Relativistic ultrafast electron diffraction at high repetition rates.

The ability to resolve the dynamics of matter on its native temporal and spatial scales constitutes a key challenge and convergent theme across chemistry, biology, and materials science. The last couple of decades have witnessed ultrafast electron diffraction (UED) emerge as one of the forefront techniques with the sensitivity to resolve atomic motions. Increasingly sophisticated UED instruments are being developed that are aimed at increasing the beam brightness in order to observe structural signatures, but so far they have been limited to low average current beams. Here, we present the technical design and capabilities of the HiRES (High Repetition-rate Electron Scattering) instrument, which blends relativistic electrons and high repetition rates to achieve orders of magnitude improvement in average beam current compared to the existing state-of-the-art instruments. The setup utilizes a novel electron source to deliver femtosecond duration electron pulses at up to MHz repetition rates for UED experiments. Instrument response function of sub-500 fs is demonstrated with < 100 fs time resolution targeted in future. We provide example cases of diffraction measurements on solid-state and gas-phase samples, including both micro- and nanodiffraction (featuring 100 nm beam size) modes, which showcase the potential of the instrument for novel UED experiments.

ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. DISCUSSION: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198.

A 5-µm pitch charge-coupled device optimized for resonant inelastic soft X-ray scattering.

We have developed a charge-coupled device (CCD) with 5 µm × 45 µm pixels on high-resistivity silicon. The fully depleted 200 µm-thick silicon detector is back-illuminated through a 10 nm-thick in situ doped polysilicon window and is thus highly efficient for soft through >8 keV hard X-rays. The device described here is a 1.5 megapixel CCD with 2496 × 620 pixels. The pixel and camera geometry was optimized for Resonant Inelastic X-ray Scattering (RIXS) and is particularly advantageous for spectrometers with limited arm lengths. In this article, we describe the device architecture, construction and operation, and its performance during tests at the Advance Light Source (ALS) 8.0.1 RIXS beamline. The improved spectroscopic performance, when compared with a current standard commercial camera, is demonstrated with a ∼280 eV (CK) X-ray beam on a graphite sample. Readout noise is typically 3-6 electrons and the point spread function for soft CK X-rays in the 5 µm direction is 4.0 µm ± 0.2 µm. The measured quantum efficiency of the CCD is greater than 75% in the range from 200 eV to 1 keV.

In situ TEM Raman spectroscopy and laser-based materials modification.

We present a modular assembly that enables both in situ Raman spectroscopy and laser-based materials processing to be performed in a transmission electron microscope. The system comprises a lensed Raman probe mounted inside the microscope column in the specimen plane and a custom specimen holder with a vacuum feedthrough for a tapered optical fiber. The Raman probe incorporates both excitation and collection optics, and localized laser processing is performed using pulsed laser light delivered to the specimen via the tapered optical fiber. Precise positioning of the fiber is achieved using a nanomanipulation stage in combination with simultaneous electron-beam imaging of the tip-to-sample distance. Materials modification is monitored in real time by transmission electron microscopy. First results obtained using the assembly are presented for in situ pulsed laser ablation of MoS2 combined with Raman spectroscopy, complimented by electron-beam diffraction and electron energy-loss spectroscopy.

Development of a compact fast CCD camera and resonant soft x-ray scattering endstation for time-resolved pump-probe experiments.

The designs of a compact, fast CCD (cFCCD) camera, together with a resonant soft x-ray scattering endstation, are presented. The cFCCD camera consists of a highly parallel, custom, thick, high-resistivity CCD, readout by a custom 16-channel application specific integrated circuit to reach the maximum readout rate of 200 frames per second. The camera is mounted on a virtual-axis flip stage inside the RSXS chamber. When this flip stage is coupled to a differentially pumped rotary seal, the detector assembly can rotate about 100°/360° in the vertical/horizontal scattering planes. With a six-degrees-of-freedom cryogenic sample goniometer, this endstation has the capability to detect the superlattice reflections from the electronic orderings showing up in the lower hemisphere. The complete system has been tested at the Advanced Light Source, Lawrence Berkeley National Laboratory, and has been used in multiple experiments at the Linac Coherent Light Source, SLAC National Accelerator Laboratory.

A high-efficiency spin-resolved photoemission spectrometer combining time-of-flight spectroscopy with exchange-scattering polarimetry.

We describe a spin-resolved electron spectrometer capable of uniquely efficient and high energy resolution measurements. Spin analysis is obtained through polarimetry based on low-energy exchange scattering from a ferromagnetic thin-film target. This approach can achieve a similar analyzing power (Sherman function) as state-of-the-art Mott scattering polarimeters, but with as much as 100 times improved efficiency due to increased reflectivity. Performance is further enhanced by integrating the polarimeter into a time-of-flight (TOF) based energy analysis scheme with a precise and flexible electrostatic lens system. The parallel acquisition of a range of electron kinetic energies afforded by the TOF approach results in an order of magnitude (or more) increase in efficiency compared to hemispherical analyzers. The lens system additionally features a 90 degrees bandpass filter, which by removing unwanted parts of the photoelectron distribution allows the TOF technique to be performed at low electron drift energy and high energy resolution within a wide range of experimental parameters. The spectrometer is ideally suited for high-resolution spin- and angle-resolved photoemission spectroscopy (spin-ARPES), and initial results are shown. The TOF approach makes the spectrometer especially ideal for time-resolved spin-ARPES experiments.

The use of video glasses at ultrasound-guided interventions.

PURPOSE: Video glasses form a virtual image in front of the user. We investigated the utility of video glasses at US-guided interventions. MATERIAL AND METHODS: The video glasses were tested at 75 consecutive US-guided interventions. The operator sees the US image in front of him, and below the glasses, simply by moving his eyes, he can see the patient and the field of intervention. RESULTS: The video glasses could be used at all 75 US-guided interventions. The image quality was below that of the US monitor, but adequate. The working posture was improved, it was easy to get accustomed to using the system, there was no increased time consumption, and the patients felt comfortable with the set-up. CONCLUSION: Use of video glasses facilitates US-guided interventions.

Effects of trichlorobenzene on natural phytoplankton populations.

Natural phytoplankton assemblages from an offshore station in Lake Michigan were exposed to individual isomers of trichlorobenzene (TCB) and incubated in situ for a 24 h period. One set of exposures was initiated with a lake assemblage collected at 0330 h from 30 m and the TCB isomers added at 0400 h. The second exposure experiment was initiated with an assemblage from 30 m collected at 1530 h and the TCB isomers added at 1600 h.Comparisons of the chlorophyll a to neutral lipid ratio and the neutral to polar lipid ratios suggest that 1,2,3-TCB is more toxic than 1,2,4-TCB. Furthermore, more effects were observed when exposures were initiated at 0400 h when compared with a parallel experiment initiated at 1600 h. These studies with natural assemblages support culture studies of effect as a function of time of exposure.