34 research outputs found

    Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

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    Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

    Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

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    Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

    Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

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    Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

    The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

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    DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

    The rise in non-fatal and fatal overdoses involving stimulants with and without opioids in the United States.

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    AIMS: To examine trends and recent changes in non-fatal and fatal stimulant overdose rates with and without opioids to improve the descriptive characterization of the US overdose epidemic. DESIGN: Secondary analysis of non-fatal (2006-16) and fatal (2006-17) drug overdose trends, focusing on the most recent years of data available to examine rate changes by demographics (2015-16 for non-fatal and 2016-17 for fatal). SETTING: Non-fatal drug overdoses from the Healthcare Cost and Utilization Project's Nationwide Emergency Department Sample; drug overdose deaths from the National Vital Statistics System. PARTICIPANTS/CASES: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) codes for cocaine, psychostimulants and opioids were used to classify non-fatal drug overdoses. Drug overdose deaths were identified using ICD-10 multiple cause-of-death codes for cocaine, psychostimulants, all opioids, heroin and synthetic opioids. MEASUREMENTS: Percentage of changes in age-adjusted non-fatal and fatal rates of cocaine and psychostimulant-involved drug overdose with and without opioids. FINDINGS: Overall, cocaine-involved non-fatal overdose rates with an opioid increased from 2006 to 2016 [annual percentage change (APC) = 14.7], while rates without an opioid increased from 2006 to 2012 (APC = 11.3) and then remained stable (APC = -7.5). Psychostimulant-involved non-fatal rates with and without an opioid increased from 2006 to 2016 (APC = 49.9 with opioids; 13.9 without opioids). Cocaine-involved death rates with and without opioids increased from 2014 to 2017 (APC = 46.0 with opioids, 23.6 without opioids). Psychostimulant-involved death rates with opioids increased from 2010 to 2015 (APC = 28.6), with a dramatic increase from 2015 to 2017 (APC = 50.5), while rates without opioids increased from 2008 to 2017 (APC = 22.6). In 2016, 27% of non-fatal cocaine- and 14% of psychostimulant-involved overdoses included a reported opioid; 72.7% of cocaine- and 50.3% of psychostimulant-involved deaths involved an opioid in 2017. From 2015 to 2016, cocaine-involved and psychostimulant-involved non-fatal overdose rates with an opioid increased 17.0 and 5.9%, respectively; cocaine-involved and psychostimulant-involved non-fatal overdoses without opioids decreased 13.6 and increased 18.9%, respectively. Death rates involving stimulants increased with and without opioids from 2016 to 2017 (cocaine with and without opioids = 37.7 and 23.3%; psychostimulants with and without opioids = 52.2 and 23.0%). Death rates involving stimulants with synthetic opioids increased dramatically from 2016 to 2017 (1.3-2.3 per 100 000 for cocaine and 0.3-0.8 for psychostimulants). CONCLUSIONS: While increases in cocaine-involved deaths in the United States from 2006 seem to be driven by opioids, particularly synthetic opioids, increases in non-fatal and fatal overdoses involving psychostimulants are occurring with and without opioids

    Trends in Suspected Opioid Overdoses from Emergency Departments in 11 States and DC

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    ObjectiveThis presentation will provide insight into how the extensive spread of illicitly-manufactured fentanyl impacted opioid overdose rates throughout the Midwest and neighboring states.IntroductionRecent reporting using data from CDC’s National Syndromic Surveillance Program indicates that rates of emergency department (ED) visits involving suspected opioid overdoses increased by 70% in the Midwest from the third quarter (Q3) 2016 (July–September) to the Q3 2017. Large increases in the use and distribution of illicitly-manufactured fentanyl (IMF) and fentanyl analogs, are a key factor driving increased opioid overdose rates in the Midwest and east of the Mississippi River. Fentanyl is a synthetic opioid 50–100 times more potent than morphine. A better understanding of the distribution of changes in opioid overdose rate from Q3 2016 to Q3 2017 within states needed to inform response and prevention efforts.MethodsThe CDC’s Enhanced State Opioid Overdose Surveillance Program currently funds 32 states and Washington DC to increase timeliness of opioid overdose reporting and detect rapid changes in trends. Data from nine states (IL, MD, MO, NC, OH, PA, VA, WI, WV) were analyzed. Midwest states sharing subregional data with CDC were selected to better understand geographic and temporal patterns driving previously reported increases in ED visits involving suspected opioid overdoses from Q3 2016 through Q3 2017. Bordering states (MD, NC, PA, VA, WV) sharing subregional data with CDC were also included to determine trends in states contiguous to the Midwest. State subregions were defined using publicly available state government sources in consultation with state public health departments and were mainly divided by public health districts. . Fifty of 56 possible state subregions across 9 states met two inclusion criteria: 1) reported 25 opioid overdose ED visits per quarter and 2) did not report a change of 50% between any two quarters. Opioid overdoses were defined according to jurisdictional and national definitions that included searches of chief complaint text (e.g., searching for words “opioid” and “overdose”) and ICD-10-CM diagnostic/billing codes. State subregional rates were defined as number of opioid overdoses divided by the total number of ED visits in the state subregion, multiplied by 10,000. Quarterly and yearly percent change in opioid overdose ED visits from Q3 2016 to Q3 2017 were described with a focus on high burden subregions reporting large yearly increases of 25% from Q3 2016 to Q3 2017. We categorized a subregion as having an opioid overdose outbreak when at least one quarterly rate increase in opioid overdoses of 50% occurred.ResultsOver 7 million ED visits were reported each quarter. Average subregional opioid overdose rates increased at a consistent quarterly rate of between 16% - 19% during Q3 2016 to Q2 2017. From Q2 2017 to Q3 2017, opioid overdose rates only increased 1%. Overall, subregions reported a mean yearly increase in opioid overdose rates of 51% from Q3 2016 to Q3 2017. This yearly increase in opioid overdose from Q3 2016 to Q3 2017 was unequally distributed across subregions with 9 (18%) of subregions reporting an increase in opioid overdose rates of 100%, 13 (26%) reporting an increase of 50% - <100%, 7 (14%) reporting an increase of 25% - <50%, 13 (26%) reporting an increases of 0% to <25%, and 8 (16%) reporting a decrease. Analyses of the 29 high burden subregions found that 16 (55%) reported at least one opioid overdose outbreak compared to 3 of 21 other subregions (14%) (Table 1). The 16 high burden subregions that reported any outbreak had a mean yearly increase in opioid overdose rates from Q3 2016 to Q3 2017 of 107%, range 33% to 266%. Eight of these 16 high burden subregions either reported two opioid overdose outbreaks or an opioid overdose outbreak and a quarterly increase of between 25% - <50%.All states had at least one subregion report an opioid overdose outbreak between Q3 2016 to Q2 2017. Also, within OH, PA, WI, and WV, half or more of their subregions reported an outbreak between Q3 2016 and Q3 2017 (Table 1). Fifteen of the 22 (68%) quarterly opioid overdose outbreaks occurred either during Q4 2016 or Q1 2017 (Table 1). Across all outbreaks, state subregions reported a mean quarterly increase of 83% with a range from 50 - 156%.ConclusionsOpioid overdose outbreaks in a subset of 16 high burden subregions across all 9 states were a key factor driving increases in the states’ opioid overdose rates. Half of these 16 subregions experienced a single opioid overdose outbreak while the other half experienced two or more sharp increases. The majority of opioid overdose outbreaks occurred during October 2016 to March 2017 were concentrated in Ohio, a state reporting extremely large increase in IMF supply and overdose deaths involving fentanyl, and states contiguous with Ohio. Although most subregions reported outbreaks at the beginning of the study period, higher opioid overdose rates persisted in the vast majority of subregions reporting opioid overdose outbreaks. This outbreak pattern is consistent with previous findings showing large increases in the supply of IMF and fentanyl analogs, including carfentanil, in Midwestern states during 2016 and in early 2017. Although opioid overdose outbreaks were concentrated in subregions in OH, PA, and WV, all 9 states included in the analysis were impacted by at least one outbreak during the study period. Findings highlight the need for targeting of hotspots within states and implementation of public health interventions to reduce harm and surge resources during an outbreak. These short-term efforts, however, must be complemented by a sustained response to reduce increased drug overdose rates that persist after an initial outbreak. A key limitation of this study was that it only included data from a single year and as a result may underestimate the length and severity of outbreaks. As changes in the illicit opioid market continue, surveillance of local outbreaks must be supplemented by broader surveillance designed to detect both localized introduction of new novel psychoactive substances as well as large scale changes in the illicit opioid market.ReferencesVivolo-Kantor, A. M., Seth, P., Gladden, R.M., et al. (2018). Vital Signs: Trends in Emergency Department Visits for Suspected Opioid Overdoses—United States, July 2016–September 2017.Morbidity and Mortality Weekly Report, 67, 279-285.O’Donnell J, Gladden RM, Mattson CL, et al. Notes from the Field: Overdose Deaths with Carfentanil and Other Fentanyl Analogs Detected — 10 States, July 2016–June 2017. Morb Mortal Wkly Rep 2018;67:767–768.O’Donnell JK, Halpin J, Mattson CL, et al. Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 — 10 States, July–December 2016. Morb Mortal Wkly Rep 2017;66:1197–1202.

    Occurrence and risk factors for acute kidney injury in patients hospitalized with acute pyelonephritis, and their clinical outcomes: A single center study from Northern India

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    Background: Acute kidney injury (AKI) associated with acute pyelonephritis (APN) is considered rare. This study is conducted to find out the occurrence and risk factors for AKI in patients hospitalized with acute pyelonephritis and their clinical outcomes. Materials and Methods: All inpatients with APN from December 2018 to May 2020 were included. Results: A total of 95 patients were included. Escherichia coli was the most common organism grown. At presentation, 79/95 (83.2%) patients had renal dysfunction. 31/79 (39.2%) patients required hemodialysis. AKI was 2.4 times common in men; P = 0.013. The mean duration of fever in patients with and without renal dysfunction was 8.30 ± 2.72 and 5.31 ± 0.91 days, respectively; P < 0.001. 73/79 (92.4%) patients with AKI had anemia as against 2/14 (14.2%) patients without AKI; P < 0.001. AKI developed in 100% of the patients with known chronic kidney disease (CKD) at baseline and 41.6% of the patients with normal baseline kidney function; P < 0.001. Diabetes mellitus was present in 29/79 (36.7%) patients with AKI and 6/16 (37.5%) patients without AKI; P = 0.31. Hospital stay in days was 11.65 ± 5.9 and 5.81 ± 0.91, respectively, in patients with and without renal dysfunction; P < 0.001. 6/95 (6.3%) patients died. All six patients had renal dysfunction. At 3 months, renal functions normalized in 38/79 (48.1%) patients and 8/31 (25.8%) patients remained dialysis-dependent. Conclusions: AKI is a common complication of APN. It is usually reversible with early and appropriate management. Male gender, anemia, bilateral pyelonephritis, baseline CKD, and delayed presentation to hospital are associated with increased risk of AKI. It is associated with an increased risk of dialysis, hospitalization days, and mortality
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