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BACKGROUND: Stress is a universal phenomenon and one of the most common precipitants of insomnia. However, not everyone develops insomnia after experiencing a stressful life event. This study aims to test aspects of Spielman's '3P model of insomnia' (during adolescence) by exploring the extent to which: (a) insomnia symptoms are predicted by polygenic scores (PGS); (b) life events predict insomnia symptoms; (c) the interaction between PGS and life events contribute to the prediction of insomnia symptoms; (d) gene-environment interaction effects remain after controlling for sex. METHODS: The sample comprised 4,629 twins aged 16 from the Twin Early Development Study who reported on their insomnia symptoms and life events. PGS for insomnia were calculated. In order to test the main hypothesis of this study (a significant interaction between PGS and negative life events), we fitted a series of mixed effect regressions. RESULTS: The best fit was provided by the model including sex, PGS for insomnia, negative life events, and their interactions (AIC\u2009=\u200926,158.7). Our results show that the association between insomnia symptoms and negative life events is stronger for those with a higher genetic risk for insomnia. CONCLUSIONS: This work sheds light on the complex relationship between genetic and environmental factors implicated for insomnia. This study has tested for the first time the interaction between genetic predisposition (PGS) for insomnia and environmental stressors (negative life events) in adolescents. This work represents a direct test of components of Spielman's 3P model for insomnia which is supported by our results.
\n \n\n \n \nSTUDY OBJECTIVES: Digital technology use is associated with poor sleep quality in adolescence and young adulthood although research findings have been mixed. No studies have addressed the association between the two using a genetically informative twin design which could extend our understanding of the etiology of this relationship. This study aimed to test: (1) the association between adolescents' perceived problematic use of digital technology and poor sleep quality, (2) whether the association between problematic use of technology and poor sleep quality remains after controlling for familial factors, and (3) genetic and environmental influences on the association between problematic use of technology and poor sleep quality. METHODS: Participants were 2232 study members (18-year-old twins) of the Environmental Risk (E-Risk) Longitudinal Twin Study. The sample was 48.9% male, 90% white, and 55.6% monozygotic. We conducted regression and twin difference analyses and fitted twin models. RESULTS: Twin differences for problematic use of technology were associated with differences for poor sleep quality in the whole sample (p < 0.001; B = 0.15) and also when we limited the analyses to identical twins only (p < 0.001; B = 0.21). We observed a substantial genetic correlation between problematic use of technology and sleep quality (rA = 0.31), whereas the environmental correlation was lower (rE = 0.16). CONCLUSIONS: Adolescent reported problematic use of digital technology is associated with poor sleep quality-even after controlling for familial factors including genetic confounds. Our results suggest that the association between adolescents' sleep and problematic digital technology use is not accounted for by shared genetic liability or familial factors but could reflect a causal association. This robust association needs to be examined in future research designed to test causal associations.
\n \n\n \n \nBACKGROUND: Periprosthetic fractures are rare but serious complications of unicompartmental knee arthroplasty (UKA). Although cementless UKA has a lower risk of loosening than cemented, there are concerns that tibial fracture risk may be higher given the reliance on interference fit for primary stability. The risk of fracture and the effect of surgical fixation are currently unknown. We compared the periprosthetic fracture rate following cemented and cementless UKA surgery. METHODS: A total of 14,122 medial mobile-bearing UKAs (7,061 cemented and 7,061 cementless) from the National Joint Registry and Hospital Episodes Statistics database were propensity score-matched. Cumulative fracture rates were calculated and Cox regressions were used to compare fixation groups. RESULTS: The three-month periprosthetic fracture rates were similar (P\u00a0= .80), being 0.10% in the cemented group and 0.11% in the cementless group. The fracture rates were highest during the first three months postoperatively, but then decreased and remained constant between one and 10 years after surgery. The one-year cumulative fracture rates were 0.2% (confidence interval [CI]: 0.1 to 0.3) for cemented and 0.2% (CI: 0.1 to 0.3) for cementless cases. The 10-year cumulative fracture rates were 0.8% (CI: 0.2 to 1.3) and 0.8% (CI: 0.3 to 1.3), respectively. The hazard ratio during the whole study period was 1.06 (CI: 0.64 to 1.77; P\u00a0= .79). CONCLUSIONS: The periprosthetic fracture rate following mobile bearing UKA surgery is low, being about 1% at 10 years. There were no significant differences in fracture rates between cemented and cementless implants after matching. We surmise that surgeons are aware of the higher theoretical risk of early fracture with cementless components and take care with tibial preparation. LEVELS OF EVIDENCE: III.
\n \n\n \n \nBACKGROUND: Myocardial inflammation and injury occur during coronary artery bypass graft (CABG) surgery. We aimed to characterise these processes during routine CABG surgery to inform the diagnosis of type 5 myocardial infarction. METHODS: We assessed 87 patients with stable coronary artery disease who underwent elective CABG surgery. Myocardial inflammation, injury and infarction were assessed using plasma inflammatory biomarkers, high-sensitivity cardiac troponin I (hs-cTnI) and cardiac magnetic resonance imaging (CMR) using both late gadolinium enhancement (LGE) and ultrasmall superparamagnetic particles of iron oxide (USPIO). RESULTS: Systemic humoral inflammatory biomarkers (myeloperoxidase, interleukin-6, interleukin-8 and c-reactive protein) increased in the post-operative period with C-reactive protein concentrations plateauing by 48\u00a0h (median area under the curve (AUC) 7530 [interquartile range (IQR) 6088 to 9027] mg/L/48\u00a0h). USPIO-defined cellular myocardial inflammation ranged from normal to those associated with type 1 myocardial infarction (median 80.2 [IQR 67.4 to 104.8] /s). Plasma hs-cTnI concentrations rose by \u226550-fold from baseline and exceeded 10-fold the upper limit of normal in all patients. Two distinct patterns of peak cTnI release were observed at 6 and 24\u00a0h. After CABG surgery, new LGE was seen in 20% (n\u2009=\u200918) of patients although clinical peri-operative type 5 myocardial infarction was diagnosed in only 9% (n\u2009=\u20098). LGE was associated with the delayed 24-h peak in hs-cTnI and its magnitude correlated with AUC plasma hs-cTnI concentrations (r\u2009=\u20090.33, p\u200910-fold the 99th centile upper limit of normal that is not attributable to inflammatory or ischemic injury alone. Peri-operative type 5 myocardial infarction is often unrecognised and is associated with a delayed 24-h peak in plasma hs-cTnI concentrations.
\n \n\n \n \nBACKGROUND: High-sensitivity cardiac troponin assays can help to identify patients who are at low risk of myocardial infarction in the emergency department. We aimed to determine whether the addition of clinical risk scores would improve the safety of early rule-out pathways for myocardial infarction. METHODS: In 1935 patients with suspected acute coronary syndrome, we evaluated the safety and efficacy of 2 rule-out pathways alone or in conjunction with low-risk TIMI (Thrombolysis In Myocardial Infarction) (0 or 1), GRACE (Global Registry of Acute Coronary Events) (\u2264108), EDACS (Emergency Department Assessment of Chest Pain Score) (<16), or HEART (History, ECG, Age, Risk factors, Troponin) (\u22643) scores. The European Society of Cardiology 3-hour pathway uses a single diagnostic threshold (99th percentile), whereas the High-STEACS (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) pathway applies different thresholds to rule out (<5 ng/L) and rule in (>99th percentile) myocardial infarction. RESULTS: Myocardial infarction or cardiac death during the index presentation or at 30 days occurred in 14.3% of patients (276/1935). The European Society of Cardiology pathway ruled out 70%, with 27 missed events giving a negative predictive value of 97.9% (95% CI, 97.1-98.6). The addition of a HEART score \u22643 reduced the proportion ruled out by the European Society of Cardiology pathway to 25% but improved the negative predictive value to 99.7% (95% CI, 99.0-100; P<0.001). The High-STEACS pathway ruled out 65%, with 3 missed events for a negative predictive value of 99.7% (95% CI, 99.4-99.9). No risk score improved the negative predictive value of the High-STEACS pathways, but all reduced the proportion ruled out (24% to 47%; P<0.001 for all). CONCLUSIONS: Clinical risk scores significantly improved the safety of the European Society of Cardiology 3-hour pathway, which relies on a single cardiac troponin threshold at the 99th percentile to rule in and rule out myocardial infarction. Where lower thresholds are used to rule out myocardial infarction, as applied in the High-STEACS pathway, risk scores halve the proportion of patients ruled out without improving safety. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01852123.
\n \n\n \n \nRATIONALE: In response to blood vessel wall injury, aberrant proliferation of vascular smooth muscle cells (SMCs) causes pathological remodeling. However, the controlling mechanisms are not completely understood. OBJECTIVE: We recently showed that the human long noncoding RNA, SMILR, promotes vascular SMCs proliferation by a hitherto unknown mechanism. Here, we assess the therapeutic potential of SMILR inhibition and detail the molecular mechanism of action. METHODS AND RESULTS: We used deep RNA-sequencing of human saphenous vein SMCs stimulated with IL (interleukin)-1\u03b1 and PDGF (platelet-derived growth factor)-BB with SMILR knockdown (siRNA) or overexpression (lentivirus), to identify SMILR-regulated genes. This revealed a SMILR-dependent network essential for cell cycle progression. In particular, we found using the fluorescent ubiquitination-based cell cycle indicator viral system that SMILR regulates the late mitotic phase of the cell cycle and cytokinesis with SMILR knockdown resulting in \u224810% increase in binucleated cells. SMILR pulldowns further revealed its potential molecular mechanism, which involves an interaction with the mRNA of the late mitotic protein CENPF (centromere protein F) and the regulatory Staufen1 RNA-binding protein. SMILR and this downstream axis were also found to be activated in the human ex vivo vein graft pathological model and in primary human coronary artery SMCs and atherosclerotic plaques obtained at carotid endarterectomy. Finally, to assess the therapeutic potential of SMILR, we used a novel siRNA approach in the ex vivo vein graft model (within the 30 minutes clinical time frame that would occur between harvest and implant) to assess the reduction of proliferation by EdU incorporation. SMILR knockdown led to a marked decrease in proliferation from \u224829% in controls to \u22485% with SMILR depletion. CONCLUSIONS: Collectively, we demonstrate that SMILR is a critical mediator of vascular SMC proliferation via direct regulation of mitotic progression. Our data further reveal a potential SMILR-targeting intervention to limit atherogenesis and adverse vascular remodeling.
\n \n\n \n \nExposure to urban particulate matter has been associated with an increased risk of cardiovascular disease and thrombosis. We studied the effects of transient exposure to diesel particles on fibrin clot structure of 16 healthy individuals (age 21-44). The subjects were randomly exposed to diesel exhaust and filtered air on two separate occasions. Blood samples were collected before exposure, and 2 and 6 hours after exposure. There were no significant changes on clot permeability, maximum turbidity, lag time, fibre diameter, fibre density and fibrinogen level between samples taken after diesel exhaust exposure and samples taken after filtered air exposure. These data show that there are no prothrombotic changes in fibrin clot structure in young, healthy individuals exposed to diesel exhaust.
\n \n\n \n \nFine particulate air pollution\u00a0<2.5\u00a0\u03bcm in diameter (PM2.5) is a major environmental threat to global public health. Multiple national and international medical and governmental organizations have recognized PM2.5 as a risk factor for cardiopulmonary diseases. A growing body of evidence indicates that several personal-level approaches that reduce exposures to PM2.5 can lead to improvements in health endpoints. Novel and forward-thinking strategies including randomized clinical trials are important to validate key aspects (e.g., feasibility, efficacy, health benefits, risks, burden, costs) of the various protective interventions, in particular among real-world susceptible and vulnerable populations. This paper summarizes the discussions and conclusions from an expert workshop, Reducing the Cardiopulmonary Impact of Particulate Matter Air Pollution in High Risk Populations, held on May 29 to 30, 2019, and convened by the National Institutes of Health, the U.S. Environmental Protection Agency, and the U.S. Centers for Disease Control and Prevention.
\n \n\n \n \nRATIONALE: More patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular causes than of respiratory causes, and patients with COPD have increased morbidity and mortality from stroke and coronary heart disease. Arterial stiffness independently predicts cardiovascular risk, is associated with atheromatous plaque burden, and is increased in patients with COPD compared with control subjects matched for cardiovascular risk factors. Elastin fragmentation and changes in collagen are found in the connective tissue of both emphysematous lungs and stiff arteries, but it is not known whether the severity of arterial stiffness in patients with COPD is associated with the severity of emphysema. OBJECTIVES: To identify whether the extent of arterial stiffness is associated with emphysema severity. METHODS: We performed a cross-sectional study in 157 patients with COPD. MEASUREMENTS AND MAIN RESULTS: We measured pulse wave velocity (a validated measure of arterial stiffness), blood pressure, smoking pack-years, glucose, cholesterol, and C-reactive protein in 157 patients with COPD. We assessed emphysema using quantitative computed tomography scanning in a subgroup of 73 patients. We found that emphysema severity was associated with arterial stiffness (r = 0.471, P < 0.001). The association was independent of smoking, age, sex, FEV(1)% predicted, highly sensitive C-reactive protein and glucose concentrations, cholesterol-high-density lipoprotein ratio, and pulse oximetry oxygen saturations. CONCLUSIONS: Emphysema severity is associated with arterial stiffness in patients with COPD. Similar pathophysiological processes may be involved in both lung and arterial tissue and further studies are now required to identify the mechanism underlying this newly described association.
\n \n\n \n \nIschemic heart disease is a complex disease process caused by the development of coronary atherosclerosis, with downstream effects on the left ventricular myocardium. It is characterized by a long preclinical phase, abrupt development of myocardial infarction, and more chronic disease states such as stable angina and ischemic cardiomyopathy. Recent advances in computed tomography (CT) and cardiac magnetic resonance (CMR) now allow detailed imaging of each of these different phases of the disease, potentially allowing ischemic heart disease to be tracked during a patient's lifetime. In particular, CT has emerged as the noninvasive modality of choice for imaging the coronary arteries, whereas CMR offers detailed assessments of myocardial perfusion, viability, and function. The clinical utility of these techniques is increasingly being supported by robust randomized controlled trial data, although the widespread adoption of cardiac CT and CMR will require further evidence of clinical efficacy and cost effectiveness.
\n \n\n \n \nEndothelium-derived hyperpolarising factor (EDHF) causes vasorelaxation and may contribute to the release of the endogenous fibrinolytic factor, tissue-plasminogen activator (t-PA). Rotigaptide enhances communication via the connexin 43 gap junction subunit and may potentiate the vascular actions of EDHF. The aims of the present study were therefore to determine whether rotigaptide influences basal and stimulated endothelium-dependent vasodilatation and t-PA release in vivo in man. Using venous occlusion plethysmography, forearm blood flow was measured in 27 healthy volunteers during intra-brachial infusions of rotigaptide (0.25-25 nmol/min) alone, or co-administered with endothelium-dependent (acetylcholine [5-20 microg/min] and bradykinin [30-300 pmol/min]) and independent (sodium nitroprusside [2-8 microg/min]) vasodilators in the presence or absence of aspirin and the 'nitric oxide clamp'. The 'nitric oxide clamp' inhibits endogenous nitric oxide synthesis with L-N-monomethylarginine and restores resting blood flow with the exogenous nitric oxide donor, sodium nitroprusside. Basal blood flow was unaffected by rotigaptide (P=NS). Acetylcholine, bradykinin and sodium nitroprusside all caused dose-dependent vasodilatation in the presence and absence of aspirin and the 'nitric oxide clamp' (P< or =0.005 for all). These responses were unaffected by rotigaptide (P=NS). Bradykinin caused t-PA antigen and activity release (P=0.04, P<0.0001, respectively) that was unaffected by rotigaptide. Augmentation of connexin 43 communication has no effect on basal vascular tone and does not enhance endothelium-dependent or independent vasodilatation, or t-PA release in the forearm arterial circulation of healthy men. It remains to be established whether augmentation of connexin 43 communication improves endothelial function in patients with vascular disease.
\n \n\n \n \nBackground It is recognized that factors beyond aortic size are important in predicting outcome in abdominal aortic aneurysm (AAA) disease. AAA is characterized by the breakdown of elastin within the aortic tunica media, leading to aortic dilatation and rupture. The aim of this study was to investigate the association of plasma desmosine (pDES), an elastin-specific degradation product, with disease severity and clinical outcome in patients with AAA. Methods and Results We measured pDES and serum biomarker concentrations in 507 patients with AAAs (94% men; mean age, 72.4\u00b16.1\u00a0years; mean AAA diameter, 48\u00b18\u00a0mm) and 162 control subjects (100% men; mean age, 71.5\u00b14.4\u00a0years) from 2 observational cohort studies. In the longitudinal cohort study (n=239), we explored the incremental prognostic value of pDES on AAA events. pDES was higher in patients with AAA compared with control subjects (mean\u00b1SD: 0.46\u00b10.22 versus 0.33\u00b10.16\u00a0ng/mL; P<0.001) and had the strongest correlation with AAA diameter (r=0.39; P<0.0001) of any serum biomarker. After adjustment for baseline AAA diameter, pDES was associated with an AAA event (hazard ratio, 2.03 per SD increase [95% CI, 1.02-4.02]; P=0.044). In addition to AAA diameter, pDES provided incremental improvement in risk stratification (continuous net reclassification improvement, 34.4% [95% CI, -10.8% to 57.5%; P=0.09]; integrated discrimination improvement, 0.04 [95% CI, 0.00-0.15; P=0.050]). Conclusions pDES concentrations predict disease severity and clinical outcomes in patients with AAA. Clinical Trial Registration http://www.isrctn.com. Unique identifier: ISRCTN76413758.
\n \n\n \n \nBACKGROUND: In the COMPLETE (Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI) trial, angiography-guided percutaneous coronary intervention (PCI) of nonculprit lesions with the aim of complete revascularization reduced major cardiovascular (CV) events in patients with ST-segment elevation myocardial infarction (MI) and multivessel coronary artery disease. OBJECTIVES: The purpose of this study was to determine the effect of nonculprit-lesion stenosis severity measured by quantitative coronary angiography (QCA) on the benefit of complete revascularization. METHODS: Among 4,041 patients randomized in the COMPLETE trial, nonculprit lesion stenosis severity was measured using QCA in the angiographic core laboratory in 3,851 patients with 5,355 nonculprit lesions. In pre-specified analyses, the treatment effect in patients with QCA stenosis\u00a0\u226560% versus\u00a0<60% on the first coprimary outcome of CV death or new MI and the second co-primary outcome of CV death, new MI, or ischemia-driven revascularization was determined. RESULTS: The first coprimary outcome was reduced with complete revascularization in the 2,479 patients with QCA stenosis\u00a0\u226560% (2.5%/year vs. 4.2%/year; hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.47 to 0.79), but not in the 1,372 patients with QCA stenosis\u00a0<60% (3.0%/year vs. 2.9%/year; HR: 1.04; 95%\u00a0CI: 0.72 to 1.50; interaction p\u00a0=\u00a00.02). The second coprimary outcome was reduced in patients with QCA stenosis\u00a0\u226560% (2.9%/year vs. 6.9%/year; HR: 0.43; 95%\u00a0CI: 0.34 to 0.54) to a greater extent than patients with QCA stenosis\u00a0<60% (3.3%/year vs. 5.2%/year; HR: 0.65; 95%\u00a0CI: 0.47 to 0.89; interaction p\u00a0=\u00a00.04). CONCLUSIONS: Among patients with ST-segment elevation MI and multivessel coronary artery disease, complete revascularization reduced major CV outcomes to a greater extent in patients with stenosis severity of\u00a0\u226560% compared with\u00a0<60%, as determined by quantitative coronary angiography.
\n \n\n \n \nBACKGROUND: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. METHODS: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123. FINDINGS: Between June 10, 2013, and March 3, 2016, we enrolled 48\u2008282 consecutive patients (61 [SD 17] years, 47% women) of whom 10\u2008360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10\u2008360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1\u00b710, 95% CI 0\u00b775 to 1\u00b761; p=0\u00b7620). INTERPRETATION: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10\u2008360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. FUNDING: The British Heart Foundation.
\n \n\n \n \nRATIONALE: Cardiovascular disease is a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), which may in part be attributable to abnormalities of systemic vascular function. It is unclear whether such associations relate to the presence of COPD or prior smoking habit. OBJECTIVES: To undertake a comprehensive assessment of vascular function in patients with COPD and healthy control subjects matched for smoking history. METHODS: Eighteen men with COPD were compared with 17 healthy male control subjects matched for age and lifetime cigarette smoke exposure. Participants were free from clinically evident cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: Pulse wave velocity and pulse wave analysis were measured via applanation tonometry at carotid, radial, and femoral arteries. Blood flow was measured in both forearms using venous occlusion plethysmography during intrabrachial infusion of endothelium-dependent vasodilators (bradykinin, 100-1,000 pmol/min; acetylcholine, 5-20 microg/min) and endothelium-independent vasodilators (sodium nitroprusside, 2-8 microg/min; verapamil, 10-100 microg/min). Tissue plasminogen activator (t-PA) was measured in venous plasma before and during bradykinin infusions. Patients with COPD have greater arterial stiffness (pulse wave velocity, 11 +/- 2 vs. 9 +/- 2 m/s; P = 0.003; augmentation index, 27 +/- 10 vs. 21 +/- 6%; P = 0.028), but there were no differences in endothelium-dependent and -independent vasomotor function or bradykinin-induced endothelial t-PA release (P > 0.05 for all). CONCLUSIONS: COPD is associated with increased arterial stiffness independent of cigarette smoke exposure. However, this abnormality is not explained by systemic endothelial dysfunction. Increased arterial stiffness may represent the mechanistic link between COPD and the increased risk for cardiovascular disease associated with this condition.
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