T heory predicts 1-4 that, with an ultrashort and extremely bright coherent X-ray pulse, a single diffraction pattern may be recorded from a large macromolecule, a virus or a cell before the sample explodes and turns into a plasma. Here we report the first experimental demonstration of this principle using the FLASH soft-X-ray free-electron laser. An intense 25 fs, 4 × 10 13 W cm −2 pulse, containing 10 12 photons at 32 nm wavelength, produced a coherent diffraction pattern from a nanostructured non-periodic object, before destroying it at 60,000 K. A novel X-ray camera assured single-photon detection sensitivity by filtering out parasitic scattering and plasma radiation. The reconstructed image, obtained directly from the coherent pattern by phase retrieval through oversampling 5-9 , shows no measurable damage, and is reconstructed at the diffraction-limited resolution. A three-dimensional data set may be assembled from such images when copies of a reproducible sample are exposed to the beam one by one 10 .X-ray free-electron lasers (FELs) are expected to permit diffractive imaging at high resolutions of nanometre-to micrometre-sized objects without the need for crystalline periodicity in the sample [1][2][3][4] . Structural studies within this size domain are particularly important in materials science, biology and medicine. Radiation-induced damage and sample movement prevent the accumulation of high-resolution scattering signals for such samples in conventional experiments 11,12 . Damage is caused by energy deposited into the sample by the very probes used for imaging, for example photons, electrons or neutrons. At X-ray frequencies, inner-shell processes dominate the ionization of the sample; photoemission is followed by Auger or fluorescence emission and shake excitations. The energies of the ejected photoelectrons, Auger electrons and shake electrons differ from each other, and these electrons are released at different times, but within about ten femtoseconds, following photoabsorption 1,13 . Thermalization of the ejected electrons through collisional electron cascades is completed within 10-100 fs (refs 14,15). Heat transport, diffusion and radical reactions take place over some picoseconds to milliseconds.The effect of X-ray-induced sample damage on the recorded image or diffraction pattern could be substantially reduced, if we could collect diffraction data faster than the relevant damage processes 1,16 . This approach requires very short and very bright X-ray pulses, such as those expected from a short-wavelength FEL. However, the large amount of energy deposited into the sample by a focused FEL pulse will ultimately turn the sample into a plasma. The question is when exactly would this happen. There are no experiments with X-rays in the relevant time and intensity nature physics VOL 2 DECEMBER 2006 www.nature.com/naturephysics

In our Petawatt laser experiments several hundred joules of 1 µm laser light in 0.5-5.0 ps pulses with intensities up to 3x10 20 Wcm -2 were incident on solid targets producing a strongly relativistic interaction. The energy content, spectra, and angular patterns of the photon, electron, and ion radiations were diagnosed in a number of ways, including several novel (to laser physics) nuclear activation techniques. From the beamed bremsstrahlung we infer that about 40-50% of the laser energy is converted to broadly beamed hot electrons. Their direction centroid varies from shot to shot, but the beam has a consistent width. Extraordinarily luminous ion beams almost precisely normal to the rear of various targets are seen -up to 3x10 13 protons with kT ion ~ several MeV representing ~6% of the laser energy.We observe ion energies up to at least 55 MeV. The ions appear to originate from the rear target surfaces.The edge of the ion beam is very sharp, and collimation increases with ion energy. At the highest energies, a narrow feature appears in the ion spectra, and the apparent size of the emitting spot is smaller than the full back surface area. Any ion emission from the front of the targets is much less than from the rear and is not sharply beamed. The hot electrons generate a Debye sheath with electrostatic fields of order MV per micron which apparently accelerate the ions.

Graves' orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patients' quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required to reduce disfigurement, double vision and occasionally, to preserve vision. Clinical trials from over the past decade [Au: edits to define "recent" OK? Please edit my changes if I have misunderstood you This is fine] have shown that considerable benefit can be derived from the addition of anti-proliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab (anti-IGF-1R), which seems to substantially reduce proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. In the last decade, the pathophysiology of Graves' orbitopathy has also been revised with identification of new potential therapeutic targets. In this review we provide an up-to-date overview of the field, [Au: addition of linking text OK? This is fine] outline the optimal management of Graves' orbitopathy and summarise the research developments in this area to highlight future research questions and direct future clinical trials.