Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease
, 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 RNA
,
and binds to guanosine
-
. We identified a de novo, previously undescribed missense TLR7
variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7
variant selectively increased sensing of guanosine and 2',3'-cGMP
, 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 Tlr7
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.
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.
Abstract Background Despite the significance and prevalence of acute respiratory distress syndrome (ARDS), its detection remains highly variable and inconsistent. In this work, we aim to develop an ...algorithm ( ARDSFlag ) to automate the diagnosis of ARDS based on the Berlin definition. We also aim to develop a visualization tool that helps clinicians efficiently assess ARDS criteria. Methods ARDSFlag applies machine learning (ML) and natural language processing (NLP) techniques to evaluate Berlin criteria by incorporating structured and unstructured data in an electronic health record (EHR) system. The study cohort includes 19,534 ICU admissions in the Medical Information Mart for Intensive Care III (MIMIC-III) database. The output is the ARDS diagnosis, onset time, and severity. Results ARDSFlag includes separate text classifiers trained using large training sets to find evidence of bilateral infiltrates in radiology reports (accuracy of 91.9%±0.5%) and heart failure/fluid overload in radiology reports (accuracy 86.1%±0.5%) and echocardiogram notes (accuracy 98.4%±0.3%). A test set of 300 cases, which was blindly and independently labeled for ARDS by two groups of clinicians, shows that ARDSFlag generates an overall accuracy of 89.0% (specificity = 91.7%, recall = 80.3%, and precision = 75.0%) in detecting ARDS cases. Conclusion To our best knowledge, this is the first study to focus on developing a method to automate the detection of ARDS. Some studies have developed and used other methods to answer other research questions. Expectedly, ARDSFlag generates a significantly higher performance in all accuracy measures compared to those methods.
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.
Recently, much of the literature on sharing in cities has focused on the sharing economy, in which people use online platforms to share underutilized assets in the marketplace. This view of sharing ...is too narrow for cities, as it neglects the myriad of ways, reasons, and scales in which citizens share in urban environments. Research presented here by the Liveable Cities team in the form of participant workshops in Lancaster and Birmingham, UK, suggests that a broader approach to understanding sharing in cities is essential. The research also highlighted tools and methods that may be used to help to identify sharing in communities. The paper ends with advice to city stakeholders, such as policymakers, urban planners, and urban designers, who are considering how to enhance sustainability in cities through sharing.
A stereoselective synthesis of the AB ring of the complex sesterterpenoid variecolin is presented. Our strategy features the development of a tandem Wolff/Cope rearrangement of α-diazo cyclobutyl ...ketones for the construction of fused, 8-membered carbocycles. Preliminary studies revealed a facile Wolff rearrangement but a difficult vinyl ketene cyclobutane Cope rearrangement. We have leveraged an efficient microwave-promoted tandem rearrangement to prepare the desired functionalized cyclooctadienones that we envision as potential key intermediates in the convergent synthesis of variecolin.
The Picosecond Imaging Circuit Analysis (PICA) technique using the Superconducting Single-Photon Detector (SSPD) allows the detailed characterization of pulse width variations along the delay chain ...of a high speed Self Timing Interface (STI). Pulses gradually shrink and finally disappear along the delay chain.
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