Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

<p>Background - Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.</p> <p>Methods - We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.</p> <p>Findings - We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.</p> <p>Interpretation - Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.</p&gt

Alkaline activation of ceramic waste materials

Ceramic materials represent around 45 % of construction and demolition waste, and originate not only from the building process, but also as rejected bricks and tiles from industry. Despite the fact that these wastes are mostly used as road sub-base or construction backfill materials, they can also be employed as supplementary cementitious materials, or even as raw material for alkali-activated binders This research aimed to investigate the properties and microstructure of alkali-activated cement pastes and mortars produced from ceramic waste materials of various origins. Sodium hydroxide and sodium silicate were used to prepare the activating solution. The compressive strength of the developed mortars ranged between 22 and 41 MPa after 7 days of curing at 65 C, depending on the sodium concentration in the solution and the water/binder ratio. These results demonstrate the possibility of using alkaliactivated ceramic materials in building applications.The authors are grateful to the Spanish Ministry of Science and Innovation for supporting this study through Project GEOCEDEM BIA 2011-26947, and also to FEDER funding. They also thank Universitat Jaume I for supporting this research through Lucia Reig's granted research stay.Reig Cerdá, L.; Mitsuuchi Tashima, M.; Soriano, L.; Borrachero Rosado, MV.; Monzó Balbuena, JM.; Paya Bernabeu, JJ. (2013). Alkaline activation of ceramic waste materials. Waste and Biomass Valorization. 4:729-736. https://doi.org/10.1007/s12649-013-9197-zS7297364Puertas, F., García-Díaz, I., Barba, A., Gazulla, M.F., Palacios, M., Gómez, M.P., Martínez-Ramírez, S.: Ceramic wastes as alternative raw materials for Portland cement clinker production. Cement Concrete Comp. 30(9), 798–805 (2008)Ministerio de Fomento de España, Catálogo de Residuos Utilizables en Construcción (2010). http://www.cedexmateriales.vsf.es/view/catalogo.aspx . Retrieved on 6 Dec 2012Stock, D.: World production and consumption of ceramic tiles. Tile Today 73, 50–58 (2011)Medina, C., Juan, A., Frías, M., Sánchez-de-Rojas, M.I., Morán, J.M., Guerra, M.I.: Characterization of concrete made with recycled aggregate from ceramic sanitary ware. Mater. Construcc. 61(304), 533–546 (2011)Pacheco-Torgal, F., Jalali, S.: Reusing ceramic wastes in concrete. Constr. Build. Mater. 24(5), 832–838 (2010)Lavat, A.E., Trezza, M.A., Poggi, M.: Characterization of ceramic roof tile wastes as pozzolanic admixture. Waste Manage. 29(5), 1666–1674 (2009)Nuran, A., Mevlut, U.: The use of waste ceramic tile in cement production. Cement Concrete Res. 30, 497–499 (2000)Pereira-de-Oliveira, L.A., Castro-Gomes, J.P., Santos, P.M.S.: The potential pozzolanic activity of glass and red-clay ceramic waste as cement mortars components. Constr. Build. Mater. 31, 197–203 (2012)Van Deventer, J.S.J., Provis, J.L., Duxson, P., Brice, D.G.: Chemical research and climate change as drivers in the commercial adoption of alkali activated materials. Waste Biomass Valor. 1, 145–155 (2010)van Deventer, J.S.J., Provis, J.L., Duxson, P., Lukey, G.C.: Reaction mechanisms in the geopolymeric conversion of inorganic waste to useful products. J. Hazard. Mater. A139, 506–513 (2007)Duxson, P., Fernández-Jiménez, A., Provis, J.L., Lukey, G.C., Palomo, A., van Deventer, J.S.J.: Geopolymer technology: the current state of the art. J. Mater. Sci. 42(9), 2917–2993 (2007)Bernal, S.A., Rodríguez, E.D., de Gutiérrez, R.M., Provis, J.L., Delvasto, S.: Activation of metakaolin/slag blends using alkaline solutions based on chemically modified silica fume and rice husk ash. Waste Biomass Valor. 3, 99–108 (2012)Fernández-Jiménez, A., Palomo, A., Criado, M.: Microstructure development of alkali-activated fly ash cement: a descriptive model. Cement Concrete Res 35, 1204–1209 (2005)Payá, J., Borrachero, M.V., Monzó, J., Soriano, L., Tashima, M.M.: A new geopolymeric binder from hydrated-carbonated cement. Mater. Lett. 74, 223–225 (2012)Kourti, I., Amutha-Rani, D., Deegan, D., Boccaccini, A.R., Cheeseman, C.R.: Production of geopolymers using glass produced from DC plasma treatment of air pollution control (APC) residues. J. Hazard. Mater. 176, 704–709 (2010)Puertas, F., Barba, A., Gazulla, M.F., Gómez, M.P., Palacios, M., Martínez-Ramírez, S.: Residuos cerámicos para su posible uso como materia prima en la fabricación de clínker de cemento Portland: caracterización y activación alcalina. Mater. Construcc. 56(281), 73–84 (2006)Reig, L., Tashima, M.M., Borrachero, M.V., Monzó, J., Payá, J.: Nuevas matrices cementantes generadas por Activación Alcalina de residuos cerámicos. II Simposio Aprovechamiento de residuos agro-industriales como fuente sostenible de materiales de construcción, November 8–9, Valencia, Spain, pp. 199–207 (2010)L. Reig, M.M. Tashima, M.V. Borrachero, J. Monzó, J. Payá: Residuos de ladrillos cerámicos en la producción de conglomerantes activados alcalinamente, I Pro-Africa Conference: Non-conventional Building Materials Based on Agroindustrial Wastes, October 18–19, Pirassununga, SP, Brazil, pp. 18–21 (2010)García Ten F.J. Descomposición durante la cocción del carbonato cálcico contenido en el soporte crudo de los azulejos. Tesis de doctorado, Departamento de Ingeniería química, UJI (2005)Baronio, G., Binda, L.: Study of the pozzolanicity of some bricks and clays. Constr. Build. Mater. 11(1), 41–46 (1997)Zanelli, C., Raimondo, M., Guarini, G., Dondi, M.: The vitreous phase of porcelain stoneware: composition, evolution during sintering and physical properties. J. Non-Cryst. Solids 357, 3251–3260 (2011)Carty, W.M., Senapati, U.: Porcelain-raw materials, processing, phase evolution, and mechanical behaviour. J. Am. Ceram. Soc. 81(1), 3–20 (1998)ASCER, COACV, COPUT, ITC-AICE, WEBER ET BROUTIN – CEMARKSA: Guía Baldosa Guía de la baldosa cerámica. IVE: Conselleria d’Obres Públiques, Urbanisme i Transports, 4ª Ed. Valencia (2003)Khater, H.M.: Effect of calcium on geopolimerization of aluminosilicate wastes. J. Mater. Civ. Eng. 24, 92–101 (2012)Bondar, D., Lynsdale, C.J., Milestone, N.B., Hassani, N., Ramezanianpour, A.A.: Effect of adding mineral additives to alkali-activated natural pozzolan paste. Constr. Build. Mater. 25, 2906–2910 (2011)Provis, J.L., Harrex, R.M., Bernal, A.S., Duxson, P., van Deventer, J.S.J.: Dilatometry of geopolymers as a means of selecting desirable fly ash sources. J. Non-Cryst. Solids 358, 1930–1937 (2012)Duxson, P., Provis, J.L., Lukey, G.C., Mallicoat, S.W., Kriven, W.M., van Deventer, J.S.J.: Understanding the relationship between geopolymer composition, microstructure and mechanical properties. Colloid Surf. A 269, 47–58 (2005)Tashima, M.M., Akasaki, J.L., Castaldelli, V.N., Soriano, L., Monzó, J., Payá, J., Borrachero, M.V.: New geopolymeric binder based on fluid catalytic cracking catalyst residue (FCC). Mater. Lett. 80, 50–52 (2012)Komnitsas, K., Zaharaki, D., Perdikatsis, V.: Geopolymerisation of low calcium ferronickel slags. J. Mater. Sci. 42, 3073–3082 (2007)Bernal, S.A., Gutierrez, R.M., Provis, J.L., Rose, V.: Effect of silicate modulus and metakaolin incorporation on the carbonation of alkali silicate-activated slags. Cement Concrete Res. 40, 898–907 (2010)Tashima, M.M. Produccion y caracterizacion de materiales cementantes a partir del silicoaluminato calcico vitreo (VCAS). Tesis de doctorado, Departamento de Ingeniería de la construcción y de proyectos de ingeniería civil, UPV (2012)Provis, J.L., van Deventer, J.S.J.: Geopolymerisation kinetics. 2. Reaction kinetic modelling. Chem. Eng. Sci. 62, 2318–2329 (2007

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries