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Blood Jun 2023The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The...
The European LeukemiaNet recently revised both the clinical (2022) and measurable residual disease testing (2021) guidelines for acute myeloid leukemia (AML). The updated World Health Organization and International Consensus Classification for myeloid neoplasms were also published in 2022. Together, these documents update the classification, risk stratification, prognostication, monitoring recommendations, and response assessment of patients with AML. Increased appreciation of the genetic drivers of AML over the past decade and our increasingly sophisticated understanding of AML biology have been translated into novel therapies and more complex clinical treatment guidelines. Somatic genetic abnormalities and germ line predispositions now define and guide treatment and counseling for the subtypes of this hematologic malignancy. In this How I Treat article, we discuss how we approach AML in daily clinical practice, considering the recent updates in the context of new treatments and discoveries over the past decade.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual; Consensus; Genotype; Hematologic Neoplasms
PubMed: 36758209
DOI: 10.1182/blood.2022017808 -
Annual Review of Pharmacology and... Jan 2024Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk... (Review)
Review
Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.
Topics: Humans; Cholesterol, LDL; Cardiovascular Diseases; Risk Factors; Lipoprotein(a); Heart Disease Risk Factors
PubMed: 37506332
DOI: 10.1146/annurev-pharmtox-031023-100609 -
Atherosclerosis Oct 2023Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density... (Review)
Review
Dyslipidemia refers to unhealthy changes in blood lipid composition and is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Usually, low-density lipoprotein-cholesterol (LDL-C) is the primary goal for dyslipidemia management. However, non-high-density lipoprotein cholesterol (non-HDL-C) has gained attention as an alternative, reliable goal. It encompasses all plasma lipoproteins like LDL, triglyceride-rich lipoproteins (TRL), TRL-remnants, and lipoprotein a [Lp(a)] except high-density lipoproteins (HDL). In addition to LDL-C, several other constituents of non-HDL-C have been reported to be atherogenic, aiding the pathophysiology of atherosclerosis. They are acknowledged as contributors to residual ASCVD risk that exists in patients on statin therapy with controlled LDL-C levels. Therefore, non-HDL-C is now considered an independent risk factor or predictor for CVD. The popularity of non-HDL-C is attributed to its ease of estimation and non-dependency on fasting status. It is also better at predicting ASCVD risk in patients on statin therapy, and/or in those with obesity, diabetes, and metabolic disorders. In addition, large follow-up studies have reported that individuals with higher baseline non-HDL-C at a younger age (<45 years) were more prone to adverse CVD events at an older age, suggesting a predictive ability of non-HDL-C over the long term. Consequently, non-HDL-C is recommended as a secondary goal for dyslipidemia management by most international guidelines. Intriguingly, geographical patterns in recent epidemiological studies showed remarkably high non-HDL-C attributable mortality in high-risk countries. This review highlights the independent role of non-HDL-C in ASCVD pathogenesis and prognosis. In addition, the need for a country-specific approach to dyslipidemia management at the community/population level is discussed. Overall, non-HDL-C can become a co-primary or primary goal in dyslipidemia management.
Topics: Humans; Middle Aged; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Cholesterol, HDL; Cardiovascular Diseases; Cholesterol; Dyslipidemias; Lipoproteins; Risk Factors; Atherosclerosis
PubMed: 37826864
DOI: 10.1016/j.atherosclerosis.2023.117312 -
Cureus Aug 2023Developmental dysplasia of the hip (DDH) is a complex disorder that refers to different hip problems, ranging from neonatal instability to acetabular or femoral... (Review)
Review
Developmental dysplasia of the hip (DDH) is a complex disorder that refers to different hip problems, ranging from neonatal instability to acetabular or femoral dysplasia, hip subluxation, and hip dislocation. It may result in structural modifications, which may lead to early coxarthrosis. Despite identifying the risk factors, the exact aetiology and pathophysiology are still unclear. Neonatal screening, along with physical examination and ultrasound, is critical for the early diagnosis of DDH to prevent the occurrence of early coxarthrosis. This review summarizes the currently practised strategies for the detection and treatment of DDH, focusing particularly on current practices for managing residual acetabular dysplasia (AD). AD may persist even after a successful hip reduction. Pelvic osteotomy is required in cases of persistent AD. It could also be undertaken simultaneously with an open hip reduction. Evaluation of the residual dysplasia (RD) of the hip and its management is still a highly active area of discussion. Recent research has opened the door to discussion on this issue and suggested treatment options for AD. But there is still room for more research to assist in managing AD.
PubMed: 37692580
DOI: 10.7759/cureus.43207 -
International Journal of Environmental... Sep 2023Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having... (Review)
Review
Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.
Topics: Humans; Cardiovascular Diseases; Lipoprotein(a); Plasminogen; Proprotein Convertase 9; Risk Factors; Serine Proteases
PubMed: 37754581
DOI: 10.3390/ijerph20186721 -
The Lancet. Neurology Aug 2023Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by...
BACKGROUND
Although meningitis is largely preventable, it still causes hundreds of thousands of deaths globally each year. WHO set ambitious goals to reduce meningitis cases by 2030, and assessing trends in the global meningitis burden can help track progress and identify gaps in achieving these goals. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we aimed to assess incident cases and deaths due to acute infectious meningitis by aetiology and age from 1990 to 2019, for 204 countries and territories.
METHODS
We modelled meningitis mortality using vital registration, verbal autopsy, sample-based vital registration, and mortality surveillance data. Meningitis morbidity was modelled with a Bayesian compartmental model, using data from the published literature identified by a systematic review, as well as surveillance data, inpatient hospital admissions, health insurance claims, and cause-specific meningitis mortality estimates. For aetiology estimation, data from multiple causes of death, vital registration, hospital discharge, microbial laboratory, and literature studies were analysed by use of a network analysis model to estimate the proportion of meningitis deaths and cases attributable to the following aetiologies: Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, group B Streptococcus, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Staphylococcus aureus, viruses, and a residual other pathogen category.
FINDINGS
In 2019, there were an estimated 236 000 deaths (95% uncertainty interval [UI] 204 000-277 000) and 2·51 million (2·11-2·99) incident cases due to meningitis globally. The burden was greatest in children younger than 5 years, with 112 000 deaths (87 400-145 000) and 1·28 million incident cases (0·947-1·71) in 2019. Age-standardised mortality rates decreased from 7·5 (6·6-8·4) per 100 000 population in 1990 to 3·3 (2·8-3·9) per 100 000 population in 2019. The highest proportion of total all-age meningitis deaths in 2019 was attributable to S pneumoniae (18·1% [17·1-19·2]), followed by N meningitidis (13·6% [12·7-14·4]) and K pneumoniae (12·2% [10·2-14·3]). Between 1990 and 2019, H influenzae showed the largest reduction in the number of deaths among children younger than 5 years (76·5% [69·5-81·8]), followed by N meningitidis (72·3% [64·4-78·5]) and viruses (58·2% [47·1-67·3]).
INTERPRETATION
Substantial progress has been made in reducing meningitis mortality over the past three decades. However, more meningitis-related deaths might be prevented by quickly scaling up immunisation and expanding access to health services. Further reduction in the global meningitis burden should be possible through low-cost multivalent vaccines, increased access to accurate and rapid diagnostic assays, enhanced surveillance, and early treatment.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Child; Humans; Global Burden of Disease; Bayes Theorem; Meningitis; Risk Factors; Global Health
PubMed: 37479374
DOI: 10.1016/S1474-4422(23)00195-3 -
Arteriosclerosis, Thrombosis, and... Sep 2023Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol (RC). We conducted a large-scale Mendelian randomization study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk.
METHODS
We extracted single-nucleotide polymorphisms for RC and LDL from large-scale genome-wide association databases. We estimated the genetic association with outcomes from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, as well as the GLGC (Global Lipids Genetics Consortium). Genetic variants were used as instruments, thereby minimizing residual confounding and reverse causation biases of observational studies.
RESULTS
By leveraging data from a combined sample of 958 434 participants, we found evidence for a significant causal effect of RC on the risk of CAD (odds ratio [OR], 1.51 per SD unit increase in RC [95% CI, 1.42-1.60]; =5.3×10), MI (OR, 1.57 [95% CI, 1.21-2.05]; =9.5×10), and stroke (OR, 1.23 [95% CI, 1.12-1.35]; =3.72×10). There was no evidence of pleiotropy. The effect of RC on CAD and MI remained consistent after accounting for the effects of RC-associated genetic variants on LDL cholesterol: OR, 1.49 (95% CI, 1.37-1.61) for CAD and OR, 1.80 (95% CI, 1.70-19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL cholesterol mediator.
CONCLUSIONS
This large-scale Mendelian randomization study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.
Topics: Humans; Coronary Artery Disease; Cholesterol, LDL; Mendelian Randomization Analysis; Genome-Wide Association Study; Myocardial Infarction; Stroke; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 37439258
DOI: 10.1161/ATVBAHA.123.319297