Intensity noise in difference frequency generation-based tunable femtosecond MIR sources.

We characterize the intensity noise of two mid-infrared (MIR) ultrafast tunable (3.5-11 µm) sources based on difference frequency generation (DFG). While both sources are pumped by a high repetition rate Yb-doped amplifier delivering 200 µJ 300 fs at a central wavelength of 1030 nm, the first is based on intrapulse DFG (intraDFG), and the second on DFG at the output of an optical parametric amplifier (OPA). The noise properties are assessed through measurement of the relative intensity noise (RIN) power spectral density and pulse-to-pulse stability. The noise transfer mechanisms from the pump to the MIR beam is empirically demonstrated. As an example, improving the pump laser noise performance allows reduction of the integrated RIN (IRIN) of one of the MIR source from 2.7% RMS down to 0.4% RMS. The intensity noise is also measured at various stages and in several wavelength ranges in both laser system architectures, allowing us to identify the physical origin of their variation. This study presents numerical values for the pulse to pulse stability, and analyze the frequency content of the RINs of particular importance for the design of low-noise high repetition rate tunable MIR sources and future high performance time-resolved molecular spectroscopy experiments.

Inline amplification of mid-infrared intrapulse difference frequency generation.

We demonstrate an ultrafast mid-infrared source architecture that implements both intrapulse difference frequency generation (iDFG) and further optical parametric amplification (OPA), in an all-inline configuration. The source is driven by a nonlinearly compressed high-energy Yb-doped-fiber amplifier delivering 7.4 fs pulses at a central wavelength of 1030 nm, at a repetition rate of 250 kHz. It delivers 1 µJ, 73 fs pulses at a central wavelength of 8 µm, tunable over more than one octave. By enrolling all the pump photons in the iDFG process and recycling the long wavelength pump photons amplified in the iDFG in the subsequent OPA, we obtain an unprecedented overall optical efficiency of 2%. These performances, combining high energy and repetition rate in a very simple all-inline setup, make this technique ideally suited for a growing number of applications, such as high harmonic generation in solids or two-dimensional infrared spectroscopy experiments.

Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

Enhanced intrapulse difference frequency generation in the mid-infrared by a spectrally dependent polarization state.

We present a technique to optimize the intrapulse difference frequency generation efficiency for mid-infrared generation. The approach employs a multi-order wave plate that is designed to selectively rotate the polarization state of the incoming spectral components on the relevant orthogonal axes for subsequent nonlinear interaction. We demonstrate a significant increase of the mid-infrared average power generated, of a factor ≥2.5 compared with the conventional scheme, owing to an optimally distributed number of photons enrolled in the difference frequency generation process.

Cascaded harmonic generation from a fiber laser: a milliwatt XUV source.

Recent progresses in femtosecond ytterbium-doped fiber laser technology are opening new perspectives in strong field physics and attosecond science. High-order harmonic generation from these systems is particularly interesting because it provides high flux beams of ultrashort extreme ultraviolet radiation. A great deal of effort has been devoted to optimize the macroscopic generation parameters. Here we investigate the possibility of enhancing the single-atom response by producing high-order harmonics from the second, third and fourth harmonics of a turnkey 50 W, 166 kHz femtosecond Yb-fiber laser providing 135 fs pulses at 1030 nm. We show that the harmonic efficiency is optimal when the process is driven by the third harmonic, producing 6.6 ± 1.3 × 1014 photons/s at 18 eV in argon, which corresponds to 1.9 ± 0.4 mW average power.

CEP-stable high-energy ytterbium-doped fiber amplifier.

We report on the carrier-envelope phase (CEP) stabilization of a Yb-doped fiber amplifier system delivering 30 µJ pulses at 100 kHz repetition rate. A single-shot, every-shot measurement of the CEP stability based on a simple f-2f interferometer is performed, yielding a CEP standard deviation of 320 mrad rms over 1 s. Long-term stability is also assessed, with 380 mrad measured over 1 h. This level of performance is allowed by a hybrid architecture, including a passively CEP-stabilized front-end based on difference frequency generation and an active CEP stabilization loop for the fiber amplifier system, acting on a telecom-grade integrated LiNbO3 phase modulator. Together with recent demonstrations of temporal compression down to the few-cycle regime, the presented results demonstrate the relevance of the Yb-doped high repetition rate laser for attoscience.

High-power two-cycle ultrafast source based on hybrid nonlinear compression.

We demonstrate a hybrid dual-stage nonlinear compression scheme, which allows the temporal compression of 330 fs-pulses down to 6.8 fs-pulses, with an overall transmission of 61%. This high transmission is obtained by using a first compression stage based on a gas-filled multipass cell, and a second stage based on a large-core gas-filled capillary. The source output is fully characterized in terms of spectral, temporal, spatial, and short- and long-term stability properties. The system's compactness, stability, and high average power makes it ideally suited to drive high photon flux XUV sources through high harmonic generation.

[Interest of robotic stereotactic radiosurgery in the management of brain metastases: Results of a retrospective, single center analysis]. / Place de la radiochirurgie stéréotaxique robotisée dans la prise en charge des métastases cérébrales : résultats d'une analyse rétrospective monocentrique.

PURPOSE: The management of malignant brain metastases becomes a main issue for the treatment of patients, because of the survival extension related to the improvement in systemic treatments. Robotic stereotactic radiosurgery (RSR) is a new approach in this indication. The purpose of this analysis was to define the efficacy of RSR, in order to determine prognostic factors of survival and factors of response. PATIENTS AND METHODS: It was a retrospective, single center (polyclinique de Bordeaux Nord Aquitaine) analysis performed from 2012 to 2015, involving patients with malignant brain metastases treated by RSR using the Cyberknife® technique. We analyzed the following parameters: response to RSR, prognostic and predictive factors of response, and survival. RESULTS: A total of 72 RSRs were performed among 55 analyzed patients; 62 treatments were assessable with a median follow-up of 9.4 months. The main delivered dose on the 80%-isodose was 20Gy. A complete response was achieved in 40.3% of patients (stability or regression=83.9%). The overall survival was 13 months. The risk of failure was significantly correlated with the increase in metastasis size and non-adenocarcinoma histology. A performance status<2 was the main prognostic factor of survival. CONCLUSIONS: The RSR allowed treating 3 to 5 brain metastases, avoiding an entire brain irradiation, and maintaining survival and quality of life.

Nonlinear pulse compression based on a gas-filled multipass cell.

We demonstrate nonlinear temporal compression of a high-energy Yb-doped fiber laser source in a multipass cell filled with argon. The 160 µJ 275 fs input pulses are compressed down to 135 µJ 33 fs at the output, corresponding to an overall transmission of 85%. We also analyze the output beam, revealing essentially no space-time couplings. We believe this technique can be scalable to higher pulse energies and shorter pulse durations, enabling access to a wider parameter range for a large variety of ultrafast laser sources.

[Spinal stereotactic body radiotherapy: French assessment in 2016]. / État des lieux de la radiothérapie en conditions stéréotaxiques vertébrale en France en 2016.

PURPOSE: Stereotactic body radiotherapy to vertebral column remains uncommon practice and only relevant in selected group of patients. The main objective of the study was to describe the current state of medical practices of stereotactic body radiotherapy to vertebral column in France in 2016 and to assess the diversity of practices to identify areas for improvement and establish a common database set for this technique. MATERIALS AND METHODS: A questionnaire was written with contribution of a medical physicist, a radiation oncologist, an information technologist and a radiotherapy resident. The questionnaire was distributed online to a radiation oncologists and a medical physicists partner of selected French radiotherapy specialized centres that provide stereotactic body radiotherapy to vertebral metastasis from April to June 2016. The questionnaire surveyed the following topics: patients' selection, simulation, targeted volume and organs at risk delineation, prescription, dosimetric implementation and image guidance. RESULTS: A total of 31 centres were surveyed. Seventy eight per cent of centres (n=21) completed the questionnaire. The "ideal" patient for spine stereotactic radiotherapy according to these institutions has a good performance status, a long life expectancy, controlled primary tumour with oligometastatic spread. The most prescribed protocol was 30Gy in three fractions. For clinical target volume delineation, about two thirds of centres used the International Spine Radiosurgery Consortium (ISRC) recommendations (Noël G et al.,2006). CONCLUSION: This study identified some consistency of practices in some aspects despite the lack of consensus guidelines. Nevertheless, further studies are needed to establish consensus of planning and treatment.

High-energy few-cycle Yb-doped fiber amplifier source based on a single nonlinear compression stage.

A simple, compact, and efficient few-cycle laser source at a central wavelength of 1 µm is presented. The system is based on a high-energy femtosecond ytterbium-doped fiber amplifier delivering 130 fs, 250 µJ pulses at 200 kHz, corresponding to 1.5 GW of peak power and an average power of 50 W. The unprecedented short pulse duration at the output of this system is obtained by use of spectral intensity and phase shaping, allowing for both gain narrowing mitigation and the compensation of the nonlinear accumulated spectral phase. This laser source is followed by a single-stage of nonlinear compression in a xenon-filled capillary, allowing for the generation of 14 fs, 120 µJ pulses at 200 kHz resulting in 24 W of average power. High-harmonic generation driven by this type of source will trigger numerous new applications in the XUV range and attosecond science.

Coherent combining efficiency in strongly saturated divided-pulse amplification systems.

Numerical simulations are performed to analyze effects that limit the combining efficiency in divided-pulse amplification setups. The model allows us to evaluate the impact of self- and cross-phase modulation between pulse replicas, Kramers-Krönig-related phase shifts, and inter- and intra-replica saturation effects. In particular, we show that when the energy per replica approaches the saturation energy, pulse reshaping induced by the gain saturation coupled with self-phase modulation imparts a temporal differential phase that decreases the combining efficiency. This effect limits the energy that can be extracted by a single replica, thereby providing design rules to scale the performances of short pulse laser sources using this technique.

Improving isopropanol tolerance and production of Clostridium beijerinckii DSM 6423 by random mutagenesis and genome shuffling.

Random mutagenesis and genome shuffling was applied to improve solvent tolerance and isopropanol/butanol/ethanol (IBE) production in the strictly anaerobic bacteria Clostridium beijerinckii DSM 6423. Following chemical mutagenesis with N-methyl-N-nitro-N-nitrosoguanidine (NTG), screening of putatively improved strains was done by submitting the mutants to toxic levels of inhibitory chemicals or by screening for their tolerance to isopropanol (>35 g/L). Suicide substrates, such as ethyl or methyl bromobutyrate or alcohol dehydrogenase inhibitors like allyl alcohol, were tested and, finally, 36 mutants were isolated. The fermentation profiles of these NTG mutant strains were characterized, and the best performing mutants were used for consecutive rounds of genome shuffling. Screening of strains with further enhancement in isopropanol tolerance at each recursive shuffling step was then used to spot additionally improved strains. Three highly tolerant strains were finally isolated and able to withstand up to 50 g/L isopropanol on plates. Even if increased tolerance to the desired end product was not always accompanied by higher production capabilities, some shuffled strains showed increased solvent titers compared to the parental strains and the original C. beijerinckii DSM 6423. This study confirms the efficiency of genome shuffling to generate improved strains toward a desired phenotype such as alcohol tolerance. This tool also offers the possibility of obtaining improved strains of Clostridium species for which targeted genetic engineering approaches have not been described yet.

High-brightness fiber laser-pumped 68 fs-2.3 W Kerr-lens mode-locked Yb:CaF2 oscillator.

By using a high-brightness fiber pump laser, we demonstrate a pure Kerr-lens mode-locked (ML) Yb:CaF(2) oscillator. The laser delivers 68 fs pulses with 2.3 W average power at 73 MHz repetition rate and an optical-to-optical efficiency of 33% is achieved. To the best of our knowledge, this is the first demonstration of Kerr-lens mode-locking in Yb:CaF(2). Incidentally, we report here the highest average power ever achieved for a sub-100-fs active Kerr-lens ML Yb-bulk oscillator.

Multi-pathogen waterborne disease outbreak associated with a dinner cruise on Lake Michigan.

We report an outbreak associated with a dinner cruise on Lake Michigan. This took place on the same day as heavy rainfall, which resulted in 42·4 billion liters of rainwater and storm runoff containing highly diluted sewage being released into the lake. Of 72 cruise participants, 41 (57%) reported gastroenteritis. Stool specimens were positive for Shigella sonnei (n=3), Giardia (n=3), and Cryptosporidium (n=2). Ice consumption was associated with illness (risk ratio 2·2, P=0·011). S. sonnei was isolated from a swab obtained from the one of the boat's ice bins. Environmental inspection revealed conditions and equipment that could have contributed to lake water contaminating the hose used to load potable water onto the boat. Knowledge of water holding and distribution systems on boats, and of potential risks associated with flooding and the release of diluted sewage into large bodies of water, is crucial for public health guidance regarding recreational cruises.

Perspective: matching, mate choice, and speciation.

Matching was developed in the 1960s to match such entities as residents and hospitals, colleges and students, or employers and employees. This approach is based on "preference lists," whereby each participant ranks potential partners according to his/her preferences and tries to match with the highest-ranking partner available. Here, we discuss the implications of matching for the study of mate choice and speciation. Matching differs from classic approaches in several respects, most notably because under this theoretical framework, the formation of mating pairs is context-dependant (i.e., it depends on the configuration of pairings in the entire population), because the stability of mating pairs is considered explicitly, and because mate choice is mutual. The use of matching to study mate choice and speciation is not merely a theoretical curiosity; its application can generate counter-intuitive predictions and lead to conclusions that differ fundamentally from classic theories about sexual selection and speciation. For example, it predicts that when mate choice is mutual and the stability of mating pairs is critical for successful reproduction, sympatric speciation is a robust evolutionary outcome. Yet the application of matching to the study of mate choice and speciation has been largely dominated by theoretical studies. We present the hamlets, a group of brightly colored Caribbean coral reef fishes in the genus Hypoplectrus (Serranidae), as a particularly apt system to test empirically specific predictions generated by the application of matching to mate choice and speciation.

Phase I study of irinotecan and cisplatin in combination with pelvic radiotherapy in the treatment of locally advanced cervical cancer: A GINECO trial.

PURPOSE: To define the recommended dose of the association of weekly irinotecan (Iri) and cisplatin (CP) with pelvic radiotherapy in Locally Advanced Cervical Cancer. PATIENTS AND METHODS: Stage IB2-IV cervix cancer patients were treated with escalating doses of Iri starting from 30 mg/m(2) and a fixed dose of CP at 20 mg/m(2), both weekly concomitantly with a 45-Gy pelvic irradiation. RESULTS: Fifteen patients entered the study, 6 at level 1 (Iri 30 mg/m(2)), 3 at level 2 (Iri 40 mg/m(2)) and 6 at intermediate dose (Iri 35 mg/m(2)). Median age was 47 years (34-72), FIGO stage IB (n=1), IIB (n=7), III (n=6), IVA (n=1). The recommended dose was weekly Iri 35 mg/m(2) and CP 20 mg/m(2). Dose limiting toxicities (grades 3-4) were diarrhea, abdominal pain, febrile neutropenia and fatigue. CONCLUSION: In cervix cancer patients, radiosensitization with weekly cisplatin and irinotecan is feasible, and the recommended doses are cisplatin 20 mg/m(2)/week and irinotecan 35 mg/m(2)/week for future phase II studies.

Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group.

ICON3 trial results have suggested that CAP and carboplatin-taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m(-2), epirubicin (E) 50 mg m(-2), and cisplatin (P) 75 mg m(-2) or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m(-2) and filgrastim 5 mug kg(-1) per day x 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3-4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3-4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC.

Competition landscapes: scaling up local biotic and abiotic processes in heterogeneous environments.

I present a model based on benthic populations by first defining a competition landscape where competitive interactions are confined to small areas, defined by the distribution of resource renewal from a global pool. Using truncated kernels and results from 1-dimensional percolation theory, I then derive an approximation allowing the scaling up of local interactions among individuals to patch and landscape levels. This approximation is used to explore how spatially structured habitats can affect competition intensity. The competition landscape is then compared to a simulation of mussel colonization under various flow velocity patterns, and is shown to predict the qualitative effect of the scale of patchiness in habitat quality on total competition intensity. The interaction between large scale hydrodynamic forcing and local competition is also shown to provide an alternate hypothesis explaining the observed among-year reversal of the relationship between topographic scale and mussel abundance in some intertidal communities. The model more generally highlights the nonlinear scaling up of competitive interactions in competition landscapes, and provides a framework for the study of self-organization in heterogeneous ecosystems.