Multiple-choice questions (MCQ) are still widely used in high stakes medical exams. We wanted to examine whether and to what extent a national licensing exam uses the concept of pattern recognition ...to test applied clinical knowledge.
We categorized all 4,134 German National medical licensing exam questions between October 2006 and October 2012 by discipline, year, and type. We analyzed questions from the four largest disciplines: internal medicine (n = 931), neurology (n = 305), pediatrics (n = 281), and surgery (n = 233), with respect to the following question types: knowledge questions (KQ), pattern recognition questions (PRQ), inverse PRQ (IPRQ), and pseudo PRQ (PPRQ).
A total 51.1% of all questions were of a higher taxonomical order (PRQ and IPRQ) with a significant decrease in the percentage of these questions (p <0.001) from 2006 (61.5%) to 2012 (41.6%). The proportion of PRQs and IPRQs was significantly lower (p <0.001) in internal medicine and surgery, compared to neurology and pediatrics. PRQs were mostly used in questions about diagnoses (71.7%). A significantly higher (p <0.05) percentage of PR/therapy questions was found for internal medicine compared with neurology and pediatrics.
The concept of pattern recognition is used with different priorities and to various extents by the different disciplines in a high stakes exam to test applied clinical knowledge. Being aware of this concept may aid in the design and balance of MCQs in an exam with respect to testing clinical reasoning as a desired skill at the threshold of postgraduate medical education.
Abstract
Background
Pro-inflammatory CD4+ T helper (Th)1 cells clear pathogens effectively but cause excessive tissue injury if not shut down appropriately. The complement (C’) system both induces ...Th1 differentiation and their shutdown, but the mechanisms regulating orderly shutdown remain unknown.
Hypothesis
C’ receptor engagement recruits transcriptional regulators essential to Th1 shutdown.
Methods
Multi-modal profiling of activated, or patient-derived Th cells, psoriatic skin, and SARS-CoV2-infected tissues was carried out by epigenome profiling, RNAseq, network modeling, phospho-arrays, confocal, and regulator knockdown.
Results
C’ receptor signaling induced the vitamin D (VitD) receptor (VDR) and CYP27B1, the enzyme that activates VitD, allowing T cells to both fully activate and respond to VitD. Active VitD shut down IFN-γ production by Th1 cells and induced IL-10. This was mediated by activation of IL-6 production by T cells and signaling through STAT3. Mechanistically, VitD reprogrammed the Th1 transcriptomes by forming super-enhancers and recruiting a transcription factor (TF) network consisting of VDR, c-JUN, STAT3, and BACH2. We mapped genome-wide targets of these TFs by CUT&RUN/Tag. As proof of principal, psoriatic skin treated with VitD induced BACH2 in Th cells, and genetic deficiency of either BACH2 or STAT3 inhibited IL-10 produced in response to VitD. Bronchoalveolar lavage fluid of COVID-19 patients, a C’-rich environment, showed excessive Th1 skewing and perturbation of the VitD-regulated program of genes.
Conclusion
We identified a C’-recruited autocrine VitD system as key to Th1 shutdown and indicate the potential for adjunct therapy with VitD in hyper-inflammatory syndromes, e.g. COVID-19.
This work was supported by the Wellcome Trust (grant 097261/Z/11/Z to B.A.), the Crohn’s and Colitis Foundation of America (grant CCFA no. 3765 — CCFA genetics initiative to A.L.), British Heart Foundation (grant RG/13/12/30395 to G.L.), the National Institute of General Medical Sciences (R35GM138283 to M.K.), the Showalter Trust (research award to M.K.), German Research Foundation (DFG scholarship to T.F.; FR 3851/2-1), the NIDDK (DK12262401A1 to D.P.) and the National Agency of Research and Development of Chile (grant PAI79170073 to E.N.L.). Research was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. This research was supported (in part) by the Intramural Research Programs of the NIDDK (project no. ZIA/DK075149 to B.A), the National Heart, Lung and Blood Institute (project nos. ZIA/Hl006223 to C.K. and ZIA/HL006193 to N.M.), the NIAID (project no. ZIA/AI001175 to M.S.L.) of the NIH. D.C. is supported by an NIH Office of Dietary Supplements research scholar award.
Abstract
Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys, and gut. Angiotensin-converting enzyme 2 (ACE2), ...the best-characterized entry receptor for the disease-causing virus SARS-CoV-2, is highly expressed in the aforementioned tissues. However, the pathways that underlie the disease are still poorly understood. Here, we unexpectedly found that the complement system was one of the intracellular pathways most highly induced by SARS-CoV-2 infection in lung epithelial cells. Infection of respiratory epithelial cells with SARS-CoV-2 generated activated complement component C3a and could be blocked by a cell-permeable inhibitor of complement factor B (CFBi), indicating the presence of an inducible cell-intrinsic C3 convertase in respiratory epithelial cells. Within cells of the bronchoalveolar lavage of patients, distinct signatures of complement activation in myeloid, lymphoid, and epithelial cells tracked with disease severity. Genes induced by SARS-CoV-2 and the drugs that could normalize these genes both implicated the interferon-JAK1/2-STAT1 signaling system and NF-κB as the main drivers of their expression. Ruxolitinib, a JAK1/2 inhibitor, normalized interferon signature genes and all complement gene transcripts induced by SARS-CoV-2 in lung epithelial cell lines but did not affect NF-κB–regulated genes. Ruxolitinib, alone or in combination with the antiviral remdesivir, inhibited C3a protein produced by infected cells. Together, we postulate that combination therapy with JAK inhibitors and drugs that normalize NF-κB signaling could potentially have clinical application for severe COVID-19.
This research was financed by the National Heart, Lung, and Blood Institute of the NIH (grant 5K22HL125593 to M. Kazemian; R01HL119215 to J.R.S.); National Institute of General Medical Sciences of the NIH (grant R35GM138283 to M. Kazemian); and Deutsche Forschungsgemeinschaft (fellowship FR3851/2-1 to T. Freiwald) and supported, in part, by the Intramural Research Program of the NIH; the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (project number ZIA/DK075149 to B.A.); the National Heart, Lung, and Blood Institute (NHLBI) (project number ZIA/Hl006223 to C.K.); and the National Institute of Allergy and Infectious Diseases (NIAID) (project number ZIA/AI001175 to M.S.L.). T. Frum is supported by T32DE007057. Funding for part of the work was provided by the University of Michigan Biological Scholars Program (to C.E.W.), LifeARC Charity (to S.K.), and CRUK KHP Centre (to S.K.).
Background
Pneumocystis jirovecii pneumonia (PcP) remains a life‐threatening opportunistic infection after solid organ transplantation, even in the era of Pneumocystis prophylaxis. The association ...between risk of developing PcP and low CD4+ T cell counts has been well established. However, it is unknown whether lymphopenia in the context of post‐renal transplant PcP increases the risk of mortality.
Methods
We carried out a retrospective analysis of a cohort of kidney transplant patients with PcP (n = 49) to determine the risk factors for mortality associated with PcP. We correlated clinical and demographic data with the outcome of the disease. For CD4+ T cell counts, we used the Wilcoxon rank sum test for in‐hospital mortality and a Cox proportional‐hazards regression model for 60‐day mortality.
Results
In univariate analyses, high CRP, high neutrophils, CD4+ T cell lymphopenia, mechanical ventilation, and high acute kidney injury network stage were associated with in‐hospital mortality following presentation with PcP. In a receiver‐operator characteristic (ROC) analysis, an optimum cutoff of ≤200 CD4+ T cells/µL predicted in‐hospital mortality, CD4+ T cell lymphopenia remained a risk factor in a Cox regression model.
Conclusions
Low CD4+ T cell count in kidney transplant recipients is a biomarker for disease severity and a risk factor for in‐hospital mortality following presentation with PcP.
While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T ...cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific
had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.
Therapeutic options for Ebola virus disease (EVD) are currently limited to (1) best supportive care, and (2) evolving virus-specific therapies, resulting from decades of analyzing one of the world's ...deadliest diseases. Supportive care ranges from oral or intravenous rehydration therapy and anti-emetics in developing countries to much more extensive life-support interventions in resource-rich countries. Current EVD-specific therapies attempt to either interfere with the earliest steps of viral replication or to elicit a strong immune response against the virus. An entirely new approach is the extracorporeal elimination of viruses and viral glycoproteins by lectin affinity plasmapheresis. Herein, we report for the first time the successful and safe use of lectin affinity plasmapheresis in a patient with severe Ebola virus disease.
The molecular mechanisms governing orderly shutdown and retraction of CD4
type 1 helper T (T
1) cell responses remain poorly understood. Here we show that complement triggers contraction of T
1 ...responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ
T
1 cells to suppressive interleukin-10
cells. This process was primed by dynamic changes in the epigenetic landscape of CD4
T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4
T cells of patients with COVID-19 were T
1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
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