Immunogenicity, Reactogenicity, and Safety of AS01E-adjuvanted RSV Prefusion F Protein-based Candidate Vaccine (RSVPreF3 OA) When Co-administered With a Seasonal Quadrivalent Influenza Vaccine in Older Adults: Results of a Phase 3, Open-Label, Randomized Controlled Trial.

BACKGROUND: Co-administration of vaccines against respiratory syncytial virus (RSV) and influenza can be considered given their overlapping seasonality, and may increase vaccine uptake and compliance. In this phase 3, open-label, randomized study, we evaluated the immunogenicity, reactogenicity, and safety of the AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) when co-administered with a seasonal quadrivalent influenza vaccine (FLU-QIV) in older adults. METHODS: Participants aged ≥60 years (randomized 1:1) received either RSVPreF3 OA and FLU-QIV simultaneously on day 1 (Co-Ad group) or FLU-QIV on day 1 followed by RSVPreF3 OA on day 31 (sequential administration [SA] group). The co-primary objectives were to demonstrate noninferiority of RSVPreF3 OA in terms of RSV-A neutralization geometric mean titer (GMT) ratio and FLU-QIV in terms of hemagglutination inhibition GMT ratio for each FLU-QIV strain, when co-administered versus when administered alone at 1-month post-vaccination. Noninferiority was demonstrated if the upper limit of the 95% confidence interview of the group GMT ratio (SA/Co-Ad) was ≤1.5. Secondary descriptive objectives comprised additional immunogenicity assessments, reactogenicity, and safety. RESULTS: Of the 885 participants who received one dose of the study vaccines, 837 were included in the per protocol set. Demographic and baseline characteristics were balanced between the groups. Both co-primary objectives were met for both vaccines. Reported adverse events in both groups were mild-to-moderate, with a low frequency of grade 3 events. CONCLUSIONS: Data from this study demonstrate that RSVPreF3 OA can be co-administered with FLU-QIV. Co-administration is well tolerated, with an acceptable safety profile. CLINICALTRIALS.GOV REGISTRATION: NCT04841577.

Efficacy and Safety of Respiratory Syncytial Virus (RSV) Prefusion F Protein Vaccine (RSVPreF3 OA) in Older Adults Over 2 RSV Seasons.

BACKGROUND: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-years-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1. METHODS: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided CIs around efficacy estimates >20%). RESULTS: The efficacy analysis comprised 24 967 participants (RSV_1dose: 6227; RSV_revaccination: 6242; placebo: 12 498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0%) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0%) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1. CONCLUSIONS: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04886596.

Nonlinear post-compression of a hybrid vortex mode in a gas-filled capillary.

We demonstrate nonlinear temporal compression of a vortex beam by propagation in a gas-filled capillary. Starting from an ytterbium-based laser delivering 700 µJ 640 fs pulses at a 100 kHz repetition rate, the vortex beam is generated using a spiral phase plate and coupled to a capillary where it excites a set of four modes that have an overlap integral of 97% with a Laguerre-Gauss LG10 mode. Nonlinear propagation of this hybrid, orbital angular momentum (OAM)-carrying mode results in temporal compression down to 74 fs at the output. Beam and pulse characterizations are carried out to determine the spatial profile and temporal duration of compressed pulses. This result in multimode nonlinear optics paves the way towards the generation of OAM-carrying few-cycle pulses, isolated attosecond XUV pulses, and tunable UV pulses through resonant dispersive wave emission.

Fast and precise chiroptical spectroscopy by photoelectron elliptical dichroism.

The photoionization of chiral molecules by elliptically polarized femtosecond laser pulses produces photoelectron angular distributions which show a strong and enantio-sensitive forward/backward asymmetry along the light propagation direction. We report on high precision measurements of this photoelectron elliptical dichroism (PEELD). Using an optical cavity to recycle the laser pulses and increase the signal-to-noise ratio, we determine enantiomeric excesses with a 0.04% precision with a low-power femtosecond laser (4 W) in a compact scheme. We perform momentum-resolved PEELD measurements in 16 molecules, from volatile terpenes to non-volatile amino acids and large iodoarenes. The results demonstrate the high structural sensitivity of PEELD, confirming the spectroscopic interest of this technique. Last, we show how a convolutional neural network can be used to retrieve the chemical and enantiomeric composition of a sample from the momentum-resolved PEELD maps.

Quantum-Path-Resolved Attosecond High-Harmonic Spectroscopy.

Strong-field ionization of molecules releases electrons which can be accelerated and driven back to recombine with their parent ion, emitting high-order harmonics. This ionization also initiates attosecond electronic and vibrational dynamics in the ion, evolving during the electron travel in the continuum. Revealing this subcycle dynamics from the emitted radiation usually requires advanced theoretical modeling. We show that this can be avoided by resolving the emission from two families of electronic quantum paths in the generation process. The corresponding electrons have the same kinetic energy, and thus the same structural sensitivity, but differ by the travel time between ionization and recombination-the pump-probe delay in this attosecond self-probing scheme. We measure the harmonic amplitude and phase in aligned CO_{2} and N_{2} molecules and observe a strong influence of laser-induced dynamics on two characteristic spectroscopic features: a shape resonance and multichannel interference. This quantum-path-resolved spectroscopy thus opens wide prospects for the investigation of ultrafast ionic dynamics, such as charge migration.

Conservative surgical treatment for metatarsal osteomyelitis in diabetic foot: experience of two French centres.

AIMS: Conservative surgery (CS) for diabetic foot osteomyelitis (DFO) consists in removing all or part of the infected bone tissues without amputation, in complement with antibiotic therapy. Data on CS for DFO therapy are scarce. MATERIAL AND METHODS: We performed a retrospective analysis of all DFO episodes treated with CS between 06/2007 and 12/2017. Remission was defined by the absence of soft-tissue infection, complete sustained (i.e. > 1 month) healing of the foot ulcer, favourable (i.e., stabilisation or improvement) radiological outcome, and no need for additional surgery during a 1-year follow-up. RESULTS: During the study period, 47 episodes (in 41 patients) were analysed. Excluding deaths (all unrelated to the DFO; n = 3) or loss to follow-up before 1 year (n = 5), the remission rate was 64.2%. Most failures occurred during the first 6 months (79%, 11/14). Patients who experienced failure had a higher rate of peripheral arterial disease with arterial stenosis than patients in remission (57% vs. 24%, P = 0.03), a higher C-reactive protein rate at admission (116 ± 112 mg/L vs. 48 ± 46 mg/L, P = 0.02), and a trend for a higher rate of abscesses (29% vs. 4%, P = 0.06). At 1-year follow-up, foot ulcers related to transfer lesion were identified in 25.5% of the cases. At the last follow-up (mean 3 ± 2 years), the remission rate was 23/25 (92%). CONCLUSIONS: Our results suggest that CS is a therapeutic option in patients with localised but severe DFO. Clinicians should, however, consider the necessity of revascularisation, and higher risk of failure if surgery is performed in patients presenting with acute foot infections.

Photoelectron elliptical dichroism spectroscopy of resonance-enhanced multiphoton ionization via the 3s, 3p and 3d Rydberg series in fenchone.

The resonance-enhanced multiphoton ionization of chiral molecules by elliptically polarized laser pulses produces photoelectron angular distributions that are forward/backward asymmetric with respect to the light propagation axis. We investigate this photoelectron elliptical dichroism in the (2 + 1)-photon ionization of fenchone molecules, using wavelength tunable femtosecond UV pulses. We show that the photoelectron elliptical asymmetry is extremely sensitive to the intermediate resonant states involved in the ionization process, and enables electronic couplings to be revealed that do not show up so clearly when using circularly polarized light.

Ultrafast relaxation investigated by photoelectron circular dichroism: an isomeric comparison of camphor and fenchone.

We study the isomeric effects using time resolved photoelectron circular dichroism (TR-PECD). Using a (1 + 1') pump-probe ionisation scheme with photoelectrons collected by the velocity map imaging technique, we compare the relaxation dynamics from the 3s-Rydberg state in 1R,4R-(+)-camphor with the one in its chiral isomer, 1R,4S-(-)-fenchone [Comby et al., 2016, JPCL, 7, 4514]. Our measurements revealed a similar lifetime for both isomers. However, the circular dichroism in the photoelectron angular distribution decays exponentially in ∼730 fs from a +9% forward amplitude during the first hundreds of femtoseconds to reach an asymptotic -2% backward amplitude. This time-scale is drastically shorter than in fenchone. Our analysis allows us to evaluate the impact of the anisotropy of excitation; the relaxation dynamics, following photoexcitation by the linearly polarized pump, is then compared to that induced by a circularly polarized pump pulse (CPL). With such a CPL pump, we then retrieve time constants of our chiral observables similar to the ones recorded in fenchone. Quantum and classical simulations are developed and used to decipher the dependence of the PECD on the anisotropy of excitation and the spatial distribution of the 3s-Rydberg electron wavefunction. Our experimental investigations, supported by our simulations, suggest that varying the pump ellipticity enables us to reveal the breakdown of the Franck-Condon approximation.

Sub-Picosecond Non-Equilibrium States in the Amorphous Phase of GeTe Phase-Change Material Thin Films.

The sub-picosecond response of amorphous germanium telluride thin film to a femtosecond laser excitation is investigated using frequency-domain interferometry and ab initio molecular dynamics. The time-resolved measurement of the surface dynamics reveals a shrinkage of the film with a dielectric properties' response faster than 300 fs. The systematic ab initio molecular dynamics simulations in non-equilibrium conditions allow the atomic configurations to be retrieved for ionic temperature from 300 to 1100 K and width of the electron distribution from 0.001 to 1.0 eV. Local order of the structures is characterized by in-depth analysis of the angle distribution, phonon modes, and pair distribution function, which evidence a transition toward a new amorphous electronic excited state close in bonding/structure to the liquid state. The results shed a new light on the optically highly excited states in chalcogenide materials involved in both important processes: phase-change materials in memory devices and ovonic threshold switching phenomenon induced by a static field.

A prospective, observational study of fidaxomicin use for Clostridioides difficile infection in France.

OBJECTIVE: To describe the characteristics, management and outcomes of hospitalised patients with Clostridioides difficile infection (CDI) treated with and without fidaxomicin. METHODS: This prospective, multicentre, observational study (DAFNE) enrolled hospitalised patients with CDI, including 294 patients treated with fidaxomicin (outcomes recorded over a 3-month period) and 150 patients treated with other CDI therapies during three 1-month periods. The primary endpoint was baseline and CDI characteristics of fidaxomicin-treated patients. RESULTS: At baseline, the fidaxomicin-treated population included immunocompromised patients (39.1%) and patients with severe (59.2%) and recurrent (36.4%) CDI. Fidaxomicin was associated with a high rate of clinical cure (92.2%) and low CDI recurrence (16.3% within 3 months). Clinical cure rates were ≥90% in patients aged ≥65 years, those receiving concomitant antibiotics and those with prior or severe CDI. There were 121/296 (40.9%) patients with adverse events (AEs), 5.4% with fidaxomicin-related AEs and 1.0% with serious fidaxomicin-related AEs. No fidaxomicin-related deaths were reported. CONCLUSIONS: Fidaxomicin is an effective and well-tolerated CDI treatment in a real-world setting in France, which included patients at high risk of adverse outcomes.Trial registration: Description of the use of fidaxomicin in hospitalised patients with documented Clostridium difficile infection and the management of these patients (DAFNE), NCT02214771, www.ClinicalTrials.gov.

Aromatic Formation Promoted by Ion-Driven Radical Pathways in EUV Photochemical Experiments Simulating Titan's Atmospheric Chemistry.

In the atmosphere of Titan, Saturn's main satellite, molecular growth is initiated by 85.6 nm extreme ultraviolet (EUV) photons triggering a chemistry with charged and free-radical species. However, the respective contribution of these species to the complexification of matter is far from being known. This work presents a chemical analysis in order to contribute to a better understanding of aromatic formation pathways. A gas mixture of N2/CH4 (90/10%) within the closed SURFACAT reactor was irradiated at a relatively low pressure (0.1 mbar) and room temperature for 6 h by EUV photons (∼85.6 nm). The neutral molecules formed at the end of the irradiation were condensed in a cryogenic trap and analyzed by electron ionization mass spectrometry. An analysis of the dominant chemical pathways highlights the identification of benzene and toluene and underlies the importance of small ion and radical reactions. On the basis of the experimental results, a speculative mechanism based on sequential H-elimination/CH3-addition reactions is proposed for the growth of aromatics in Titan's atmosphere. Elementary reactions to be studied are given to instill future updates of photochemical models of Titan's atmosphere.

High-power sub-15 fs nonlinear pulse compression at 515 nm of an ultrafast Yb-doped fiber amplifier.

We present an efficient and robust scheme to produce energetic sub-15 fs pulses centered at 515 nm with a peak power exceeding 3 GW. Combining efficient second-harmonic generation of a 135 fs, 50 W Yb-doped fiber amplifier with a low-loss capillary-based visible pulse compression stage, we reach an overall efficiency higher than >20%. The system is also designed to take advantage of the repetition rate flexibility of the fiber amplifier, leading sub-15 fs pulse generation from 166 to 500 kHz with an average power exceeding the 10 watt level. The combined reduction of the laser wavelength and pulse duration is expected to highly improve the yield of high-order harmonic generation to provide high photon flux of ultrashort extreme ultraviolet radiation.

Laser Generation of Sub-Micrometer Wrinkles in a Chalcogenide Glass Film as Physical Unclonable Functions.

Laser interaction with solids is routinely used for functionalizing materials' surfaces. In most cases, the generation of patterns/structures is the key feature to endow materials with specific properties like hardening, superhydrophobicity, plasmonic color-enhancement, or dedicated functions like anti-counterfeiting tags. A way to generate random patterns, by means of generation of wrinkles on surfaces resulting from laser melting of amorphous Ge-based chalcogenide thin films, is presented. These patterns, similar to fingerprints, are modulations of the surface height by a few tens of nanometers with a sub-micrometer periodicity. It is shown that the patterns' spatial frequency depends on the melted layer thickness, which can be tuned by varying the impinging laser fluence. The randomness of these patterns makes them an excellent candidate for the generation of physical unclonable function tags (PUF-tags) for anti-counterfeiting applications. Two specific ways are tested to identify the obtained PUF-tag: cross-correlation procedure or using a neural network. In both cases, it is demonstrated that the PUF-tag can be compared to a reference image (PUF-key) and identified with a high recognition ratio on most real application conditions. This paves the way to straightforward non-deterministic PUF-tag generation dedicated to small sensitive parts such as, for example, electronic devices/components, jewelry, or watchmak.

Using photoelectron elliptical dichroism (PEELD) to determine real-time variation of enantiomeric excess.

In this work, the photoionization of chiral molecules by an elliptically polarized, high repetition rate, femtosecond laser is probed. The resulting 3D photoelectron angular distribution shows a strong forward-backward asymmetry, which is highly dependent not only on the molecular structure but also on the ellipticity of the laser pulse. By continuously varying the laser ellipticity, we can observe molecular and enantiomer changes in real time at a previously unseen speed and precision. The technique allows enantiomeric excess of a pure compound to be measured with a 5% precision within 3 s, and a 10-min acquisition yields a precision of 0.4%. The isomers camphor and fenchone can be easily distinguished, unlike with conventional mass spectrometry. Preliminary results for the pharmaceutically interesting ibuprofen are also given, showing the capability of photoionization as a means of distinguishing larger molecular systems.

Immunogenicity and safety of the AS04-HPV-16/18 and HPV-6/11/16/18 human papillomavirus vaccines in asymptomatic young women living with HIV aged 15-25 years: A phase IV randomized comparative study.

BACKGROUND: Women living with HIV (WLWH) are at higher risk of acquisition and progression of human papillomavirus (HPV) infection. Evidence on effect of HPV vaccination in this population is limited. METHODS: This phase IV randomized controlled observer-blind study assessed immunogenicity and safety of two HPV vaccines (AS04-HPV-16/18 vs. 4vHPV) given in WLWH (stage 1) and HIV- females aged 15-25 years. Co-primary endpoints were to demonstrate, in WLWH subjects, non-inferiority (and if demonstrated, superiority) of AS04-HPV-16/18 vs. 4vHPV for HPV-16 and HPV-18 by pseudovirion-based neutralization assay (PBNA) at month 7 and safety. Non-inferiority criteria was lower limit (LL) of the 95% confidence interval (CI) of the GMT ratio AS04-HPV-16/18/4vHPV above 0.5, in the according to protocol population. NCT01031069. FINDINGS: Among 873 subjects recruited between 26-Oct-2010 and 14-May-2015, 546 were randomized (1:1) and received at least one vaccine dose (total vaccinated cohort, TVC): 257 were WLWH (129 AS04-HPV-16/18; 128 4vHPV) and 289 were subjects without HIV (144 AS04-HPV-16/18; 145 4vHPV). Baseline CD4 cell count in WLWH was at least 350 cells/mm3.At month 7, AS04-HPV-16/18 showed immunological superiority to 4vHPV in WLWH. Neutralizing anti-HPV-16 and HPV-18 antibody GMTs were 2·74 (95% CI: 1·83; 4·11) and 7·44 (95% CI: 4·79; 11·54) fold higher in AS04-HPV-16/18 vs. 4vHPV (LL of the GMT ratio >1 in TVC, p<0·0001), respectively. Similar results were observed by ELISA up to month 24.Solicited local and general symptoms were in line with product labels. The number of reported serious adverse events (SAEs) was balanced throughout the study. INTERPRETATION: Both vaccines showed an acceptable safety profile in all subjects. Despite the absence of an immunological correlate of protection for HPV, differences in immune responses elicited by the vaccines especially for HPV-18 may translate into longer lasting or more robust protection against cervical cancer with the AS04-HPV-16/18 vaccine in WLWH.

On an EUV Atmospheric Simulation Chamber to Study the Photochemical Processes of Titan's Atmosphere.

The in situ exploration of Titan's atmosphere requires the development of laboratory experiments to understand the molecular growth pathways initiated by photochemistry in the upper layers of the atmosphere. Key species and dominant reaction pathways are used to feed chemical network models that reproduce the chemical and physical processes of this complex environment. Energetic UV photons initiate highly efficient chemistry by forming reactive species in the ionospheres of the satellite. We present here a laboratory experiment based on a new closed and removable photoreactor coupled here to an Extreme Ultraviolet (EUV) irradiation beam produced by the high-order harmonic generation of a femtosecond laser. This type of EUV stable source allow long-term irradiation experiments in which a plethora of individual reactions can take place. In order to demonstrate the validity of our approach, we irradiated for 7 hours at 89.2 nm, a gas mixture based on N2/CH4 (5%). Using only one wavelength, products of the reaction reveal an efficient photochemistry with the formation of large hydrocarbons but especially organic compounds rich in nitrogen similar to Titan. Among these nitrogen compounds, new species had never before been identified in the mass spectra obtained in situ in Titan's atmosphere. Their production in this experiment, on the opposite, corroborates previous experimental measurements in the literature on the chemical composition of aerosol analogues produced in the laboratory. Diazo-compounds such as dimethyldiazene (C2H6N2), have been observed and are consistent with the large nitrogen incorporation observed by the aerosols collector pyrolysis instrument of the Huygens probe. This work represents an important step forward in the use of a closed cell chamber irradiated by the innovative EUV source for the generation of photochemical analogues of Titan aerosols. This approach allows to better constrain and understand the growth pathways of nitrogen incorporation into organic aerosols in Titan's atmosphere.

Ultrafast electronic relaxations from the S3 state of pyrene.

The ultrafast relaxation occurring in pyrene upon excitation at 4.68 eV was studied in a supersonic gas-jet fs pump-probe experiment. Mass spectrometry and velocity map imaging of photoelectrons produced by probing via multiphoton ionisation at 800 nm reveal that the initially prepared wave packet exhibits a fast relaxation (<80 fs), followed by a slower one of 200 fs. By comparing the propensity rules of photoionisation observed at one color with ab initio calculations, we tentatively assign these two timescales to a first internal conversion to the dark bB3g state followed by a second one to the long lived aB2u first excited state. Vertical excitation energies determined using ab initio Multi-State Complete Active Space 2nd order Perturbation Theory (MS-CASPT2), as well as oscillator strengths between several electronic states, are reported.

Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial.

Background: We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9-14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15-25 years. Here, we report the results at study end (month 36 [M36]). Methods: Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety. Results: At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36. Conclusions: Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls.

Relaxation Dynamics in Photoexcited Chiral Molecules Studied by Time-Resolved Photoelectron Circular Dichroism: Toward Chiral Femtochemistry.

Unravelling the main initial dynamics responsible for chiral recognition is a key step in the understanding of many biological processes. However, this challenging task requires a sensitive enantiospecific probe to investigate molecular dynamics on their natural femtosecond time scale. Here we show that, in the gas phase, the ultrafast relaxation dynamics of photoexcited chiral molecules can be tracked by recording time-resolved photoelectron circular dichroism (TR-PECD) resulting from the photoionization by a circularly polarized probe pulse. A large forward-backward asymmetry along the probe propagation axis is observed in the photoelectron angular distribution. Its evolution with pump-probe delay reveals ultrafast dynamics that are inaccessible in the angle-integrated photoelectron spectrum or via the usual electron emission anisotropy parameter (ß). PECD, which originates from the electron scattering in the chiral molecular potential, appears as a new sensitive observable for ultrafast molecular dynamics in chiral systems.