| 1. |
- Holmes, Michael V., et al.
(författare)
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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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| 2. |
- Yang, Yaohua, et al.
(författare)
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Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
- 2019
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:3, s. 505-517
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
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| 3. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 4. |
- Emaus, Marleen J., et al.
(författare)
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Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:12, s. 2887-2899
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Tidskriftsartikel (refereegranskat)abstract
- Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (-0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3: 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3: 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood.
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| 5. |
- Christiansen, Evald H, et al.
(författare)
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Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI.
- 2017
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Ingår i: The New England journal of medicine. - : Massachussetts Medical Society. - 1533-4406 .- 0028-4793. ; 376:19, s. 1813-1823
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Tidskriftsartikel (refereegranskat)abstract
- The instantaneous wave-free ratio (iFR) is an index used to assess the severity of coronary-artery stenosis. The index has been tested against fractional flow reserve (FFR) in small trials, and the two measures have been found to have similar diagnostic accuracy. However, studies of clinical outcomes associated with the use of iFR are lacking. We aimed to evaluate whether iFR is noninferior to FFR with respect to the rate of subsequent major adverse cardiac events.We conducted a multicenter, randomized, controlled, open-label clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2037 participants with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary-artery stenosis were randomly assigned to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 12 months after the procedure.A primary end-point event occurred in 68 of 1012 patients (6.7%) in the iFR group and in 61 of 1007 (6.1%) in the FFR group (difference in event rates, 0.7 percentage points; 95% confidence interval [CI], -1.5 to 2.8; P=0.007 for noninferiority; hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P=0.53); the upper limit of the 95% confidence interval for the difference in event rates fell within the prespecified noninferiority margin of 3.2 percentage points. The results were similar among major subgroups. The rates of myocardial infarction, target-lesion revascularization, restenosis, and stent thrombosis did not differ significantly between the two groups. A significantly higher proportion of patients in the FFR group than in the iFR group reported chest discomfort during the procedure.Among patients with stable angina or an acute coronary syndrome, an iFR-guided revascularization strategy was noninferior to an FFR-guided revascularization strategy with respect to the rate of major adverse cardiac events at 12 months. (Funded by Philips Volcano; iFR SWEDEHEART ClinicalTrials.gov number, NCT02166736 .).
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| 6. |
- Escaned, Javier, et al.
(författare)
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Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes
- 2018
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Ingår i: JACC. - : Elsevier. - 1936-8798 .- 1876-7605. ; 11:15, s. 1437-1449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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| 7. |
- Isaksson, B, et al.
(författare)
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Chronically administered islet amyloid polypeptide in rats serves as an adiposity inhibitor and regulates energy homeostasis
- 2005
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Ingår i: Pancreatology. - : Elsevier BV. - 1424-3903. ; 5:1, s. 29-36
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Tidskriftsartikel (refereegranskat)abstract
- Aims/Hypothesis: Islet amyloid polypeptide ( IAPP) reduces food intake and body weight in laboratory animals. In addition, IAPP appears to regulate nutrient metabolism. In the present studies, we investigated the effect of chronic IAPP treatment on different aspects of energy homeostasis. Methods: IAPP was infused ( 25 pmol/kg/min) from subcutaneous osmotic pumps for 2 - 7 days. Rats in 2 saline-infused control groups were fed ad libitum (AF) or pair-fed (PF) against the IAPP-treated rats. Results: As expected, the IAPP infusion reduced food intake and body weight gain. In addition, the IAPP treatment decreased the epididymal fat pad ( vs. PF rats, p < 0.05) and lowered circulating levels of triglycerides (vs. PF rats, p < 0.05), free fatty acids ( vs. PF rats, p < 0.05), leptin ( vs. both AF and PF rats, p < 0.05) and insulin ( vs. AF rats, p < 0.05). In contrast, glucose and protein metabolism in the IAPP-treated rats was largely unchanged, as shown in results regarding serum glucose, glucose transport in skeletal muscle, blood urea nitrogen, and glycogen and protein content in the liver and in skeletal muscle. Conclusion/Interpretation: In summary, chronic IAPP exposure led to a changed lipid metabolism, which was characterized by decreased adiposity, hypolipidemia and hypoleptinemia, and to unchanged glucose and protein homeostasis. These results were similar to those seen in rodents during chronic exposure to another satiety/adiposity regulator, leptin. In conclusion, chronically administered IAPP plays a role as a satiety and adiposity signal in rats, and helps regulate energy homeostasis.
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| 8. |
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| 9. |
- Andersson, Åsa, Professor, 1960-, et al.
(författare)
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Serum Protein Response To A Single High-Intensity Interval Training Bout – Comparison Between Individuals With Spondyloarthritis And Healthy Controls
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:Suppl 1, s. 780-781
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Tidskriftsartikel (refereegranskat)abstract
- Axial spondyloarthritis (axSpA) is a chronic inflammatory disease affecting mainly the axial skeleton. To decrease the risk of cardiovascular comorbidity, aerobic training is recommended as a part of disease management in patients with axSpA. High-intensity interval training (HIIT) interventions are, in addition to other recommended treatments, believed to positively affect the disease activity (1). However, the knowledge about the acute effects of HIIT on the inflammatory process at the molecular level is less studied. Understanding the acute HIIT effects on cytokines and additional serum proteins in axSpA is important for further long-term HIIT interventions and recording of the effect of HIIT on the axSpA disease profile.ObjectivesTo study the acute effects on serum proteins, such as cytokines, myokines, and inflammatory- and bone-related proteins, in response to a single bout of HIIT, and to compare the levels between baseline and post-HIIT in patients with axSpA and healthy controls (HC).MethodsThe pilot study included twenty-one participants (10 female, 11 male), mean (SD) age 40 (7) years, ten with axSpA, and eleven age and sex matched HC, who performed a single HIIT on a cycle ergometer consisting of 4x4 minutes interval (90% heart rate, HR-max) with three minutes active rest in between (70% of HR-max). Disease activity (BASDAI, 0-10) in patients with axSpA was 1.6 (0.8). Health status EuroQol (EQ5D, 0-1) were 0.87 (0.11) for axSpA, and 0.93 (0.10) for HC. The groups were well matched with no difference in baseline data for weight, BMI, EQ5D, blood pressure or aerobic capacity.Blood samples were taken before (baseline) and one hour after the single HIIT. The following serum proteins were analyzed on a Luminex MAGPIX System (Luminex corporation, Austin, TX USA): Interleukin (IL)-6, IL-17, IL-18, TNFαAGPIX System (Luminex corporatiosteoprotegerin, osteocalcin, osteopontin, and FGF-23. A three-way analysis of variance (ANOVA) was used to detect differences between groups, between sexes, and before and after a HIIT bout in a 2(group)*2(sex)*2(time) design. For main effects or interactions significant at p≤0.05, simple effect t-tests were used to determine the specific effects.ResultsA group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in the HC, 0.4 pg/ml (SD±0.4) at baseline vs. post-HIIT 1.8 (2.0). The concentration of the cytokines/chemokine IL-17, IL-18, TNFα group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in30) in VEGF-A showed that the axSpA group had significantly lower VEGF-A at baseline, 159 pg/ml (138) vs 326 (184) in the control group (which might be due to anti-inflammatory medication). A sex main effect (p=0.029) was observed from baseline to post-HIIT for the bone hormone osteocalcin, with a more pronounced decrease of serum osteocalcin in women with axSpA, 14.0 ng/ml (8.3) vs. post HIIT 13.2 (6.9). Moreover, the level of the multifunctional protein osteopontin was significantly lower (sex main effect, p=0.021) in women, 10.7 ng/ml (7.0) vs. men 20.4 (10.1), post-HIIT.ConclusionThis pilot study shows that one bout of HIIT influences the expression of proteins involved in inflammation and metabolism, and that sex is an important factor in the response to HIIT. The results should be followed up in longer intervention studies including higher numbers of participants.References[1]Sveaas, S. H. et al. (2019). High intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients. British journal of sports medicine, 54(5), 292-297.Disclosure of InterestsÅsa Andersson: None declared, Emma Haglund Consultant of: Novartis, Emma Berthold: None declared, Elisabeth Mogard Consultant of: Novartis, Anna Torell: None declared, M Charlotte Olsson: None declared
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| 10. |
- Arakelyan, Arsen, et al.
(författare)
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Functional Genetic Polymorphisms of Monocyte Chemoattractant Protein 1 and C-C Chemokine Receptor Type 2 in Ischemic Stroke
- 2014
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Ingår i: Journal of Interferon and Cytokine Research. - New Rochelle, NY : Mary Ann Liebert. - 1079-9907 .- 1557-7465. ; 34:2, s. 100-105
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings indicated that monocyte chemoattractant protein 1 (MCP1) and its C-C chemokine receptor type 2 (CCR2) play a key role in ischemic stroke (IS) progression. This study was aimed at evaluating the potential association of the MCP1 gene (MCP1) rs1024611 (-2518 A>G) and CCR2 gene (CCR2) rs1799864 (V64I; 190 G>A) functional single nucleotide polymorphisms (SNPs) with IS in the Armenian population. For the purpose of this study, genomic DNA samples of 100 patients with the first-episode IS and 115 healthy subjects (controls) were genotyped for the selected SNPs using a polymerase chain reaction with sequence-specific primers. The results obtained demonstrated that while the CCR2 rs1799864 SNP genotypes were equally distributed among patients and controls, the frequency and carriage rate of the of the MCP1 rs1024611*G minor allele were higher in patients. While a potential association between IS and CCR2 rs1799864 SNP was evaluated for the first time, the latest finding was in agreement with the earlier data reported for some other populations. In summary, this study revealed no association of CCR2 rs1799864 SNP with IS, and a positive association between G minor allele of MCP1 rs1024611 SNP and IS in the Armenian population. Based on the present and earlier reported data, we concluded that the minor G allele of the MCP1 rs1024611 SNP might be considered a risk factor for IS.
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