Solving DCOPs with Distributed Large Neighborhood Search

The field of Distributed Constraint Optimization has gained momentum in recent years, thanks to its ability to address various applications related to multi-agent cooperation. Nevertheless, solving Distributed Constraint Optimization Problems (DCOPs) optimally is NP-hard. Therefore, in large-scale, complex applications, incomplete DCOP algorithms are necessary. Current incomplete DCOP algorithms suffer of one or more of the following limitations: they (a) find local minima without providing quality guarantees; (b) provide loose quality assessment; or (c) are unable to benefit from the structure of the problem, such as domain-dependent knowledge and hard constraints. Therefore, capitalizing on strategies from the centralized constraint solving community, we propose a Distributed Large Neighborhood Search (D-LNS) framework to solve DCOPs. The proposed framework (with its novel repair phase) provides guarantees on solution quality, refining upper and lower bounds during the iterative process, and can exploit domain-dependent structures. Our experimental results show that D-LNS outperforms other incomplete DCOP algorithms on both structured and unstructured problem instances

Cost-utility analysis of opportunistic and systematic diabetic retinopathy screening strategies from the perspective of the Brazilian Public Healthcare System

Objective: To perform a cost-utility analysis of diabetic retinopathy (DR) screening strategies from the perspective of the Brazilian Public Healthcare System. Methods: A model-based economic evaluation was performed to estimate the incremental costs per quality-adjusted life-year (QALY) gained between three DR screening strategies: (1) the opportunistic ophthalmology referral-based (usual practice), (2) the systematic ophthalmology referral-based, and (3) the systematic teleophthalmology-based. The target population included individuals with type 2 diabetes (T2D) aged 40 years, without retinopathy, followed over a 40-year time horizon. A Markov model was developed with five health states and a 1-year cycle. Model parameters were based on literature and country databases. One-way and probabilistic sensitivity analyses were performed to assess model parameters’ uncertainty. WHO willingness-to-pay (WHO-WTP) thresholds were used as reference (i.e. one and three times the Brazilian per capita Gross Domestic Product of R$32747 in 2018). Results: Compared to usual practice, the systematic teleophthalmology-based screening was associated with an incremental cost of R$21445/QALY gained ($9792/QALY gained). The systematic ophthalmology referral-based screening was more expensive (incremental costs = R$4) and less effective (incremental QALY = −0.012) compared to the systematic teleophthalmology-based screening. The probability of systematic teleophthalmology-based screening being cost-effective compared to usual practice was 0.46 and 0.67 at the minimum and the maximum WHO-WTP thresholds, respectively. Conclusion: Systematic teleophthalmology-based DR screening for the Brazilian population with T2D would be considered very cost effective compared to the opportunistic ophthalmology referral-based screening according to the WHO-WTP threshold. However, there is still a considerable amount of uncertainty around the results

Compara??o do efeito do plasma rico em plaquetas e fibrina rica em plaquetas no reparo do tend?o de Aquiles em ratos

Made available in DSpace on 2015-04-14T13:35:30Z (GMT). No. of bitstreams: 1 438171.pdf: 6920524 bytes, checksum: f5e5c6d7e177dfd60f3b3303552cc797 (MD5) Previous issue date: 2012-03-28OBJECTIVE : To evaluate and compare the effect of using Platelet-Rich Plasma (PRP) and Platelet-Rich Fibrin (PRF) in the repair of the Achilles tendon (TA) of rats. MATERIAL and METHODS : Forty-eight adult male rats randomized into three experimental groups: PRP, PRF and Control (saline 0.9%). A 3 cm longitudinal incision was made in the right leg of each rat in order to expose the TA. Later, it was a break in the same horizontal, and the repair performed with suture Kessler-type, when the sequence was applied 50 &#956;L of the treatment in question. After 14 and 28 days postoperatively, the targeted part of the TA was removed, thus initializing the histological processing (Hematoxylin/Eosin; Sirius Red) to obtain results. The data obtained were expressed at 5% significance level (p <0.05) with mean ? SE. RESULTS : When comparing the three groups together, as to time and area of collagen type I and III, only statistical difference between the control group (16.22%) and the PRP group (37.16%) at 14 days after the treatment, no statistically significant difference was observed in the other groups. In the same way, when compared within groups of 14 and 28 days, the PRF group showed a significant difference for collagen I (27.76% and 47.74%) and III (66.94% and 46%) respectively. Control group showed significant difference in collagen type I (14.20% and 40.90%), not observed any significant difference in the PRP group. When evaluated on Hematoxylin/Eosin staining, PRP and control were similar in the times studied, differing only in the presence of hemorrhage, that was more expressed in the PRP group. Already the group PRF has shown to be more organized, especially in time of 28 days compared to the other two treatments. CONCLUSION : The data from this study suggest that the Platelet-Rich Fibrin tends to promote the accelerated regeneration of the Achilles tendon of rats, bringing promising prospects for future use in the clinic.OBJETIVO : Avaliar e comparar o efeito do uso de plasma rico em plaquetas (PRP) e fibrina rica em plaquetas (PRF) no reparo do tend?o de Aquiles (TA) de ratos. MATERIAL e M?TODOS : Foram utilizados 48 ratos machos adultos distribu?dos randomicamente em tr?s grupos experimentais: PRP, PRF e Controle (solu??o salina 0,9%). Uma incis?o longitudinal de 3 cm foi realizada na perna direita de cada rato, a fim de expor o TA. Posteriormente, fez-se uma ruptura horizontal no mesmo, sendo a repara??o realizada com sutura do tipo Kessler, onde na seq??ncia foi aplicado 50 &#956;L do tratamento em quest?o. Passados 14 e 28 dias p?s- operat?rio, a parte segmentada do TA foi removida, inicializando assim o processo histol?gico (Hematoxilina/Eosina; Picros?rius Red) para obten??o de resultados. Os dados obtidos foram expressos ao n?vel de 5% de signific?ncia (p < 0.05) com m?dia ? EP. RESULTADOS : Ao comparar os tr?s grupos entre si, quanto ao tempo e ?rea de col?geno tipo I e III, houve diferen?a estat?stica somente entre o grupo Controle (16.22%) e o grupo PRP (37.16%) aos 14 dias ap?s o tratamento, n?o sendo observada diferen?a estatisticamente significativa nos outros grupos. Da mesma forma, quando comparados intra-grupos em 14 e 28 dias, o grupo PRF apresentou diferen?a significativa para col?geno I (27.76% e 47.74%) e III (66.94% e 46%) respectivamente. Grupo Controle demonstrou diferen?a significativa para col?geno tipo I (14.20% e 40.90%), n?o sendo observada qualquer diferen?a significativa no grupo PRP. Quando avaliados na colora??o Hematoxilina e Eosina, PRP e Controle apresentaram-se semelhantes nos tempos avaliados, diferindo apenas quanto a presen?a de hemorragia, que foi mais expressa no grupo PRP. J? o grupo PRF demonstrou-se mais organizado, principalmente no tempo de 28 dias quando comparado aos outros dois tratamentos. CONCLUS?O : Os dados obtidos neste trabalho sugerem que a Fibrina Rica em Plaquetas tem tend?ncia a promover a regenera??o acelerada do tend?o de Aquiles de ratos, trazendo perspectivas promissoras para futuras utiliza??es na cl?nica

Efeito do plasma rico em plaquetas no reparo do tend?o de aquiles em ratos

Submitted by PPG Medicina e Ci?ncias da Sa?de ([email protected]) on 2017-11-23T10:48:18Z No. of bitstreams: 1 FRANCIELE_DIETRICH_TES.pdf: 3499792 bytes, checksum: c6cf1d1c8ad84ed3af5c5b4a075c3eb9 (MD5)Approved for entry into archive by Caroline Xavier ([email protected]) on 2017-12-01T11:50:39Z (GMT) No. of bitstreams: 1 FRANCIELE_DIETRICH_TES.pdf: 3499792 bytes, checksum: c6cf1d1c8ad84ed3af5c5b4a075c3eb9 (MD5)Made available in DSpace on 2017-12-01T11:54:10Z (GMT). No. of bitstreams: 1 FRANCIELE_DIETRICH_TES.pdf: 3499792 bytes, checksum: c6cf1d1c8ad84ed3af5c5b4a075c3eb9 (MD5) Previous issue date: 2017-07-26Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESThe increasing incidence of tendon injuries is a constant challenge in orthopaedic medicine. The use of platelet-rich plasma (PRP) is a strategy widely explored in the clinic because it is believed to accelerate the tendon repair process. However, the PRP clinical efficacy is uncertain, and more studies that aim to a better understanding of this treatment are needed. The aim of this research was to evaluate the PRP effect on the Achilles tendon (AT) repair of rats. A total of 242 rats were used, where 181 animals were randomly distributed in 6 different experiments. The remaining animals were used as blood donors (n=49) and for flow cytometry (n=12). The lesion was performed by transection of the right AT. The repair evaluation occurred after 11 and 14 postoperative days, with a mechanical testing machine. Peak force was considered the primary variable. Variations in the PRP production protocols, leukocyte concentration and physical activity of the rats were tested. ELISA test was performed to quantify platelet-derived growth factor (PDGF-AB) present in PRP. Pathogenfree animals and animals contaminated with Staphylococcus aureus (S. aureus) were used. Standard PRP platelet concentration was at least 5 times higher than that of the peripheral blood, and it was possible to have either a high or a low leukocyte concentration in the preparation. PDGF-AB levels in inactivated PRP were 7.3 ?g/mL (SD 6.0; n=4) and in plasma were below the detection levels (0.03 ng/mL). In the experiments performed with pathogen-free rats, no significant effect of PRP could be observed on tendon repair. In the same way, no significant difference could be found in the rats treated with PRP with higher or lower leukocyte concentration. In contrast, rats contaminated with S. aureus showed increased tendon force after PRP treatment. Significant interaction between bacteriological status and PRP treatment was verified (p=0.003). It was further observed that healthy rats had higher levels of cytotoxic T cells in their spleens. The difference in response to treatment in contaminated rats suggests that the PRP effect is dependent on the immune status of the animals. This is the first study that suggests the possibility of interaction between microbiota and tendon repair. Extrapolation of this treatment to the clinic remains dubious.A crescente incid?ncia de les?es tend?neas constituem um desafio constante na medicina ortop?dica. A utiliza??o do plasma rico em plaquetas (PRP) ? uma estrat?gia amplamente explorada na cl?nica por creditar-se que acelera o processo de reparo tend?neo. Contudo, a efic?cia cl?nica do PRP ? question?vel, e mais estudos que visem uma melhor compreens?o deste tratamento s?o necess?rios. O objetivo desta pesquisa foi avaliar o efeito do PRP no reparo do tend?o de Aquiles (TA) de ratos. Um total de 242 ratos foram utilizados, sendo 181 animais randomicamente distribu?dos em 6 diferentes experimentos. Os animais restantes foram utilizados como doadores sangu?neos (n= 49) e para realiza??o de citometria de fluxo (n=12). A les?o foi executada atrav?s de transec??o do TA direito. A avalia??o do reparo foi feita 11 e 14 dias p?s-cir?rgico, atrav?s de m?quina de teste mec?nico. O pico de for?a foi considerado a vari?vel principal. Varia??es no protocolo de produ??o de PRP, concentra??o de leuc?citos e atividade f?sica dos ratos foram testados. O teste de ELISA foi realizado a fim de quantificar o fator de crescimento derivado das plaquetas (PDGF-AB) presente no PRP. Foram utilizados animais livres de pat?genos e animais contaminados com Staphylococcus aureus (S. aureus). A concentra??o plaquet?ria do PRP padr?o foi pelo menos 5 vezes maior que a do sangue perif?rico, e foi poss?vel obtermos tanto uma alta ou baixa concentra??o de leuc?citos no preparado. Os n?veis de PDGF-AB no PRP inativado foram de 7.3 ?g/mL (DP 6.0; n=4) e no plasma sangu?neo foram abaixo dos n?veis de detec??o (0.03 ng/mL). Nos experimentos realizados com ratos livres de pat?genos, nenhum efeito significativo do PRP p?de ser observado no reparo tend?neo. Da mesma forma, nenhuma diferen?a significativa p?de ser encontrada nos ratos tratados com PRP com alta ou baixa concentra??o de leuc?citos. Em contraste, os ratos contaminados com S. aureus demonstraram aumento da for?a tend?nea ap?s o tratamento com PRP. Significante intera??o entre estado bacteriol?gico e tratamento PRP foi verificada (p=0.003). Observou-se ainda, que ratos saud?veis possu?am maiores n?veis de c?lulas T citot?xicas em seus ba?os. A diferen?a na resposta ao tratamento em ratos contaminados sugere que o efeito do PRP ? dependente do estado imune dos animais. Esse ? o primeiro estudo que sugere a possibilidade de intera??o entre microbiota e reparo tend?neo. A extrapola??o deste tratamento para a cl?nica permanece d?bia

Dexamethasone Enhances Achilles Tendon Healing in an Animal Injury Model, and the Effects Are Dependent on Dose, Administration Time, and Mechanical Loading Stimulation

Background: Corticosteroid treatments such as dexamethasone are commonly used to treat tendinopathy but with mixed outcomes. Although this treatment can cause tendon rupture, it can also stimulate the tendon to heal. However, the mechanisms behind corticosteroid treatment during tendon healing are yet to be understood. Purpose: To comprehend when and how dexamethasone treatment can ameliorate injured tendons by using a rat model of Achilles tendon healing. Study Design: Controlled laboratory study. Methods: An overall 320 rats were used for a sequence of 6 experiments. We investigated whether the drug effect was time-, dose-, and load-dependent. Additionally, morphological data and drug administration routes were examined. Healing tendons were tested mechanically or used for histological examination 12 days after transection. Blood was collected for flow cytometry analysis in 1 experiment. Results: We found that the circadian rhythm and drug injection timing influenced the treatment outcome. Dexamethasone treatment at the right time point (days 7-11) and dose (0.1 mg/kg) significantly improved the material properties of the healing tendon, while the adverse effects were reduced. Local dexamethasone treatment did not lead to increased peak stress, but it triggered systemic granulocytosis and lymphopenia. Mechanical loading (full or moderate) is essential for the positive effects of dexamethasone, as complete unloading leads to the absence of improvements. Conclusion: We conclude that dexamethasone treatment to improve Achilles tendon healing is dose- and time-dependent, and positive effects are perceived even in a partly unloaded condition

Effect of storage and preconditioning of healing rat Achilles tendon on structural and mechanical properties

Tendon tissue storage and preconditioning are often used in biomechanical experiments and whether this generates alterations in tissue properties is essential to know. The effect of storage and preconditioning on dense connective tissues, like tendons, is fairly understood. However, healing tendons are unlike and contain a loose connective tissue. Therefore, we investigated if storage of healing tendons in the fridge or freezer changed the mechanical properties compared to fresh tendons, using a pull-to-failure or a creep test. Tissue morphology and cell viability were also evaluated. Additionally, two preconditioning levels were tested. Rats underwent Achilles tendon transection and were euthanized 12 days postoperatively. Statistical analyzes were done with one-way ANOVA or Students t-test. Tissue force and stress were unaltered by storage and preconditioning compared to fresh samples, while high preconditioning increased the stiffness and modulus (p &amp;lt;= 0.007). Furthermore, both storage conditions did not modify the viscoelastic properties of the healing tendon, but altered transverse area, gap length, and water content. Cell viability was reduced after freezing. In conclusion, preconditioning on healing tissues can introduce mechanical data bias when having extensive tissue strength diversity. Storage can be used before biomechanical testing if structural properties are measured on the day of testing.Funding Agencies|Linkoping University Library</p

Response to mechanical loading in rat Achilles tendon healing is influenced by the microbiome.

We have previously shown that changes in the microbiome influence how the healing tendon responds to different treatments. The aim of this study was to investigate if changes in the microbiome influence the response to mechanical loading during tendon healing. 90 Sprague-Dawley rats were used. Specific Opportunist and Pathogen Free (SOPF) rats were co-housed with Specific Pathogen Free (SPF) rats, carrying Staphylococcus aureus and other opportunistic microbes. After 6 weeks of co-housing, the SOPF rats were contaminated which was confirmed by Staphylococcus aureus growth. Clean SOPF rats were used as controls. The rats were randomized to full loading or partial unloading by Botox injections in their calf muscles followed by complete Achilles tendon transection. Eight days later, the healing tendons were tested mechanically. The results were analysed by a 2-way ANOVA with interaction between loading and contamination on peak force as the primary outcome and there was an interaction for both peak force (p = 0.049) and stiffness (p = 0.033). Furthermore, partial unloading had a profound effect on most outcome variables. In conclusion, the response to mechanical loading during tendon healing is influenced by changes in the microbiome. Studies aiming for clinical relevance should therefore consider the microbiome of laboratory animals

Early Growth Response Genes Increases Rapidly After Mechanical Overloading and Unloading in Tendon Constructs

Tendon cells exist in a dense extracellular matrix and mechanical loading is important for the strength development of this matrix. We therefore use a three-dimensional (3D) culture system for tendon formation in vitro. The objectives of this study were to elucidate the temporal expression of tendon-related genes during the formation of artificial tendons in vitro and to investigate if early growth response-1 (EGR1), EGR2, FOS, and cyclooxygenase-1 and -2 (PTGS1 and PTGS2) are sensitive to mechanical loading. First, we studied messenger RNA (mRNA) levels of several tendon-related genes during formation of tendon constructs. Second, we studied the mRNA levels of, for example, EGR1 and EGR2 after different degrees of loading; dynamic physiologic-range loading (2.5% strain), dynamic overloading (approximately 10% strain), or tension release. The gene expression for tendon-related genes (i.e., EGR2, MKX, TNMD, COL3A1) increased with time after seeding into this 3D model. EGR1, EGR2, FOS, PTGS1, and PTGS2 did not respond to physiologic-range loading. But overloading (and tension release) lead to elevated levels of EGR1 and EGR2 (p amp;lt;= 0.006). FOS and PTGS2 were increased after overloading (both p amp;lt; 0.007) but not after tension release (p = 0.06 and 0.08). In conclusion, the expression of tendon-related genes increases during the formation of artificial tendons in vitro, including EGR2. Furthermore, the gene expression of EGR1 and EGR2 in human tendon cells appear to be sensitive to overloading and unloading but did not respond to the single episode of physiologic-range loading. These findings could be helpful for the understanding of tendon tensional homeostasis. (c) 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop ResFunding Agencies|Lundbeck FoundationLundbeckfonden [R198-2015-207]; Nordea Foundation (Center of Healthy Aging) [NF-007IOC]; IOC Sports Medicine Copenhagen; Danish Medical Research CouncilDanish Medical Research Council [0602-02960B]; Swedish Society for Medical Research; Lions Research Foundation; Magnus Bergvall Foundation [2015-01169, 2016-01811]; Swedish Research Council for Sport Science [P2017-0109, D2017-0021]; Swedish Fund for Research without Animal Experiments</p

Early Growth Response Genes Increases Rapidly After Mechanical Overloading and Unloading in Tendon Constructs

Tendon cells exist in a dense extracellular matrix and mechanical loading is important for the strength development of this matrix. We therefore use a three-dimensional (3D) culture system for tendon formation in vitro. The objectives of this study were to elucidate the temporal expression of tendon-related genes during the formation of artificial tendons in vitro and to investigate if early growth response-1 (EGR1), EGR2, FOS, and cyclooxygenase-1 and -2 (PTGS1 and PTGS2) are sensitive to mechanical loading. First, we studied messenger RNA (mRNA) levels of several tendon-related genes during formation of tendon constructs. Second, we studied the mRNA levels of, for example, EGR1 and EGR2 after different degrees of loading; dynamic physiologic-range loading (2.5% strain), dynamic overloading (approximately 10% strain), or tension release. The gene expression for tendon-related genes (i.e., EGR2, MKX, TNMD, COL3A1) increased with time after seeding into this 3D model. EGR1, EGR2, FOS, PTGS1, and PTGS2 did not respond to physiologic-range loading. But overloading (and tension release) lead to elevated levels of EGR1 and EGR2 (p amp;lt;= 0.006). FOS and PTGS2 were increased after overloading (both p amp;lt; 0.007) but not after tension release (p = 0.06 and 0.08). In conclusion, the expression of tendon-related genes increases during the formation of artificial tendons in vitro, including EGR2. Furthermore, the gene expression of EGR1 and EGR2 in human tendon cells appear to be sensitive to overloading and unloading but did not respond to the single episode of physiologic-range loading. These findings could be helpful for the understanding of tendon tensional homeostasis. (c) 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop ResFunding Agencies|Lundbeck FoundationLundbeckfonden [R198-2015-207]; Nordea Foundation (Center of Healthy Aging) [NF-007IOC]; IOC Sports Medicine Copenhagen; Danish Medical Research CouncilDanish Medical Research Council [0602-02960B]; Swedish Society for Medical Research; Lions Research Foundation; Magnus Bergvall Foundation [2015-01169, 2016-01811]; Swedish Research Council for Sport Science [P2017-0109, D2017-0021]; Swedish Fund for Research without Animal Experiments</p

Dexamethasone treatment influences tendon healing through altered resolution and a direct effect on tendon cells

Funder: Linköping UniversityAbstractInflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p &lt; 0.05), while resolution-related genes were unaltered (p &gt; 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p &lt; 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.</jats:p