siRNA-induced liver ApoB knockdown lowers serum LDL-cholesterol in a mouse model with human-like serum lipids[S]

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE–/– and low density lipoprotein receptor (LDLr)–/– mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP+/– hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP+/– mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project

PURPOSE:: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS:: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS:: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION:: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders. © 2011 Lippincott Williams & Wilkins

Enhanced interpretation of newborn screening results without analyte cutoff values

A collaboration among 157 newborn screening programs in 47 countries has lead to the creation of a database of 705,333 discrete analyte concentrations from 11,462 cases affected with 57 metabolic disorders, and from 631 heterozygotes for 12 conditions. This evidence was first applied to establish disease ranges for amino acids and acylcarnitines, and clinically validate 114 cutoff target ranges. Objective: To improve quality and performance with an evidence-based approach, multivariate pattern recognition software has been developed to aid in the interpretation of complex analyte profiles. The software generates tools that convert multiple clinically significant results into a single numerical score based on overlap between normal and disease ranges, penetration within the disease range, differences between specific conditions, and weighted correction factors. Design: Eighty-five on-line tools target either a single condition or the differential diagnosis between two or more conditions. Scores are expressed as a numerical value and as the percentile rank among all cases with the condition chosen as primary target, and are compared to interpretation guidelines. Tools are updated automatically after any new data submission (2009- 2011: 5.2 new cases added per day on average). Main outcome measures: Retrospective evaluation of past cases suggest that these tools could have avoided at least half of 277 false positive outcomes caused by carrier status for fatty acid oxidation disorders, and could have prevented 88% of false negative events caused by cutoff 7 values set inappropriately. In Minnesota, their prospective application has been a major contributing factor to the sustained achievement of a false positive rate below 0.1% and a positive predictive value above 60%. Conclusions: Application of this computational approach to raw data could make cutoff values for single analytes effectively obsolete. This paradigm is not limited to newborn screening and is applicable to the interpretation of diverse multi-analyte profiles utilized in laboratory medicine. Abstract wor

Worldwide Disparities in Recovery of Cardiac Testing 1 Year Into COVID-19

BACKGROUND The extent to which health care systems have adapted to the COVID-19 pandemic to provide necessary cardiac diagnostic services is unknown.OBJECTIVES The aim of this study was to determine the impact of the pandemic on cardiac testing practices, volumes and types of diagnostic services, and perceived psychological stress to health care providers worldwide.METHODS The International Atomic Energy Agency conducted a worldwide survey assessing alterations from baseline in cardiovascular diagnostic care at the pandemic's onset and 1 year later. Multivariable regression was used to determine factors associated with procedure volume recovery.RESULTS Surveys were submitted from 669 centers in 107 countries. Worldwide reduction in cardiac procedure volumes of 64% from March 2019 to April 2020 recovered by April 2021 in high- and upper middle-income countries (recovery rates of 108% and 99%) but remained depressed in lower middle- and low-income countries (46% and 30% recovery). Although stress testing was used 12% less frequently in 2021 than in 2019, coronary computed tomographic angiography was used 14% more, a trend also seen for other advanced cardiac imaging modalities (positron emission tomography and magnetic resonance; 22%-25% increases). Pandemic-related psychological stress was estimated to have affected nearly 40% of staff, impacting patient care at 78% of sites. In multivariable regression, only lower-income status and physicians' psychological stress were significant in predicting recovery of cardiac testing.CONCLUSIONS Cardiac diagnostic testing has yet to recover to prepandemic levels in lower-income countries. Worldwide, the decrease in standard stress testing is offset by greater use of advanced cardiac imaging modalities. Pandemic-related psychological stress among providers is widespread and associated with poor recovery of cardiac testing. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation