TLR7 gain-of-function genetic variation causes human lupus.

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Laparoscopic Magnetic Sphincter Augmentation vs Laparoscopic Nissen Fundoplication: A Matched-Pair Analysis of 100 Patients.

BACKGROUND: The efficacy and safety of magnetic sphincter augmentation (MSA) with the LINX device (Torax Medical) has been reported in several short-and long-term studies, rivaling historic results of laparoscopic Nissen fundoplication (LNF), but with fewer side effects. However, there have been no studies comparing patients with similar disease to validate these results. STUDY DESIGN: We conducted a retrospective analysis of 1-year outcomes of patients undergoing MSA and LNF from June 2010 to June 2013. Patients were matched using propensity scores incorporating multiple preoperative variables. Outcomes were measured by GERD Health Related Quality of Life scores, proton-pump inhibitor use, satisfaction, and complications. RESULTS: One hundred and seventy-nine patients met inclusion criteria, 62 MSA and 117 LNF. Propensity score matching identified 50 patients in both groups using the "best-fit" model with a caliper of 0.5 SD. At 1 year after surgery, both groups had similar GERD Health Related Quality of Life scores (4.2 MSA and 4.3 LNF; p = 0.897) and proton-pump inhibitor use (17% of MSA and 8.5% of LNF; p = 0.355). Although there was no difference in the number of patients reporting mild gas and bloating (27.6% MSA and 27.6% LNF; p = 1.000), there were no patients with severe gas and bloating in the MSA group compared with 10.6% in the LNF group (p = 0.022). More LNF patients were unable to belch (8.5% of MSA and 25.5% of LNF; p = 0.028) or vomit (4.3% of MSA and 21.3% of LNF; p = 0.004). The incidence of postoperative dysphagia was similar between the groups (46.8% MSA and 44.7% LNF; p = 0.766). CONCLUSIONS: Analogous GERD patients had similar control of reflux symptoms after both MSA and LNF. The inabilities to belch and vomit were significantly fewer with MSA, along with a significantly lower incidence of severe gas-bloat symptoms. These results support the use of MSA as first-line therapy in patients with mild to moderate GERD.

Paradoxical embolism: role of imaging in diagnosis and treatment planning.

Paradoxical embolism (PDE) is an uncommon cause of acute arterial occlusion that may have catastrophic sequelae. The possibility of its presence should be considered in all patients with an arterial embolus in the absence of a cardiac or proximal arterial source. Despite advancements in radiologic imaging technology, the use of various complementary modalities is usually necessary to exclude other possibilities from the differential diagnosis and achieve an accurate imaging-based diagnosis of PDE. In current practice, the imaging workup of a patient with symptoms of PDE usually starts with computed tomography (CT) and magnetic resonance (MR) imaging to identify the cause of the symptoms and any thromboembolic complications in target organs (eg, stroke, peripheral arterial occlusion, or visceral organ ischemia). Additional imaging studies with modalities such as peripheral venous Doppler ultrasonography (US), transcranial Doppler US, echocardiography, and CT or MR imaging are required to detect peripheral and central sources of embolism, identify cardiac and/or extracardiac shunts, and determine whether arterial disease is present. To guide radiologists in selecting the optimal modalities for use in various diagnostic settings, the article provides detailed information about the imaging of PDE, with numerous radiologic and pathologic images illustrating the wide variety of features that may accompany and contribute to the pathologic process. The roles of CT and MR imaging in the diagnosis and exclusion of PDE are described, and the use of imaging for planning surgical treatment and interventional procedures is discussed.