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1.
Biochem Med (Zagreb) ; 34(3): 031001, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39171087

RESUMO

This case report describes interference from heterophilic antibodies in D-dimer assay. The interference was suspected due to discrepancies between D-dimer concentrations in the original sample and diluted samples, as well as inconsistent clinical findings. The patient's medical history, laboratory results, and imaging studies were considered in the investigation. Heterophilic antibodies, likely developed during the SARS-CoV-2 infection, were identified as the probable cause of interference. The interference was confirmed through various methods, including dilution studies, blocking heterophilic antibodies, and comparing results with an alternative D-dimer method. This case highlights the importance of recognizing and addressing interference in D-dimer testing, emphasizing the need for collaboration between clinicians and laboratory specialists.


Assuntos
COVID-19 , Produtos de Degradação da Fibrina e do Fibrinogênio , SARS-CoV-2 , Humanos , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , COVID-19/diagnóstico , COVID-19/sangue , SARS-CoV-2/isolamento & purificação , Anticorpos Heterófilos/sangue , Masculino , Feminino
2.
Alzheimers Res Ther ; 16(1): 14, 2024 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-38245754

RESUMO

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.


Assuntos
Estudo de Associação Genômica Ampla , MicroRNAs , Humanos , Idoso , Estudo de Associação Genômica Ampla/métodos , Multiômica , Memória , Cognição , Polimorfismo de Nucleotídeo Único/genética
3.
Arterioscler Thromb Vasc Biol ; 39(12): 2542-2552, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31597446

RESUMO

OBJECTIVE: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (ßs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (ßs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation. CONCLUSIONS: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.


Assuntos
Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Doenças Retinianas/genética , Vasos Retinianos/anormalidades , Vênulas/anormalidades , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/etiologia , Humanos , Fenótipo , Doenças Retinianas/complicações , Doenças Retinianas/diagnóstico , Vasos Retinianos/diagnóstico por imagem , Fatores de Risco
4.
Transl Vis Sci Technol ; 7(2): 12, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29600120

RESUMO

PURPOSE: Semiautomated software applications derive quantitative retinal vascular parameters from fundus camera images. However, the extent of agreement between measurements from different applications is unclear. We evaluate the agreement between retinal measures from two software applications, the Singapore "I" Vessel Assessment (SIVA) and the Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE), and examine respective associations between retinal and systemic outcomes. METHOD: Fundus camera images from 665 Lothian Birth Cohort 1936 participants were analyzed with SIVA and VAMPIRE. Intraclass correlation coefficients (ICC) and Bland-Altman plots assessed agreement between retinal parameters: measurements of vessel width, fractal dimension, and tortuosity. Retinal-systemic variable associations were assessed with Pearson's correlation, and intersoftware correlation magnitude differences were examined with Williams's test. RESULTS: ICC values indicated poor to limited agreement for all retinal parameters (0.159-0.410). Bland-Altman plots revealed proportional bias in the majority, and systematic bias in all measurements. SIVA and VAMPIRE measurements were associated most consistently with systemic variables relating to blood pressure (SIVA r's from -0.122 to -0.183; VAMPIRE r's from -0.078 to -0.177). Williams's tests indicated significant differences in the magnitude of association between retinal and systemic variables for 7 of 77 comparisons (P < 0.05). CONCLUSIONS: Agreement between two common software applications was poor. Further studies are required to determine whether associations with systemic variables are software-dependent. TRANSLATIONAL RELEVANCE: Standardization of the measurement of retinal vascular parameters is warranted to ensure that they are reliable and application-independent. This would be an important step towards realizing the potential of the retina as a source of imaging-derived biomarkers that are clinically useful.

5.
J Hypertens ; 35(8): 1646-1659, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28509723

RESUMO

OBJECTIVES: To examine factors influencing retinal vasculature in two environmentally contrasted, cross-sectional studies of adult participants of European descent and to estimate the extent and specificity of genetic contributions to each retinal vasculature feature. METHODS: Retinal images from 1088 participants in the Orkney Complex Disease Study and 387 in the CROATIA-Korcula study, taken using the same nonmydriatic camera system and graded by the same person, were evaluated. Using general linear models, we estimated the influence of an extensive range of systemic risk factors, calculated retinal traits heritabilities and genetic correlations. MAIN RESULTS: Systemic covariates explained little (<4%) of the variation in vessel tortuosity, substantially more (>10%, up to 31.7%) of the variation in vessel width and monofractal dimension. Suggestive not well trodden associations of biological interest included that of urate, tissue plasminogen activator and cardiac PR interval with arteriolar narrowing, that of carotid intima-media thickness with less-tortuous arterioles and of cardiac QT interval with more tortuous venules. The genetic underpinning of tortuosity is largely distinct from that of the other retinal vascular features, whereas that of fractal dimension and vessel width greatly overlaps. The previously recognized influence of ocular axial length on vessel widths was high and can be expected to lead to artefactual genetic associations [genetic correlation with central retinal arteriolar equivalent: -0.53 (standard error 0.11)]. The significant genetic correlation between SBP and central retinal arteriolar equivalent, -0.53 (standard error 0.22) (after adjusting for age, sex and axial length of the eye), augurs more favourably for the discovery of genetic variants relevant to vascular physiology.


Assuntos
Doença da Artéria Coronariana/fisiopatologia , Vasos Retinianos/fisiopatologia , População Branca , Fatores Etários , Pressão Sanguínea , Doença da Artéria Coronariana/genética , Croácia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Escócia
6.
Br J Ophthalmol ; 101(7): 993-998, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28400371

RESUMO

AIM: To examine the relationship between retinal vascular morphology and cognitive abilities in a narrow-age cohort of community-dwelling older people. METHODS: Digital retinal images taken at age ∼73 years from 683 participants of the Lothian Birth Cohort 1936 (LBC1936) were analysed with Singapore I Vessel Assessment (SIVA) software. Multiple regression models were applied to determine cross-sectional associations between retinal vascular parameters and general cognitive ability (g), memory, processing speed, visuospatial ability, crystallised cognitive ability and change in IQ from childhood to older age. RESULTS: After adjustment for cognitive ability at age 11 years and cardiovascular risk factors, venular length-to-diameter ratio was nominally significantly associated with processing speed (ß=-0.116, p=0.01) and g (ß=-0.079, p=0.04). Arteriolar length-to-diameter ratio was associated with visuospatial ability (ß=0.092, p=0.04). Decreased arteriolar junctional exponent deviation and increased arteriolar branching coefficient values were associated with less relative decline in IQ between childhood and older age (arteriolar junctional exponent deviation: ß=-0.101, p=0.02; arteriolar branching coefficient: ß=0.089, p=0.04). Data are presented as standardised ß coefficients (ß) reflecting change in cognitive domain score associated with an increase of 1 SD unit in retinal parameter. None of these nominally significant associations remained significant after correction for multiple statistical testing. CONCLUSIONS: Retinal parameters contributed <1% of the variance in the majority of associations observed. Whereas retinal analysis may have potential for early detection of some types of age-related cognitive decline and dementia, our results present little evidence that retinal vascular features are associated with non-pathological cognitive ageing.


Assuntos
Envelhecimento , Cognição/fisiologia , Microvasos/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Idoso , Arteríolas/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Retrospectivos , Singapura , Vênulas/diagnóstico por imagem
7.
Sci Rep ; 5: 16119, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26524966

RESUMO

Host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. We identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. We performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, SARS-Coronavirus and pneumonia. One single-nucleotide polymorphism from IL4 gene was significant for pooled respiratory infections (rs2070874; 1.66 [1.29-2.14]). We also detected an association of TLR2 gene with tuberculosis (rs5743708; 3.19 [2.03-5.02]). Subset analyses identified CCL2 as an additional risk factor for tuberculosis (rs1024611; OR = 0.79 [0.72-0.88]). The IL4-TLR2-CCL2 axis could be a highly interesting target for translation towards clinical use. However, this conclusion is based on low credibility of evidence - almost 95% of all identified studies had strong risk of bias or confounding. Future studies must build upon larger-scale collaborations, but also strictly adhere to the highest evidence-based principles in study design, in order to reduce research waste and provide clinically translatable evidence.


Assuntos
Infecções Respiratórias/patologia , Quimiocina CCL2/genética , Bases de Dados Factuais , Humanos , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Infecções Respiratórias/genética , Infecções Respiratórias/metabolismo , Receptor 2 Toll-Like/genética , Tuberculose/genética , Tuberculose/mortalidade , Tuberculose/patologia
8.
Biol Psychiatry ; 77(8): 749-63, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25648963

RESUMO

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.


Assuntos
Envelhecimento/genética , Transtornos da Memória/genética , Polimorfismo de Nucleotídeo Único/genética , Aprendizagem Verbal/fisiologia , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Claudina-5/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Proteínas/genética , Proteoglicanas/genética , Análise de Regressão , Sulfotransferases/genética
9.
Hum Mol Genet ; 22(15): 3174-85, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23585552

RESUMO

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.


Assuntos
Oftalmopatias Hereditárias/genética , Estudo de Associação Genômica Ampla , Descolamento Retiniano/genética , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Metanálise como Assunto , Razão de Chances , Polimorfismo de Nucleotídeo Único
10.
Nat Genet ; 45(1): 76-82, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23202124

RESUMO

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.


Assuntos
Peso ao Nascer/genética , Estatura/genética , Desenvolvimento Fetal/genética , Ligação Genética , Locos de Características Quantitativas , Adulto , Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único
11.
PLoS One ; 5(11): e13996, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21085596

RESUMO

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.


Assuntos
Consanguinidade , Genética Populacional/estatística & dados numéricos , Genoma Humano/genética , Haplótipos/genética , Povo Asiático/genética , Feminino , Homozigoto , Humanos , Indígenas Norte-Americanos/genética , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genética
12.
Hum Mol Genet ; 19(21): 4304-11, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20719862

RESUMO

Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (ß = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (ß = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (ß = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (ß = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (ß = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (ß = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Colágeno Tipo V/genética , Epitélio Corneano/patologia , Proteínas Proto-Oncogênicas/genética , Estudos de Coortes , Humanos , Antígenos de Histocompatibilidade Menor , Polimorfismo de Nucleotídeo Único
13.
Nat Genet ; 42(5): 430-5, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20372150

RESUMO

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 x 10(-35)) and rs9883204 in ADCY5 (P = 7 x 10(-15)) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113 g (95% CI 89-137 g) lighter at birth than the 24% with zero or one alleles (P(trend) = 7 x 10(-30)). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.


Assuntos
Adenilil Ciclases/genética , Ciclinas/genética , Isoenzimas/genética , Alelos , Peso ao Nascer , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Etnicidade , Feminino , Predisposição Genética para Doença , Genótipo , Glucose/metabolismo , Humanos , Masculino , Modelos Genéticos , Gravidez
14.
Eur J Hum Genet ; 17(6): 848-52, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19156170

RESUMO

To investigate the male genetic legacy of the Arab rule in southern Europe during medieval times, we focused on specific Northwest African haplogroups and identified evolutionary close STR-defined haplotypes in Iberia, Sicily and the Italian peninsula. Our results point to a higher recent Northwest African contribution in Iberia and Sicily in agreement with historical data. southern Italian regions known to have experienced long-term Arab presence also show an enrichment of Northwest African types. The forensic and genomic implications of these findings are discussed.


Assuntos
Árabes/genética , Cromossomos Humanos Y/genética , Genética Populacional , África do Norte/etnologia , Europa (Continente) , Evolução Molecular , Geografia , Haplótipos , Humanos , Masculino
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