Femtosecond free-electron laser by chirped pulse amplification

In this work we combine elements of chirped pulse amplification techniques, now familiar in solid-state lasers, with an amplifier based upon a seeded free-electron laser (FEL). The resulting device would produce amplified pulses of unprecedented brevity at wavelengths shorter than can be currently obtained by any tunable laser system. We use a subharmonically seeded FEL to illustrate the concept. Radiation from a Ti:sapphire laser is frequency tripled and stretched optically to provide a coherent seed pulse for the FEL. When coupled to an electron beam inside a magnetic wiggler, the seed radiation introduces an additional energy modulation on the electron bunch, which has been prepared with an energy chirp to match the chirp in the optical pulse. The energy modulated electrons are then spatially bunched in a dispersion magnet and introduced to a wiggler configured to be resonant to a harmonic of the seed laser, providing additional frequency multiplication. The coherent radiation produced by these electrons is amplified as it traverses the wiggler and is recompressed optically. The preservation of phase coherence provided by this scheme results in a device which can yield 4-fs pulses with 0.3 mJ at a central wavelength of ca. 8 nm, easily the shortest duration of amplified pulses produced by any laser. In this paper we discuss various aspects of the concept, including the generation of short pulses, temporal stretching and compression, and potential applications of the device. The phase distortion during the wide bandwidth FEL amplification is discussed in detail, and is shown to be within the bounds required to produce a 4-fs pulse upon compression

Femtosecond free-electron laser by chirped pulse amplification

In this work we combine elements of chirped pulse amplification techniques, now familiar in solid-state lasers, with an amplifier based upon a seeded free-electron laser (FEL). The resulting device would produce amplified pulses of unprecedented brevity at wavelengths shorter than can be currently obtained by any tunable laser system. We use a subharmonically seeded FEL to illustrate the concept. Radiation from a Ti:sapphire laser is frequency tripled and stretched optically to provide a coherent seed pulse for the FEL. When coupled to an electron beam inside a magnetic wiggler, the seed radiation introduces an additional energy modulation on the electron bunch, which has been prepared with an energy chirp to match the chirp in the optical pulse. The energy modulated electrons are then spatially bunched in a dispersion magnet and introduced to a wiggler configured to be resonant to a harmonic of the seed laser, providing additional frequency multiplication. The coherent radiation produced by these electrons is amplified as it traverses the wiggler and is recompressed optically. The preservation of phase coherence provided by this scheme results in a device which can yield 4-fs pulses with 0.3 mJ at a central wavelength of ca. 8 nm, easily the shortest duration of amplified pulses produced by any laser. In this paper we discuss various aspects of the concept, including the generation of short pulses, temporal stretching and compression, and potential applications of the device. The phase distortion during the wide bandwidth FEL amplification is discussed in detail, and is shown to be within the bounds required to produce a 4-fs pulse upon compression

Template-stripped gold surfaces with 0.4 nm rms roughness suitable for force measurements. Application to the Casimir force in the 20-100 nm range

Using a template-stripping method, macroscopic gold surfaces with root-mean-square (rms) roughness less than 0.4 nm have been prepared, making them useful for studies of surface interactions in the nanometer range. The utility of such substrates is demonstrated by measurements of the Casimir force at surface separations between 20 and 100 nm, resulting in good agreement with theory. The significance and quantification of this agreement is addressed, as well as some methodological aspects regarding the measurement of the Casimir force with high accuracy.Comment: 7 figure

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON).

In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs). Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression. 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1. Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC

Brownian motion of a charged particle in electromagnetic fluctuations at finite temperature

The fluctuation-dissipation theorem is a central theorem in nonequilibrium statistical mechanics by which the evolution of velocity fluctuations of the Brownian particle under a fluctuating environment is intimately related to its dissipative behavior. This can be illuminated in particular by an example of Brownian motion in an ohmic environment where the dissipative effect can be accounted for by the first-order time derivative of the position. Here we explore the dynamics of the Brownian particle coupled to a supraohmic environment by considering the motion of a charged particle interacting with the electromagnetic fluctuations at finite temperature. We also derive particle's equation of motion, the Langevin equation, by minimizing the corresponding stochastic effective action, which is obtained with the method of Feynman-Vernon influence functional. The fluctuation-dissipation theorem is established from first principles. The backreaction on the charge is known in terms of electromagnetic self-force given by a third-order time derivative of the position, leading to the supraohmic dynamics. This self-force can be argued to be insignificant throughout the evolution when the charge barely moves. The stochastic force arising from the supraohmic environment is found to have both positive and negative correlations, and it drives the charge into a fluctuating motion. Although positive force correlations give rise to the growth of the velocity dispersion initially, its growth slows down when correlation turns negative, and finally halts, thus leading to the saturation of the velocity dispersion. The saturation mechanism in a suparohmic environment is found to be distinctly different from that in an ohmic environment. The comparison is discussed.Comment: accepter by Foundation of Physics, for IARD 6, 200

Health, employment and relationships: Correlates of personal wellbeing in young adults with and without a history of childhood language impairment

Objective: We examine the potential associations between self-rated health, employment situation, relationship status and personal wellbeing in young adults with and without a history of language impairment (LI). Methods: A total of 172 24-year-olds from the UK participated. Approximately half (N = 84) had a history of LI. Personal wellbeing was measured using ratings from three questions from the Office for National Statistics regarding life satisfaction, happiness and life being worthwhile. Results: There were similarities between individuals with a history of LI and their age-matched peers in self-rated personal wellbeing. However, regression analyses revealed self-rated health was the most consistent predictor of personal wellbeing for individuals with a history of LI in relation to life satisfaction (21% of variance), happiness (11%) and perceptions that things one does in life are worthwhile (32%). None of the regression analyses were significant for their peers. Conclusions: Similarities on ratings of wellbeing by young adults with and without a history of LI can mask heterogeneity and important differences. Young adults with a history of LI are more vulnerable to the effects of health, employment and relationship status on their wellbeing than their peers

Green function techniques in the treatment of quantum transport at the molecular scale

The theoretical investigation of charge (and spin) transport at nanometer length scales requires the use of advanced and powerful techniques able to deal with the dynamical properties of the relevant physical systems, to explicitly include out-of-equilibrium situations typical for electrical/heat transport as well as to take into account interaction effects in a systematic way. Equilibrium Green function techniques and their extension to non-equilibrium situations via the Keldysh formalism build one of the pillars of current state-of-the-art approaches to quantum transport which have been implemented in both model Hamiltonian formulations and first-principle methodologies. We offer a tutorial overview of the applications of Green functions to deal with some fundamental aspects of charge transport at the nanoscale, mainly focusing on applications to model Hamiltonian formulations.Comment: Tutorial review, LaTeX, 129 pages, 41 figures, 300 references, submitted to Springer series "Lecture Notes in Physics

Detection of long repeat expansions from PCR-free whole-genome sequence data

Identifying large expansions of short tandem repeats (STRs) such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI [0.98, 1.00]) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789, 95% CI [0.997, 1.00]) of the wild type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub

Implementation of a billable transitional care model for stroke patients: The COMPASS study

Background: The COMprehensive Post-Acute Stroke Services (COMPASS) pragmatic trial compared the effectiveness of comprehensive transitional care (COMPASS-TC) versus usual care among stroke and transient ischemic attack (TIA) patients discharged home from North Carolina hospitals. We evaluated implementation of COMPASS-TC in 20 hospitals randomized to the intervention using the RE-AIM framework. Methods: We evaluated hospital-level Adoption of COMPASS-TC; patient Reach (meeting transitional care management requirements of timely telephone and face-to-face follow-up); Implementation using hospital quality measures (concurrent enrollment, two-day telephone follow-up, 14-day clinic visit scheduling); and hospital-level sustainability (Maintenance). Effectiveness compared 90-day physical function (Stroke Impact Scale-16), between patients receiving COMPASS-TC versus not. Associations between hospital and patient characteristics with Implementation and Reach measures were estimated with mixed logistic regression models. Results: Adoption: Of 95 eligible hospitals, 41 (43%) participated in the trial. Of the 20 hospitals randomized to the intervention, 19 (95%) initiated COMPASS-TC. Reach: A total of 24% (656/2751) of patients enrolled received a billable TC intervention, ranging from 6 to 66% across hospitals. Implementation: Of eligible patients enrolled, 75.9% received two-day calls (or two attempts) and 77.5% were scheduled/offered clinic visits. Most completed visits (78% of 975) occurred within 14 days. Effectiveness: Physical function was better among patients who attended a 14-day visit versus those who did not (adjusted mean difference: 3.84, 95% CI 1.42-6.27, p = 0.002). Maintenance: Of the 19 adopting hospitals, 14 (74%) sustained COMPASS-TC. Conclusions: COMPASS-TC implementation varied widely. The greatest challenge was reaching patients because of system difficulties maintaining consistent delivery of follow-up visits and patient preferences to pursue alternate post-acute care. Receiving COMPASS-TC was associated with better functional status. Trial registration: ClinicalTrials.gov number: NCT02588664. Registered 28 October 201