Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation

BACKGROUND: Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR).

OBJECTIVES: The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP?

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) for efficacy but other designs also used.

REVIEW METHODS: Systematic review and economic modelling.

RESULTS: The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO.

LIMITATION: The current evidence is insufficient to recommend PRP for severe NPDR.

CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005408.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Selective deuterium ion acceleration using the Vulcan petawatt laser

We report on the successful demonstration of selective acceleration of deuterium ions by target-normal sheath acceleration (TNSA) with a high-energy petawatt laser. TNSA typically produces a multi-species ion beam that originates from the intrinsic hydrocarbon and water vapor contaminants on the target surface. Using the method first developed by Morrison et al. [Phys. Plasmas 19, 030707 (2012)], an ion beam with >99% deuterium ions and peak energy 14 MeV/nucleon is produced with a 200 J, 700 fs, > 10 20 W/cm 2 laser pulse by cryogenically freezing heavy water (D<inf>2</inf>O) vapor onto the rear surface of the target prior to the shot. Within the range of our detectors (0°-8.5°), we find laser-to-deuterium-ion energy conversion efficiency of 4.3% above 0.7 MeV/nucleon while a conservative estimate of the total beam gives a conversion efficiency of 9.4%.

Geometry- and diffraction-independent ionization probabilities in intense laser fields: Probing atomic ionization mechanisms with effective intensity matching

We report an experimental technique for the comparison of ionization processes in ultrafast laser pulses irrespective of pulse ellipticity. Multiple ionization of xenon by 50 fs 790 nm, linearly and circularly polarized laser pulses is observed over the intensity range 10 TW/cm(2) to 10 PW/cm(2) using effective intensity matching (EIM), which is coupled with intensity selective scanning (ISS) to recover the geometry-independent probability of ionization. Such measurements, made possible by quantifying diffraction effects in the laser focus, are compared directly to theoretical predictions of multiphoton, tunnel and field ionization, and a remarkable agreement demonstrated. EIM-ISS allows the straightforward quantification of the probability of recollision ionization in a linearly polarized laser pulse. Furthermore, the probability of ionization is discussed in terms of the Keldysh adiabaticity parameter gamma, and the influence of the precursor ionic states present in recollision ionization is observed.

Ultrafast ionization study of N-2 in intense linearly and circularly polarized laser fields

A detailed investigation has been carried out of N-2 molecules in intense 55 and 220 fs, linear and circular polarized, 790 nm laser pulses. Using an intensity selective scanning technique, ionization, dissociation, and dissociative ionization channels have been studied. Remarkably similar enhancements of signal with linear polarization observed for double ionization and dissociation channels demonstrate the dominance of dynamic alignment over rescattering effects. Fragmentation energies from dissociative ionization are reasonably well reproduced by classical trajectory calculations, the higher charged fragments displaying evidence of post dissociative ionization.

Ultrafast coherent control and quantum encoding of molecular vibrations in D2+ using intense laser pulses

Intense, few-femtosecond pulse technology has enabled studies of the fastest vibrational relaxation processes. The hydrogen group vibrations can be imaged and manipulated using intense infrared pulses. Through numerical simulation, we demonstrate an example of ultrafast coherent control that could be effected with current experimental facilities, and observed using high-resolution time-of-flight spectroscopy. The proposal is a pump-probe-type technique to manipulate the D2+ ion with ultrashort pulse sequences. The simulations presented show that vibrational selection can be achieved through pulse delay. We find that the vibrational system can be purified to a two-level system thus realizing a vibrational qubit. A novel scheme for the selective transfer of population between these two levels, based on a Raman process and conditioned upon the delay time of a second control-pulse is outlined, and may enable quantum encoding with this system.

Intense-field dissociation dynamics of D2+ molecular ions using ultrafast laser pulses

The dynamics of dissociation of pre-ionized D2+ molecules using intense (10^12–10^15 W cm-2), ultrashort (50 fs), infrared (? = 790 nm) laser pulses are examined. Use of an intensity selective scan technique has allowed the deuterium energy spectrum to be measured over a broad range of intensity. It is found that the dominant emission shifts to lower energies as intensity is increased, in good agreement with corresponding wavepacket simulations. The results are consistent with an interpretation in terms of bond softening, which at high intensity (approximately >3 × 10^14 W cm-2) becomes dominated by dissociative ionization. Angular distribution measurements reveal the presence of slow molecular dissociation, an indication that vibrational trapping mechanisms occur in this molecule.

Pathways to state-selective control of vibrational wavepackets in the deuterium molecular ion

The capability of intense ultrashort laser pulses to initiate, control and image vibrational wavepacket dynamics in the deuterium molecular ion has been simulated with a view to inform and direct future femtosecond pump-control-probe experiments. The intense-field coherent control of the vibrational superposition has been studied as a function of pulse intensity and delay time, to provide an indication of key constraints for experimental studies. For selected cases of the control mechanism, probing of the subsequent vibrational wavepacket dynamics has been simulated via the photodissociation (PD) channel. Such PD probing is shown to elucidate the modified wavepacket dynamics where the position of the quantum revival is sensitive to the control process. Through Fourier transform analysis the PD yield is also shown to provide a characterisation of the vibrational distribution. It has been shown that a simple 'critical R cut-off' approximation can be used to reproduce the effect of a probe pulse interaction, providing a convenient and efficient alternative to intensive computer simulations of the PD mechanism in the deuterium molecular ion.

Selective Imaging of Damaged Bone Structure (Microcracks) Using a Targeting Supramolecular Eu(III) Complex As a Lanthanide Luminescent Contrast Agent

The synthesis and photophysical evaluation of a new supramolecular lanthanide complex is described which was developed as a luminescent contrast agent for bone structure analysis. We show that the Eu(III) emission of this complex is not pH dependent within the physiological pH range, and that its steady state emission is not significantly modulated by a series of group I and II as well as d-metal ions, and that this agent can be successfully employed to image mechanically formed cracks (scratches) in bone samples after 4 or 24 hours, using confocal laser-scanning microscopy.

Selective Inhibition of Retinal Angiogenesis by Targeting PI3 Kinase

Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.

Nano-structural investigation of Ag/Al2O3 catalyst for selective removal of O-2 with excess H-2 in the presence of C2H4

Ag/gamma-Al2O3 catalysts have been characterized in-depth during different thermo-chemical treatments by in situ diffuse reflectance UV-visible spectroscopy and quasi in situ Transmission Electron Microscopy. The combination of these techniques indicates that sintering and redispersion of silver is clearly observed from the increases and decreases in the absorption band intensity over the range of 250-600 nm due to the presence of silver clusters and silver nanoparticles. These results allow us to study the effect of the reaction feed on the metal dispersion at different operation conditions and discuss the formation of active sites during the selective catalytic reduction of O-2 with excess H-2 in the presence of unsaturated hydrocarbons. In this case high catalytic activity and selectivity toward the oxygen removal was achieved for this catalyst. (C) 2010 Elsevier B.V. All rights reserved.

Ultrafast charge dynamics initiated by high-intensity, ultrashort laser-matter interaction

The interaction of high‐intensity laser pulses with matter releases instantaneously ultra‐large currents of highly energetic electrons, leading to the generation of highly‐transient, large‐amplitude electric and magnetic fields. We report results of recent experiment in which such charge dynamics have been studied by using proton probing techniques able to provide maps of the electrostatic fields with high spatial and temporal resolution. The dynamics of ponderomotive channelling in underdense plasmas have been studied in this way, as also the processes of Debye sheath formation and MeV ion front expansion at the rear of laser‐irradiated thin metallic foils. An application employing laser‐driven impulsive fields for energy‐selective ion beam focusing is also presented.