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Introduction: To determine the publication rate of registered clinical trials evaluating therapeutic approaches for diabetic macular edema (DME). Methods: Using the search terms “Diabetic Macular Edema,” the National Institute of Health’s ClinicalTrials.gov online registry was searched to identify all clinical trials concerning DME. Non-interventional trials, terminated trials, trials not concerning DME, and those not completed between 2005 and 2015 were excluded. Publication status of each trial was determined using searches of the study title, keywords, author(s), and NCT number on PubMed.gov and Google Scholar. Results: A total of two hundred and forty-seven studies were identified in the primary analysis. Of the 97 trials meeting inclusion criteria, 60 (61.9%) were published. Late-phase trials were published at higher rate (74.5% [35/47]) than early phase trials (50% [25/50]) (p = 0.01). Trial location, date of completion, and industry involvement did not significantly affect the publication rate. Conclusion: Of the registered trials listed in the ClinicalTrials.gov registry investigating DME, 61.9% were published.

Virtual prototyping in engineering design rely on modern numerical models of contacting structures with accurate resolution of interface mechanics, which strongly affect the system-level stiffness and energy dissipation due to frictional losses. High-fidelity modeling within the localized interfaces is required to resolve local quantities of interest that may drive design decisions. The high-resolution finite element meshes necessary to resolve inter-component stresses tend to be computationally expensive, particularly when the analyst is interested in response time histories. The Hurty/Craig-Bampton (HCB) transformation is a widely used method in structural dynamics for reducing the interior portion of a finite element model while having the ability to retain all nonlinear contact degrees of freedom (DOF) in physical coordinates. These models may still require many DOF to adequately resolve the kinematics of the interface, leading to inadequate reduction and computational savings. This study proposes a novel interface reduction method to overcome these challenges by means of system-level characteristic constraint (SCC) modes and properly orthogonal interface modal derivatives (POIMDs) for transient dynamic analyses. Both SCC modes and POIMDs are computed using the reduced HCB mass and stiffness matrices, which can be directly computed from many commercial finite element analysis software. Comparison of time history responses to an impulse-type load in a mechanical beam assembly indicate that the interface-reduced model correlates well with the HCB truth model. Localized features like slip and contact area are well-represented in the time domain when the beam assembly is loaded with a broadband excitation. The proposed method also yields reduced-order models with greater critical timestep lengths for explicit integration schemes.

Modeling of the seismic isolation system plays a key role in simulating the seismic response of base isolated nuclear power plants (NPP), including estimation of peak isolator displacement and potential to exceed the clearance to stop. Under beyond design basis shaking, seismic isolators such as lead rubber bearings (LRB) may undergo large displacements and exhibit complex behavior including cyclic heating causing strength degradation of the lead and strain hardening in the rubber at large strains. Displacement demands on the isolation system can be limited by a stop such as a moat wall to prevent bearing failure, with the impact to the moat having potential to increase the transfer of forces to the superstructure. Towards a more accurate seismic assessment of NPP subjected to beyond design basis shaking, a model of a seismically isolated NPP is developed with advanced modeling capabilities for LRB isolators and simulation of moat wall impact. The bearing models capture the cyclic behavior of LRB as observed in measured experimental data from full-scale bearings designed for NPP applications. The moat wall model considers a concrete retaining wall with backfill soil and contact elements developed based on experimental data and high-fidelity Finite Element Method (FEM) simulations. The simulation tools are used to evaluate the consequences of bearing modelling and impact to moat walls on the seismic performance of NPP and further develop effective mitigation measures for the seismic protection of NPP. As a result of the studies presented here, a simplified design methodology to estimate impact response parameters including moat wall deformation due to impact, impact velocities, and forces is proposed.

Contact in structures with mechanical interfaces has the ability to significantly influence the system dynamics, such that the energy dissipation and resonant frequencies vary as a function of the response amplitude. Finite element analysis is commonly used to study the physics of such problems, particularly when examining the local behavior at the interfaces. These high fidelity, nonlinear models are computationally expensive to run with time-stepping solvers due to their large mesh densities at the interface, and because of the high expense required to update the tangent operators. Hurty/Craig-Bampton substructuring and interface reduction techniques are commonly utilized to reduce computation time for jointed structures. In the past, these methods have only been applied to substructures rigidly attached to one another, resulting in a linear model. The present work explores the performance of a particular interface reduction technique (system-level characteristic constraint modes) on a nonlinear model with node-to-node contact for a benchmark structure consisting of two c-shape beams bolted together at each end.

Change in organizations can be frequent, but change is not always necessary. In pursuit of innovation, and at times their own agenda, leaders who exhibit a pseudotransformational leadership style can have a catastrophic effect on the workplace. Promoting change under the guise of innovation benefits self and not the organization and sponsors a workplace in turmoil. These leaders practice organizational laundering, which is proposed as an introductory term resulting from employing a combination of destructive and pseudotransformational leadership styles in an attempt to be innovative and make organizational change.

Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.

The effect of lyophilization on the physical characteristics of two different molecular mass hyaluronates (164 and 741 kDa) has been evaluated using dynamic oscillatory viscometry and size exclusion chromatography. The hyaluronates were prepared as either the free acid or the sodium salt. The reological and SEC profiles of sodium hyaluronate were not affected by lyophilization. In contrast, the complex viscosity and related dynamic moduli were markedly decreased after lyophilization of the hyaluronates in the free acid form. Size exclusion chromatography indicated a reduction in molecular mass of these samples. These data indicate that lyophilization of hyaluronates as the free acid, as opposed to a sodium salt form, can have a detrimental effect on their physical characteristics.

The Microlithographic Mask Development Center (MMD) has been the focal point of X-ray mask development efforts in the United States since its inception in 1993. Funded by the Advanced Research Projects Agency (ARPA), and with technical support from the Proximity X-ray Lithography Association (AT&T, IBM, Loral Federal Systems, and Motorola) the MMD has recently made dramatic advances in mask fabrication. Numerous defect-free 64Mb and 256Mb DRAM masks have been made on both boron-doped silicon and silicon carbide substrates. Image-placement error of less than 35nm 3 sigma is achieved with high yield. Image-size (critical dimension) control of 25nm 3 sigma on 250nm nominal images is representative performance. This progress is being made in a manufacturing environment with significant volumes, multiple customers, multiple substrate configurations, and fast turnaround-time (TAT) requirements. The MMD state-of-the-art equipment infrastructure has made much of this progress possible. This year the MMD qualified the EL-4, an IBM-designed-and-built variable-shaped-spot e-beam system. The fundamental performance parameters of this system will be described. Operational techniques of multiple partial exposure writing and product specific emulation (PSE) have been implemented to improve image-placement accuracy with remarkable success. Image-size control was studied in detail with contributory components separated. Defect density was systematically reduced to yield defect-free masks while simultaneously tightening inspection criteria. Information about these and other recent engineering highlights will be reported. An outline of the primary engineering challenges and goals for 1996 and status of progress toward 100 nm design rule capability will also be given.

The Microlithographic Mask Development Center (MMD) was established as the X-ray mask manufacturing facility at the IBM Microelectronics Division semiconductor fabricator in Essex Junction, Vermont. This center, in operation for over two years, produces high yielding, defect-free X-ray masks for competitive logic and memory products at 250nm groundrules and below. The MMD is a complete mask facility that manufactures silicon membrane mask blanks in the NIST format and finished masks with electroplated gold X-ray absorber. Mask patterning, with dimensions as small as 180 nm, is accomplished using IBM-built variable shaped spot e-beam systems. Masks are routinely inspected and repaired using state-of-the-art equipment: two KLA SEM Specs for defect inspection, a Leica LMS 2000 for image placement characterization, an Amray 2040c for image dimension characterization and a Micrion 8000 XMR for defect repair. This facility maintains a baseline mask process with daily production of 250nm, 32Mb SRAM line monitor masks for the continuous improvement of mask quality and processes. Development masks are produced for several semiconductor manufacturers including IBM, Motorola, Loral, and Sanders. Masks for 64Mb and 256Mb DRAM (IBM) and advanced logic/SRAM (IBM and Motorola) designs have also been delivered. This paper describes the MMD facility and its technical capabilities. Key manufacturing metrics such as mask turnaround time, parametric yield learning and defect reduction activities are highlighted. The challenges associated with improved mask quality, sub-180nm mask fabrication, and the transition to refractory metal absorber are discussed.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We evaluated the utility of medium molecular weight hyaluronic acid for prolonging the local anesthetic activity of lidocaine in a rabbit model of epidural analgesia. Equiviscous formulations were prepared as either a physical mixture of lidocaine hydrochloride and sodium hyaluronate (where drug release occurred via diffusion) or as a lidocaine-hyaluronate complex (where drug release occurred via diffusional and electrostatic processes). The novel hyaluronic acid formulations were functionally evaluated, relative to lidocaine solution, in an intact, conscious rabbit model. The hyaluronate formulations were well tolerated. The duration of sensory block and loss of weight-bearing was prolonged twofold by the lidocaine-hyaluronate complex relative to the solution (P < 0.05). In terms of motor block, flaccid paresis occurred after administration of the solution formulation, whereas only partial motor block was evident after administration of the viscous formulations. Pharmacokinetic modeling of the lidocaine plasma concentration-time data indicated that the rate of drug absorption from the lidocaine-hyaluronate complex was decreased fourfold relative to the solution (P < 0.05). These observations indicate that ionic complexes of local anesthetics with medium molecular weight hyaluronic acid may offer advantages for the prolongation of epidural analgesia.

In order to compare the effects of acute and chronic beta-blockade on infact size, the left circumflex coronary artery was occluded for 6 hours in 33 anesthetized dogs. The dogs (18 to 22 kg) were divided into three groups; group 1 (N = 10) served as controls, group 2 received intravenous nadolol (average dose 1.25 mg/kg) just prior to coronary occlusion, and group 3 received oral nadolol (80 mg) twice daily for 16 days prior to coronary occlusion. To ensure equivalent degrees of beta-blockade at the time of occlusion, group 2 and 3 dogs were given incremental doses of intravenous nadolol to abolish the chronotropic response to isoproterenol (2 mu/kg IV). Left ventricular pressure, its first derivative (dP/dt), and heart rate were monitored. The anatomic risk region was determined antemortem by Evan's blue staining while the infarct zone was delineated postmortem by tetrazolium staining. Compared to Group 1, heart rate was 22% lower in group 2 and 15% lower in group 3 dogs 6 hours after occlusion (p less than 0.05). There were no differences among groups in peak left ventricular systolic pressure or mean arterial pressure. Infarct size as a function of the area at risk was 68 +/- 3% in group 1, 52 +/- 7% in group 2, and 44 +/- 8% in group 3. A significant difference was found only between groups 3 and 1. The data suggest that chronic beta-blockade provides greater protection against ischemic-induced necrosis than does acute beta-blockade. The greater protective effect of chronic beta-blockade may be due to chronic adaptive changes in either blood flow or metabolism.