.Methods: UK General Practice Research Database (GPRD) information was used to detect acute liver disorder associated with the use of amoxicillin/clavulanic acid (hepatotoxic) or low-dose aspirin (acetylsalicylic acid [non-hepatotoxic]). Individuals newly prescribed these drugs between 1 October 2005 and 31 March 2006 were identified. Acute liver disorder cases were assessed using GPRD computer records in combination with case validation by an independent endpoint adjudication committee. Signal generation thresholds were based on the background rate of acute liver disorder in the general population.Results: Over a 6-month period, 8148 patients newly prescribed amoxicillin/clavulanic acid and 5577 patients newly prescribed low-dose aspirin were identified. Within this cohort, searches identified 11 potential liver disorder cases from computerized records: six for amoxicillin/clavulanic acid and five for low-dose aspirin. The independent endpoint adjudication committee refined this to four potential acute liver disorder cases for whom paper-based information was requested for final case assessment. Final case assessments confirmed no cases of acute liver disorder. The time taken for this study was 18 months (6 months for recruitment and 12 months for data management and case validation). To reach the estimated target exposure necessary to raise or rule out a signal of concern to public health, we determined that a recruitment period 2-3 times longer than that used in this study would be required. Based on the real market uptake of six commonly used medicinal products launched between 2001 and 2006 in the UK (budesonide/eformoterol [fixed-dose combination], duloxetine, ezetimibe, metformin/rosiglitazone [fixed-dose combination], tiotropium bromide and tadalafil) the target exposure would not have been reached until the fifth year of marketing using a single database.Conclusion: It is feasible to set up a system that actively monitors drug safety using a healthcare database and an independent endpoint adjudication committee. However, future successful implementation will require multiple databases to be queried so that larger study populations are included. This requires further development and harmonization of international healthcare databases. [ABSTRACT FROM AUTHOR]

To determine the evolution and trends of amoxicillin-clavulanic acid resistance among Escherichia coli isolates in Spain, we tested 9,090 blood isolates from 42 Spanish hospitals and compared resistance with trends in outpatient consumption. These isolates were collected by Spanish hospitals that participated in the European Antimicrobial Resistance Surveillance System network from April 2003 through December 2006. [ABSTRACT FROM AUTHOR]

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1-326.5) per 10,000 person-years. In the nested case-control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73-0.99 and AOR = 0.89; 95%CI: 0.74-1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56-0.94 and AOR = 0.64; 95%CI: 0.46-0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD.

Control of circularly polarized light (CPL) is important for next-generation optical communications as well as for investigating the optical properties of materials. In this study, we explore dielectric-sphere oligomers for chiral nanoantenna applications, leveraging the cathodoluminescence (CL) technique, which employs accelerated free electrons for excitation and allows mapping the optical response on the nanoscale. For a certain particle-dimers configuration, one of the spheres becomes responsible for the left-handed circular polarization of the emitted light, while right-handed circular polarization is selectively yielded when the other sphere is excited by the electron beam. Similar patterns are also observed in trimers. These phenomena are understood in terms of optical coupling between the electric and magnetic modes hosted by the dielectric spheres. Our research not only expands the understanding of CPL generation mechanisms in dielectric-sphere oligomer antennas but also underscores the potential of such structures in optical applications. We further highlight the utility of CL as a powerful analytical tool for investigating the optical properties of nanoscale structures as well as the potential of electron beams for light generation with switchable CPL parities., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Narrow gaps between plasmon-supporting materials can confine infrared electromagnetic energy at the nanoscale, thus enabling applications in areas such as optical sensing. However, in nanoparticle dimers, the nature of the transition between touching (zero gap) and nearly nontouching (nonzero gap ≲15 nm) regimes is still a subject of debate. Here, we observe both singular and nonsingular transitions in infrared plasmons confined to dimers of fluorine-doped indium oxide nanocubes when moving from touching to nontouching configurations depending on the dimensionality of the contact region. Through spatially resolved electron energy-loss spectroscopy, we find a continuous spectral evolution of the lowest-order plasmon mode across the transition for finite touching areas, in excellent agreement with the simulations. This behavior challenges the widely accepted idea that a singular transition always emerges in the near-touching regime of plasmonic particle dimers. The apparent contradiction is resolved by theoretically examining different types of gap morphologies, revealing that the presence of a finite touching area renders the transition nonsingular, while one-dimensional and point-like contacts produce a singular behavior in which the lowest-order dipolar mode in the touching configuration, characterized by a net induced charge in each of the particles, becomes unphysical as soon as they are separated. Our results provide valuable insights into the nature of dimer plasmons in highly doped semiconductors.

Free electrons are excellent tools to probe and manipulate nanoscale optical fields with emerging applications in ultrafast spectromicroscopy and quantum metrology. However, advances in this field are hindered by the small probability associated with the excitation of single optical modes by individual free electrons. Here, we theoretically investigate the scaling properties of the electron-driven excitation probability for a wide variety of optical modes including plasmons in metallic nanostructures and Mie resonances in dielectric cavities, spanning a broad spectral range that extends from the ultraviolet to the infrared region. The highest probabilities for the direct generation of three-dimensionally confined modes are observed at low electron and mode energies in small structures, with order-unity (∼100%) coupling demanding the use of <100 eV electrons interacting with eV polaritons confined down to tens of nanometers in space. Electronic transitions in artificial atoms also emerge as practical systems to realize strong coupling to few-eV free electrons. In contrast, conventional dielectric cavities reach a maximum probability in the few-percent range. In addition, we show that waveguide modes can be generated with higher-than-unity efficiency by phase-matched interaction with grazing electrons, suggesting a practical method to create multiple excitations of a localized optical mode by an individual electron through funneling the so-generated propagating photons into a confining cavity─an alternative approach to direct electron-cavity interaction. Our work provides a roadmap to optimize electron-photon coupling with potential applications in electron spectromicroscopy as well as nonlinear and quantum optics at the nanoscale.

Tightly confined optical near fields in plasmonic nanostructures play a pivotal role in important applications ranging from optical sensing to light harvesting. Energetic electrons are ideally suited to probing optical near fields by collecting the resulting cathodoluminescence (CL) light emission. Intriguingly, the CL intensity is determined by the near-field profile along the electron propagation direction, but the retrieval of such field from measurements has remained elusive. Furthermore, the conditions for optimum electron near-field coupling in plasmonic systems are critically dependent on such field and remain experimentally unexplored. In this work, we use electron energy-dependent CL spectroscopy to study the tightly confined dipolar mode in plasmonic gold nanoparticles. By systematically studying gold nanoparticles with diameters in the range of 20-100 nm and electron energies from 4 to 30 keV, we determine how the coupling between swift electrons and the optical near fields depends on the energy of the incoming electron. The strongest coupling is achieved when the electron speed equals the mode phase velocity, meeting the so-called phase-matching condition. In aloof experiments, the measured data are well reproduced by electromagnetic simulations, which explain that larger particles and faster electrons favor a stronger electron near-field coupling. For penetrating electron trajectories, scattering at the particle produces severe corrections of the trajectory that defy existing theories based on the assumption of nonrecoil condition. Therefore, we develop a first-order recoil correction model that allows us to account for inelastic electron scattering, rendering better agreement with measured data. Finally, we consider the albedo of the particles and find that, to approach unity coupling, a highly confined electric field and very slow electrons are needed, both representing experimental challenges. Our findings explain how to reach unity-order coupling between free electrons and confined excitations, helping us understand fundamental aspects of light-matter interaction at the nanoscale.

Polaritons are well-established carriers of light, electrical signals, and even heat at the nanoscale in the setting of on-chip devices. However, the goal of achieving practical polaritonic manipulation over small distances deeply below the light diffraction limit remains elusive. Here, we implement nanoscale polaritonic in-plane steering and cloaking in a low-loss atomically layered van der Waals (vdW) insulator, α-MoO 3 , comprising building blocks of customizable stacked and assembled structures. Each block contributes specific characteristics that allow us to steer polaritons along the desired trajectories. Our results introduce a natural materials-based approach for the comprehensive manipulation of nanoscale optical fields, advancing research in the vdW polaritonics domain and on-chip nanophotonic circuits., (© 2024. The Author(s).)

Luminescence constitutes a unique source of insight into hot carrier processes in metals, including those in plasmonic nanostructures used for sensing and energy applications. However, being weak in nature, metal luminescence remains poorly understood, its microscopic origin strongly debated, and its potential for unraveling nanoscale carrier dynamics largely unexploited. Here, we reveal quantum-mechanical effects in the luminescence emanating from thin monocrystalline gold flakes. Specifically, we present experimental evidence, supported by first-principles simulations, to demonstrate its photoluminescence origin (i.e., radiative emission from electron/hole recombination) when exciting in the interband regime. Our model allows us to identify changes to the measured gold luminescence due to quantum-mechanical effects as the gold film thickness is reduced. Excitingly, such effects are observable in the luminescence signal from flakes up to 40 nm in thickness, associated with the out-of-plane discreteness of the electronic band structure near the Fermi level. We qualitatively reproduce the observations with first-principles modeling, thus establishing a unified description of luminescence in gold monocrystalline flakes and enabling its widespread application as a probe of carrier dynamics and light-matter interactions in this material. Our study paves the way for future explorations of hot carriers and charge-transfer dynamics in a multitude of material systems., (© 2024. The Author(s).)

Control over the optical properties of atomically thin two-dimensional (2D) layers, including those of transition metal dichalcogenides (TMDs), is needed for future optoelectronic applications. Here, the near-field coupling between TMDs and graphene/graphite is used to engineer the exciton line shape and charge state. Fano-like asymmetric spectral features are produced in WS 2 , MoSe 2 , and WSe 2 van der Waals heterostructures combined with graphene, graphite, or jointly with hexagonal boron nitride ( h -BN) as supporting or encapsulating layers. Furthermore, trion emission is suppressed in h -BN encapsulated WSe 2 /graphene with a neutral exciton red shift (44 meV) and binding energy reduction (30 meV). The response of these systems to electron beam and light probes is well-described in terms of 2D optical conductivities of the involved materials. Beyond fundamental insights into the interaction of TMD excitons with structured environments, this study opens an unexplored avenue toward shaping the spectral profile of narrow optical modes for application in nanophotonic devices.

The ability to confine light down to atomic scales is critical for the development of applications in optoelectronics and optical sensing as well as for the exploration of nanoscale quantum phenomena. Plasmons in metallic nanostructures with just a few atomic layers in thickness can achieve this type of confinement, although fabrication imperfections down to the subnanometer scale hinder actual developments. Here, narrow plasmons are demonstrated in atomically thin crystalline silver nanostructures fabricated by prepatterning silicon substrates and epitaxially depositing silver films of just a few atomic layers in thickness. Specifically, a silicon wafer is lithographically patterned to introduce on-demand lateral shapes, chemically process the sample to obtain an atomically flat silicon surface, and epitaxially deposit silver to obtain ultrathin crystalline metal films with the designated morphologies. Structures fabricated by following this procedure allow for an unprecedented control over optical field confinement in the near-infrared spectral region, which is here illustrated by the observation of fundamental and higher-order plasmons featuring extreme spatial confinement and high-quality factors that reflect the crystallinity of the metal. The present study constitutes a substantial improvement in the degree of spatial confinement and quality factor that should facilitate the design and exploitation of atomic-scale nanoplasmonic devices for optoelectronics, sensing, and quantum-physics applications., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Optical coupling between propagating light and confined surface polaritons plays a pivotal role in the practical design of nanophotonic devices. However, the coupling efficiency decreases dramatically with the degree of mode confinement due to the mismatch that exists between the light and polariton wavelengths, and despite the intense efforts made to explore different mechanisms proposed to circumvent this problem, the realization of a flexible scheme to efficiently couple light to polaritons remains a challenge. Here, we experimentally demonstrate an efficient coupling of light to surface-plasmon polaritons assisted by engineered dipolar scatterers placed at an optimum distance from the surface. Specifically, we fabricate gold disks separated by a silica spacer from a planar gold surface and seek to achieve perfect coupling conditions by tuning the spacer thickness for a given scatterer geometry that resonates at a designated optical frequency. We measure a maximum light-to-plasmon coupling cross section of the order of the square of the light wavelength at an optimum distance that results from the interplay between a large particle-surface interaction and a small degree of surface-driven particle-dipole quenching, both of which are favored at small separations. Our experiments, in agreement with both analytical theory and electromagnetic simulations, support the use of optimally placed engineered scatterers as a disruptive approach to solving the long-standing problem of in/out-coupling in nanophotonics., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Quantum physics rules the dynamics of small objects as they interact over microscopic length scales. Nevertheless, quantum correlations involving macroscopic distances can be observed between entangled photons as well as in atomic gases and matter waves at low temperatures. The long-range nature of the electromagnetic coupling between charged particles and extended objects could also trigger quantum phenomena over large distances. Here, we reveal a manifestation of quantum mechanics that involves macroscopic distances and results in a nearly complete depletion of coherence associated with which-way free-electron interference produced by electron-radiation coupling in the presence of distant extended objects. This is a ubiquitous effect that we illustrate through a rigorous theoretical analysis of a two-path electron beam interacting with a semi-infinite metallic plate and find the inter-path coherence to vanish proportionally to the path separation at zero temperature and exponentially at finite temperature. The investigated regime of large distances originates in the coupling of the electron to radiative modes assisted by diffraction at material structures but without any involvement of material excitations. Besides the fundamental interest of this macroscopic quantum phenomenon, our results suggest an approach to measuring the vacuum temperature and nondestructively sensing the presence of distant objects., (© 2024. The Author(s).)

Energy exchange between electrons and photons enables ultrafast probing of materials.

Background: electronic health records (EHRs) are helpful tools in epidemiology despite not being primarily collected for research. In Spain, primary care physicians play a central role and manage patients even in specialized care. All of this introduces variability that may lead to diagnostic inconsistencies. Therefore, data validation studies are crucial, so we aimed to develop and validate case-finding algorithms for digestive cancer in the primary care database BIFAP., Methods: from 2001 to 2019, subjects aged 40-89 without a cancer history were included. Case-finding algorithms using diagnostic codes and text-mining were built. We randomly sampled, clustered, and manually reviewed 816 EHRs. Then, positive predictive values (PPVs) and 95% confidence intervals (95% CIs) for each cancer were computed. Age and sex standardized incidence rates (SIRs) were compared with those reported by the National Cancer Registry (REDECAN)., Results: we identified 95,672 potential cases. After validation, the PPV (95% CI) for hepato-biliary cancer was 87.6% (81.8-93.4), for esophageal cancer, it was 96.2% (93.1-99.2), for pancreatic cancer, it was 89.4% (84.5-94.3), for gastric cancer, it was 92.5% (88.3-96.6), and for colorectal cancer, it was 95.2% (92.1-98.4). The SIRs were comparable to those reported by the REDECAN., Conclusions: the case-finding algorithms demonstrated high performance, supporting BIFAP as a suitable source of information to conduct epidemiologic studies of digestive cancer.

The transformation of electromagnetic energy into matter represents a fascinating prediction of relativistic quantum electrodynamics that is paradigmatically exemplified by the creation of electron-positron pairs out of light. However, this phenomenon has a very low probability, so positron sources rely instead on beta decay, which demands elaborate monochromatization and trapping schemes to achieve high-quality beams. Here, we propose to use intense, strongly confined optical near fields supported by a nanostructured material in combination with high-energy photons to create electron-positron pairs. Specifically, we show that the interaction between near-threshold γ-rays and polaritons yields higher pair-production cross sections, largely exceeding those associated with free-space photons. Our work opens an unexplored avenue toward generating tunable pulsed positrons from nanoscale regions at the intersection between particle physics and nanophotonics., (© 2023. The Author(s).)

Traditionally, clinical pharmacology has focused its activities on drug-organism interaction, from an individual or collective perspective. Drug efficacy assessment by performing randomized clinical trials and analysis of drug use in clinical practice by carrying out drug utilization studies have also been other areas of interest. From now on, Clinical pharmacology should move from the analysis of the drug-individual interaction to the analysis of the drug-individual-society interaction. It should also analyze the clinical and economic consequences of the use of drugs in the conditions of normal clinical practice, beyond clinical trials. The current exponential technological development that facilitates the analysis of real-life data offers us a golden opportunity to move to all these other areas of interest. This review describes the role that clinical pharmacology has played at the beginning and during the evolution of pharmacovigilance, pharmacoepidemiology and economic drug evaluations in Spain. In addition, the challenges that clinical pharmacology is going to face in the following years in these three areas are going to be outlined too., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In electron microscopy, detailed insights into nanoscale optical properties of materials are gained by spontaneous inelastic scattering leading to electron-energy loss and cathodoluminescence. Stimulated scattering in the presence of external sample excitation allows for mode- and polarization-selective photon-induced near-field electron microscopy (PINEM). This process imprints a spatial phase profile inherited from the optical fields onto the wave function of the probing electrons. Here, we introduce Lorentz-PINEM for the full-field, non-invasive imaging of complex optical near fields at high spatial resolution. We use energy-filtered defocus phase-contrast imaging and iterative phase retrieval to reconstruct the phase distribution of interfering surface-bound modes on a plasmonic nanotip. Our approach is universally applicable to retrieve the spatially varying phase of nanoscale fields and topological modes., (© 2023. Springer Nature Limited.)

The control of elastic and inelastic electron tunnelling relies on materials with well-defined interfaces. Two-dimensional van der Waals materials are an excellent platform for such studies. Signatures of acoustic phonons and defect states have been observed in current-to-voltage measurements. These features can be explained by direct electron-phonon or electron-defect interactions. Here we use a tunnelling process that involves excitons in transition metal dichalcogenides (TMDs). We study tunnel junctions consisting of graphene and gold electrodes separated by hexagonal boron nitride with an adjacent TMD monolayer and observe prominent resonant features in current-to-voltage measurements appearing at bias voltages that correspond to TMD exciton energies. By placing the TMD outside of the tunnelling pathway, we demonstrate that this tunnelling process does not require any charge injection into the TMD. The appearance of such optical modes in electrical transport introduces additional functionality towards van der Waals material-based optoelectronic devices., (© 2023. The Author(s).)

Conflicting results about the association of calcium supplements (CS) with ischemic stroke (IS) have been reported. We tested this hypothesis by differentiating between CS alone (CaM) and CS with vitamin D (CaD) and between cardioembolic and non-cardioembolic IS. We examined the potential interaction with oral bisphosphonates (oBs). A nested case-control study was carried out. We identified incident IS cases aged 40-90 and randomly sampled five controls per case matched by age, sex, and index date. Current users were compared to non-users. An adjusted odds ratios (AOR) and 95% CI were computed through conditional logistic regression. Only new users were considered. We included 13,267 cases (4400 cardioembolic, 8867 non-cardioembolic) and 61,378 controls (20,147 and 41,231, respectively). CaM use was associated with an increased risk of cardioembolic IS (AOR = 1.88; 95% CI: 1.21-2.90) in a duration-dependent manner, while it showed no association with non-cardioembolic IS (AOR = 1.05; 95% CI: 0.74-1.50); its combination with oBs increased the risk of cardioembolic IS considerably (AOR = 2.54; 95% CI: 1.28-5.04), showing no effect on non-cardioembolic. CaD use was not associated with either cardioembolic (AOR = 1.08; 95% CI: 0.88-1.31) or non-cardioembolic IS (AOR = 0.98; 95% CI: 0.84-1.13) but showed a small association with cardioembolic IS when combined with oBs (AOR = 1.35; 95% CI: 1.03-1.76). The results support the hypothesis that CS increases the risk of cardioembolic IS, primarily when used concomitantly with oBs.

The synergy between free electrons and light has recently been leveraged to reach an impressive degree of simultaneous spatial and spectral resolution, enabling applications in microscopy and quantum optics. However, the required combination of electron optics and light injection into the spectrally narrow modes of arbitrary specimens remains a challenge. Here, we demonstrate microelectronvolt spectral resolution with a sub-nanometer probe of photonic modes with quality factors as high as 10 4 . We rely on mode matching of a tightly focused laser beam to whispering gallery modes to achieve a 10 8 -fold increase in light-electron coupling efficiency. By adapting the shape and size of free-space optical beams to address specific physical questions, our approach allows us to interrogate any type of photonic structure with unprecedented spectral and spatial detail., (© 2023. The Author(s).)

Plasmons can be excited during photoemission and produce spectral photoelectron features that yield information on the nanoscale optical response of the probed materials. However, these so-called plasmon satellites have so far been observed only for planar surfaces, while their potential for the characterization of nanostructures remains unexplored. Here, we theoretically demonstrate that core-level photoemission from nanostructures can display spectrally narrow plasmonic features, reaching relatively high probabilities similar to the direct peak. Using a nonperturbative quantum-mechanical framework, we find a dramatic effect of nanostructure morphology and dimensionality as well as universal scaling laws for the plasmon-satellite probabilities. In addition, we introduce a pump-probe scheme in which plasmons are optically excited prior to photoemission, leading to plasmon losses and gains in the photoemission spectra and granting us access to the ultrafast dynamics of the sampled nanostructure. These results emphasize the potential of plasmon satellites to explore multi-plasmon effects and ultrafast electron-plasmon dynamics in metal-based nanoparticles and two-dimensional nanoislands.

The ability to modulate free electrons with light has emerged as a powerful tool to produce attosecond electron wave packets. However, research has so far aimed at the manipulation of the longitudinal wave function component, while the transverse degrees of freedom have primarily been utilized for spatial rather than temporal shaping. Here, we show that the coherent superposition of parallel light-electron interactions in transversally separate zones allows for a simultaneous spatial and temporal compression of a convergent electron wave function, enabling the formation of sub-Ångström focal spots of attosecond duration. Specifically, spots spanning just ∼3% of the light optical cycle are shown to be formed, accompanied by an increase by only a factor of 2 in spatial extension relative to an unperturbed beam. The proposed approach will facilitate the exploration of previously inaccessible ultrafast atomic-scale phenomena, in particular enabling attosecond scanning transmission electron microscopy.

The science and technology of X-ray optics have come far, enabling the focusing of X-rays for applications in high-resolution X-ray spectroscopy, imaging, and irradiation. In spite of this, many forms of tailoring waves that had substantial impact on applications in the optical regime have remained out of reach in the X-ray regime. This disparity fundamentally arises from the tendency of refractive indices of all materials to approach unity at high frequencies, making X-ray-optical components such as lenses and mirrors much harder to create and often less efficient. Here, we propose a new concept for X-ray focusing based on inducing a curved wavefront into the X-ray generation process, resulting in the intrinsic focusing of X-ray waves. This concept can be seen as effectively integrating the optics to be part of the emission mechanism, thus bypassing the efficiency limits imposed by X-ray optical components, enabling the creation of nanobeams with nanoscale focal spot sizes and micrometer-scale focal lengths. Specifically, we implement this concept by designing aperiodic vdW heterostructures that shape X-rays when driven by free electrons. The parameters of the focused hotspot, such as lateral size and focal depth, are tunable as a function of an interlayer spacing chirp and electron energy. Looking forward, ongoing advances in the creation of many-layer vdW heterostructures open unprecedented horizons of focusing and arbitrary shaping of X-ray nanobeams., (© 2023. The Author(s).)

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS., Competing Interests: FD received unrestricted grants from Sanofi, the Osteoarthritis International Foundation (OAFI) and Fundación Renal Íñigo Alvarez de Toledo, for research projects different from the present one. RM received grants from Pfizer, Roche and Sociedad de Reumatología de la Comunidad de Madrid, for research projects different from the present one. The remaining 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 © 2023 Rodríguez-Martín, Barreira-Hernández, Mazzucchelli, Gil, García-Lledó, Izquierdo-Esteban, Pérez-Gómez, Rodríguez-Miguel and De Abajo.)

A rigorous account of quantum nonlocal effects is paramount for understanding the optical response of metal nanostructures and for designing plasmonic devices at the nanoscale. Here, we present a scheme for retrieving the quantum surface response of metals, encapsulated in the Feibelman d -parameters, from electron energy-loss spectroscopy (EELS) and cathodoluminescence (CL) measurements. We theoretically demonstrate that quantum nonlocal effects have a dramatic impact on EELS and CL spectra, in the guise of spectral shifts and nonlocal damping, when either the system size or the inverse wave vector in extended structures approaches the nanometer scale. Our concept capitalizes on the unparalleled ability of free electrons to supply deeply subwavelength near-fields and, thus, probe the optical response of metals at length scales in which quantum-mechanical effects are apparent. These results pave the way for a widespread use of the d -parameter formalism, thereby facilitating a rigorous yet practical inclusion of nonclassical effects in nanoplasmonics.

Dense micron-sized electron plasmas, such as those generated upon irradiation of nanostructured metallic surfaces by intense femtosecond laser pulses, constitute a rich playground to study light-matter interactions, many-body phenomena, and out-of-equilibrium charge dynamics. Besides their fundamental interest, laser-induced plasmas hold great potential for the generation of localized terahertz radiation pulses. However, the underlying mechanisms ruling the formation and evolution of such plasmas are not yet well understood. Here, we develop a comprehensive microscopic theory to predictably describe the spatiotemporal dynamics of laser-pulse-induced plasmas. Through detailed analysis of electron emission, metal screening, and plasma cloud interactions, we investigate the spatial, temporal, and spectral characteristics of the so-generated terahertz fields, which can be extensively controlled through the metal morphology and the illumination conditions. We further describe the interaction with femtosecond electron beams to explain recent ultrafast electron microscopy experiments, whereby the position and temporal dependence of the observed electron acceleration permits assessing the associated terahertz field. Besides its potential application to the design of low-frequency light sources, our work contributes fundamental insight into the generation and dynamics of micron-scale electron plasmas and their interaction with ultrafast electron pulses., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Light confinement in nanostructures produces an enhanced light-matter interaction that enables a vast range of applications including single-photon sources, nanolasers and nanosensors. In particular, nanocavity-confined polaritons display a strongly enhanced light-matter interaction in the infrared regime. This interaction could be further boosted if polaritonic modes were moulded to form whispering-gallery modes; but scattering losses within nanocavities have so far prevented their observation. Here, we show that hexagonal BN nanotubes act as an atomically smooth nanocavity that can sustain phonon-polariton whispering-gallery modes, owing to their intrinsic hyperbolic dispersion and low scattering losses. Hyperbolic whispering-gallery phonon polaritons on BN nanotubes of ～4 nm radius (sidewall of six atomic layers) are characterized by an ultrasmall nanocavity mode volume (V m  ≈ 10 -10 λ 0 3 at an optical wavelength λ 0  ≈ 6.4 μm) and a Purcell factor (Q/V m ) as high as 10 12 . We posit that BN nanotubes could become an important material platform for the realization of one-dimensional, ultrastrong light-matter interactions, with exciting implications for compact photonic devices., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Single-pixel imaging, originally developed in light optics, facilitates fast three-dimensional sample reconstruction as well as probing with light wavelengths undetectable by conventional multi-pixel detectors. However, the spatial resolution of optics-based single-pixel microscopy is limited by diffraction to hundreds of nanometers. Here, we propose an implementation of single-pixel imaging relying on attainable modifications of currently available ultrafast electron microscopes in which optically modulated electrons are used instead of photons to achieve subnanometer spatially and temporally resolved single-pixel imaging. We simulate electron beam profiles generated by interaction with the optical field produced by an externally programmable spatial light modulator and demonstrate the feasibility of the method by showing that the sample image and its temporal evolution can be reconstructed using realistic imperfect illumination patterns. Electron single-pixel imaging holds strong potential for application in low-dose probing of beam-sensitive biological and molecular samples, including rapid screening during in situ experiments., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

2D monolayers supporting a wide variety of highly confined plasmons, phonon polaritons, and exciton polaritons can be vertically stacked in van der Waals heterostructures (vdWHs) with controlled constituent layers, stacking sequence, and even twist angles. vdWHs combine advantages of 2D material polaritons, rich optical structure design, and atomic scale integration, which have greatly extended the performance and functions of polaritons, such as wide frequency range, long lifetime, ultrafast all-optical modulation, and photonic crystals for nanoscale light. Here, the state of the art of 2D material polaritons in vdWHs from the perspective of design principles and potential applications is reviewed. Some fundamental properties of polaritons in vdWHs are initially discussed, followed by recent discoveries of plasmons, phonon polaritons, exciton polaritons, and their hybrid modes in vdWHs. The review concludes with a perspective discussion on potential applications of these polaritons such as nanophotonic integrated circuits, which will benefit from the intersection between nanophotonics and materials science., (© 2023 Wiley-VCH GmbH.)

A spherical dielectric particle can sustain the so-called whispering-gallery modes (WGMs), which can be regarded as circulating electromagnetic waves, resulting in the spatial confinement of light inside the particle. Despite the wide adoption of optical WGMs as a major light confinement mechanism in salient practical applications, direct imaging of the mode fields is still lacking and only partially addressed by simple photography and simulation work. The present study comprehensively covers this research gap by demonstrating the nanoscale optical-field visualization of self-interference of light extracted from excited modes through experimentally obtained photon maps that directly portray the field distributions of the excited eigenmodes. To selectively choose the specific modes at a given light emission detection angle and resonance wavelength, we use cathodoluminescence-based scanning transmission electron microscopy supplemented with angle-, polarization-, and wavelength-resolved capabilities. Equipped with semi-analytical simulation tools, the internal field distributions of the whispering-gallery modes reveal that radiation emitted by a spherical resonator at a given resonance frequency is composed of the interference between multiple modes, with one or more of them being comparatively dominant, leading to a resulting distribution featuring complex patterns that explicitly depend on the detection angle and polarization. Direct visualization of the internal fields inside resonators enables a comprehensive understanding of WGMs that can shed light on the design of nanophotonic applications., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Understanding and actively controlling the spatiotemporal dynamics of nonequilibrium electron clouds is fundamental for the design of light and electron sources, high-power electronic devices, and plasma-based applications. However, electron clouds evolve in a complex collective fashion on the nanometer and femtosecond scales, producing electromagnetic screening that renders them inaccessible to existing optical probes. Here, we solve the long-standing challenge of characterizing the evolution of electron clouds generated upon irradiation of metallic structures using an ultrafast transmission electron microscope to record the charged plasma dynamics. Our approach to charge dynamics electron microscopy (CDEM) is based on the simultaneous detection of electron-beam acceleration and broadening with nanometer/femtosecond resolution. By combining experimental results with comprehensive microscopic theory, we provide a deep understanding of this highly out-of-equilibrium regime, including previously inaccessible intricate microscopic mechanisms of electron emission, screening by the metal, and collective cloud dynamics. Beyond the present specific demonstration, the here-introduced CDEM technique grants us access to a wide range of nonequilibrium electrodynamic phenomena involving the ultrafast evolution of bound and free charges on the nanoscale.