Can we predict if patients will require more than one cycle of rituximab?

OBJECTIVE: To identify clinical and serological features that distinguish patients with systemic lupus erythematosus (SLE) who require single as opposed to repeated rituximab (RTX) cycles. METHODS: All 175 SLE patients followed-up at University College hospital from 2000 onwards were retrospectively reviewed. They were divided into a one RTX cycle and multiple-cycle groups (2 or more). Patients included had a follow-up of at least 3 years after their first RTX cycle, unless they needed a second infusion sooner. RESULTS: 131 patients were included; 44 (33.6%) received one cycle of RTX and 87 (66.4%) received two or more. The former were older at diagnosis (31.4 vs 21 years, p< 0.001) and at first RTX infusion (39.9 vs 29 years, p< 0.001). This group of patients had more organs/systems involved (p= 0.044), more leukopenia, lymphopenia and thrombocytopenia (p= 0.001, <0.0001 and 0.003 respectively) and lower C3 levels (p= 0.035). They also had fewer immunosuppressive (IS) drugs before RTX therapy compared with those who required multiple RTX cycles (p= 0.003). There was no statistical difference in the clinical and serological response after the first RTX cycle between both groups.Furthermore, patients who had received more IS treatments were more likely to require more than one cycle of RTX infusions (p= 0.007). CONCLUSIONS: RTX is an effective option for SLE patients with severe flares. Patients who received more immunosuppressive drugs are more likely to receive more than one set of RTX infusions. This suggests that RTX is best used for SLE patients with no history of refractory disease

The strong emergence of molecular structure

One of the most plausible and widely discussed examples of strong emergence is molecular structure. The only detailed account of it, which has been very influential, is due to Robin Hendry and is formulated in terms of downward causation. This paper explains Hendry’s account of the strong emergence of molecular structure and argues that it is coherent only if one assumes a diachronic reflexive notion of downward causation. However, in the context of this notion of downward causation, the strong emergence of molecular structure faces three challenges that have not been met and which have so far remained unnoticed. First, the putative empirical evidence presented for the strong emergence of molecular structure equally undermines supervenience, which is one of the main tenets of strong emergence. Secondly, it is ambiguous how the assumption of determinate nuclear positions is invoked for the support of strong emergence, as the role of this assumption in Hendry’s argument can be interpreted in more than one way. Lastly, there are understandings of causation which render the postulation of a downward causal relation between a molecule’s structure and its quantum mechanical entities, untenable

Current and emerging diagnosis tools and therapeutics for giant cell arteritis

Introduction: Giant cell arteritis (GCA) is the most common large-vessel vasculitis in individuals older than 50 years from Western countries. The goal of the treatment is to achieve improvement of symptoms and clinical remission as well as decrease the risk of severe vascular complications. Areas covered: The review summarizes the main epidemiological and clinical features of GCA and discusses in depth both the classic and the new therapies used in the management of GCA. Expert commentary: Prednisone/prednisolone of 40-60 mg/day is the mainstay in GCA therapy. It yields improvement of clinical features and reduces the risk of permanent visual loss in patients with GCA. Other drugs are used in patients who experience relapses (flares of the disease) or side effects related to glucocorticoids. Methotrexate is the most common conventional immunosuppressive drug used as a glucocorticoid sparing agent. Among the new biologic agents, the most frequently used is the recombinant humanized anti-IL-6 receptor antibody, which is effective to improve clinical symptoms, decrease the cumulative prednisone dose and reduce the frequency of relapses in these patients. Anti-tumor necrosis factor-α therapy is not useful in GCA. Experience with other biologic agents, such as abatacept or ustekinumab, looks promising but it is still scarce

Phase transitions in contagion processes mediated by recurrent mobility patterns

Human mobility and activity patterns mediate contagion on many levels, including the spatial spread of infectious diseases, diffusion of rumors, and emergence of consensus. These patterns however are often dominated by specific locations and recurrent flows and poorly modeled by the random diffusive dynamics generally used to study them. Here we develop a theoretical framework to analyze contagion within a network of locations where individuals recall their geographic origins. We find a phase transition between a regime in which the contagion affects a large fraction of the system and one in which only a small fraction is affected. This transition cannot be uncovered by continuous deterministic models due to the stochastic features of the contagion process and defines an invasion threshold that depends on mobility parameters, providing guidance for controlling contagion spread by constraining mobility processes. We recover the threshold behavior by analyzing diffusion processes mediated by real human commuting data.Comment: 20 pages of Main Text including 4 figures, 7 pages of Supplementary Information; Nature Physics (2011

Mangrove diversity is more than fringe deep

AbstractMangroves form coastal tropical forests in the intertidal zone and are an important component of shoreline protection. In comparison to other tropical forests, mangrove stands are thought to have relatively low genetic diversity with population genetic structure gradually increasing with distance along a coastline. We conducted genetic analyses of mangrove forests across a range of spatial scales; within a 400 m2 parcel comprising 181 Rhizophora mangle (red mangrove) trees, and across four sites ranging from 6–115 km apart in Honduras. In total, we successfully genotyped 269 R. mangle trees, using a panel of 677 SNPs developed with 2b-RAD methodology. Within the 400 m2 parcel, we found two distinct clusters with high levels of genetic differentiation (FST = 0.355), corresponding to trees primarily located on the seaward fringe and trees growing deeper into the forest. In contrast, there was limited genetic differentiation (FST = 0.027–0.105) across the sites at a larger scale, which had been predominantly sampled along the seaward fringe. Within the 400 m2 parcel, the cluster closest to the seaward fringe exhibited low genetic differentiation (FST = 0.014–0.043) with the other Honduran sites, but the cluster further into the forest was highly differentiated from them (FST = 0.326–0.414). These findings contradict the perception that genetic structure within mangroves forests occurs mainly along a coastline and highlights that there is greater genetic structure at fine spatial scales.</jats:p

The submarine volcano eruption at the island of El Hierro: physical-chemical perturbation and biological response

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On the effects of the fix geometric constraint in 2D profiles on the reusability of parametric 3D CAD models

[EN] In order to be reusable, history-based feature-based parametric CAD models must reliably allow for modifications while maintaining their original design intent. In this paper, we demonstrate that relations that fix the location of geometric entities relative to the reference system produce inflexible profiles that reduce model reusability. We present the results of an experiment where novice students and expert CAD users performed a series of modifications in different versions of the same 2D profile, each defined with an increasingly higher number of fix geometric constraints. Results show that the amount of fix constraints in a 2D profile correlates with the time required to complete reusability tasks, i.e., the higher the number of fix constraints in a 2D profile, the less flexible and adaptable the profile becomes to changes. In addition, a pilot software tool to automatically track this type of constraints was developed and tested. Results suggest that the detection of fix constraint overuse may result in a new metric to assess poor quality models with low reusability. The tool provides immediate feedback for preventing high semantic level quality errors, and assistance to CAD users. Finally, suggestions are introduced on how to convert fix constraints in 2D profiles into a negative metric of 3D model quality.The authors would like to thank Raquel Plumed for her support in the statistical analysis. This work has been partially funded by Grant UJI-A02017-15 (Universitat Jaume I) and DPI201784526-R (MINECO/AEI/FEDER, UE), project CAL-MBE. The authors also wish to thank the editor and reviewers for their valuable comments and suggestions that helped us improve the quality of the paper.González-Lluch, C.; Company, P.; Contero, M.; Pérez Lopez, DC.; Camba, JD. (2019). On the effects of the fix geometric constraint in 2D profiles on the reusability of parametric 3D CAD models. International Journal of Technology and Design Education. 29(4):821-841. https://doi.org/10.1007/s10798-018-9458-zS821841294Ait-Aoudia, S., & Foufou, S. (2010). A 2D geometric constraint solver using a graph reduction method. Advances in Engineering Software, 41(10), 1187–1194. https://doi.org/10.1016/j.advengsoft.2010.07.008 .Ault, H. K. (1999). Using geometric constraints to capture design intent. Journal for Geometry and Graphics, 3(1), 39–45.Ault, H. K. (2004). Over-constrained, under-constrained or just right? Goldilocks evaluates DOF of sketched profiles. Paper presented at American Society for Engineering Education, 59th annual midyear meeting past, present and future? Williamsburg, November 21–23.Ault, H. K., Bu, L., & Liu, K. (2014). Solid modeling strategies-analyzing student choices. Paper presented at proceedings of the 121st ASEE annual conference and exposition, Indianapolis, June 15–18.Ault, H. K., & Fraser, A. (2013). A comparison of manual vs. online grading for solid models. Paper presented at 120th ASEE annual conference and exposition, Atlanta, GA, June 23–26, 2013, Paper ID #7233.Barbero, B. R., Pedrosa, C. M., & Samperio, R. Z. (2016). Learning CAD at university through summaries of the rules of design intent. International Journal of Technology and Design Education. https://doi.org/10.1007/s10798-016-9358-z .Bodein, Y., Bertrand, R., & Caillaud, E. (2014). Explicit reference modeling methodology in parametric CAD system. Computers in Industry, 65(1), 136–147. https://doi.org/10.1016/j.compind.2013.08.004 .Bouma, W., Fudos, I., Hoffmann, C., Cai, J., & Paige, R. (1995). Geometric constraint solver. Computer-Aided Design, 27(6), 487–501. https://doi.org/10.1016/0010-4485(94)00013-4 .Briggs, J. C., Hepworth, A. I., Stone, B. R., Cobum, J. Q., Jensen, C. G., & Red, E. (2015). Integrated, synchronous multi-user design and analysis. Journal of Computing and Information Science in Engineering, 15(3), 031002. https://doi.org/10.1115/1.4029801 .Buckley, J., Seery, N., & Canty, D. (2017). Heuristics and CAD modelling: An examination of student behaviour during problem solving episodes within CAD modelling activities. International Journal of Technology and Design Education. https://doi.org/10.1007/s10798-017-9423-2 .Camba, J. D., & Contero, M. (2015). Assessing the impact of geometric design intent annotations on parametric model alteration activities. Computers in Industry, 71, 35–45. https://doi.org/10.1016/j.compind.2015.03.006 .Camba, J. D., Contero, M., & Company, P. (2016). Parametric CAD modeling: An analysis of strategies for design reusability. Computer-Aided Design, 74, 18–31. https://doi.org/10.1016/j.cad.2016.01.003 .Camba, J. D., Contero, M., & Company, P. (2017). CAD reusability and the role of modeling information in the MBE context. Model-based enterprise summit 2017. National Institute of Standards and Technology (NIST), Gaithersburg, MD, April 3–7. MBE17-020. https://www.nist.gov/file/361581 .Cheng, Z., & Ma, Y. (2017). A functional feature modeling method. Advanced Engineering Informatics, 33, 1–15. https://doi.org/10.1016/j.aei.2017.04.003 .Cheng, Z., Xie, Y., & Ma, Y. (2018). Graph centrality analysis of feature dependencies to unveil modeling intents. Computer-Aided Design and Applications. https://doi.org/10.1080/16864360.2018.1441236 .Chester, I. (2007). Teaching for CAD expertise. International Journal of Technology and Design Education, 17, 23–35. https://doi.org/10.1007/s10798-006-9015-z .Company, P., Contero, M., Otey, J., & Plumed, R. (2015). Approach for developing coordinated rubrics to convey quality criteria in CAD training. Computer-Aided Design, 63, 101–117. https://doi.org/10.1016/j.cad.2014.10.00 .Company, P., & González-Lluch, C. (2013). CAD 3D con SolidWorks ® Tomo I: Diseño básico. Publicacions de la Universitat Jaume I. (Colección Sapientia, Núm. 86). http://cad3dconsolidworks.uji.es .Contero, M., Company, P., Vila, C., & Aleixos, N. (2002). Product data quality and collaborative engineering. IEEE Computer Graphics Applications, 22(3), 32–42. https://doi.org/10.1109/MCG.2002.999786 .Dixon, B. M., & Dannenhoffer, J. F., III. (2014). Geometric sketch constraint solving with user feedback. Journal of Aerospace Information Systems, 11(5), 316–325. https://doi.org/10.2514/1.I010110 .Fudos, I., & Hoffmann, C. M. (1997). A graph-constructive approach to solving systems of geometric constraints. ACM Transactions on Graphics, 16(2), 179–216. https://doi.org/10.1145/248210.248223 .Ge, J. X., Chou, S. C., & Gao, X. S. (1999). Geometric constraint satisfaction using optimization methods. Computer-Aided Design, 31(14), 867–879. https://doi.org/10.1016/S0010-4485(99)00074-3 .González-Lluch, C., Company, P., Contero, M., Camba, J. D., & Colom, J. (2017a). A case study on the use of model quality testing tools for the assessment of MCAD models and drawings. International Journal of Engineering Education, 33(5), 1643–1653.González-Lluch, C., Company, P., Contero, M., Camba, J. D., & Plumed, R. (2017b). A survey on 3D CAD model quality assurance and testing tools. Computer-Aided Design, 83, 64–79. https://doi.org/10.1016/j.cad.2016.10.003 .Hamade, R. F. (2009). Profiling the desirable CAD trainee: Technical background, personality attributes, and learning preferences. Journal of Mechanical Design, 131(12), 121009–121019. https://doi.org/10.1115/1.4000455 .Hekman, K. A., & Gordon, M. T. (2013). Automated grading of first year student CAD work. Paper presented at the 120th ASEE annual conference and exposition 2013, Atlanta, GA, June 23–26. Paper ID #6379.Hepworth, A., Tew, K., Trent, M., Ricks, R., Jensen, C. G., & Red, E. R. (2014). Model consistency and conflict resolution with data preservation in multi-user computer aided design. Journal of Computing and Information Science in Engineering, 14(2), 021008. https://doi.org/10.1115/1.4026553 .Jackson, C., & Buxton, M. (2007). The design reuse benchmark report: Seizing the opportunity to shorten product development. Boston: Aberdeen Group.Joan-Arinyo, R., Soto-Riera, A., Vila-Marta, S., & Vilaplana-Pastó, J. (2003). Transforming an under-constrained geometric constraint problem into a well-constrained one. Paper presented at proceedings of ACM SM03, Seatle, June 16–20.Kirstukas, S. J. (2016). Development and evaluation of a computer program to assess student CAD models. Paper presented at ASEE annual conference and exposition, New Orleans, June 26.Kramer, G. (1991). Using degrees of freedom analysis to solve geometric constraint systems. Paper presented at proceedings of the first ACM symposium on solid modeling foundations and CAD/CAM applications 1991, Austin, June 05–07.Kwon, S., Kim, B. C., Mun, D., & Han, S. (2015). Graph-based simplification of feature-based three-dimensional computer-aided design models for preserving connectivity. Journal of Computing and Information Science in Engineering, 15(3), 031010. https://doi.org/10.1115/1.4030748 .Leea, J. Y., & Kimb, K. (1998). A 2-D geometric constraint solver using DOF-based graph reduction. Computer-Aided Design, 30(11), 883–896. https://doi.org/10.1016/S0010-4485(98)00045-1 .Mata Burgarolas, N. (1997). Solving incidence and tangency constraints in 2D. Technical report LSI-97-3R, Departament LiSI, Universitat Politècnica de Catalunya.Petrina, S. (2003). Two cultures of technical courses and discourses: The case of computer aided design. International Journal of Technology and Design Education, 13, 47–73.Race, P. (2001). The lecturers toolkit—A practical guide to learning, teaching and assessment. Great Britain: Glasgow.Red, E., French, D., Jensen, G., Walker, S. S., & Madsen, P. (2013). 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New insights into the classification and nomenclature of cortical GABAergic interneurons.

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus

Visceral and somatic pain modalities reveal NaV 1.7-independent visceral nociceptive pathways.

KEY POINTS: Voltage-gated sodium channels play a fundamental role in determining neuronal excitability. Specifically, voltage-gated sodium channel subtype NaV 1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown. Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV 1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling. These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics. ABSTRACT: Voltage-gated sodium channel NaV 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV 1.7 knockout mouse (NaV 1.7Nav1.8 ) and selective small-molecule NaV 1.7 antagonist PF-5198007. NaV 1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV 1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV 1.7 (in NaV 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV 1.7 antagonist PF-5198007. Our data demonstrate that NaV 1.7 (in NaV 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.University of Granada Dr Hadwen Trust for Humane Researc

Diverse tick-borne microorganisms identified in free-living ungulates in Slovakia

Background: Free-living ungulates are hosts of ixodid ticks and reservoirs of tick-borne microorganisms in central Europe and many regions around the world. Tissue samples and engorged ticks were obtained from roe deer, red deer, fallow deer, mouflon, and wild boar hunted in deciduous forests of south-western Slovakia. DNA isolated from these samples was screened for the presence of tick-borne microorganisms by PCR-based methods. Results: Ticks were found to infest all examined ungulate species. The principal infesting tick was Ixodes ricinus, identified on 90.4% of wildlife, and included all developmental stages. Larvae and nymphs of Haemaphysalis concinna were feeding on 9.6% of wildlife. Two specimens of Dermacentor reticulatus were also identified. Ungulates were positive for A. phagocytophilum and Theileria spp. Anaplasma phagocytophilum was found to infect 96.1% of cervids, 88.9% of mouflon, and 28.2% of wild boar, whereas Theileria spp. was detected only in cervids (94.6%). Importantly, a high rate of cervids (89%) showed mixed infections with both these microorganisms. In addition to A. phagocytophilum and Theileria spp., Rickettsia helvetica, R. monacensis, unidentified Rickettsia sp., Coxiella burnetii, "Candidatus Neoehrlichia mikurensis", Borrelia burgdorferi (s.l.) and Babesia venatorum were identified in engorged I. ricinus. Furthermore, A. phagocytophilum, Babesia spp. and Theileria spp. were detected in engorged H. concinna. Analysis of 16S rRNA and groEL gene sequences revealed the presence of five and two A. phagocytophilum variants, respectively, among which sequences identified in wild boar showed identity to the sequence of the causative agent of human granulocytic anaplasmosis (HGA). Phylogenetic analysis of Theileria 18S rRNA gene sequences amplified from cervids and engorged I. ricinus ticks segregated jointly with sequences of T. capreoli isolates into a moderately supported monophyletic clade. Conclusions: The findings indicate that free-living ungulates are reservoirs for A. phagocytophilum and Theileria spp. and engorged ixodid ticks attached to ungulates are good sentinels for the presence of agents of public and veterinary concern. Further analyses of the A. phagocytophilum genetic variants and Theileria species and their associations with vector ticks and free-living ungulates are required.Fil: Kazimírová, Mária. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Hamšíková, Zuzana. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Spitalská, Eva. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; EslovaquiaFil: Minichová, Lenka. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; EslovaquiaFil: Mahríková, Lenka. Slovak Academy of Sciences. Institute of Zoology; EslovaquiaFil: Caban, Radoslav. Široká ; EslovaquiaFil: Sprong, Hein. National Institute for Public Health and Environment.Laboratory for Zoonoses and Environmental Microbiology; Países BajosFil: Fonville, Manoj. National Institute for Public Health and Environment.Laboratory for Zoonoses and Environmental Microbiology; Países BajosFil: Schnittger, Leonhard. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Patobiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kocianová, Elena. Slovak Academy of Sciences. Institute of Virology. Biomedical Research Center,; Eslovaqui