This targeted analysis involving NOTCH1 exons previously implicated in familial and sporadic bicuspid aortic valve demonstrates overrepresentation of NOTCH1 missense variants among patients with bicuspid aortic valves and thoracic aortic aneurysms. Identification of aneurysm-predisposing susceptibility genes may lead to gene-directed surgical therapy of the ascending aorta for patients with bicuspid aortic valves.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, COVID-19, is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of COVID-19 individuals undergoing postmortem evaluation is provided, with four aims: 1) describe the pathologic spectrum of the myocardium; 2) compare to an alternate viral illness; 3) investigate angiotensin converting enzyme 2 (ACE2) expression; and 4) provide the first description of the cardiac findings in patients with cleared infection. Methods: Study cases were identified from institutional files and included COVID-19 (n=15; 12 active, 3 cleared), influenza A/B (n=6), and non-virally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An ACE2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction (ddPCR). Results: Male sex was more common in the COVID-19 group (p=0.05). Non-occlusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls), and were more common in the active COVID-19 cohort (p=0.006). Four active COVID-19 cases showed focal myocarditis, while one case of cleared COVID-19 showed extensive disease. Arteriolar ACE2 endothelial expression was lower in COVID-19 cases versus controls (p=0.004). ACE2 myocardial expression did not differ by disease category, sex, age or number of patient comorbidities (p=0.69, p=1.00, p=0.46, p=0.65, respectively). SARS-CoV-2 immunohistochemistry showed non-specific staining, while ultrastructural examination and ddPCR were negative for viral presence. Four (26.7%) COVID-19 patients had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. Conclusions: This detailed histopathologic, immunohistochemical, ultrastructural and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of active and cleared COVID-19 patients, but is usually limited in extent. Histologic features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

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Newborn screening for one or more lysosomal disorders has been implemented in several US states, Japan and Taiwan by multiplexed enzyme assays using either tandem mass spectrometry or digital microfluidics. Another multiplex assay making use of immunocapture technology has also been proposed. To investigate the potential variability in performance of these analytical approaches, we implemented three high-throughput screening assays for the simultaneous screening for four lysosomal disorders: Fabry disease, Gaucher disease, mucopolysaccharidosis type I, and Pompe disease. These assays were tested in a prospective comparative effectiveness study using nearly 100,000 residual newborn dried blood spot specimens. In addition, 2nd tier enzyme assays and confirmatory molecular genetic testing were employed. Post-analytical interpretive tools were created using the software Collaborative Laboratory Integrated Reports (CLIR) to determine its ability to improve the performance of each assay vs. the traditional result interpretation based on analyte-specific reference ranges and cutoffs. This study showed that all three platforms have high sensitivity, and the application of CLIR tools markedly improves the performance of each platform while reducing the need for 2nd tier testing by 66% to 95%. Moreover, the addition of disease-specific biochemical 2nd tier tests ensures the lowest false positive rates and the highest positive predictive values for any platform.

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