Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.This work was supported by the NIH (Grants AI124474 and AI131639 to R.P. and Grant AI136534 to R.M.T.). It was also supported in part by NIH National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards Grant UL1 TR002535. The contents are the authors’sole responsibility anddo not necessarily represent official NIH views.S

The distribution of Dishevelled in convergently extending mesoderm

Convergent extension (CE) is a conserved morphogenetic movement that drives axial lengthening of the primary body axis and depends on the planar cell polarity (PCP) pathway. In Drosophila epithelia, a polarised subcellular accumulation of PCP core components, such as Dishevelled (Dvl) protein, is associated with PCP function. Dvl has long been thought to accumulate in the mediolateral protrusions in Xenopus chordamesoderm cells undergoing CE. Here we present a quantitative analysis of Dvl intracellular localisation in Xenopus chordamesoderm cells. We find that, surprisingly, accumulations previously observed at mediolateral protrusions of chordamesodermal cells are not protrusion-specific but reflect yolk-free cytoplasm and are quantitatively matched by the distribution of the cytoplasm-filling lineage marker dextran. However, separating cell cortex-associated from bulk Dvl signal reveals a statistical enrichment of Dvl in notochord–somite boundary-(NSB)-directed protrusions, which is dependent upon NSB proximity. Dvl puncta were also observed, but only upon elevated overexpression. These puncta showed no statistically significant spatial bias, in contrast to the strongly posteriorly-enriched GFP-Dvl puncta previously reported in zebrafish. We propose that Dvl distribution is more subtle and dynamic than previously appreciated and that in vertebrate mesoderm it reflects processes other than protrusion as such

Do physician outcome judgments and judgment biases contribute to inappropriate use of treatments? Study protocol

<p>Abstract</p> <p>Background</p> <p>There are many examples of physicians using treatments inappropriately, despite clear evidence about the circumstances under which the benefits of such treatments outweigh their harms. When such over- or under- use of treatments occurs for common diseases, the burden to the healthcare system and risks to patients can be substantial. We propose that a major contributor to inappropriate treatment may be how clinicians judge the likelihood of important treatment outcomes, and how these judgments influence their treatment decisions. The current study will examine the role of judged outcome probabilities and other cognitive factors in the context of two clinical treatment decisions: 1) prescription of antibiotics for sore throat, where we hypothesize overestimation of benefit and underestimation of harm leads to over-prescription of antibiotics; and 2) initiation of anticoagulation for patients with atrial fibrillation (AF), where we hypothesize that underestimation of benefit and overestimation of harm leads to under-prescription of warfarin.</p> <p>Methods</p> <p>For each of the two conditions, we will administer surveys of two types (Type 1 and Type 2) to different samples of Canadian physicians. The primary goal of the Type 1 survey is to assess physicians' perceived outcome probabilities (both good and bad outcomes) for the target treatment. Type 1 surveys will assess judged outcome probabilities in the context of a representative patient, and include questions about how physicians currently treat such cases, the recollection of rare or vivid outcomes, as well as practice and demographic details. The primary goal of the Type 2 surveys is to measure the specific factors that drive individual clinical judgments and treatment decisions, using a 'clinical judgment analysis' or 'lens modeling' approach. This survey will manipulate eight clinical variables across a series of sixteen realistic case vignettes. Based on the survey responses, we will be able to identify which variables have the greatest effect on physician judgments, and whether judgments are affected by inappropriate cues or incorrect weighting of appropriate cues. We will send antibiotics surveys to family physicians (300 per survey), and warfarin surveys to both family physicians and internal medicine specialists (300 per group per survey), for a total of 1,800 physicians. Each Type 1 survey will be two to four pages in length and take about fifteen minutes to complete, while each Type 2 survey will be eight to ten pages in length and take about thirty minutes to complete.</p> <p>Discussion</p> <p>This work will provide insight into the extent to which clinicians' judgments about the likelihood of important treatment outcomes explain inappropriate treatment decisions. This work will also provide information necessary for the development of an individualized feedback tool designed to improve treatment decisions. The techniques developed here have the potential to be applicable to a wide range of clinical areas where inappropriate utilization stems from biased judgments.</p

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development