Corrigendum: Transcriptional inhibition of STAT1 functions in the nucleus alleviates Th1 and Th17 cell-mediated inflammatory diseases.

[This corrects the article DOI: 10.3389/fimmu.2022.1054472.].

Identification of Mitral Valve Prolapse on Non-electrocardiography-gated Enhanced Chest Computed Tomography.

PURPOSE: The primary imaging modality for the diagnosis of mitral valve prolapse (MVP) is echocardiography supplemented by electrocardiography (ECG)-gated cardiac computed tomography (CT) angiography. However, we have recently encountered patients with MVP who were initially identified on non-ECG-gated enhanced chest CT. The purpose of this study is to evaluate the diagnostic accuracy of non-ECG-gated enhanced chest CT to predict the presence of MVP. PATIENTS AND METHODS: Of 92 patients (surgically confirmed MVP who underwent non-ECG-gated chest CT), 27 patients were excluded for motion artifact or insufficient surgical correlation, and 65 patients were ultimately included. As a control, 65 patients with dyspnea and without MVP (non-ECG-gated chest CT and echocardiography were performed within 1 month) were randomly selected. We retrospectively analyzed an asymmetric double line sign on axial CT images for the presence of MVP. The asymmetric double line sign was defined as the presence of a linear structure, not located in the plane traversing the mitral annulus. RESULTS: Use of the asymmetric double line sign to predict MVP on non-ECG-gated CT showed modest sensitivity, high specificity, modest negative predictive value, and high positive predictive value of 59% (38/65), 99% (64/65), 70% (64/91), and 97% (38/39), respectively. CONCLUSION: The asymmetric double line sign on non-ECG-gated enhanced chest CT may be a valuable finding to predict the presence of MVP. Familiarity with this CT finding may lead to prompt diagnosis and proper management of MVP.

Utilization of Genomic Tumor Profiling in Pediatric Liquid Tumors: A Clinical Series.

Hematologic tumors are mostly treated with chemotherapies that have poor toxicity profiles. While molecular tumor profiling can expand therapeutic options, our understanding of potential targetable drivers comes from studies of adult liquid tumors, which does not necessarily translate to efficacious treatment in pediatric liquid tumors. There is also no consensus on when profiling should be performed and its use in guiding therapies. We describe a single institution's experience in integrating profiling for liquid tumors. Pediatric patients diagnosed with leukemia or lymphoma and who underwent tumor profiling were retrospectively reviewed. Ten (83.3%) patients had relapsed disease prior to tumor profiling. Eleven (91.7%) patients had targetable alterations identified on profiling, and three (25%) received targeted therapy based on these variants. Of the three patients that received targeted therapy, two (66.7%) were living, and one (33.3%) decreased. For a portion of our relapsing and/or treatment-refractory patients, genetic profiling was feasible and useful in tailoring therapy to obtain stable or remission states. Practitioners may hesitate to deviate from the 'standard of therapy', resulting in the underutilization of profiling results. Prospective studies should identify actionable genetic variants found more frequently in pediatric liquid tumors and explore the benefits of proactive tumor profiling prior to the first relapse.

Screening unfixed cadavers with handheld ultrasound as a new teaching modality.

INTRODUCTION: With the introduction of portable handheld ultrasounds, higher levels of technology are more easily available for patients in rural and underserved communities. Point-of-care ultrasound (POCUS) increases accessibility for patients with limited resources, thus reducing costs and decreasing the risk of non-compliance or subsequent loss to follow-up. Despite the increasing utility of ultrasonography, literature demonstrates a lack of sufficient training in POCUS and ultrasound-guided techniques for Family Medicine residents. Integrating unfixed cadavers into the preclinical curriculum may be an ideal adjunct to simulating pathologies and screening sensitive regions. METHODS: In total, 27 unfixed, de-identified cadavers were scanned with a handheld portable ultrasound. Sixteen body systems were screened: ocular, thyroid, carotid artery/internal jugular vein, brachial plexus, heart, kidneys, pancreas, gallbladder, liver, aorta and inferior vena cava, femoral artery and vein, knee, popliteal vessels, uterus, scrotum, and shoulder. RESULTS: Eight of the sixteen body systems, including the ocular, thyroid, carotid artery/internal jugular vein, brachial plexus, liver, knee, scrotum, and shoulder, consistently showed accurate anatomy and pathology. A physician skilled in ultrasound reviewed images obtained from the cadavers and concluded that differences in anatomy and common pathologies of unfixed cadavers were indiscernible compared with live patient ultrasound images. DISCUSSION: Using unfixed cadavers in POCUS training can be a valuable educational tool in preparing Family Medicine Physicians for rural or remote practices because the cadavers display accurate anatomy and pathology under ultrasound evaluation in multiple body systems. Further studies should explore creating artificial pathologies in cadaveric models to broaden the scope of application.

Transcriptional inhibition of STAT1 functions in the nucleus alleviates Th1 and Th17 cell-mediated inflammatory diseases.

T helper 1 cells (Th1 cells) and T helper 17 cells (Th17 cells) play pivotal roles in the pathogenesis of various autoimmune diseases, including psoriasis and inflammatory bowel disease (IBD). Signal transducer and activator of transcription 1 (STAT1) regulates the Th1 and Th17 cell lineage commitment at an early stage and maintains their immunological functions in vitro and in vivo. The previous strategies to block STAT1 functions to treat autoimmune diseases inhibit Th1 cell activity but simultaneously cause hyper-activation of Th17 cells. Herein, to modulate the functions of pathogenic Th1 and Th17 cells without genetic modification in normal physiological conditions, we generated the nucleus-deliverable form of the transcription modulation domain of STAT1 (ndSTAT1-TMD), which can be transduced into the nucleus of the target cells in a dose- and time-dependent manner without affecting the cell viability and T cell activation signaling events. ndSTAT1-TMD significantly blocked the differentiation of naïve CD4+ T cells into Th1 or Th17 cells via competitive inhibition of endogenous STAT1-mediated transcription, which did not influence Th2 and Treg cell differentiation. When the gene expression profile of Th1 or Th17 cells after ndSTAT1-TMD treatment was analyzed by mRNA sequencing, the expression of the genes involved in the differentiation capacity and the immunological functions of Th1 or Th17 cells were substantially reduced. The therapeutic potential of ndSTAT1-TMD was tested in the animal model of psoriasis and colitis, whose pathogenesis is mainly contributed by Th1 or/and Th17 cells. The symptoms and progression of psoriasis and colitis were significantly alleviated by ndSTAT1-TMD treatment, comparable to anti-IL-17A antibody treatment. In conclusion, our study demonstrates that ndSTAT1-TMD can be a new therapeutic reagent for Th1/17 cell-mediated autoimmune diseases by modulating the functions of pathogenic Th1 and Th17 cells together.

The Patent Ductus Arteriosus in Adults with Special Focus on Role of CT.

The primary imaging modality for the diagnosis of patent ductus arteriosus (PDA) is echocardiography. However, CT may be the technique on which an incidental PDA is first recognized because of the increasing number of chest CT scans performed for a variety of causes. Identification of PDA on CT may lead to earlier closure using a PDA occluder device. Immediate identification of incidental PDA is important, but a high rate of missed diagnosis of PDA has been reported due to its small size and anatomic location. In addition, echocardiography may overlook the presence of even a large PDA due to decrease in the amount of shunting through the PDA caused by high pulmonary artery pressures. This review provides the basic CT anatomy and clinical perspective of PDA, and discusses the role of CT in the evaluation of PDA as well as methods to avoid overlooking a small PDA on CT.

Diagnostic Accuracy of Coronary Artery Occlusion and Myocardial Perfusion Defect on Non-Gated Enhanced Chest CT in Predicting Acute Myocardial Infarction.

The purpose of this study was to evaluate the diagnostic accuracy of coronary artery occlusion (CAO) and myocardial perfusion defect (MPD) identified on non-gated enhanced chest CT in patients with acute myocardial infarction (AMI). We retrospectively assessed 99 patients with AMI (group 1, n = 33) and without AMI (group 2, n = 66) who underwent non-gated chest CT. We analyzed the presence of MPD and CAO on non-gated chest CT. MPD on the CT was categorized using a three-point scale (0 = no definite MPD; 1 = probable artifact or questionable MPD; 2 = probable MPD). Presence of CAO was defined as an abrupt change of contrast enhancement in a coronary artery segment with no or minimal coronary motion on the CT. There were 42.4% and 12.1% patients with probable MPD (p = 0.002), and 18.2% and 0% patients with CAO (p = 0.001) in groups 1 and 2, respectively. Probable MPD alone and simultaneous presence of CAO and probable MPD to predict AMI resulted in sensitivity, specificity, negative predictive value, and positive predictive valve of 42.4%, 87.9%, 75.3%, and 63.6%, respectively, and 12.1%, 100%, 69.5%, and 100%, respectively. In conclusion, probable MPD alone on non-gated chest CT demonstrated a relatively low sensitivity, high specificity, and modest positive predictive value for the prediction of AMI on non-gated enhanced chest CT. Although it is rare, simultaneous presence of CAO and probable MPD had a high positive predictive value to predict AMI on non-gated enhanced chest CT.

Current Role of Computed Tomography in the Evaluation of Acute Coronary Syndrome.

This review article provides an overview regarding the role of computed tomography (CT) in the evaluation of acute chest pain (ACP) in the emergency department (ED), focusing on characteristic CT findings.

CT Diagnosis of Paradoxical Embolism via a Patent Foramen Ovale in a Patient with a Pulmonary Embolism and Prominent Eustachian Valve.

While there is a high prevalence of patent foramen ovale in adults, paradoxical embolism via a patent foramen ovale is rare. Previous echocardiographic studies indicated that paradoxical embolism might only occur in patients with high-risk features of patent foramen ovale (i.e., large defect size, presence of a Eustachian valve, and high right atrial pressure). Here, we present a case of patent foramen ovale with high-risk CT features for paradoxical embolism.

High prevalence of a linear valve-like structure on CT at the pulmonary artery terminus of patent ductus arteriosus in adult patients, mimicking endarteritis.

PURPOSE: A linear valve-like structure at the pulmonary artery terminus is identified on CT in some patients with patent ductus arteriosus (PDA) and can potentially be mistaken for endarteritis. The purpose of this study was to evaluate the differences in CT features between adult patients with PDA and a linear structure and those without. MATERIALS AND METHODS: We retrospectively evaluated ECG-gated cardiac CT of 38 patients with PDA dividing them into two groups [patients with linear symmetrical valve-like structure (group1, n = 16), and those without (group 2, n = 22)]. We analyzed CT findings of the PDA including length, minimal and maximal diameter, presence of calcification, and PDA type, comparing the two subgroups. The authors also investigated the prevalence of endarteritis. RESULTS: There was no difference in CT findings between the two groups in the prevalence of calcification and length, and minimal and maximal diameter of PDA. Notably the linear valve-like structure was only identified in type 1 PDA (cone-shaped PDA) (p = 0.04), while there were variable types of PDA in group 2. There was only one case of endarteritis as a complication of PDA in group 1. In contrast to a linear valve-like structure, asymmetrical nodular thickening was noted in the patient with endarteritis on CT overlying the pre-existing linear valve-like structure at the pulmonary end of PDA. CONCLUSION: A linear valve-like structure is frequently identified at the pulmonary end in type 1 PDA. This CT finding should not be mistaken for endarteritis in the absence of other clinical evidence.

Phlegmonous Appearance in the Ipsilateral Paracardiac Fat without Paracardiac Lymph Node Enlargement on Chest CT Favors the Diagnosis of Pleural Tuberculosis over Malignant Pleural Effusion.

This study investigated the potential role of paracardiac fat stranding (FS) interspersed with multiple fluid collections (FC) as a clue to differentiate between pleural tuberculosis (pleural TB) and malignant pleural effusion (MPE). The authors retrospectively analyzed chest computed tomography (CT) findings of 428 patients, 351 with pleural TB and 77 with MPE, focusing on the paracardiac fat, and level of pleural adenosine deaminase (ADA) and blood C-reactive protein (CRP). Two radiologists independently evaluated the chest CT findings regarding the paracardiac fat pad ipsilateral to the effusion, including FS, FC, phlegmonous appearance (a combination of the FS and multiple FC), and the presence of lymph node enlargement (>1 cm in short axis diameter). There were significant differences between patients with pleural TB and those with MPE with respect to the prevalence of phlegmonous appearance in the ipsilateral paracardiac fat (47.6% and 10.4%, p < 0.001, OR = 7.8; 95% CI 3.7-16.8) and paracardiac lymph node enlargement (1.4% and 19.5%, p < 0.001, OR = 0.06; 95% CI 0.02-0.2) on CT. In contrast, there was no difference in the prevalence of isolated FS or multiple FC within the ipsilateral paracardiac fat between the two groups. Median pleural ADA and serum CRP level were higher in patients with pleural TB accompanied by phlegmonous appearance in paracardiac fat compared to those without that appearance (ADA: median 104 IU/L versus 90 IU/L, p < 0.001; CRP: 6.5 mg/dL versus 4.2 mg/dL, p < 0.001). In conclusion, phlegmonous appearance in the ipsilateral paracardiac fat without paracardiac lymph node enlargement on chest CT favors a diagnosis of pleural TB over MPE.

Genetic Variation and Autism: A Field Synopsis and Systematic Meta-Analysis.

This study aimed to verify noteworthy findings between genetic risk factors and autism spectrum disorder (ASD) by employing the false positive report probability (FPRP) and the Bayesian false-discovery probability (BFDP). PubMed and the Genome-Wide Association Studies (GWAS) catalog were searched from inception to 1 August, 2019. We included meta-analyses on genetic factors of ASD of any study design. Overall, twenty-seven meta-analyses articles from literature searches, and four manually added articles from the GWAS catalog were re-analyzed. This showed that five of 31 comparisons for meta-analyses of observational studies, 40 out of 203 comparisons for the GWAS meta-analyses, and 18 out of 20 comparisons for the GWAS catalog, respectively, had noteworthy estimations under both Bayesian approaches. In this study, we found noteworthy genetic comparisons highly related to an increased risk of ASD. Multiple genetic comparisons were shown to be associated with ASD risk; however, genuine associations should be carefully verified and understood.

Can Ultrasonographic Vascular and Elastographic Features of Invasive Ductal Breast Carcinoma Predict Histologic Aggressiveness?

RATIONALE AND OBJECTIVES: To investigate if preoperative ultrasonographic vascular and shear-wave elastographic examinations can predict histologic aggressiveness. MATERIALS AND METHODS: Preoperative ultrasonographic vascular features and shear-wave elasticities were retrospectively evaluated for 147 invasive ductal carcinomas. Vascular feature was assessed using four-tier vascularity score. Mean and maximum elasticities (Emean and Emax), and the lesion-to-fat ratio (Eratio) were documented. Histologic parameters were reviewed for tumor size, multiplicity, axillary lymph node status, lymphovascular invasion, histologic grade, estrogen receptor, progesterone receptor, human epidermal growth factor receptor2 (HER2), Ki-67, p53, and histologic subtype. Vascularity score and elasticities were correlated with histologic parameters and histologic parameters were compared between the group with low vascularity score and elasticities and the group with high vascularity score and elasticities using ANOVA, chi-squared test, and regression analysis. RESULTS: Vascularity score was independently associated with tumor size (p = 0.010) and HER2 (p = 0.007). Emean and Emax were associated with tumor size, histologic grade, and lymphovascular invasion, and Eratio was associated with tumor size, histologic grade, estrogen receptor, progesterone receptor, Ki-67, and histologic subtype (p < 0.05). Emean and Emax were independently associated with tumor size (p < 0.001). The group with high vascularity score and Eratio showed large tumor size (p < 0.001) and HER2 positivity (p = 0.039) in comparison to the group with low vascularity score and Eratio. CONCLUSION: Ultrasonographic vascular features were associated with tumor size and HER2. SWE elasticities were associated with tumor size, histologic grade, hormonal receptor, and histologic subtype. Therefore, preoperative vascular and elastographic examinations could predict histologic aggressiveness of invasive ductal breast carcinoma.

Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.

BACKGROUND: Numerous studies have identified potential risk factors and biomarkers for autism spectrum disorder. We aimed to study the strength and validity of the suggested environmental risk factors or biomarkers of autism spectrum disorder. METHODS: We did an umbrella review and systematically appraised the relevant meta-analyses of observational studies. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for papers published between database inception and Oct 17, 2018, and screened the reference list of relevant articles. We obtained the summary effect, 95% CI, heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We did analyses under credibility ceilings. This review is registered with PROSPERO, number CRD42018091704. FINDINGS: 46 eligible articles yielded data on 67 environmental risk factors (544 212 cases, 81 708 787 individuals) and 52 biomarkers (15 614 cases, 15 433 controls). Evidence of association was convincing for maternal age of 35 years or over (relative risk [RR] 1·31, 95% CI 1·18-1·45), maternal chronic hypertension (odds ratio [OR] 1·48, 1·29-1·70), maternal gestational hypertension (OR 1·37, 1·21-1·54), maternal overweight before or during pregnancy (RR 1·28, 1·19-1·36), pre-eclampsia (RR 1·32, 1·20-1·45), prepregnancy maternal antidepressant use (RR 1·48, 1·29-1·71), and maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy (OR 1·84, 1·60-2·11). Only two associations, maternal overweight before or during pregnancy and SSRI use during pregnancy, retained their high level of evidence under subset sensitivity analyses. Evidence from biomarkers was scarce, being supported by p values close to the significance threshold and too few cases. INTERPRETATION: Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders. FUNDING: None.

Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review.

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of inflammatory bowel disease (IBD). We conducted a comprehensive review of meta-analyses to summarize the reported effectiveness of different drugs for IBD. We performed a literature search and a total of 110 meta-analyses from 66 articles were summarized and re-analyzed (62 in UC and 48 in CD). In summary, 5-ASA was more effective than placebo in both induction and maintenance treatment of UC, but there were conflicting results on the effect of 5-ASA on the induction treatment or relapse of CD. The use of immunomodulatory agents in the induction or maintenance phase of UC and CD using immunomodulators appeared to be more effective than placebo, but the results were impacted by small number of patients, discordant results with the largest study and risk of biases. Anti-TNF-α and anti-integrin therapeutic antibodies in both, induction and maintenance, showed a better efficacy than placebo in a large proportion of patients analyzed. Other agents, such as probiotics, antibiotics, omega-3, were shown to be more effective than placebo, but the same issues arose as stated above with the use of immunomodulatory agents. In conclusion, we performed a comprehensive review of meta-analysis on comparative efficacy of pharmacotherapy used in the management of IBD. Our review will augment our understanding of the treatment of UC and CD by providing a guideline for interpreting the statistically significant findings and discusses the optimal choice for IBD treatment.

Imperforate Hymen: A Comprehensive Systematic Review.

Imperforate hymen (IH) is an uncommon congenital anomaly of the female genital tract, with the hymen completely obstructing the vaginal opening. Despite the simple diagnosis and treatment of IH, missed or delayed diagnosis is often a clinical problem owing to its low incidence, nonspecific symptoms, or insufficient physical examination. The aim of this study is to identify the characteristics, clinical presentations, treatment modalities, and outcomes of imperforate hymen patients. In this study, a literature search of PubMed, Scopus and Medline databases was performed for sources published up to 3 July 2018 for English-language studies with the term "imperforate hymen". The literature review identified 251 citations and 155 articles (143 case reports, 12 case series) containing 253 patients who were finally included (two papers were not written in English). Among 236 postnatal patients, the mean age of the patients was 10.7 ± 4.7 years. Abdominal pain (54.2%), urinary retention (20.3%), abnormal menstruation (14.0%), dysuria (9.7%), increased urinary frequency (5.1%), severe presentation of renal failure (n = 5, 2.1%), and urinary tract infection (n = 1, 0.4%) were presented. Most patients diagnosed with the condition underwent surgical treatment (83.5%), most of whom were treated via a hymenotomy (35.2%) and hymenectomy (36.4%), and the use of prophylactic antibiotics were only used in 7 patients. There were no differences in outcomes between two surgical methods. In addition, 141 (59.7%) patients showed improvement and 5 deceased patients were not related to IH or the operation itself; Complications, such as vaginal adhesion, were only noted in 6.6% of patients. In addition, among 17 cases of newborns with a diagnosis of IH before birth, hymenectomy (n = 5, 29.4%) and hymenotomy (n = 9, 52.9%) were the main treatment modalities and showed improved prognosis in 52.9% of newborns. Because IH diagnosis is easy and postsurgical prognosis is good, clinicians should carefully examine every female patient at birth. IH should be considered regarding adolescent girls with abdominal pain, lower back pain, or urinary retention, and perform appropriate physical examinations of the genital introitus. In addition, accurate diagnosis as IH, not misdiagnosing as vaginal septum or agenesis, is important to prevent severe complications such as stricture and ascending infection.

Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm.

All animals have body burdens of polychlorinated biphenyls (PCBs) despite their ban decades ago. These and modern endocrine-disrupting chemicals (EDCs) such as the fungicide vinclozolin (VIN) perturb hormone signaling and lead to dysfunctions following prenatal exposures. Beyond direct exposures, transgenerational disease phenotypes can persist for multiple generations without subsequent exposure. The mechanisms of action of these EDCs differ: VIN is anti-androgenic while the PCB mixture Aroclor 1221 (A1221) is weakly estrogenic. Based on limited evidence for the inheritance of epimutations in germline, we measured DNA methylation in brain and sperm of rats. Pregnant dams were exposed from day 8-18 of gestation to low dosages of VIN, A1221, or the vehicle. To produce paternal lineages, exposed F1 males were bred with untreated females, creating the F2 and subsequently F3 generations. In adult F1 and F3 males, mature sperm was collected, and brain nuclei involved in anxiety and social behaviors (CA3 of the hippocampus; central amygdala) were selected for assays of epimutations in CpG islands using reduced representation bisulfite sequencing. In F1 sperm, VIN and PCBs induced differential methylation in 215 and 284 CpG islands, respectively, compared to vehicle. The majority of effects were associated with hypermethylation. Fewer epimutations were detected in the brain. A subset of differentially methylated regions were retained from the F1 to the F3 generation, suggesting a common mechanism of EDC and germline epigenome interaction. Thus, EDCs can cause heritable epimutations in the sperm that may embody the future phenotype of brain-behavior disorders caused by direct or transgenerational exposures.