A robust enhancement to the Clarke-Wright savings algorithm

We address the Clarke and Wright (CW) savings algorithm proposed for the Capacitated Vehicle Routing Problem (CVRP). We first consider a recent enhancement which uses the put first larger items idea originally proposed for the bin packing problem and show that the conflicting idea of putting smaller items first has a comparable performance. Next, we propose a robust enhancement to the CW savings formulation. The proposed formulation is normalized to efficiently solve different problems, independent from the measurement units and parameter intervals. To test the performance of the proposed savings function, we conduct an extensive computational study on a large set of well-known instances from the literature. Our results show that the proposed savings function provides shorter distances in the majority of the instances and the average performance is significantly better than previously presented enhancements

Integrative Assessment of Mitigation, Impacts, and Adaptation to Climate Change

This volume presents the proceedings of the second international workshop held at IIASA in October 1993 assessing the current state of integrated assessments. Numerous models and less formalized approaches analyze anthropogenic sources of greenhouse gas emissions, their concentrations in the atmosphere, the resulting climate forcing, impacts of the induced climate change on the economy and other human activities, as well as possible mitigation and adaptation strategies. Studies that include all or several of these salient aspects of the climate change problematique are known as integrative assessments. The number of such studies is increasing, highlighting the need for consistent analytic frameworks and comparative analyses. This volume reviews the current practice of integrative assessments, directions for improvement and further research, and implications for climate change policies. The workshop covered issues such as the role of science, integrated assessment, impacts and benefits, mitigation and adaptation, intergenerational assessments, and the role of technology. The volume includes the original papers presented at the workshop

Costs, Impacts, and Benefits of CO2 Mitigation

This volume presents the proceedings of the first international workshop on "Costs, Impacts, and Possible Benefits of CO2 Mitigation" held at IIASA in October 1992. The workshop was co-organized by the Japanese Central Research Institute of the Electric Power Industry (CRIEPI), IIASA, the National Science Foundation (NSF), Yale University, and the Intergovernmental Panel on Climate Change (IPCC). The workshop was held to review current research and analysis of economic costs and possible benefits of measures for responding to global climate change, and to critically evaluate knowledge gaps and future research activities. Technological and economic measures for achieving environmentally compatible development have been and continue to be studied. There are a few studies on the comparative assessment of mitigation and adaptation costs, and the potential benefits of these measures. Since these are long-term issues ranging into the next century, their assessment also requires a degree of understanding of possible development paths the world may take in the absence of global warming. The workshop covered the economics of climate change, its impacts, mitigation costs, policy instruments, and modeling issues. This volume summarizes these proceedings and presents the papers from the workshop

Effective Doses of Recombinant Human Bone Morphogenetic Protein-2 in Experimental Spinal Fusion

Study Design Nineteen dogs underwent L4-L5 intertransverse process fusions with either 58 μg, 115 μg, 230 μg, 460 μg, or 920 μg of recombinant human bone morphogenetic protein-2 carried by a polylactic acid polymer. A previous study (12 dogs) compared 2300 μg of recombinant human bone morphogenetic protein-2, autogenous iliac bone, and carrier alone in this model. All fusions subsequently were compared. Objectives To characterize the dose-response relationship of recombinant human bone morphogenetic protein-2 in a spinal fusion model. Summary of Background Data Recombinant osteoinductive morphogens, such as recombinant human bone morphogenetic protein-2, are effective in vertebrate diaphyseal defect and spinal fusion models. It is hypothesized that the quality of spinal fusion produced with recombinant human bone morphogenetic protein-2, above a threshold dose, does not change with increasing amounts of inductive protein. Methods After decortication of the posterior elements, the designated implants were placed along the intertransverse process space bilaterally. The fusion sites were evaluated after 3 months by computed tomography imaging, high-resolution radiography, manual testing, mechanical testing, and histologic analysis. Results As in the study using 2300 μg of recombinant human bone morphogenetic protein-2, implantation of 58–920 μg of recombinant human bone morphogenetic protein-2 successfully resulted in intertransverse process fusion in the dog by 3 months. This had not occurred in animals containing autograft or carrier alone. The cross-sectional area of the fusion mass and mechanical stiffness of the L4-L5 intersegment were not dose-dependent. Histologic findings varied but were not related to rhBMP-2 dose. Inflammatory reaction to the composite implant was proportional inversely to the volume of the fusion mass. Conclusions No mechanical, radiographic, or histologic differences in the quality of intertransverse process fusion resulted from a 40-fold variation in dose of recombinant human bone morphogenetic protein-2

Dense Packings of Congruent Circles in Rectangles with a Variable Aspect Ratio

We use computational experiments to find the rectangles of minimum area into which a given number n of non-overlapping congruent circles can be packed. No assumption is made on the shape of the rectangles. Most of the packings found have the usual regular square or hexagonal pattern. However, for 1495 values of n in the tested range n =< 5000, specifically, for n = 49, 61, 79, 97, 107,... 4999, we prove that the optimum cannot possibly be achieved by such regular arrangements. The evidence suggests that the limiting height-to-width ratio of rectangles containing an optimal hexagonal packing of circles tends to 2-sqrt(3) as n tends to infinity, if the limit exists.Comment: 21 pages, 13 figure

L^{2}-restriction bounds for eigenfunctions along curves in the quantum completely integrable case

We show that for a quantum completely integrable system in two dimensions,the $L^{2}$-normalized joint eigenfunctions of the commuting semiclassical pseudodifferential operators satisfy restriction bounds ofthe form $\int_{\gamma} |\phi_{j}^{\hbar}|^2 ds = {\mathcal O}(|\log \hbar|)$ for generic curves $\gamma$ on the surface. We also prove that the maximal restriction bounds of Burq-Gerard-Tzvetkov are always attained for certain exceptional subsequences of eigenfunctions.Comment: Correct some typos and added some more detail in section

The Use of Recombinant Human Bone Morphogenetic Protein 2 (rhBMP-2) to Promote Spinal Fusion in a Nonhuman Primate Anterior Interbody Fusion Model

Study Design. A study on the efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in a nonhuman primate anterior interbody fusion model. Objectives. To investigate the efficacy of rhBMP-2 with an absorbable collagen sponge carrier to promote spinal fusion in a nonhuman primate anterior interbody fusion model. Summary of Background Data. RhBMP-2 is an osteoinductive growth factor capable of inducing new bone formation in vivo. Although dosage studies using rhBMP-2 have been performed on species of lower phylogenetic level, they cannot be extrapolated to the primate. Dosage studies on nonhuman primates are essential before proceeding with human primate application. Methods. Six female adult Macaca mulatta (rhesus macaque) monkeys underwent an anterior L7-S1 interbody lumbar fusion. All six sites were assigned randomly to one of two fusion methods: 1) autogenous bone graft within a single freeze-dried smooth cortical dowel allograft cylinder (control) or 2) rhBMP-2-soaked absorbable collagen sponges within a single freeze-dried smooth cortical dowel allograft cylinder also soaked in rhBMP-2. The animals underwent a baseline computed tomography scan followed by 3- and 6-month postoperation scans. Anteroposterior and lateral radiographs of the lumbosacral spine were performed monthly. After the monkeys were killed, the lumbar spine fusionsites were evaluated. Histologic evaluation of all fusion sites was performed. Results. The three monkeys receiving rhBMP-2-soaked collagen sponges with a freeze-dried allograft demonstrated radiographic signs of fusion as early as 8 weeks. The control animals were slower to reveal new bone formation. The computed tomography scans revealed extensive fusion of the L7-S1 lumbar vertebrae in the group with rhBMP-2. A pseudarthrosis was present in two of the control animals. Conclusions. This study was able to document the efficacy of rhBMP-2 with an absorbable collagen sponge carrier and a cortical dowel allograft to promote anterior interbody fusion in a nonhuman primate model at a dose of 0.4 mg per implant site (1.5 mg/mL concentration). The rate of new bone formation and fusion with the use of rhBMP-2 and cortical dowel allograft appears to be far superior to that of autogenous cancellous iliac crest graft with cortical dowel allograft

Opioids Delay Healing of Spinal Fusion: A Rabbit Posterolateral Lumbar Fusion Model

Background Context Opioid use is prevalent in the management of pre- and postoperative pain in patients undergoing spinal fusion. There is evidence that opioids downregulate osteoblasts in vitro, and a previous study found that morphine delays the maturation and remodeling of callus in a rat femur fracture model. However, the effect of opioids on healing of spinal fusion has not been investigated before. Isolating the effect of opioid exposure in humans would be limited by the numerous confounding factors that affect fusion healing. Therefore, we have used a well-established rabbit model to study the process of spinal fusion healing that closely mimics humans. Purpose The objective of this work was to study the effect of systemic opioids on the process of healing of spinal fusion in a rabbit posterolateral spinal fusion model. Study Design/Setting This is a preclinical animal study. Materials and Methods Twenty-four adult New Zealand white rabbits were studied in two groups after approval from the Institutional Animal Care and Use Committee (IACUC). The opioid group (n=12) received 4 weeks\u27 preoperative and 6 weeks\u27 postoperative transdermal fentanyl. Serum fentanyl levels were measured just before surgery and 4 weeks postoperatively to ensure adequate levels. The control group (n=12) received only perioperative pain control as necessary. All animals underwent a bilateral L5–L6 posterolateral spinal fusion using iliac crest autograft. Animals were euthanized at the 6-week postoperative time point, and assessment of fusion was done by manual palpation, plain radiographs, microcomputed tomography (microCT), and histology. Results Twelve animals in the control group and 11 animals in the opioid group were available for analysis at the end of 6 weeks. The fusion scores on manual palpation, radiographs, and microCT were not statistically different. Three-dimensional microCT morphometry found that the fusion mass in the opioid group had a lower bone volume (p=.09), a lower trabecular number (p=.02), and a higher trabecular separation (p=.02) compared with the control group. Histologic analysis found areas of incorporation of autograft and unincorporated graft fragments in both groups. In the control group, there was remodeling of de novo woven bone to lamellar organization with incorporation of osteocytes, formation of mature marrow, and relative paucity of hypertrophied osteoblasts lining new bone. Sections from the opioid group showed formation of de novo woven bone, and hypertrophied osteoblasts were seen lining the new bone. There were no sections showing lamellar organization and development of mature marrow elements in the opioid group. Less dense trabeculae on microCT correlated with histologic findings of relatively immature fusion mass in the opioid group. Conclusions Systemic opioids led to an inferior quality fusion mass with delay in maturation and remodeling at 6 weeks in this rabbit spinal fusion model. These preliminary results lay the foundation for further research to investigate underlying cellular mechanisms, the temporal fusion process, and the dose-duration relationship of opioids responsible for our findings

A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation

Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients' lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICO