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Background Upper-extremity venous thrombosis is associated with the use of peripherally inserted central catheters (PICCs). Few pediatric studies have focused on this issue. Objectives To determine the incidence and risk factors for PICC-related superficial vein thrombosis (SVT) and deep vein thrombosis (DVT) in children. Patients/methods An observational follow-up cohort study was conducted at a single hospital between June 2012 and June 2015. All patients receiving a PICC were enrolled and followed up, with weekly Doppler ultrasound examination of the catheterized limb until PICC removal. Patient, procedural and follow-up data were analyzed. Results In the study period, 265 PICCs were inserted (median age of patients 6.5 years, interquartile range [IQR] 2.4-13 years; median weight 20 kg, IQR 11-38 kg; 54% males; 67.9% chronically ill), and patients were followed up for a total of 9743 days. The median indwelling time was 21 days (IQR 12-37 days). During follow-up, 88 (33.2% of insertions) PICC-related thromboses (incidence rate [IR] 9.03 per 1000 catheter-days) were diagnosed, 66 (24.9%) as isolated SVT, seven (2.6%) as isolated DVT, and 15 (5.7%) as SVT with associated DVT (IR 6.78, 0.71 and 1.54 per 1000 catheter-days, respectively). Only 9.9% of patients with SVT and 18.2% of those with DVT were symptomatic. The main risk factors for PICC-related SVT and DVT were a catheter/vein ratio of > 0.33 and thrombosis of the catheterized superficial vein, respectively. Conclusions PICC-related thrombosis is a common and nearly always asymptomatic complication in children, the SVT rate being approximately three times higher than the DVT rate. Optimal vein and catheter selection, yielding the lowest possible catheter/vein ratio, may decrease the rate of PICC-related thrombosis.

Human 2′-5′ oligoadenylate synthetase-1 (OAS1) is central in innate immune system detection of cytoplasmic double-stranded RNA (dsRNA) and promotion of host antiviral responses. However, the molecular signatures that promote OAS1 activation are currently poorly defined. We show that the 3′-end polyuridine sequence of viral and cellular RNA polymerase III non-coding transcripts is critical for their optimal activation of OAS1. Potentiation of OAS1 activity was also observed with a model dsRNA duplex containing an OAS1 activation consensus sequence. We determined that the effect is attributable to a single appended 3′-end residue, is dependent upon its single-stranded nature with strong preference for pyrimidine residues and is mediated by a highly conserved OAS1 residue adjacent to the dsRNA binding surface. These findings represent discovery of a novel signature for OAS1 activation, the 3′-single-stranded pyrimidine (3′-ssPy) motif, with potential functional implications for OAS1 activity in its antiviral and other anti-proliferative roles.

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

The double-stranded RNA (dsRNA)-activated protein kinase (PKR) senses dsRNA produced during viral infection and halts cellular protein synthesis to block viral replication. How basal PKR activity is controlled in the absence of infection was unclear until the recent identification of a potential endogenous regulator, the cellular noncoding RNA 886 (nc886). However, nc886 adopts two distinct conformations for which the structural details and potential functional differences remain unclear. Here, we isolated and separately dissected the function of each form of nc886 to more clearly define the molecular mechanism of nc886-mediated PKR inhibition. We show that nc886 adopts two stable, noninterconverting RNA conformers that are functionally nonequivalent using complementary RNA structure probing and mutational analyses combined with PKR binding and activity assays. One conformer acts as a potent inhibitor, while the other is a pseudoinhibitor capable of weakly activating the kinase. We mapped the nc886 region necessary for high affinity binding and potent inhibition of PKR to an apical stem-loop structure present in only one conformer of the RNA. This structural feature is not only critical for inhibiting PKR autophosphorylation, but also the phosphorylation of its cellular substrate, the eukaryotic translation initiation factor 2α subunit. The identification of different activities of the nc886 conformers suggests a potential mechanism for producing a gradient of PKR regulation within the cell and reveals a way by which a cellular noncoding RNA can mask or present a structural feature to PKR for inhibition.