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Background The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. Methods TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50–75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2–3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15–45 mg) or a sulfonylurea (5–15 mg glibenclamide, 2–6 mg glimepiride, or 30–120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Findings Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74–1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p

Background and aims Metformin is the first-line therapy in type 2 diabetes. In patients inadequately controlled with metformin, the addition of a sulfonylurea or pioglitazone are equally plausible options to improve glycemic control. However, these drugs have profound differences in their mechanism of action, side effects, and impact on cardiovascular risk factors. A formal comparison of these two therapies in terms of cardiovascular morbidity and mortality is lacking. The TOSCA.IT study was designed to explore the effects of adding pioglitazone or a sulfonylurea on cardiovascular events in type 2 diabetic patients inadequately controlled with metformin. Methods Multicentre, randomized, open label, parallel group trial of 48 month duration. Type 2 diabetic subjects, 50–75 years, BMI 20–45 Kg/m 2 , on secondary failure to metformin monotherapy will be randomized to add-on a sulfonylurea or pioglitazone. The primary efficacy outcome is a composite endpoint of all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned coronary revascularization. Principal secondary outcome is a composite ischemic endpoint of sudden death, fatal and non-fatal myocardial infarction and stroke, endovascular or surgical intervention on the coronary, leg or carotid arteries, major amputations. Side effects, quality of life and economic costs will also be evaluated. Efficacy, safety, tolerability, and study conduct will be monitored by an independent Data Safety Monitoring Board. End points will be adjudicated by an independent external committee. Conclusions TOSCA.IT is the first on-going study investigating the head-to-head comparison of adding a sulfonylurea or pioglitazone to existing metformin treatment in terms of hard cardiovascular outcomes. Registration: Clinicaltrials.gov ID NCT00700856.

We present a protocol for the design of an illumination system (front end) for a soft-x-ray projection lithography tool. The protocol is illustrated by specific front-end designs. The most complete design analysis is for a laser-driven system. Other drivers; undulator, synchrotron orbital radiation, and plasma discharge, are also discussed.

We report an explicit demonstration of classical guided-wave propagation at XUV and soft-x-ray wavelengths. Experiments were performed using narrow-band synchrotron radiation at 5, 20.8, 21, and 30 nm. Free-standing gold transmission gratings served as waveguide structures. These structures had a 300-nm grating period with waveguide channel widths as small as 100 nm and were as thick as 700 nm in the direction of guided-wave transmission. Guided-wave phenomena were manifest in strongly asymmetric diffraction patterns resulting from the angular tilt of the transmission-grating normal from the incident-beam direction.

We report the first demonstration to our knowledge of multipass amplification of soft x rays. A gain medium of neonlike selenium ions was placed within a resonant cavity composed of a multilayer mirror and a beam splitter designed for normal-incidence use at the 20.63- and 20.96-nm laser lines of the neonlike selenium. The laser-cavity output was time resolved and exhibited three distinct temporal components identifiable as the single-, double-, and triple-pass amplified emission. In these experiments, multipass amplification was limited by the finite duration of the gain medium.

Soft x-ray projection lithography (SXPL) requires uniform, high reflectivity multilayer (ML) coatings on figured optical surfaces with lens speeds (f) between 3 and 6 and diameters of 10 to 15 cm. High reflectivity Mo-Si ML coatings for operation near 13 nm were deposited on f 3.4 and f 6 optics 5 and 7.5 cm in diameter using planar dc magnetron sputtering. Measurements of the normal incidence reflectivity (NIR) of 63% at 13 nm uniform over the central 5 cm of the figured surface were obtained. Comparison of the measured values to model calculations of the wavelength dependent reflectivity indicate that the ML period is uniform to better than 0.04 nm over this region.

A baseline model providing technical performance specifications and preliminary cost assessments for a prototype Soft X-ray Projection Lithography (SXPL) system is presented. We find that the technical performance requirements for components of the SXPL system are beyond the current state of the technology. We have also conducted a wafer cost analysis for the proposed SXPL system. In our parametric analysis of normalized wafer exposure costs we find that variations in direct cost items (e.g., resist, mask optics, laser) have a small effect on wafer costs. More important are variations in variations in the performance of technical parameters which affect wafer throughput. Of these, mirror reflectivity is by far the most important, followed by optical design (which can reduce the number of mirrors), then parameters related to x-ray generation and collection, and finally resist sensitivity. The lifetime of multilayer coatings is not by itself a critical parameter in determining wafer exposure costs. However, the repairability of such coatings can be important. Indeed, if mirror replacement is required when coatings degrade (i.e., nonrepairable), then mirror lifetime becomes about as important as resist sensitivity in determining wafer exposure costs.

Soft X-ray Project Lithography (SXPL) may be used to fabricate high resolution structures for future integrated circuits. This technique will use a reflection mask which is a substrate coated with an x-ray multilayer mirror and patterned with a thin ({approximately}50 nm) layer of x-ray absorber. Mask patterning processes must not degrade the reflectivity of the x-ray mirror and mask repair techniques must be developed. The technical challenges of conventional reflecting optical imaging system designs are severe and mask technology can have a significant impact on this issue. Specifically, innovative mask designs can reduce the complexity of the optical system by decreasing the number of mirrors and replacing aspheric optical surfaces with spherical surfaces. We have developed a technique, called Encoded Mask Lithography, with which we have designed an optical system which uses only two (spherical) imaging mirrors and has 30 mm diameter field of view.

Recent advances in x‐ray optics have made possible the practical consideration of soft x‐ray projection imaging for the fabrication of high density integrated circuits.

We report observations of amplified spontaneous emission at soft x-ray wavelengths. An optical laser ionized thin foils of selenium to produce a population inversion of the $2{p}^{5}3p$ and $2{p}^{5}3s$ levels of the neonlike ion. Using three time-resolved, spectroscopic measurements we demonstrated gain-length products up to 6.5 and gain coefficients of 5.5\ifmmode\pm\else\textpm\fi{}1.0 ${\mathrm{cm}}^{\ensuremath{-}1}$ for the $J=2 \mathrm{to} 1$ lines at 206.3 and 209.6 \AA{}. We also observed considerable amplification for the same transitions in yttrium at 155.0 and 157.1 \AA{}.

Recent progress in experimental laboratory soft X-ray laser research at Lawrence Livermore National Laboratory (LLNL) is reviewed. Research at LLNL in this area has concentrated on further characterising and understanding neon-like X-ray laser plasmas, investigating soft X-ray amplification at shorter wavelengths, and demonstrating examples of X-ray laser applications. For the standard 200 AA neon-like selenium collisional excitation laser, the output source size as well as the beam time history, divergence, energy and spatial profile have been measured. Gain has been demonstrated at wavelengths as short as 50.3 AA in nickel-like ytterbium. Several recombination X-ray laser schemes have also been investigated. X-ray laser holography, cavity operation of an X-ray laser, and the capability to point and focus the output laser beam have been demonstrated.

We report an explicit demonstration of double pass amplification of soft X-ray laser radiation at 131 A, the shortest wavelength demonstration to date. Using efficient ( R =60%), narrowband ( λ Δλ =13 ), normal incidence, multilayer mirrors, double pass amplification was achieved on the 131 A and 132.7 A laser lines of neon-like molybdenum. The laser output was time resolved, exhibiting two distinct temporal components clearly identifiable as the single pass and double pass amplified emission.

Gold gratings with spatial periods of 0.3 and 0.2 μm have been fabricated in thicknesses of 0.6 and 0.25 μm, respectively, and used in x‐ray spectroscopy and spatial‐period‐division. Fabrication techniques included: holographic lithography, shadowing, x‐ray lithography, and gold microplating. Control of linewidth to tolerance of the order of 10 nm has been demonstrated for gratings of 0.2 μm period. A high resolution imaging spectrometer, composed of a 22× Wolter x‐ray microscope in conjunction with a gold transmission grating, was tested. At a wavelength of 0.69 nm, a resolving power, λ/Δλ, of 200 was demonstrated. Resolution in this case was source‐size limited. Gratings of 99.5 nm period were exposed in PMMA by x‐ray (λ = 4.5 nm) spatial‐period‐division.

Fresnel zone plate patterns, free of spherical aberration, with diameters of up to 0.63 mm and linewidths as small as 1000 A were fabricated on polyimide membrane x‐ray masks using scanning electron beam lithography. Distortion of the electron beam scan raster was reduced to ?2500 A over a 2×2 mm field by applying deflection corrections, while viewing the distortion using a Moire method. CK x‐ray lithography was used to replicate the zone plate pattern in thick PMMA over a 100 A thick plating base on a glass substrate. Zones plates in 1.3 μm thick gold were fabricated by plating, and made free‐standing by removal of the plating base and the supporting glass substrate. Zone plates were tested as imaging elements with visible light and soft x‐rays.

Multilayered structures containing thin (1–12 nm) layers of W or Mo, alternating with C or Si, have been prepared to produce thin cross‐sectional specimens, and direct structural information on the atomic scale has been obtained using an ultrahigh resolution electron microscope. Layer thickness and flatness have been analyzed—the average layer thickness varies by up to 0.6 nm from the average value, and the flatness of the layers depends on the quality of the substrate surface. The degree of crystallinity and crystal orientation within the layers has also been examined. This information should enable more accurate theoretical models to be proposed for the multilayer materials and their x‐ray optical properties. The results for the Mo/Si multilayers suggest a model for their growth when prepared by sputtering.

We report the absolute conversion efficiency ξx from the incident laser light energy to x‐ray photons for laser‐produced plasmas. Potential x‐ray backlighting (radiography) line sources having photon energies from 1.4 to 8.6 keV are studied as a function of laser wavelength, pulsewidth, and intensity. The laser intensity and pulsewidth range from 1014 to 1016 W/cm2, 100 ps to 2 ns and include incident wavelengths of 1.06, 0.53, and 0.35 μm. We found that K‐shell x‐ray line emission ξx : (1) decreases with increasing x‐ray energy, (2) decreases with increasing laser intensity, (3) decreases rapidly with pulselength, and (4) moderately increases with decreasing laser wavelength. On the contrary, for Au M band emission, at a fixed laser intensity and pulsewidth, ξx significantly increases (∼25×) upon decreasing the laser wavelength from 1.06 to 0.35 μm.

Coded imaging techniques using thick, micro‐Fresnel zone plates as coded apertures have been used to image x‐ray emission (2–20 keV) and 3.5 MeV Alpha particle emissions from laser driven micro‐implosions. Image resolution in these experiments was 3–8 μm. Extension of this coded imaging capability to higher energy x rays (∠100 KeV) and more penetrating charged particles (e.g., ∠15 MeV protons) requires the fabrication of very thick (50–200 μm), high aspect ratio (10:1), gold Fresnel zone plates with narrow linewidths (5–25 μm) for use as coded apertures. A reactive ion etch technique in oxygen has been used to produce thick zone plate patterns in polymer films. The polymer patterns serve as electroplating molds for the subsequent fabrication of the free‐standing gold zone plate structures.

We report progress in the development of multilayer components for use in multiple pass soft x-ray laser cavities operating in the 100A to 300A spectral range. Our work includes fabrication and characterization of multilayer components; simple resonant cavity design; damage threshold assessment for multilayers in the x-ray laser environment; and multipass cavity experiments for efficiency enhancement and transverse mode selection. 14 refs., 9 figs.

We have measured the spatial extent of heliumlike and hydrogenlike argon x‐ray lines that were emitted from the fuel region of an imploded laser fusion target directly illuminated by the Argus laser. The diameter of the fuel region measured in this way agrees with that obtained from images of the thermonuclear burn region recorded simultaneously by an alpha‐particle zone plate camera. Time‐averaged electron temperatures in the target core were determined from argon line intensity ratios and compared to ion temperatures determined from measurements of neutron yield.

X -ray laser cavity experiments*N. M. Ceglio, D. P. Gaines, J. Trebes,A. M. Hawryluk, D. G. Stearns, G. L. HoweLawrence Livermore National Laboratory, University of CaliforniaP. O. Box 5508, L -473, Livermore, California 94550AbstractWe report progress toward the development of multipass, soft x -ray laser cavitiesoperating in a spectral range around 200 A. Experimental results on the characteri-zation of normal incidence multilayer mirrors, the survival of multilayer mirrors in thehostile x -ray laser environment, and the performance of double pass cavities at 206 A to209 A are presented.IntroductionThere are a number of strong motivations for x -ray laser cavity development: enhance-ment of laser output efficiency, correction of refractive effects associated with inhomo-geneities in the gain medium, and improvement of the spatial coherence of the output

Publisher Summary This chapter discusses the theory and applications of zone plate coded imaging and presents comprehensive mathematical framework for a specific coded imaging (CI) technique, zone plate coded imaging (ZPCI), in which the coded aperture is a Fresnel zone plate and the image decoding method is coherent optical reconstruction. The chapter also discusses the applications of zone plate coded imaging in laser fusion experiments. As coded apertures offer a significant improvement in radiation collection over pinhole optics of equivalent resolution, and as laser fusion targets are small, ZPCI is particularly well-suited for imaging low level x-ray and particle emissions from these experiments. In addition, a compilation of ZPCI data is presented in the chapter, including 3.5 MeV alpha particle images of the region of thermonuclear burn and multispectral x-rays images covering the spectral range from 3–30 keV.

Significant progress toward the goal of producing high Power, high coherence x-ray lasers has been made. Lasing at wavelengths as low as 66 A has been achieved in a nickel like laser scheme which is scalable to sub-44 A wavelengths. In addition, x-ray laser cavities, x-ray holography, and an applications beamline have been demonstrated.

We have fabricated and tested transmissin diffraction gratings with spatial periods of 0.2 and 0.3 μm and gold thicknesses of 0.25 and 0.65 μm respectively. The fabrication process included holographic lithography, ion milling, x‐ray lithography and gold and gold microplating. The gratings were coupled to a Wolter‐type 22x grazing incidence microscope, forming a high resolution imaging spectrometer. This spectrometer demonstrated a spatial resolution of ∼1 μm and a resolving power, λ/Δλ, ≳200 at .69 nm. The observed spectral resolution, Δλ, was source size limited.

Recent demonstrations of the generation of amplified spontaneous emission (ASE) at soft x-ray wavelengths have spurred interest in normal incidence multilayer structures for use as x-ray laser (XRL) cavity mirrors. Calculations indicate that cavity mirrors can provide significant enhancement of XRL output, and drive the oscillations to the saturation limit. Novel ideas for cavity output coupling may expand the versatility of XRL devices, while encouraging the marriage of lithographic and multilayer technologies to the general benefit of x-ray optics. Preliminary tests of a double pass cavity have already been conducted. These tests point out the importance of detailed cavity design issues, such as precision mirror alignment, mirror damage dynamics, and detailed mirror calibration to the future success of this field.

Recent advances in the development of lasers at soft x-ray wavelengths has spurred increasing interest in the production of cavity components using multilayer technology. We have established a comprehensive capability to design, fabricate, and characterize multilayer x-ray optics directed towards the goal of building the first x-ray laser cavity. High quality multilayer structures have been fabricated using magnetron sputtering. In addition, we have applied microfabrication technology to create freestanding beamsplitters and three-dimensional diffracting structures, as is discussed in another paper at this conference. The x-ray reflectivity and transmission of the multilayer components have been measured using synchrotron radiation. We have also characterized the microstructure of these devices using high-resolution transmission electron microscopy (TEM). This information provides structural parameters that are incorporated into computer codes to calculate the theoretical performance of the multilayer components. Comparison of the calculated reflectivity and transmission with the measured performance of the multilayer optics provides insight into the physics of these devices. In addition, a successful modeling capability allows us to iterate the fabrication cycle, modifying the design of the multilayer components to optimize their performance.

Data are presented from three different x-ray laser inversion schemes tested on the Novette laser facility at LLNL: collisional excitation of neon-like selenium (λ = 206, 209, 220A); resonant photoexcitation of hydrogen-like fluorine (λ = 81A); and recombination of hydrogen-like magnesium (λ = 130A). The data illustrate the measurement capabilities of a new, time resolved imaging spectrometer (TGSS-EM), and provide insight to the dynamics and emission characteristicts of a new class of laser produced plasmas.

Recent experiments conducted with the multi-terrawatt Novette laser have demonstrated substantial amplification of soft x rays in laser-produced plasmas. Gains at wavelengths of 206 and 209 A in neonlike selenium and at 153 A in neonlike yttrium have been observed.

Gold transmission gratings with 0.3 um spatial period, 0.6 μm thick have been fabricated, and are being used for the spectroscopy of high temperature, laser produced plasmas. A transmission grating has been coupled with a soft x-ray streak camera, producing the first time resolved (20 psec resolution) continuous x-ray spectrum over the range 0.1-1.5 keV from a laser produced plasma. In audition, a transmission grating has been coupled with a high resolution, Winter-design x-ray microscope to produce an imaging spectrometer of unprecedented spatial and spectral resolution. In laboratory experiments the imaging spectrometer demonstrated a spectral resolving power, λ of 200 and a spacial resolution of 1 μm.

A reflectometer has been set up at the radiometric laboratory of PTB at the Berlin electron storage ring BESSY. Special attention has been paid to optimize the instrumentation for the characterization of multilayer structures suitable for laboratory soft x-ray laser research. The instrumentation is described and its performance demonstrated showing examples of optical component characterization.

The development of a new time-resolved x-ray spectrometer is reported in which a free-standing x-ray transmission grating is coupled to a soft x-ray streak camera. The instrument measures continuous x-ray spectra with 20-psec temporal resolution and moderate spectral resolution (deltalambda/= 1 A) over a broad spectral range (0.1-5 keV) with high sensitivity and large information recording capacity. Its capabilities are well suited to investigation of laser-generated plasmas, and they nicely complement the characteristics of other time-resolved spectroscopic techniques presently in use. The transmission grating spectrometer has been used on a variety of laser-plasma experiments. We report the first measurements of the temporal variation of continuous low-energy x-ray spectra from laser-irradiated disk targets.

Two-dimensional modeling of magnesium exploding-foil experiments shows that spontaneous emission from regions outside of line focus makes the measurement of induced emission and gain difficult. An improved target design is proposed that solves the spontaneous-emission problem by replacing the foil by a ribbon. The new targets consist of an aluminum ribbon on a Formvar sheet with the potential 4–3 lasing line at lll A for H-like Al. We comment on what conditions are required for lasing in the 3–2 line of H-like Al at 39 A.

We have fabricated new, efficient x‐ray optical components (x‐ray mirrors, beamsplitters, and highly dispersive multilayer mirrors) and have used them to build an x‐ray laser cavity. With our laser cavity, we have demonstrated multipass amplification of soft x rays with significant enhancement (>20×) of the x‐ray laser emission. This is an important first step in the ultimate conversion of x‐ray amplifier media into true x‐ray lasers with optimized coherence and divergence properties. We used advanced microfabrication techniques to fabricate the key laser cavity components which require precise layering of alternating materials, thin‐film membrane technology, and precise patterning. The x‐ray laser requirements, fabrication details, and characterization results for these cavity components are discussed.

We describe the experiments and supporting theoretical modelling to develop and characterize soft x-ray lasers. The x-ray lasers are created in dense plasmas produced by optical laser irradiation of solid targets with line focussed beams. We use mainly thin foil targets, which upon appropriate illumination, produce rather uniform plasmas. We consider laser schemes pumped by electron collisional excitation and dielectronic recombination in Ne-like and Ni-like ions, and schemes pumped by collisional and radiative recombination following rapid cooling for H-like and Li-like ions.Experimental measurements of the time and space resolved spectra taken both along the lasing axis and at other viewing angles, in addition to data on the angular pattern of x-ray laser radiation and on the absorption and scattering of the optical laser light are presented. These data allow us the determine the characteristics of the plasmas which have been created, as well as the properties of the x-ray lasers, such as the gain coefficients for the inverted transitions, and their spatial and temporal distributions. The modelling includes calculations of the absorption of the optical laser light, the hearing and hydrodynamics of the targets and the evolution of the atomic level populations within the plasma. Transfer of the emitted radiation is calculated, including resonance line trapping, amplification for inverted transitions, and refraction of the x-ray laser beam due to electron density gradients. Results are used to optimize x-ray laser designs before the experiments and to interpret the measured spectra.The latest experimental results from the NOVA laser facility on the performance of several laser schemes and on the use of multilayer mirrors to produce x-ray laser cavities are reported. These results arc compared to the models to test and improve our understanding of the complex physics involved in making x-ray lasers. Based on current experiments, we show how the modelling can be use to design shorter wavelength and more efficient schemes for use in applications such as x-ray holography.

Zone‐plate coded imaging techniques are routinely used to image nonpenetrating emissions from laser fusion targets. Only highly penetrating radiations like 14‐MeV neutrons will escape the dense compressed core region of future targets to provide information about the burn region. A zone plate for 14‐MeV neutrons must be several centimeters thick to produce adequate modulation in the coded image. Computer modeling of zone‐plate systems show that a thick, tapered zone plate acts like a thin zone plate for points within its field of view and depth of field. Equations developed for thin zone‐plate systems that describe quantities such as planar and tomographic resolution may be applied to thick zone‐plate systems. System simulations of a 100‐zone, 5‐cm‐thick zone plate with 5‐μm outer zone width constructed of alternating layers of gold and aluminum produce images with 10‐μm resolution. The source strength required to image a 20‐μm‐diam source is 100 to 1000 times less than that needed with an equivalent pinh...

We report the first time-resolved measurements of emission from a double-pass soft x-ray laser cavity. In these experiments the output signal from a selenium x-ray laser had two temporal components clearly identifiable as the single- and double-pass emission, with the double-pass amplified signal more intense than the single pass. In addition to an unequivocal demonstration of double-pass amplification of soft x rays, the data provide information about of the time-dependent gain in these x-ray laser media, suggesting an effective gain-length profile which rises more slowly and falls-off more rapidly than predicted by state of the art hydrodynamics and kinetics codes.

We report the first demonstration of the fabrication and characterization of soft x‐ray reflecting masks suitable for x‐ray projection lithography. We have patterned efficient (R>50%) normal‐incidence x‐ray mirrors to produce reflecting masks with measured x‐ray contrasts>500:1 over a sufficiently wide spectral range. Calculations indicate that masks on silicon substrates are thermally stable for a production‐type lithographic facility.

Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors. Copyright © 2018 by the American Society of Nephrology Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP,130/80 in patients with moderate or severe albuminuria and diabetes or other cardiovascular risk factors. End points included a primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for cardiovascular causes and a revised end point of all-cause mortality. Additional end points included ESRD, doubling of serum creatinine, albuminuria, eGFR, BP, and adverse events. Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

Water distribution networks (WDNs) are among the most important civil networks, because they deliver drinking and industrial water to metropolitan areas, supporting economic prosperity and quality of life. Therefore, they constitute critical infrastructures (CIs) as systems whose operability are of crucial importance to ensure social survival and welfare. In the last years, extreme natural events and intentional malicious attacks have shown that global safeguard of systems cannot be ever performed. In this regard, critical infrastructure protection (CIP) strategies should be focused both on the prevention of these events and on the procedures for the functioning recovery and damage limitation. In this paper, starting from previous works of the authors, the impact of an intentional contamination attack to water distribution network and a possible strategy to mitigate the user risk have been studied, simulating the introduction of potassium cyanide with a backflow attack into water system. As protection technique, the water network partitioning (WNP) has been adopted in order to improve the management and also to reduce the extent of damage showing a dual use-value. WNP reveals to be an efficient way to protect water networks from malicious contamination, through the closure of gate valves by a remote control system creating semi-independent District Meter Areas (DMAs). The study also investigates the possibility to identify a priori the most critical point of a water distribution network for the malicious attack through a novel procedure based on topological metric. The methodology, tested on a real medium size water network in Italy, shows very interesting results in terms of mitigation risk.