We read with great interest the letter by Ji et al. 1 Obesity is a wellrecognized risk factor for the development of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MAFLD) and is associated with adverse outcomes in COVID-19 patients. 2,3 Qatar's population has a high prevalence of obesity 4 and also has one of the highest rates of COVID-19 cases per million population, with one of the lowest mortality rates. 5 We hypothesized that NAFLD is an independent risk factor for worse outcomes in hospitalized COVID-19 patients in our population.

Heart failure (HF) has proven to be a major burden on the health system. The continuing prevalence of the condition and its rising associated costs and care, has amplified the need for earlier diagnosis, better risk stratification and cost-effective treatment to cut rates of hospitalization. Biomarkers seem poised to undertake such tasks, with biomarker management of patients with HF quickly evolving over the past several years. Biomarker guided diagnosis and treatment has become vital, especially during the acute setting in which the majority of patients with HF, were initially present. An adequate assessment of risk requires a multi-marker approach to a given HF patient. Established markers including brain natriuretic peptide and NT-proBNP are a significant clinical aid to physicians, though their utility is limited. In the past few years, momentous effort has been put into the discovery of new biomarkers. These endeavors have led to the emergence of several capable and promising biomarkers for HF management including troponins, mid-regional pro-adrenomedullin, GDF-15, C-reactive protein, Galectin-3, IL-6, ST-2, neutrophil gelatinase-associated lipocalin, copeptin and procalcitonin. This review will offer an insight into the novel biomarkers considered as the cutting-edge in the diagnosis and management of HF.

Introduction:Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.Methods:ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.Conclusions:ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Inflammatory processes arising from metabolic abnormalities are known to precipitate the development of CVD. Several metabolic and inflammatory markers have been proposed for predicting the progression of CVD, including high density lipoprotein cholesterol (HDL-C). For~50 years, HDL-C has been considered as the atheroprotective 'good' cholesterol because of its strong inverse association with the progression of CVD. Thus, interventions to increase the concentration of HDL-C have been successfully tested in animals; however, clinical trials were unable to confirm the cardiovascular benefits of pharmaceutical interventions aimed at increasing HDL-C levels. Based on these data, the significance of HDL-C in the prevention of CVD has been called into question. Fundamental in vitro and animal studies suggest that HDL-C functionality, rather than HDL-C concentration, is important for the CVD-preventive qualities of HDL-C. Our current review of the literature positively demonstrates the negative impact of systemic and tissue (i.e. adipose tissue) inflammation in the healthy metabolism and function of HDL-C. Our survey indicates that HDL-C may be a good marker of adipose tissue health, independently of its atheroprotective associations. We summarize the current findings on the use of antiinflammatory drugs to either prevent HDL-C clearance or improve the function and production of HDL-C particles. It is evident that the therapeutic agents currently available may not provide the optimal strategy for altering HDL-C metabolism and function, and thus, further research is required to supplement this mechanistic approach for preventing the progression of CVD. LINKED ARTICLES IntroductionThere have been several sharp turns in the evidence trail marking the atheroprotective role of high density lipoproteins (HDLs). Very early studies on dyslipidaemia highlighted the positive correlation between total triglycerides (TGs) with the risk of developing cardiovascular disease (CVD). Since the mid-1970s, numerous epidemiological and animal studies, including the Framingham Study (Gordon et al., 1977), reported that HDL cholesterol (HDL-C) has the strongest inverse relationship with the development of CVD of the known serum lipid factors (Badimon et al., 1990;Rubin et al., 1991;Liu et al., 1994;Plump et al., 1994). This association is underpinned by reverse cholesterol transport (RCT) -a process by which HDL-C transfers the cholesterol from peripheral cells, for example, lipid-laden foam cells, to the liver for secretion into bile and faeces. The promotion of RCT is considered a major anti-atherogenic function of HDL-C (Gofman et al., 1966;Miller and Miller, 1975;Rhoads et al., 1976). Based on these findings, interventions to increase the levels of HDL-C were developed but found to be ineffective for preventing cardiovascular outcomes in several large clinical trials (Brousseau et al., 2004;McKenney et al., 2006;Barter et al., 2007;Boden et al., 2011;Lü...