Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort.

Essential thrombocythaemia (ET) is driven by somatic mutations involving the JAK2, CALR and MPL genes. Approximately 10% of patients lack driver mutations and are referred as 'triple-negative' ET (TN-ET). The diagnosis of TN-ET, however, relies on bone marrow examination that is not always performed in routine practice, and thus in the real-world setting, there are a group of cases with suspected TN-myeloproliferativeneoplasm.In this real-world cohort, patients with suspected TN-ET were initially rescreened for JAK2, CALR and MPL and then targeted next-generation sequencing (NGS) was applied.The 35 patients with suspected TN-ET had a median age at diagnosis of 43 years (range 16-79) and a follow-up of 10 years (range 2-28). The median platelet count was 758×109/L (range 479-2903). Thrombosis prior to and following diagnosis was noted in 20% and 17% of patients. Six patients were JAK2V617F and two patients were CALR positive on repeat screening. NGS results showed that 24 of 27 patients harboured no mutations. Four mutations were noted in three patients.There was no evidence of clonality for the majority of patients with suspected TN-ET with targeted NGS analysis. Detection of driver mutations in those who were previously screened suggests that regular rescreening is required. This study also questions the diagnosis of TN-ET without the existence of a clonal marker.

Hypoxia-induced hypomyelination in the developing brain is mammalian target of rapamycin-4E-binding protein-1 signaling dependent.

We hypothesized that changes in the expression levels of genes in the mammalian target of rapamycin are involved in the hypoxia-induced growth retardation in the brain including hypomyelination. Microarray and proteomic studies showed a 2.3-fold increase in the expression levels of eukaryotic translation initiation factor 4E-binding protein-1 and a 3-fold decrease in the levels of FK506-binding protein-1 in a neonatal model of hypoxia, indicating a signal transduction impairment through mammalian target of rapamycin (mTOR). Analysis of hypoxic brain showed a marked decrease in the phosphorylation levels of 4E-binding protein-1, suggesting a reduction of mTOR activity. These data suggest that suppression of mTOR may be the mechanism underlying hypoxia-induced hypomyelination observed in the developing brain.

De Novo Pediatric Ulcerative Colitis Triggered by SARS-CoV-2 Infection: a Tale of 2 Sisters.

We present a report of 2 sisters who developed acute onset hematochezia concurrently with SARS-CoV-2 infection. One patient recovered completely, whereas the sibling developed chronic symptoms leading to a diagnosis of ulcerative colitis requiring biologic therapy.

Presidential inability: Filling in the gaps.

This article focuses on potential gaps caused by the absence from the Twenty-Fifth Amendment of provisions to deal with the disability of a Vice President and the omission from the statutory line of succession law of provisions comparable to Sections 3 and 4 of the Twenty-Fifth Amendment for when there is an able Vice President. The analysis offers a critical review of the latent ambiguities in the succession provision to the United States Constitution, noting problems that have arisen from the time of the Constitutional Convention, to John Tyler's accession to office, to numerous disability crises that presented themselves throughout the twentieth century, to the present day. As the world becomes more complex and threats to the presidency more common, continued examination of our succession structure and its adequacy for establishing clear and effective presidential succession provisions under a broad range of circumstances is of paramount concern. This article embraces this robust discussion by offering some suggestions for improving the system in a way that does not require a constitutional amendment. The first part of the analysis traces the events that have driven the development of the nation's succession procedures. The second part examines the inadequacies, or "gaps," that remain in the area of presidential inability, and the third part sets forth recommendations for resolving these gaps.