Approximation of reachable sets using optimal control and support vector machines

We propose and discuss a new computational method for the numerical approximation of reachable sets for nonlinear control systems. It is based on the support vector machine algorithm and represents the set approximation as a sublevel set of a function chosen in a reproducing kernel Hilbert space. In some sense, the method can be considered as an extension to the optimal control algorithm approach recently developed by Baier, Gerdts and Xausa. The convergence of the method is illustrated numerically for selected examples

Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service

In 2013, as part of our genetic investigation of patients with inherited retinal disease, we utilized multigene panel testing of 105 genes known to cause retinal disease in our patient cohorts. This test was performed in a UK National Health Service (NHS) accredited laboratory. The results of all multigene panel tests requested between 1.4.13 and 31.8.14 were retrospectively reviewed. All patients had been previously seen at Moorfields Eye Hospital, London, UK and diagnosed with an inherited retinal dystrophy after clinical examination and detailed retinal imaging. The results were categorized into three groups: (i) Testing helped establish a certain molecular diagnosis in 45 out of 115 (39%). Variants in USH2A (n = 6) and RP1 (n = 4) were most common. (ii) Definitive conclusions could not be drawn from molecular testing alone in 13 out of 115 (11%) as either insufficient pathogenic variants were discovered or those identified were not consistent with the phenotype. (iii) Testing did not identify any pathogenic variants responsible for the phenotype in 57 out of 115 (50%). Multigene panel testing performed in an NHS setting has enabled a molecular diagnosis to be confidently made in 40% of cases. Novel variants accounted for 38% of all identified variants. Detailed retinal phenotyping helped the interpretation of specific variants. Additional care needs to be taken when assessing polymorphisms in genes that have been infrequently associated with disease, as historical techniques were not as rigorous as contemporary ones. Future iterations of sequencing are likely to offer higher sensitivity, testing a broader range of genes, more rapidly and at a reduced cost

Functional and Anatomical Outcomes of Choroidal Neovascularization Complicating Best1-related Retinopathy

PURPOSE: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). METHODS: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. RESULTS: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P 0.05 Mann-Whitney U test). CONCLUSION: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone

Characterization of CDH3-Related Congenital Hypotrichosis With Juvenile Macular Dystrophy.

IMPORTANCE: Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is a rare disorder presenting in childhood and adolescence with central visual disturbance and sparse scalp hair. Reported retinal imaging is lacking, and whether the condition is progressive remains unclear. OBJECTIVE: To investigate a series of patients with HJMD due to biallelic mutations in CDH3 and thereby characterize the disorder. DESIGN, SETTING, AND PARTICIPANTS: Ten patients from 10 families underwent detailed clinical assessment, including serial retinal imaging and electrophysiologic evaluation, at Moorfields Eye Hospital, St James's University Hospital, and Calderdale Royal Infirmary. Patients ranged in age from 3 to 17 years at onset and 5 to 57 years at last assessment. The molecular genetic investigation included bidirectional Sanger sequencing of all exons and intron-exon boundaries of CDH3 and whole-exome sequencing in 2 patients. The study was conducted from June 5, 2013, to January 15, 2016, with final follow-up completed on December 15, 2015. MAIN OUTCOMES AND MEASURES: Results of clinical assessment and molecular genetic testing. RESULTS: All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair. Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging. Optical coherence tomography (OCT) demonstrated variable degrees of atrophy of the outer retina, retinal pigment epithelium, and choroid, with outer retinal tubulations frequently observed. One patient had mild disruption of the inner segment ellipsoid band on OCT and additional mild digit abnormalities. Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients. Eight patients had more than 1 evaluation; of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration. The area of atrophy did not progress with time, but retinal thickness decreased on OCT. Electrophysiologic evaluation in 1 patient found deterioration of macular function after 13 years of follow-up, but the mild, generalized photoreceptor dysfunction remained stable. Biallelic mutations were identified in all patients, including 6 novel mutations. CONCLUSIONS AND RELEVANCE: These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole. The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair. Patients may have additional limb abnormalities

Detailed Retinal Imaging In Carriers Of Ocular Albinism

BACKGROUND: Albinism refers to a group of disorders primarily characterized by hypopigmentation. Affected individuals usually manifest both ocular and cutaneous features of the disease, but occasionally hair and skin pigmentation may appear normal. This is the case in ocular albinism, an X chromosome linked disorder resulting from mutation of GPR143. Female carriers may be recognized by a "mud-splatter" appearance in the peripheral retina. The macula is thought to be normal, however. METHODS: Obligate female carriers of pathogenic GPR143 alleles were recruited. Molecular confirmation of disease was performed only for atypical cases. Detailed retinal imaging was performed (colour fundus photography, optical coherence tomography, fundus autofluorescence. RESULTS: Eight individuals were ascertained. A novel GPR143 mutation was identified in one family (p.Gln328Ter). Foveal fundus autofluorescence was subjectively reduced in 6/6 patients imaged. A "tapetal-like" pattern of autofluorescence was visible at the macula in 3/6. Persistence of the inner retinal layers at the fovea was observed in 6/8 females. CONCLUSION: Female carriers of ocular albinism may manifest signs of retinal pigment epithelium mosaicism at the macula and the peripheral fundus. A tapetal-like reflex on fundus autofluorescence may be considered the macular correlate of "mud-splatter.

Normal Electrooculography in Best Disease and Autosomal Recessive Bestrophinopathy

PURPOSE: To evaluate the electrooculogram (EOG) in a large series of patients with Best disease and autosomal recessive bestrophinopathy. METHODS: A retrospective review of consecutive cases at Moorfields Eye Hospital, London, United Kingdom. Patients with Best disease or autosomal recessive bestrophinopathy who, after electrophysiologic testing, had a normal or atypical EOG light rise were identified. Main outcome measure was EOG amplitude, clinical phenotype and genotype. RESULTS: One hundred thirteen patients were identified with likely disease-causing sequence variants in BEST1 (99 Best disease and 14 autosomal recessive bestrophinopathy). Electrooculograms had been performed in 75 patients. Twenty patients (27%) had no detectable light rise (Arden ratio of 100%) and 49 (65%) had Arden ratios of between 100% to 165%. Six patients (8%) were found to have an EOG light rise of >165%. No cases demonstrated significant interocular asymmetry in EOG amplitude. CONCLUSION: The current work provides significant clinical evidence that the EOG phenotype in Best disease and autosomal recessive bestrophinopathy is more variable than currently appreciated. As a normal EOG may occur in the presence of a classical fundus appearance, the consequences of BEST1 mutation may be independently expressed, possibly mediated through differential effects on intracellular calcium homeostasis

Guidelines for the deployment and implementation of manufacturing scheduling systems

It has frequently been stated that there exists a gap between production scheduling theory and practice. In order to put theoretical findings into practice, advances in scheduling models and solution procedures should be embedded into a piece of software - a scheduling system - in companies. This results in a process that entails (1) determining its functional features, and (2) adopting a successful strategy for its development and deployment. In this paper we address the latter question and review the related literature in order to identify descriptions and recommendations of the main aspects to be taken into account when developing such systems. These issues are then discussed and classified, resulting in a set of guidelines that can help practitioners during the process of developing and deploying a scheduling system. In addition, identification of these issues can provide some insights to drive theoretical scheduling research towards those topics more in demand by practitioners, and thus help to close the aforementioned gap.Framiñan Torres, JM.; Ruiz García, R. (2012). Guidelines for the deployment and implementation of manufacturing scheduling systems. International Journal of Production Research. 50(7):1799-1812. doi:10.1080/00207543.2011.564670S17991812507Baek, D. H. (1999). A visualized human-computer interactive approach to job shop scheduling. International Journal of Computer Integrated Manufacturing, 12(1), 75-83. doi:10.1080/095119299130489Comesaña Benavides, J. A., & Carlos Prado, J. (2002). Creating an expert system for detailed scheduling. International Journal of Operations & Production Management, 22(7), 806-819. doi:10.1108/01443570210433562Bensana, E. 1986. An expert-system approach to industrial job-shop scheduling. In: Proceedings of the 1986 IEEE international conference on robotics and automation. 1986. Vol. 3, pp.1645–1650.Berglund, M., & Karltun, J. (2007). Human, technological and organizational aspects influencing the production scheduling process. International Journal of Production Economics, 110(1-2), 160-174. doi:10.1016/j.ijpe.2007.02.024Besbes, W., Teghem, J., & Loukil, T. (2010). Scheduling hybrid flow shop problem with non-fixed availability constraints. European J. of Industrial Engineering, 4(4), 413. doi:10.1504/ejie.2010.035652Bhattacharyya, S., & Koehler, G. J. (1998). Learning by Objectives for Adaptive Shop-Floor Scheduling. Decision Sciences, 29(2), 347-375. doi:10.1111/j.1540-5915.1998.tb01580.xBitran, G. R., & Tirupati, D. (1988). OR Practice—Development and Implementation of a Scheduling System for a Wafer Fabrication Facility. Operations Research, 36(3), 377-395. doi:10.1287/opre.36.3.377Buxey, G. (1989). Production scheduling: Practice and theory. European Journal of Operational Research, 39(1), 17-31. doi:10.1016/0377-2217(89)90349-4Chen, J.-F. (2004). Unrelated parallel machine scheduling with secondary resource constraints. The International Journal of Advanced Manufacturing Technology, 26(3), 285-292. doi:10.1007/s00170-003-1622-1Collinot, A., Le Pape, C., & Pinoteau, G. (1988). SONIA: A knowledge-based scheduling system. Artificial Intelligence in Engineering, 3(2), 86-94. doi:10.1016/0954-1810(88)90024-6Cowling, P. (2003). A flexible decision support system for steel hot rolling mill scheduling. Computers & Industrial Engineering, 45(2), 307-321. doi:10.1016/s0360-8352(03)00038-xDudek, R. A., Panwalkar, S. S., & Smith, M. L. (1992). The Lessons of Flowshop Scheduling Research. Operations Research, 40(1), 7-13. doi:10.1287/opre.40.1.7Dumond, E. J. (2005). Understanding and using the capabilities of finite scheduling. Industrial Management & Data Systems, 105(4), 506-526. doi:10.1108/02635570510592398Fox, M. S., & Smith, S. F. (1984). ISIS?a knowledge-based system for factory scheduling. Expert Systems, 1(1), 25-49. doi:10.1111/j.1468-0394.1984.tb00424.xFraminan, J. M., & Ruiz, R. (2010). Architecture of manufacturing scheduling systems: Literature review and an integrated proposal. European Journal of Operational Research, 205(2), 237-246. doi:10.1016/j.ejor.2009.09.026Freed, T., Doerr, K. H., & Chang, T. (2007). In-house development of scheduling decision support systems: case study for scheduling semiconductor device test operations. International Journal of Production Research, 45(21), 5075-5093. doi:10.1080/00207540600818351Gao, C and Tang, L. 2008. A decision support system for color-coating line in steel industry. In: Proceedings of the IEEE international conference on automation and logistics, ICAL 2008. 2008. pp.1463–1468.Grant, T. J. (1986). Lessons for O.R. from A.I.: A Scheduling Case Study. Journal of the Operational Research Society, 37(1), 41-57. doi:10.1057/jors.1986.7Graves, S. C. (1981). A Review of Production Scheduling. Operations Research, 29(4), 646-675. doi:10.1287/opre.29.4.646HALSALL, D. N., MUHLEMANN, A. P., & PRICE, D. H. R. (1994). A review of production planning and scheduling in smaller manufacturing companies in the UK. Production Planning & Control, 5(5), 485-493. doi:10.1080/09537289408919520Higgins, P. G. (1996). Interaction in hybrid intelligent scheduling. International Journal of Human Factors in Manufacturing, 6(3), 185-203. doi:10.1002/(sici)1522-7111(199622)6:33.0.co;2-6Kanet, J. J., & Adelsberger, H. H. (1987). Expert systems in production scheduling. European Journal of Operational Research, 29(1), 51-59. doi:10.1016/0377-2217(87)90192-5Kathawala, Y., & Allen, W. R. (1993). Expert Systems and Job Shop Scheduling. International Journal of Operations & Production Management, 13(2), 23-35. doi:10.1108/01443579310025286Kerr, R. M. (1992). Expert systems in production scheduling: Lessons from a failed implementation. Journal of Systems and Software, 19(2), 123-130. doi:10.1016/0164-1212(92)90063-pKnolmayer, G., Mertens, P., & Zeier, A. (2002). Supply Chain Management Based on SAP Systems. doi:10.1007/978-3-540-24816-3Leachman, R. C., Benson, R. F., Liu, C., & Raar, D. J. (1996). IMPReSS: An Automated Production-Planning and Delivery-Quotation System at Harris Corporation—Semiconductor Sector. Interfaces, 26(1), 6-37. doi:10.1287/inte.26.1.6MACCARTHY, B. L., & LIU, J. (1993). Addressing the gap in scheduling research: a review of optimization and heuristic methods in production scheduling. International Journal of Production Research, 31(1), 59-79. doi:10.1080/00207549308956713McKay, K. N., & Black, G. W. (2007). The evolution of a production planning system: A 10-year case study. Computers in Industry, 58(8-9), 756-771. doi:10.1016/j.compind.2007.02.002McKay, K. N., Safayeni, F. R., & Buzacott, J. A. (1988). Job-Shop Scheduling Theory: What Is Relevant? Interfaces, 18(4), 84-90. doi:10.1287/inte.18.4.84McKay, K. N., Morton, T. E., Ramnath, P., & Wang, J. (2000). ?Aversion dynamics? scheduling when the system changes. Journal of Scheduling, 3(2), 71-88. doi:10.1002/(sici)1099-1425(200003/04)3:23.0.co;2-0MCKAY, K., PINEDO, M., & WEBSTER, S. (2009). PRACTICE-FOCUSED RESEARCH ISSUES FOR SCHEDULING SYSTEMS*. Production and Operations Management, 11(2), 249-258. doi:10.1111/j.1937-5956.2002.tb00494.xMissbauer, H., Hauber, W., & Stadler, W. (2009). A scheduling system for the steelmaking-continuous casting process. A case study from the steel-making industry. International Journal of Production Research, 47(15), 4147-4172. doi:10.1080/00207540801950136Numao, M and Morishita, S. 1989. A scheduling environment for steel-making processes. In: Proceedings of the 5th conference on artificial intelligence applications. 1989. pp.279–286.Olhager, J., & Rapp, B. (1995). Operations Research Techniques in Manufacturing Planning and Control Systems. International Transactions in Operational Research, 2(1), 29-43. doi:10.1111/j.1475-3995.1995.tb00003.xPerez-Gonzalez, P., & Framinan, J. M. (2009). Scheduling permutation flowshops with initial availability constraint: Analysis of solutions and constructive heuristics. Computers & Operations Research, 36(10), 2866-2876. doi:10.1016/j.cor.2008.12.018Pinedo, M., & Yen, B. P.-C. (1997). Annals of Operations Research, 70, 359-378. doi:10.1023/a:1018986524234Portougal, V., & Robb, D. J. (2000). Production Scheduling Theory: Just Where Is It Applicable? Interfaces, 30(6), 64-76. doi:10.1287/inte.30.6.64.11623Reisman, A., Kumar, A., & Motwani, J. (1997). Flowshop scheduling/sequencing research: a statistical review of the literature, 1952-1994. IEEE Transactions on Engineering Management, 44(3), 316-329. doi:10.1109/17.618173Steffen, MS. 1986. A survey of artificial intelligence-based scheduling systems. In: Proceedings of the fall industrial engineering conference. 1986.Storer, R. H., Wu, S. D., & Vaccari, R. (1992). New Search Spaces for Sequencing Problems with Application to Job Shop Scheduling. Management Science, 38(10), 1495-1509. doi:10.1287/mnsc.38.10.1495Tang, L., & Wang, G. (2008). Decision support system for the batching problems of steelmaking and continuous-casting production. Omega, 36(6), 976-991. doi:10.1016/j.omega.2007.11.002T’kindt, V., Billaut, J.-C., Bouquard, J.-L., Lenté, C., Martineau, P., Néron, E., … Tacquard, C. (2005). The e-OCEA project: towards an Internet decision system for scheduling problems. Decision Support Systems, 40(2), 329-337. doi:10.1016/j.dss.2004.04.001Wiers, VCS. 1997. Human–computer interaction in production scheduling: Analysis and design of decision support systems for production scheduling tasks. Ph.D. Thesis, Technische Universiteit Eindhoven, NetherlandsWiers, V. C. S. (2002). A case study on the integration of APS and ERP in a steel processing plant. Production Planning & Control, 13(6), 552-560. doi:10.1080/09537280210160321Wiers, V. C. S., & Van Der Schaaf, T. W. (1997). A framework for decision support in production scheduling tasks. Production Planning & Control, 8(6), 533-544. doi:10.1080/095372897234876Zhang, L., Krishnamurthy, A., Malmborg, C. J., & Heragu, S. S. (2009). Variance-based approximations of transaction waiting times in autonomous vehicle storage and retrieval systems. European J. of Industrial Engineering, 3(2), 146. doi:10.1504/ejie.2009.02360

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. Results: Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. Conclusions: This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease

Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy

Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features. Design, Setting and Participants: Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. Main Outcomes and Measures: Detailed clinical phenotypes as well as genetic and biochemical results. Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. Conclusions and Relevance: Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression