Background
The expression of chronic rhinosinusitis (CRS) is multidimensional. Disease heterogeneity in patients with CRS remains poorly understood. This study aimed to identify endotypes of CRS ...using cluster analysis by integrating multidimensional characteristics and to explore their association with treatment outcomes.
Methods
A total of 28 clinical variables and 39 mucosal cellular and molecular variables were analyzed using principal component analysis. Cluster analysis was performed on 246 prospectively recruited Chinese CRS patients with at least 1‐year postoperative follow‐up. Difficult‐to‐treat CRS was characterized in each generated cluster.
Results
Seven subject clusters were identified. Cluster 1 (13.01%) was comparable to the classic well‐defined eosinophilic CRS with polyps, having severe disease and the highest proportion of difficult‐to‐treat CRS. Patients in cluster 2 (16.26%) and cluster 4 (13.82%) had relatively lower proportions of presence of polyps and presented mild inflammation with moderate proportions of difficult‐to‐treat cases. Subjects in cluster 2 were highly atopic. Cluster 3 (7.31%) and cluster 6 (21.14%) were characterized by severe or moderate neutrophilic inflammation, respectively, and with elevated levels of IL‐8 and high proportions of difficult‐to‐treat CRS. Cluster 5 (4.07%) was a unique group characterized by the highest levels of IL‐10 and lacked difficult‐to‐treat cases. Cluster 7 (24.39%) demonstrated the lowest symptom severity, a low proportion of difficult‐to‐treat CRS, and low inflammation load. Finally, we found that difficult‐to‐treat CRS was associated with distinct clinical features and biomarkers in the different clusters.
Conclusions
Distinct clinicopathobiologic clusters of CRS display differences in clinical response to treatments and characteristics of difficult‐to‐treat CRS.
Pathogenesis of thrombotic thrombocytopenic purpura (TTP) was a mystery for over half a century until the discovery of ADAMTS13. ADAMTS13 is primarily synthesized in the liver, and its main function ...is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury. Deficiency of plasma ADAMTS13 activity (<10%) resulting from mutations of the
ADAMTS13
gene or autoantibodies against ADAMTS13 causes hereditary or acquired (idiopathic) TTP. ADAMTS13 activity is usually normal or modestly reduced (>20%) in other forms of thrombotic microangiopathy secondary to hematopoietic progenitor cell transplantation, infection, and disseminated malignancy or in hemolytic uremic syndrome. Plasma infusion or exchange remains the initial treatment of choice to date, but novel therapeutics such as recombinant ADAMTS13 and gene therapy are under development. Moreover, ADAMTS13 deficiency has been shown to be a risk factor for the development of myocardial infarction, stroke, cerebral malaria, and preeclampsia.
Lower lip hypoesthesia is the most common complication following osseous genioplasty. Concentrated growth factor (CGF) has recently been shown to improve neural regeneration. The aim of this study ...was to evaluate the effect of concentrated growth factor on neurosensory recovery after osseous genioplasty. Patients who underwent osseous genioplasty between June 2017 and February 2020 were enrolled. CGF was applied to the mental nerve on one side. The treatment side was randomized, and the other side was considered as the control. Lower lip hypoesthesia was assessed preoperatively and postoperatively (1 week, 1, 3, 6, and 9 months) using the two-point discrimination test and a 10-point visual analogue scale (self-reported paresthesia). The assessor was blinded. Twenty-six female patients completed the study. At 1 and 3 months, both the mean two-point discrimination value and mean visual analogue scale score were significantly lower in the CGF group than in the control group (P < 0.001). At 3 months, the percentage of patients with lower lip hypoesthesia in the CGF group was significantly lower than that in the control group (P < 0.001). Both groups showed resolution of lower lip hypoesthesia at 6 months. Concentrated growth factor may accelerate the recovery of long-standing sensory nerve impairment following mental osteotomy.
Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly.
The ...evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP.
In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document.
The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab.
There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.
Immune-mediated thrombotic thrombocytopenic purpura is caused by autoantibodies against ADAMTS-13, a plasma enzyme that cleaves von Willebrand factor. However, the mechanism resulting in severe ...deficiency of plasma ADAMTS-13 activity remains controversial.
To determine the mechanism of autoantibody-mediated severe deficiency of plasma ADAMTS13 activity in immune-mediated thrombotic thrombocytopenic purpura.
Fluorescence resonance energy transfer-VWF73 was used to determine plasma ADAMTS-13 activity. Enzyme-linked immunosorbent assay (ELISA) was used to determine anti-ADAMTS-13 immunoglobulin G. ELISA and capillary electrophoresis-based Western blotting were employed to assess plasma ADAMTS-13 antigen.
We showed that plasma ADAMTS-13 antigen levels varied substantially in the samples collected on admission despite all showing plasma ADAMTS-13 activity of <10 IU/dL (or <10% of normal level) using either ELISA or Western blotting. More severe deficiency of plasma ADAMTS-13 antigen (<10%) was detected in admission samples by ELISA than by capillary Western blotting. There was a significant but moderate correlation between plasma ADAMTS-13 activity and ADAMTS-13 antigen by either assay method, suggesting that severe deficiency of plasma ADAMTS-13 activity is not entirely associated with low levels of ADAMTS-13 antigen.
We conclude that severe deficiency of plasma ADAMTS-13 activity primarily resulted from antibody-mediated inhibition, but the accelerated clearance of plasma ADAMTS-13 antigen via immune complexes may also contribute significantly to severe deficiency of plasma ADAMTS-13 activity in a subset of patients with acute immune-mediated thrombotic thrombocytopenic purpura.
Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment.
In June 2018, ...the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations.
The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy.
The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.
Summary
Background
CD8+ T cells are important effectors of cell‐mediated immunity; however, their contribution to the pathogenesis of CRS is unclear.
Objective
This study aimed to characterize the ...cytokine‐producing features and cytotoxic activity of CD8+ T cells, and their correlation with inflammation patterns in CRS with nasal polyps.
Methods
The expression of IFN‐γ, IL‐4, IL‐5, IL‐17A, forkhead box P3 (FOXP3), perforin, and granzyme B in CD8+ T cells was studied by means of flow cytometry, immunohistochemistry, and immunofluorescence. The expression of CD8+ T‐cell subset relevant chemokines and chemokine receptors was detected by means of real‐time RT‐PCR or ELISA. The cytotoxic activity of sorted CD8+ T cells was defined by anti‐CD3‐redirected killing assay.
Results
Compared with controls, elevated percentages of total CD8+ T cells and cytotoxic T lymphocyte (Tc) 1 (IFN‐γ+), Tc2 (IL‐4+), and Tc17 (IL‐17A+) cell subset, and decreased percentages of FOXP3+CD8+ regulatory T cells, were found in both eosinophilic and non‐eosinophilic polyps with a Tc2‐skewed and Tc1/Tc17‐dominated response in eosinophilic and non‐eosinophilic polyps, respectively. Nasal CD8+ T cells were found to produce similar or even higher levels of IFN‐γ and IL‐4 compared with CD4+ T cells. Tc1 and Tc17, and Tc2 (IL‐4+ and IL‐5+) cell subset percentages positively correlated with neutrophil and eosinophil counts in sinonasal mucosa, respectively. Strikingly, the expression of perforin and granzyme B and cytotoxic activity were significantly reduced in nasal CD8+ T cells compared with their counterparts in peripheral blood. The expression of CXCL16, CCL17, and CCL20 positively correlated with Tc1, Tc2, and Tc17 cell subset number in sinonasal mucosa, respectively.
Conclusion and Clinical Relevance
CD8+ T cells have low cytotoxic activity; nevertheless, they are a significant and previously underappreciated source of inflammatory cytokine production in polyps. Different Tc cell subset domination may contribute to distinctly biased granulocyte inflammation in eosinophilic and non‐eosinophilic polyps.
Severe deficiency of plasma ADAMTS13 activity is the primary cause of thrombotic thrombocytopenic purpura (TTP) whereas overwhelming activation of complement via an alternative pathway results in ...atypical hemolytic uremic syndrome (aHUS), the prototypes of thrombotic microangiopathy (TMA). However, clinical and pathogenic distinctions between TTP and aHUS are often quite challenging. Clinical reports have suggested that complement activation may play a role in the development of TTP, which is caused by severe deficiency of plasma ADAMTS13 activity. However, the experimental evidence to support this hypothesis is still lacking. Here, we show that mice with either Adamts13−/− or a heterozygous mutation of complement factor H (cfh) at amino acid residue of 1206 (ie, cfhW/R) alone remain asymptomatic despite the presence of occasional microvascular thrombi in various organ tissues. However, mice carrying both Adamts13−/− and cfhW/R exhibit thrombocytopenia, low haptoglobin, increased fragmentation of erythrocytes in peripheral blood smear, increased plasma levels of lactate dehydrogenase activity, blood urea nitrogen, and creatinine, as well as an increased mortality rate, consistent with the development of TMA. Moreover, mice with a homozygous mutation of cfh (ie, cfhR/R) with or without Adamts13−/− developed severe TMA. The mortality rate in mice with Adamts13−/−cfhR/R was significantly higher than that in mice with cfhR/R alone. Histological and immunohistochemical analyses demonstrated the presence of disseminated platelet-rich thrombi in terminal arterioles and capillaries of major organ tissues in these mice that were either euthanized or died. Together, our results support a synergistic effect of severe ADAMTS13 deficiency and complement activation in pathogenesis of TMA in mice.
•Mice with Adamts13−/− or a heterozygous cfh mutation (ie, chfW1206R) do not develop spontaneous TMA.•However, mice carrying Adamts13−/−cfhW1206R or cfhR1206R develop TMA with a significantly increased mortality rate.
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