Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA

Ductility of wide-beam RC frames as lateral resisting system

[EN] Some Mediterranean seismic codes consider wide-beam reinforced concrete moment resisting frames (WBF) as horizontal load carrying systems that cannot guarantee high ductility performances. Conversely, Eurocode 8 allows High Ductility Class (DCH) design for such structural systems. Code prescriptions related to WBF are systematically investigated. In particular, lesson learnt for previous earthquakes, historical reasons, and experimental and numerical studies underpinning specific prescriptions on wide beams in worldwide seismic codes are discussed. Local and global ductility of WBF are then analytically investigated through (1) a parametric study on chord rotations of wide beams with respect to that of deep beams, and (2) a spectral-based comparison of WBF with conventional reinforced concrete moment resisting frames (i.e. with deep beams). Results show that the set of prescriptions given by modern seismic codes provides sufficient ductility to WBF designed in DCH. In fact, global capacity of WBF relies more on the lateral stiffness of the frames and on the overstrength of columns rather than on the local ductility of wide beams, which is systematically lower with respect to that of deep beams.Gómez-Martínez, F.; Alonso Durá, A.; De Luca, F.; Verderame, GM. (2016). Ductility of wide-beam RC frames as lateral resisting system. Bulletin of Earthquake Engineering. 14(6):1545-1569. doi:10.1007/s10518-016-9891-xS15451569146ACI (1989) Building code requirements for reinforced concrete (ACI 318-89). ACI Committee 318, American Concrete Institute, Farmington Hills, Michigan, USAACI (2008) Building code requirements for structural concrete (ACI 318-08) and commentary (318-08). ACI Committee 318, American Concrete Institute, Farmington Hills, Michigan, USAACI-ASCE (1991) Recommendations for design of beam-column connections in monolithic reinforced concrete structures (ACI 352R-91). Joint ACI-ASCE Committee 352, American Concrete Institute, Farmington Hills, Michigan, USAACI-ASCE (2002) Recommendations for design of beam-column connections in monolithic reinforced concrete structures (ACI 352R-02). Joint ACI-ASCE Committee 352, American Concrete Institute, Farmington Hills, Michigan, USAArslan MH, Korkmaz HH (2007) What is to be learned from damage and failure of reinforced concrete structures during recent earthquakes in Turkey? Eng Fail Anal 14(1):1–22ASCE (2007) Seismic Rehabilitation of Existing Buildings, ASCE/SEI 41-06. American Society of Civil Engineers, RestonASCE (2010) Minimum Design Loads for Building and Other Structures, ASCE/SEI 7-10. American Society of Civil Engineers, RestonBenavent-Climent A (2007) Seismic behavior of RC side beam-column connections under dynamic loading. J Earthquake Eng 11:493–511Benavent-Climent A, Zahran R (2010) An energy-based procedure for the assessment of seismic capacity of existing frames: application to RC wide beam systems in Spain. Soil Dyn Earthq Eng 30:354–367Benavent-Climent A, Cahís X, Zahran R (2009) Exterior wide beam-column connections in existing RC frames subjected to lateral earthquake loads. Eng Struct 31:1414–1424Benavent-Climent A, Cahís X, Vico JM (2010) Interior wide beam-column connections in existing RC frames subjected to lateral earthquake loading. Bull Earthq Eng 8:401–420BHRC (2004) Iranian Code of Practice for Seismic Resistant Design of Buildings. Standard Nº 2800, 3rd edn. Building and Housing Research Center, TehranBorzi B, Elnashai AS (2000) Refined force reduction factors for seismic design. Eng Struct 22:1244–1260Borzi B, Pinho R, Crowley H (2008) Simplified pushover-based vulnerability analysis for large-scale assessment of RC buildings. Eng Struct 30:804–820BSI (2004) Eurocode 2: Design of concrete structures: Part 1-1: General rules and rules for buildings. British Standards Institutions, LondonCalvi GM (1999) A displacement-based approach for vulnerability evaluation of classes of buildings. J Earthquake Eng 3(3):411–438CDSC (1994) Seismic construction code, NCSR-94. Committee for the Development of Seismic Codes, Spanish Ministry of Construction, Madrid, Spain (in Spanish)CDSC (2002) Seismic construction code, NCSE-02. Committee for the Development of Seismic Codes, Spanish Ministry of Construction, Madrid, Spain (in Spanish)CEN (2004) Eurocode 8: design of structures for earthquake resistance—part 1: general rules, seismic actions and rules for buildings. European Standard EN 1998-1:2003—Comité Européen de Normalisation, Brussels, BelgiumCEN (2005) Eurocode 8: design of structures for earthquake resistance—part 3: assessment and retrofitting of buildings. European Standard EN 1998-1:2005—Comité Européen de Normalisation, Brussels, BelgiumCheung PC, Paulay T, Park R (1991) Mechanisms of slab contributions in beam-column subassemblages. ACI Spec Publ 123Cosenza E, Manfredi G, Polese M, Verderame GM (2005) A multilevel approach to the capacity assessment of existing RC buildings. J Earthquake Eng 9(1):1–22Crowley H, Pinho R (2010) Revisiting Eurocode 8 formulae for periods of vibration and their employment in linear seismic analysis. Earthquake Eng Struct Dynam 39:223–235CS.LL.PP (2009) Instructions for the application of the technique code for the Constructions. Official Gazette of the Italian Republic, 47, Regular Supplement no. 27 (in Italian)De Luca F, Vamvatsikos D, Iervolino I (2013) Near-optimal piecewise linear fits of static pushover capacity curves for equivalent SDOF analysis. Earthquake Eng Struct Dynam 42(4):523–543De Luca F, Verderame GM, Gómez-Martínez F, Pérez-García A (2014) The structural role played by masonry infills on RC building performances after the 2011 Lorca, Spain, earthquake. Bull Earthq Eng 12(5):1999–2026Decanini LD, Mollaioli F (2000) Analisi di vulnerabilità sismica di edifici in cemento armato pre-normativa. In: Cosenza E (ed) Comportamento sismico di edifici in cemento armato progettati per carichi verticali. CNR—Gruppo Nazionale per la Difesa dei Terremoti, Rome (in Italian)Dolšek M, Fajfar P (2004) IN2—a simple alternative for IDA. In: Proceedings of the 13th World conference on Earthquake Engineering. August 1–6, Vancouver, Canada. Paper 3353Domínguez D, López-Almansa F, Benavent-Climent A (2014) Comportamiento para el terremoto de Lorca de 11-05-2011, de edificios de vigas planas proyectados sin tener en cuenta la acción sísmica. Informes de la Construcción 66(533):e008 (in Spanish)Domínguez D, López-Almansa F, Benavent-Climent A (2016) Would RC wide-beam buildings in Spain have survived Lorca earthquake (11-05-2011)? Eng Struct 108:134–154Dönmez C (2013) Seismic Performance of Wide-Beam Infill-Joist Block RC Frames in Turkey. J Perform Constr Facil 29(1):04014026Fadwa I, Ali TA, Nazih E, Sara M (2014) Reinforced concrete wide and conventional beam-column connections subjected to lateral load. Eng Struct 76:34–48Fardis MN (2009) Seismic design, assessment and retrofitting of concrete, Buildings edn. Springer, LondonGentry TR, Wight JK (1992) Reinforced concrete wide beam-column connections under earthquake-type loading. Report no. UMCEE 92-12. Department of Civil and Environmental Engineering, University of Michigan, Ann Arbor, Michigan, USAGómez-Martínez F (2015) FAST simplified vulnerability approach for seismic assessment of infilled RC MRF buildings and its application to the 2011 Lorca (Spain) earthquake. Ph.D. Thesis, Polytechnic University of Valencia, SpainGómez-Martínez F, Pérez García A, De Luca F, Verderame GM (2015a) Comportamiento de los edificios de HA con tabiquería durante el sismo de Lorca de 2011: aplicación del método FAST. Informes de la Construcción 67(537):e065 (in Spanish)Gómez-Martínez F, Pérez-García A, Alonso Durá A, Martínez Boquera A, Verderame GM (2015b) Eficacia de la norma NCSE-02 a la luz de los daños e intervenciones tras el sismo de Lorca de 2011. In: Proceedings of Congreso Internacional sobre Intervención en Obras Arquitectónicas tras Sismo: L’Aquila (2009), Lorca (2011) y Emilia Romagna (2012), May 13–14, Murcia, Spain (in Spanish)Gómez-Martínez F, Verderame GM, De Luca F, Pérez-García A, Alonso-Durá, A (2015c). High ductility seismic performances of wide-beam RC frames. In; XVI Convegno ANIDIS. September 13–17, L'Aquila, ItalyHawkins NM, Mitchell D (1979) Progressive collapse of flat plate structures. ACI J 76(7):775–808Iervolino I, Manfredi G, Polese M, Verderame GM, Fabbrocino G (2007) Seismic risk of RC building classes. Eng Struct 29(5):813–820Inel M, Ozmen HB, Akyol E (2013) Observations on the building damages after 19 May 2011 Simav (Turkey) earthquake. Bull Earthq Eng 11(1):255–283Kurose Y, Guimaraes GN, Zuhua L, Kreger ME, Jirsa JO (1991) Evaluation of slab-beam-column connections subjected to bidirectional loading. ACI Spec Publ 123:39–67LaFave JM, Wight JK (1997) Behavior of reinforced exterior wide beam-column-slab connections subjected to lateral earthquake loading. Report no. UMCEE 97-01. Department of Civil and Environmental Engineering, University of Michigan, Ann Arbor, Michigan, USALaFave JM, Wight JK (1999) Reinforced concrete exterior wide beam-column-slab connections subjected to lateral earthquake loading. ACI Struct J 96(4):577–586LaFave JM, Wight JK (2001) Reinforced concrete wide-beam construction vs. conventional construction: resistance to lateral earthquake loads. Earthq Spectra 17(3):479–505Li B, Kulkarni SA (2010) Seismic behavior of reinforced concrete exterior wide beam-column joints. J Struct Eng (ASCE) 136(1):26–36López-Almansa F, Domínguez D, Benavent-Climent A (2013) Vulnerability analysis of RC buildings with wide beams located in moderate seismicity regions. Eng Struct 46:687–702Masi A, Santarsiero G, Nigro D (2013a) Cyclic tests on external RC beam-column joints: role of seismic design level and axial load value on the ultimate capacity. J Earthquake Eng 17(1):110–136Masi A, Santarsiero G, Mossucca A, Nigro D (2013b) Seismic behaviour of RC beam-column subassemblages with flat beam. In: Proceedings of XV Convegno della Associazione Nazionale Italiana di Ingegneria Sismica, ANIDIS. Padova, ItalyMazzolani FM, Piluso V (1997) Plastic design of seismic resistant steel frames. Earthquake Eng Struct Dynam 26:167–191MEPP (2000a) Greek earthquake resistant design code, EAK 2000. Ministry of Environment, Planning and Public Works, AthensMEPP (2000b) Greek code for the design and construction of concrete works, EKOS 2000. Ministry of Environment, Planning and Public Works, Athens (in Greek)Miranda E, Bertero VV (1994) Evaluation of strength reduction factors for earthquake-resistant design. Earthq Spectra 10(2):357–379MPWS (2007) Specifications for buildings to be built in seismic areas. Turkish Standards Institution, Ministry of Public Works and Settlement, Ankara (in Turkish)Mwafy AM, Elnashai AS (2002) Calibration of force reduction factors of RC buildings. J Earthquake Eng 6(2):239–273NZS (2004) Structural design actions. Part 5: earthquake actions, NZS 1170.5. New Zealand Standards, WellingtonNZS (2006) Concrete structures standard: part 1—the design of concrete structures, NZS 3101 part 1. New Zealand Standards, WellingtonPan A, Moehle JP (1989) Lateral displacement ductility of reinforced concrete flat plates. ACI Struct J 86(3):250–258Panagiotakos TB, Fardis MN (2001) Deformations of reinforced concrete members at yielding and ultimate. ACI Struct J 98(2):135–148 [and Appendix 1 (69 pp)]Paulay T, Priestley MJN (1992) Seismic design of concrete and masonry structures. Wiley, New York, USAQuintero-Febres CG, Wight JK (1997) Investigation on the seismic behavior of RC interior wide beam-column connections. Report no. UMCEE 97-15. Department of Civil and Environmental Engineering, University of Michigan, Ann Arbor, Michigan, USAQuintero-Febres CG, Wight JK (2001) Experimental study of Reinforced concrete interior wide beam-column connections subjected to lateral loading. ACI Struct J 98(4):572–582Serna-Ros P, Fernández-Prada MA, Miguel-Sosa P, Debb OAR (2001) Influence of stirrup distribution and support width on the shear strength of reinforced concrete wide beams. Mag Concr Res 54(00):1–11Shuraim AB (2012) Transverse stirrup configurations in RC wide shallow beams supported on narrow columns. J Struct Eng 138(3):416–424Siah WL, Stehle JS, Mendis P, Goldsworthy H (2003) Interior wide beam connections subjected to lateral earthquake loading. Eng Struct 25:281–291Tore E, Demiral T (2014) A parametric study of code-based performance limits for wide beams. e-GFOS 5(8):1–11Vamvatsikos D, Cornell CA (2002) Incremental Dynamic Analysis. Earthquake Eng Struct Dynam 31:491–514Vidic T, Fajfar P, Fischinger M (1994) Consistent inelastic design spectra: strength and displacement. Earthquake Eng Struct Dynam 23:507–521Vielma JC, Barbat AH, Oller S (2010) Seismic safety of low ductility structures used in Spain. Bull Earthq Eng 8:135–15

Crystal structure of the membrane attack complex assembly inhibitor BGA71 from the Lyme disease agent Borrelia bavariensis

Funding Information: This work was supported by the European Regional Development Fund (ERDF) grant Nr. 1.1.1.2/VIAA/1/16/144 “Structural and functional studies of Lyme disease agent Borrelia burgdorferi outer surface proteins to reveal the mechanisms of pathogenesis with the intention to create a new vaccine”. Diffraction data have been collected on BL14.1 at the BESSY II electron storage ring operated by the Helmholtz-Zentrum, Berlin. We would particularly like to acknowledge the help and support of Manfred S. Weiss and Christian Feiler during the experiment. Publisher Copyright: © 2018, The Author(s).Borrelia (B.) bavariensis, B. burgdorferi, B. afzelii, B. garinii, B. spielmanii, and B. mayonii are the causative agents in Lyme disease. Lyme disease spirochetes reside in infected Ixodes ticks and are transferred to mammalian hosts during tick feeding. Once transmitted, spirochetes must overcome the first line of defense of the innate immune system either by binding complement regulators or by terminating the formation of the membrane attack complex (MAC). In B. bavariensis, the proteins BGA66 and BGA71 inhibit complement activation by interacting with the late complement components C7, C8, and C9, as well as with the formed MAC. In this study, we have determined the crystal structure of the potent MAC inhibitor BGA71 at 2.9 Ǻ resolution. The structure revealed a cysteine cross-linked homodimer. Based on the crystal structure of BGA71 and the structure-based sequence alignment with CspA from B. burgdorferi, we have proposed a potential binding site for C7 and C9, both of which are constituents of the formed MAC. Our results shed light on the molecular mechanism of immune evasion developed by the human pathogenic Borrelia species to overcome innate immunity. These results will aid in the understanding of Lyme disease pathogenesis and pave the way for the development of new strategies to prevent Lyme disease.publishersversionPeer reviewe

Diverse Roles and Interactions of the SWI/SNF Chromatin Remodeling Complex Revealed Using Global Approaches

A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate, and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function, and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate, we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5′ ends, RNA Polymerases II and III, and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins, and DNA replication origins). Interestingly we also find that certain configurations of SWI/SNF subunits are associated with transcripts that have higher levels of expression, whereas other configurations of SWI/SNF factors are associated with transcripts that have lower levels of expression. To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins, we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members, as well as with cellular constituents such as nuclear matrix proteins, key transcription factors, and centromere components, implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams