No abstract

Early extubation appears safe and is associated with reduction in length of ICU and hospital stay without adverse effects on mortality or morbidity. However, studies to date are poor, heterogeneous, and not suitable to determine a causal effect. Therefore, there is need for a well-designed randomized clinical trial to demonstrate the potential significant benefits of early extubation.

Background Cardiovascular outcomes for people with familial hypercholesterolaemia can be improved with diagnosis and medical management. However, 90% of individuals with familial hypercholesterolaemia remain undiagnosed in the USA. We aimed to accelerate early diagnosis and timely intervention for more than 1•3 million undiagnosed individuals with familial hypercholesterolaemia at high risk for early heart attacks and strokes by applying machine learning to large health-care encounter datasets. MethodsWe trained the FIND FH machine learning model using deidentified health-care encounter data, including procedure and diagnostic codes, prescriptions, and laboratory findings, from 939 clinically diagnosed individuals with familial hypercholesterolaemia (395 of whom had a molecular diagnosis) and 83 136 individuals presumed free of familial hypercholesterolaemia, sampled from four US institutions. The model was then applied to a national health-care encounter database (170 million individuals) and an integrated health-care delivery system dataset (174 000 individuals). Individuals used in model training and those evaluated by the model were required to have at least one cardiovascular disease risk factor (eg, hypertension, hypercholesterolaemia, or hyperlipidemia). A Health Insurance Portability and Accountability Act of 1996-compliant programme was developed to allow providers to receive identification of individuals likely to have familial hypercholesterolaemia in their practice. Findings Using a model with a measured precision (positive predictive value) of 0•85, recall (sensitivity) of 0•45, area under the precision-recall curve of 0•55, and area under the receiver operating characteristic curve of 0•89, we flagged 1 331 759 of 170 416 201 patients in the national database and 866 of 173 733 individuals in the health-care delivery system dataset as likely to have familial hypercholesterolaemia. Familial hypercholesterolaemia experts reviewed a sample of flagged individuals (45 from the national database and 103 from the health-care delivery system dataset) and applied clinical familial hypercholesterolaemia diagnostic criteria. Of those reviewed, 87% (95% Cl 73-100) in the national database and 77% (68-86) in the health-care delivery system dataset were categorised as having a high enough clinical suspicion of familial hypercholesterolaemia to warrant guideline-based clinical evaluation and treatment.Interpretation The FIND FH model successfully scans large, diverse, and disparate health-care encounter databases to identify individuals with familial hypercholesterolaemia. FundingThe FH Foundation funded this study. Support was received from Amgen, Sanofi, and Regeneron.

Background Augmentation of tissue blood flow by therapeutic ultrasound is thought to rely on convective shear. Microbubble contrast agents that undergo ultrasound-mediated cavitation markedly amplify these effects. We hypothesized that purinergic signalling is responsible for shear-dependent increases in muscle perfusion during therapeutic cavitation. Methods Unilateral exposure of the proximal hindlimb of mice (with or without ischemia produced by iliac ligation) to therapeutic ultrasound (1.3 MHz, mechanical index 1.3) was performed for ten minutes after intravenous injection of 2×108 lipid microbubbles. Microvascular perfusion was evaluated by low-power contrast ultrasound perfusion imaging. In vivo muscle ATP release and in vitro ATP release from endothelial cells or erythrocytes were assessed by a luciferin-luciferase assay. Purinergic signalling pathways were assessed by studying interventions that either (1) accelerated ATP degradation; (2) inhibited P2Y receptors, adenosine receptors, or KATP channels; or (3) inhibited downstream signalling pathways involving endothelial nitric oxide synthase (eNOS) or prostanoid production (indomethacin). Augmentation in muscle perfusion by ultrasound cavitation was assessed in a proof-of-concept clinical trial in 12 subjects with stable sickle cell disease (SCD). Results Therapeutic ultrasound cavitation increased muscle perfusion by 7-fold in normal mice, reversed tissue ischemia for up to 24 hrs in the murine model of peripheral artery disease, and doubled muscle perfusion in patients with SCD. Augmentation in flow extended well beyond the region of ultrasound exposure. Ultrasound cavitation produced a nearly 40-fold focal and sustained increase in ATP, the source of which included both endothelial cells and erythrocytes. Inhibitory studies indicated that ATP was a critical mediator of flow augmentation that acts primarily through either P2Y receptors or through adenosine produced by ectonucleotidase activity. Combined indomethacin and inhibition of eNOS abolished the effects of therapeutic ultrasound, indicating downstream signalling through both NO and prostaglandins. Conclusions Therapeutic ultrasound using microbubble cavitation to increase muscle perfusion relies on shear-dependent increases in ATP which can act through a diverse portfolio of purinergic signalling pathways. These events can reverse hindlimb ischemia in mice for >24 hours, and increase muscle blood flow in patients with sickle cell disease. Clinical Trial Registration NCT01566890 (https://clinicaltrials.gov/ct2/show/NCT01566890)