Smart E-Skin Cancer Care in Europe During and After the COVID-19 Pandemic: A Multidisciplinary Expert Consensus

Introduction: Melanoma is the deadliest of all the skin cancers and its incidence is increasing every year in Europe. Patients with melanoma often present late to the specialist and treatment is delayed for many reasons (delay in patient consultation, misdiagnosis by general practitioners, and/or limited access to dermatologists). Beyond this, there are significant inequalities in skin cancer between population groups within the same country and between countries across Europe. The emergence of the COVID-19 pandemic only aggravated these health deficiencies. Objectives: The aim was to create an expert opinion about the challenges in skin cancer management in Europe during the post COVID-19 acute pandemic and to identify and discuss the implementation of new technologies (including e-health and artificial intelligence defined as "Smart Skin Cancer Care") to overcome them. Methods: For this purpose, an ad-hoc questionnaire with items addressing topics of skin cancer care was developed, answered independently and discussed by a multidisciplinary European panel of experts comprising dermatologists, dermato-oncologists, patient advocacy representatives, digital health technology experts, and health technology assessment experts. Results: After all panel of experts discussions, a multidisciplinary expert opinion was created. Conclusions: As a conclusion, the access to dermatologists is difficult and will be aggravated in the near future. This fact, together with important differences in Skin Cancer Care in Europe, suggest the need of a new approach to skin health, prevention and disease management paradigm (focused on integration of new technologies) to minimize the impact of skin cancer and to ensure optimal quality and equity

The potential of eupraxia@sparc_lab for radiation based techniques

A proposal for building a Free Electron Laser, EuPRAXIA@SPARC_LAB, at the Laboratori Nazionali di Frascati, is at present under consideration. This FEL facility will provide a unique combination of a high brightness GeV-range electron beam generated in a X-band RF linac, a 0.5 PW-class laser system and the first FEL source driven by a plasma accelerator. The FEL will produce ultra-bright pulses, with up to 1012 photons/pulse, femtosecond timescale and wavelength down to 3 nm, which lies in the so called “water window”. The experimental activity will be focused on the realization of a plasma driven short wavelength FEL able to provide high-quality photons for a user beamline. In this paper, we describe the main classes of experiments that will be performed at the facility, including coherent diffraction imaging, soft X-ray absorption spectroscopy, Raman spectroscopy, Resonant Inelastic X-ray Scattering and photofragmentation measurements. These techniques will allow studying a variety of samples, both biological and inorganic, providing information about their structure and dynamical behavior. In this context, the possibility of inducing changes in samples via pump pulses leading to the stimulation of chemical reactions or the generation of coherent excitations would tremendously benefit from pulses in the soft X-ray region. High power synchronized optical lasers and a TeraHertz radiation source will indeed be made available for THz and pump–probe experiments and a split-and-delay station will allow performing XUV-XUV pump–probe experiments.Fil: Balerna, Antonella. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Bartocci, Samanta. Università degli studi di Sassari; ItaliaFil: Batignani, Giovanni. Università degli studi di Roma "La Sapienza"; ItaliaFil: Cianchi, Alessandro. Universita Tor Vergata; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Chiadroni, Enrica. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Coreno, Marcello. Istituto Nazionale Di Fisica Nucleare.; Italia. Istituto di Struttura della Materia; ItaliaFil: Cricenti, Antonio. Istituto di Struttura della Materia; ItaliaFil: Dabagov, Sultan. Istituto Nazionale Di Fisica Nucleare.; Italia. National Research Nuclear University; Rusia. Lebedev Physical Institute; RusiaFil: Di Cicco, Andrea. Universita Degli Di Camerino; ItaliaFil: Faiferri, Massimo. Università degli studi di Sassari; ItaliaFil: Ferrante, Carino. Università degli studi di Roma “La Sapienza”; Italia. Center for Life Nano Science @Sapienza; ItaliaFil: Ferrario, Massimo. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Fumero, Giuseppe. Università degli studi di Roma “La Sapienza”; ItaliaFil: Giannessi, Luca. Elettra-Sincrotrone Trieste; Italia. ENEA C.R. Frascati; ItaliaFil: Gunnella, Roberto. Universita Degli Di Camerino; ItaliaFil: Leani, Juan Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Lupi, Stefano. Università degli studi di Roma “La Sapienza”; Italia. Istituto Nazionale di Fisica Nucleare (INFN) Sezione di Roma La Sapienza; ItaliaFil: Macis, Salvatore. Università degli Studi di Roma Tor Vergata; Italia. Istituto Nazionale di Fisica Nucleare (INFN) Sezione di Roma Tor Vergata; ItaliaFil: Manca, Rosa. Università degli studi di Sassari; ItaliaFil: Marcelli, Augusto. Istituto Nazionale Di Fisica Nucleare.; Italia. Consiglio Nazionale delle Ricerche; ItaliaFil: Masciovecchio, Claudio. Elettra-Sincrotrone Trieste; ItaliaFil: Minicucci, Marco. Universita Degli Di Camerino; ItaliaFil: Morante, Silvia. Universita Tor Vergata; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Perfetto, Enrico. Universita Tor Vergata; Italia. Consiglio Nazionale delle Ricerche; ItaliaFil: Petrarca, Massimo. Università degli studi di Roma "La Sapienza"; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Pusceddu, Fabrizio. Università degli studi di Sassari; ItaliaFil: Rezvani, Javad. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Robledo, José Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Rossi, Giancarlo. Centro Fermi—Museo Storico della Fisica e Centro Studi e Ricerche “Enrico Fermi”; Italia. Istituto Nazionale Di Fisica Nucleare.; Italia. Universita Tor Vergata; ItaliaFil: Sanchez, Hector Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Física Enrique Gaviola. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; ArgentinaFil: Scopigno, Tullio. Center for Life Nano Science @Sapienza; Italia. Università degli studi di Roma "La Sapienza"; ItaliaFil: Stefanucci, Gianluca. Universita Tor Vergata; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Stellato, Francesco. Universita Tor Vergata; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Trapananti, Angela. Universita Degli Di Camerino; ItaliaFil: Villa, Fabio. Istituto Nazionale Di Fisica Nucleare.; Itali

Novel control knobs for multidimensional stimulated Raman spectroscopy

Understanding the behavior of complex systems is greatly simplified when the proper energy and time scales over which their evolution occurs are investigated. Consequently, deciphering the dynamics of atoms and molecules requires to access the domain of femtoseconds, and even shorter timescales are involved in the case of electrons. Probing such extreme phenomena is the challenging task at which ultrafast spectroscopy aims. In the last forty years, the development of pulsed laser sources and nonlinear optical techniques has allowed the study of phenomena invisible to electronic devices, through the manipulation of matter macroscopic phases on picosecond and sub-picosecond timescales. This technological leap provided sophisticated and customized ultrashort spectroscopic protocols in a wide energy range, from terahertz to x rays, fully realizing the pioneering view of the ultrafast stroboscope, dreamed by the father of femtochemistry Ahmed Zewail. Indeed, using the proper technique, short flashes of light are currently able to record stop-motion images of a dynamic processes as fast as a chemical reaction. The study of the nonlinear response due to external impulsive optical perturbations has been applied to a wide range of scientific cases, fueling a parallel boost in electronic and vibrational spectroscopies. The frontier in ultrafast sciences is now gradually shifting to tackle the interplay between these two degrees of freedom. Vibronic coupling is considered at the grounds of fascinating processes which connect conceptual topics from the foundation of quantum mechanics, as the breakdown of the Born-Oppenheimer approximation, to technological application, as the coherent energy transfer in biomimic photosynthetic devices or the bewildering effects of strong electron-phonon coupling in novel materials as graphene and third generation semiconductors. Probing electronic and vibrational interactions at the same time is complicated by the time and energy scale separation between the two. Thus, one dimensional spectroscopies are weakened by resolution limits which may partially hamper their use in this direction. Multidimensional techniques can cope this limit spreading the information on separate spectroscopic axes, consequently disentangling the relative resolutions. Couplings between different agents in the microscopic description of the sample dynamics are directly revealed through the presence of cross peaks in the multidimensional maps. In this context, the research presented in this thesis has been devoted to the design, realization and interpretation of novel approaches to multidimensional Impulsive Stimulated Raman Spectroscopy (ISRS). Coherent Raman techniques are indeed able to measure vibrational spectra using visible light, which provides at the same time information about the electronic degrees of freedom when tuned resonant with the absorption edges of the sample. A concerted combination between theory and experiments is the key to successfully probe the quantum properties of the matter on which the vibronic interactions rely. For this reason, the experimental efforts have been flanked by a powerful theoretical toolbox given by the nonlinear response formalism. This framework represents a natural link between theory and experiments and supplies a common language to describe very different techniques, gathering their features to design new experimental protocols. We found that the properties of the probe spectral envelope, the wise tuning of resonant conditions and the choice of the pulses scheme may be used to built multidimensional ISRS maps. The developed schemes have been experimentally tested in three different contexts: the coherent control of ground and excited state vibrations in a liquid solvent, the study of charge photogeneration in a hybrid organic-inorganic perovskite and the vibronic coupling in a prototypical fluorescent protein. The research work presented here is structured in seven chapters and one appendix, which summarize the main theoretical and experimental results achieved during the preparation of this doctoral thesis. The core of the thesis is contained in Chapters 4, 5 and 6, which discuss the application of multidimensional ISRS in different scenarios. Since the investigated scientific problems belong to quite different backgrounds, each of these result chapters is introduced by a brief summary of the relevant field. Specifically: In Chapter 1, we introduce the context in which this thesis is developed. The basics features of ultrafast spectroscopy based on the pump-probe scheme and nonlinear Raman techniques are briefly discussed. We then present the classical mechanism underlying spontaneous and coherent Raman effects, while the detailed, microscopic derivation is postponed to Chapter 2. The remaining part of the chapter is devoted to introduce how multidimensional information can be encoded in the parameters of time and frequency domain stimulated Raman spectroscopies, following the key words in the title of the thesis. As an example, the lineshapes from stimulated Raman spectra measured in hemeproteins are studied as a function of the resonance and the vibrational mode. In Chapter 2, the nonlinear response theory is presented as the unifying framework in which all the different experiments in the thesis are conceived, designed and interpreted. In the first part, the principles of quantum mechanics in the density matrix framework are briefly revised, defining the properties of the Liouville space. Then, the concept of nonlinear polarization is introduced and calculated perturbatively in this space. The light matter interaction is derived from both the classical and quantum treatment of electromagnetism, showing that Feynman diagrams are a convenient way to isolate the relevant terms in the perturbative expansion. Finally, we report the rules to derive expressions for the nonlinear signal in the time and frequency domains directly from the diagrams. In Chapter 3, the experimental setups and the data acquisition are described in detail. We analyze the tools and the physical mechanisms at the base of the generation and handling of the ultrashort pulses used in the experiments and also provide an overview of the data analysis routine applied to the impulsive stimulated Raman measurements presented in the thesis. Chapter 4 is the first of the three chapters presenting the main results of this work. Here, we discuss how the broadband envelope of a supercontinuum probe pulse can be shaped to manipulate vibrational coherences in ISRS. In particular, probe wavelength resolved ISRS maps of a liquid solvent are measured changing the chirp of the probe pulse and interpreted in the light of the diagrammatic framework. As a starting point, the effect of the probe chirp and sample length are investigated to rationalize previously unexplained dependencies of low frequency modes on the dispersed probe wavelength. Then, the probe chirp is demonstrated as a control knob to coherently control ISRS modes and to assign spectral features to specific electronic states. In Chapter 5, broadband ISRS is applied to study electron-phonon coupling in lead halide hybrid perovskites. After briefly revising the field of organic-inorganic perovskite optoelectronics, we present experimental measurements on methylammonium lead bromide thin films, comparing the ISRS response of the system upon excitation above and below the band gap. The results are interpreted in the light of the recently proposed polaronic nature of photocarriers in these materials. In Chapter 6, we present a novel multidimensional ISRS scheme, which combines the capabilities of two dimensional Fourier transform techniques with the structural sensitivity of resonant stimulated Raman. We show how this technique can be used to probe mode couplings between different active sites in molecular compounds and determine the shape of vibrationally structured excited state potential energy surfaces. We apply the diagrammatic approach to design 2D ISRS and assign the origin of the different spectral features in a model system. Then, the proposed scheme is benchmarked by addressing vibronic coupling in Green Fluorescent Protein during the first steps of its photoinduced dynamics. Finally, in Chapter 7, the main results obtained in this work are summarized and analyzed under a common perspective. The appendix reports the calculation of transition integrals for the linearly displaced harmonic model. A list of the publications and contributions to international conferences of the author is included at the end of the thesis

Energy flow between spectral components in 2D broadband stimulated Raman spectroscopy

We introduce a general theoretical description of non resonant impulsive femtosecond stimulated Raman spectroscopy in a multimode harmonic model. In this technique an ultrashort actinic pulse createscoherences of low frequency modes and is followed by a paired narrowband Raman pulse and abroadband probe pulse. Using closed-time-path-loop (CTPL) diagrams, the response on both the redand the blue sides of the broadband pulse with respect to the narrowband Raman pulse is calculated, theprocess couples high and low frequency modes, which share the same ground state. The transmittedintensity oscillates between the red and the blue side, while the total number of photons is conserved.The total energy of the probe signal is periodically modulated in time by the coherence created in the lowfrequency modes

Absolute excited state molecular geometries revealed by resonance Raman signals

Ultrafast reactions activated by light absorption are governed by multidimensional excited-state (ES) potential energy surfaces (PESs), which describe how the molecular potential varies with the nuclear coordinates. ES PESs ad-hoc displaced with respect to the ground state can drive subtle structural rearrangements, accompanying molecular biological activity and regulating physical/chemical properties. Such displacements are encoded in the Franck-Condon overlap integrals, which in turn determine the resonant Raman response. Conventional spectroscopic approaches only access their absolute value, and hence cannot determine the sense of ES displacements. Here, we introduce a two-color broadband impulsive Raman experimental scheme, to directly measure complex Raman excitation profiles along desired normal modes. The key to achieve this task is in the signal linear dependence on the Frank-Condon overlaps, brought about by non-degenerate resonant probe and off-resonant pump pulses, which ultimately enables time-domain sensitivity to the phase of the stimulated vibrational coherences. Our results provide the tool to determine the magnitude and the sensed direction of ES displacements, unambiguously relating them to the ground state eigenvectors reference frame

Excited-State Energy Surfaces in Molecules Revealed by Impulsive Stimulated Raman Excitation Profiles.

Photophysical and photochemical processes are ruled by the interplay between transient vibrational and electronic degrees of freedom, which are ultimately determined by the multidimensional potential energy surfaces (PESs). Differences between ground and excited PESs are encoded in the relative intensities of resonant Raman bands, but they are experimentally challenging to access, requiring measurements at multiple wavelengths under identical conditions. Herein, we perform a two-color impulsive vibrational scattering experiment to launch nuclear wavepacket motions by an impulsive pump and record their coupling with a targeted excited-state potential by resonant Raman processes with a delayed probe, generating in a single measurement background-free vibrational spectra across the entire sample absorption. Building on the interference between the multiple pathways resonant with the excited-state manifold that generate the Raman signal, we show how to experimentally tune their relative phase by varying the probe chirp, decoding nuclear displacements along different normal modes and revealing the multidimensional PESs. Our results are validated against time-dependent density functional theory

Manipulating impulsive stimulated raman spectroscopy with a chirped probe pulse

Photophysical and photochemical processes are often dominated by molecular vibrations in various electronic states. Dissecting the corresponding -often overlapping- spectroscopic signals from different electronic states is a challenge hampering their interpretation. Here we address impulsive stimulated Raman spectroscopy (ISRS), a powerful technique allowing to coherently stimulate and record Raman active modes using broadband pulses. Using a quantum-mechanical treatment of the ISRS process, we show the mode specific way the diverse components of the broadband probe contribute to the signal generated at a given wavelength. We experimentally demonstrate how to manipulate the signal by varying the probe chirp and the phase-matching across the sample thereby affecting the relative phase between the various processes contributing to the signal. These novel control knobs allow to selectively enhance desired vibrational features and distinguish spectral features arising from different excited states

Electronic resonances in broadband stimulated Raman spectroscopy

Spontaneous Raman spectroscopy is a formidable tool to probe molecular vibrations. Under electronic resonance conditions, the cross section can be selectively enhanced enabling structural sensitivity to specific chromophores and reaction centers. The addition of an ultrashort, broadband femtosecond pulse to the excitation field allows for coherent stimulation of diverse molecular vibrations. Within such a scheme, vibrational spectra are engraved onto a highly directional field, and can be heterodyne detected overwhelming fluorescence and other incoherent signals. At variance with spontaneous resonance Raman, however, interpreting the spectral information is not straightforward, due to the manifold of field interactions concurring to the third order nonlinear response. Taking as an example vibrational spectra of heme proteins excited in the Soret band, we introduce a general approach to extract the stimulated Raman excitation profiles from complex spectral lineshapes. Specifically, by a quantum treatment of the matter through density matrix description of the third order nonlinear polarization, we identify the contributions which generate the Raman bands, by taking into account for the cross section of each process

Excited-State Energy Surfaces in Molecules Revealed by Impulsive Stimulated Raman Excitation Profiles.

Photophysical and photochemical processes are ruled by the interplay between transient vibrational and electronic degrees of freedom, which are ultimately determined by the multidimensional potential energy surfaces (PESs). Differences between ground and excited PESs are encoded in the relative intensities of resonant Raman bands, but they are experimentally challenging to access, requiring measurements at multiple wavelengths under identical conditions. Herein, we perform a two-color impulsive vibrational scattering experiment to launch nuclear wavepacket motions by an impulsive pump and record their coupling with a targeted excited-state potential by resonant Raman processes with a delayed probe, generating in a single measurement background-free vibrational spectra across the entire sample absorption. Building on the interference between the multiple pathways resonant with the excited-state manifold that generate the Raman signal, we show how to experimentally tune their relative phase by varying the probe chirp, decoding nuclear displacements along different normal modes and revealing the multidimensional PESs. Our results are validated against time-dependent density functional theory