ABSTRACT
Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that, paradoxically, contain similar assortments of sequence-specific transcription factor (TF) binding sites1-3. Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease4,5. Here, by studying gene regulation from the perspective of individual transcription start sites (TSSs), using natural genetic variation, perturbation of endogenous TF protein levels and massively parallel analysis of natural and synthetic regulatory elements, we show that the effect of TF binding on transcription initiation is position dependent. Analysing TF-binding-site occurrences relative to the TSS, we identified several motifs with highly preferential positioning. We show that these patterns are a combination of a TF's distinct functional profiles-many TFs, including canonical activators such as NRF1, NFY and Sp1, activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.
Subject(s)
Gene Expression Regulation , Nucleotide Motifs , Promoter Regions, Genetic , Transcription Factors , Transcription Initiation Site , Transcription Initiation, Genetic , Humans , Binding Sites , Gene Expression Regulation/genetics , Genome, Human/genetics , Nucleotide Motifs/genetics , Promoter Regions, Genetic/genetics , Protein Binding , Transcription Factors/metabolism , Genetic VariationABSTRACT
BACKGROUND AND OBJECTIVES: Current research implies overuse of diagnostic testing and overtreatment in children with tracheostomies. There are no guidelines for obtaining sputum cultures for these patients, yet they are commonly obtained without significantly affecting management or outcomes. The aim of our quality improvement project was to decrease rate of sputum cultures in this population by 50%, from 64% to 32%. METHODS: This was a single-center quality improvement project conducted in a pediatric emergency department (ED). Key drivers included: Standardized decision-making, appropriate culture collection, knowledge regarding colonization versus clinically relevant growth, and viral versus bacterial infections in this population. The study team developed an algorithm, used modification to electronic medical records orders, and provided education to drive change. Six months of preintervention and 12 months postintervention data were collected. Run charts/statistical process charts were created for the rate of cultures, length of stay, and return to the ED. RESULTS: There were 159 patient encounters and the rate of sputum cultures decreased from 64% at baseline to 25% without change in length of stay or increased rate at which patients returned to the ED, including during local coronavirus disease 2019 and respiratory syncytial virus surges. We observed nonrandom data patterns after introduction of algorithm resulting in centerline shifts. CONCLUSIONS: The study team was able to introduce an algorithm coinciding with a reduction in number of sputum cultures obtained. Next steps would be determining safety and efficacy of such an algorithm over a larger population.
Subject(s)
Emergency Service, Hospital , Quality Improvement , Sputum , Tracheostomy , Humans , Sputum/microbiology , Child , Male , Female , Child, Preschool , Infant , Algorithms , AdolescentABSTRACT
Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the impact of lactational TCS on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) neonatal mice. In hUGT1 mice, expression of the hepatic UGT1A1 gene is developmentally delayed resulting in elevated total serum bilirubin (TSB) levels. We found that newborn hUGT1 mice breastfed or orally treated with TCS presented lower TSB levels along with induction of hepatic UGT1A1. Lactational and oral treatment by gavage with TCS leads to the activation of hepatic nuclear receptors constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPARα), and stress sensor, activating transcription factor 4 (ATF4). When CAR-deficient hUGT1 mice (hUGT1/Car-/-) were treated with TCS, TSB levels were reduced with a robust induction of hepatic UGT1A1, leaving us to conclude that CAR is not tied to UGT1A1 induction. Alternatively, when PPARα-deficient hUGT1 mice (hUGT1/Pparα-/-) were treated with TCS, hepatic UGT1A1 was not induced. Additionally, we had previously demonstrated that TCS is a potent inducer of ATF4, a transcriptional factor linked to the integrated stress response. When ATF4 was deleted in liver of hUGT1 mice (hUGT1/Atf4ΔHep) and these mice treated with TCS, we observed superinduction of hepatic UGT1A1. Oxidative stress genes in livers of hUGT1/Atf4ΔHep treated with TCS were increased, suggesting that ATF4 protects liver from excessive oxidative stress. The increase oxidative stress may be associated with superinduction of UGT1A1. The expression of ATF4 in neonatal hUGT1 hepatic tissue may play a role in the developmental repression of UGT1A1.
Subject(s)
Activating Transcription Factor 4 , Animals, Newborn , Bilirubin , Glucuronosyltransferase , Liver , PPAR alpha , Triclosan , Animals , Glucuronosyltransferase/metabolism , Glucuronosyltransferase/genetics , PPAR alpha/metabolism , PPAR alpha/genetics , Mice , Activating Transcription Factor 4/metabolism , Activating Transcription Factor 4/genetics , Triclosan/pharmacology , Humans , Bilirubin/pharmacology , Bilirubin/metabolism , Liver/metabolism , Liver/drug effects , Mice, Knockout , Female , Constitutive Androstane Receptor , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Cytoplasmic and Nuclear/geneticsABSTRACT
Helicobacter pylori (H. pylori) infection is a known cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the underlying mechanisms by which H. pylori infection triggers these disorders are still not clearly understood. Gastric cancer is a slow progressing disease, which makes it difficult to study. We have developed an accelerated disease progression mouse model, which leverages mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) infected with Helicobacter felis (H. felis). Using this model and gastric biopsy samples from patients, we report that activation of the Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-ß (TRIF)-type I interferon (IFN-I) signaling pathway promotes Helicobacter-induced disease progression toward severe gastric pathology and gastric cancer development. Further, results implicated downstream targets of this pathway in disease pathogenesis. These findings may facilitate stratification of Helicobacter-infected patients and thus enable treatment prioritization of patients.
ABSTRACT
Many machine learning applications in bioinformatics currently rely on matching gene identities when analyzing input gene signatures and fail to take advantage of preexisting knowledge about gene functions. To further enable comparative analysis of OMICS datasets, including target deconvolution and mechanism of action studies, we develop an approach that represents gene signatures projected onto their biological functions, instead of their identities, similar to how the word2vec technique works in natural language processing. We develop the Functional Representation of Gene Signatures (FRoGS) approach by training a deep learning model and demonstrate that its application to the Broad Institute's L1000 datasets results in more effective compound-target predictions than models based on gene identities alone. By integrating additional pharmacological activity data sources, FRoGS significantly increases the number of high-quality compound-target predictions relative to existing approaches, many of which are supported by in silico and/or experimental evidence. These results underscore the general utility of FRoGS in machine learning-based bioinformatics applications. Prediction networks pre-equipped with the knowledge of gene functions may help uncover new relationships among gene signatures acquired by large-scale OMICs studies on compounds, cell types, disease models, and patient cohorts.
Subject(s)
Deep Learning , Humans , Machine Learning , Computational Biology , Drug DevelopmentABSTRACT
Hybrid immunity (vaccination + natural infection) to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. The mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed for T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera, reflected by smaller antigenic cartography distances. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B- and T-cell responses.
Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Cricetinae , Humans , BNT162 Vaccine , Breakthrough Infections , COVID-19/prevention & control , Mesocricetus , Antibodies, Neutralizing , Postoperative Complications , RNA, Messenger/genetics , Immunity , Antibodies, Viral , VaccinationABSTRACT
OBJECTIVES: Blunt trauma in pediatric patients accounts for a significant proportion of pediatric death from traumatic injury. Currently, there are no clinical decision-making tools available to guide imaging choice in the evaluation of pediatric patients with blunt thoracic trauma (BTT). This study aimed to analyze the rates of missed major intrathoracic injuries on chest x-ray (CXR) and identify clinical risk factors associated with major intrathoracic injuries to formulate a clinical decision-making tool for computed tomography (CT) use in pediatric patients with BTT. METHODS: We performed a retrospective single-center study using an institutional trauma database of pediatric patients. Inclusion criteria included age, blunt trauma, and patients who received a CXR and thoracic CT within 24 hours of presentation. Thoracic CT findings were graded as major, minor, or none, and comparison CXR was used to determine the rate of missed thoracic injuries. Eighty-four patient variables were then collected, and clinically relevant variables associated with major intrathoracic injuries were placed in a logistic regression model to determine the best predictors of major injury in pediatric BTT patients. RESULTS: A total of 180 patients (48.3%) had CXR that missed an injury that was seen on thoracic CT. In our cohort, 20 patients (5.4%) had major injuries that were missed on CXR. Characteristics correlating with major thoracic injuries were older age (odds ratio [OR], 1.125; 95% confidence interval [CI], 1.015-1.247), chest pain (OR, 4.907; 95% CI, 2.173-11.083), abnormal chest auscultation (OR, 3.564; 95% CI, 1.406-9.035), and tachycardia (OR, 2.876; 95% CI, 1.256-6.586). Using these 4 variables, receiver operating characteristic analysis revealed an area under the curve of 0.7903. CONCLUSIONS: Pediatric BTT patients older than 15 years with tachycardia, chest pain, or abnormal chest auscultation are at increased risk for major intrathoracic injuries and may benefit from thoracic CT.
Subject(s)
Thoracic Injuries , Wounds, Nonpenetrating , Humans , Child , Retrospective Studies , Trauma Centers , Wounds, Nonpenetrating/diagnostic imaging , Thoracic Injuries/diagnostic imaging , Chest Pain , Tachycardia , Radiography, Thoracic/methodsABSTRACT
BACKGROUND: Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults. OBJECTIVES: The present study examined how oral iAs administration to neonatal mice impacts the intestinal tract, which acts as an early mediator for NAFLD. METHODS: Neonatal mice were treated with a single dose of iAs via oral gavage. Effects on the small intestine were determined by histological examination, RNA sequencing, and biochemical analysis. Serum lipid profiling was analyzed by fast protein liquid chromatography (FPLC), and hepatosteatosis was characterized histologically and biochemically. Liver X receptor-alpha (LXRα) knockout (Lxrα-/-) mice and liver-specific activating transcription factor 4 (ATF4)-deficient (Atf4ΔHep) mice were used to define their roles in iAs-induced effects during the neonatal stage. RESULTS: Neonatal mice exposed to iAs via oral gavage exhibited accumulation of dietary fat in enterocytes, with higher levels of enterocyte triglycerides and free fatty acids. These mice also showed accelerated enterocyte maturation and a longer small intestine. This was accompanied by higher levels of liver-derived very low-density lipoprotein and low-density lipoprotein triglycerides, and a lower level of high-density lipoprotein cholesterol in the serum. Mice exposed during the neonatal period to oral iAs also developed hepatosteatosis. Compared with the control group, iAs-induced fat accumulation in enterocytes became more significant in neonatal Lxrα-/- mice, accompanied by accelerated intestinal growth, hypertriglyceridemia, and hepatosteatosis. In contrast, regardless of enterocyte fat accumulation, hepatosteatosis was largely reduced in iAs-treated neonatal Atf4ΔHep mice. CONCLUSION: Exposure to iAs in neonatal mice resulted in excessive accumulation of fat in enterocytes, disrupting lipid homeostasis in the serum and liver, revealing the importance of the gut-liver axis and endoplasmic reticulum stress in mediating iAs-induced NAFLD at an early age. https://doi.org/10.1289/EHP12381.
Subject(s)
Arsenic , Non-alcoholic Fatty Liver Disease , Animals , Mice , Non-alcoholic Fatty Liver Disease/chemically induced , Animals, Newborn , Dietary Fats , HomeostasisABSTRACT
Hybrid immunity to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B- and T-cell responses.
ABSTRACT
Cis-regulatory elements (CREs) can be classified by the shapes of their transcription start site (TSS) profiles, which are indicative of distinct regulatory mechanisms. Massively parallel reporter assays (MPRAs) are increasingly being used to study CRE regulatory mechanisms, yet the degree to which MPRAs replicate individual endogenous TSS profiles has not been determined. Here, we present a new low-input MPRA protocol (TSS-MPRA) that enables measuring TSS profiles of episomal reporters as well as after lentiviral reporter chromatinization. To sensitively compare MPRA and endogenous TSS profiles, we developed a novel dissimilarity scoring algorithm (WIP score) that outperforms the frequently used earth mover's distance on experimental data. Using TSS-MPRA and WIP scoring on 500 unique reporter inserts, we found that short (153 bp) MPRA promoter inserts replicate the endogenous TSS patterns of â¼60% of promoters. Lentiviral reporter chromatinization did not improve fidelity of TSS-MPRA initiation patterns, and increasing insert size frequently led to activation of extraneous TSS in the MPRA that are not active in vivo. We discuss the implications of our findings, which highlight important caveats when using MPRAs to study transcription mechanisms. Finally, we illustrate how TSS-MPRA and WIP scoring can provide novel insights into the impact of transcription factor motif mutations and genetic variants on TSS patterns and transcription levels.
Subject(s)
Gene Expression Regulation , Regulatory Sequences, Nucleic Acid , Transcription Initiation Site , Promoter Regions, Genetic , Transcription Factors/genetics , High-Throughput Nucleotide SequencingABSTRACT
Helicobacter pylori ( H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori -induced disease progression. We have established a Helicobacter -induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene ( Myd88 -/- ) with H. felis . Using this model, we report here that that progression of H. felis -induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis -induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-ß (TRIF, Trif Lps 2 ) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.
ABSTRACT
Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices. In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration. The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism. In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid addiction process.
Subject(s)
Opioid-Related Disorders , Oxycodone , Rats , Female , Male , Animals , Rats, Inbred ACI , Rats, Inbred F344 , Rats, Inbred WKY , Analgesics, Opioid , Opioid-Related Disorders/drug therapy , Self AdministrationABSTRACT
Alcohol intoxication is a common ingestion in pediatrics with close to 10,000 reports to poison control centers annually. Hypoglycemia, neurological depression (ataxia, coma, nystagmus, etc.) and unstable vitals (hypothermia, hypotension, bradycardia, and respiratory depression) are common presentations. The patient is a 3 month old female who was brought into the Emergency Department (ED) for one day of decreased oral intake and inconsolability. Vital signs were reassuring. Physical exam revealed gaze preference to the right with inability to look left, dysconjugate gaze, and hypotonia. Work-up including CT of the head, and urinalysis was unremarkable. Urine drug screen was found to be positive for ethanol with follow up serum ethanol at 162 mg/dL. With conservative management the patient returned to her baseline. On follow-up with her pediatrician, it was elicited that the mother inadvertently used a water bottle of vodka to mix the patient's formula. This case adds to the paucity of literature of abnormal presentations of alcohol intoxication in an infant.
Subject(s)
Alcoholic Intoxication , Ethanol , Humans , Infant , Child , Female , Alcoholic Intoxication/complications , Alcoholic Intoxication/diagnosis , Coma , Alcoholic Beverages , MothersABSTRACT
Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.
Subject(s)
COVID-19 , Transcription Factors , Humans , Transcription Factors/genetics , Gene Expression Regulation , Leukocytes/metabolism , Intensive Care UnitsABSTRACT
Inorganic arsenic (iAs) is an environmental toxicant that can lead to severe health consequences, which can be exacerbated if exposure occurs early in development. Here, we evaluated the impact of oral iAs treatment on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) mice. We found that oral administration of iAs to neonatal hUGT1 mice that display severe neonatal hyperbilirubinemia leads to induction of intestinal UGT1A1 and a reduction in total serum bilirubin values. Oral iAs administration accelerates neonatal intestinal maturation, an event that is directly associated with UGT1A1 induction. As a reactive oxygen species producer, oral iAs treatment activated the Keap-Nrf2 pathway in the intestinal tract and liver. When Nrf2-deficient hUGT1 mice (hUGT1/Nrf2-/-) were treated with iAs, it was shown that activated Nrf2 contributed significantly toward intestinal maturation and UGT1A1 induction. However, hepatic UGT1A1 was not induced upon iAs exposure. We previously demonstrated that the nuclear receptor PXR represses liver UGT1A1 in neonatal hUGT1 mice. When PXR was deleted in hUGT1 mice (hUGT1/Pxr-/-), derepression of UGT1A1 was evident in both liver and intestinal tissue in neonates. Furthermore, when neonatal hUGT1/Pxr-/- mice were treated with iAs, UGT1A1 was superinduced in both tissues, confirming PXR release derepressed key regulatory elements on the gene that could be activated by iAs exposure. With iAs capable of generating reactive oxygen species in both liver and intestinal tissue, we conclude that PXR deficiency in neonatal hUGT1/Pxr-/- mice allows greater access of activated transcriptional modifiers such as Nrf2 leading to superinduction of UGT1A1.
Subject(s)
Arsenic , Glucuronosyltransferase , NF-E2-Related Factor 2 , Pregnane X Receptor , Animals , Mice , Animals, Newborn , Arsenic/toxicity , Bilirubin/blood , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , Liver/enzymology , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Reactive Oxygen Species/metabolism , Pregnane X Receptor/genetics , Pregnane X Receptor/metabolismABSTRACT
Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1's previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.
Subject(s)
Membrane Proteins , Protein Folding , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Membrane Proteins/metabolism , Molecular Chaperones/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolismABSTRACT
BACKGROUND: Upper respiratory infections can be complicated by acute bacterial sinusitis in pediatric patients, and usually resolve with antibiotic therapy (DeMuri and Wald, 2011). However, intracranial complications such as: epidural abscess, meningitis and more rarely cerebral sinus venous thrombosis (CSVT) can occur (Germiller et al., 2006). We report an unusual case of sinusitis complicated by an epidural abscess and later a CSVT in a young previously healthy patient. CASE DESCRIPTION: A 12-year-old female presented to the emergency department with a 9-day history of headaches and a 3-day history of fevers, rigors, nasal congestion and nonproductive cough. She later tested positive for Covid-19. CT and MRI showed extensive paranasal sinus disease and a right frontal epidural collection. MRV showed no sinovenous thrombosis. Washout and burr hole drainage alongside endoscopic sinus surgery was completed and post-op imaging showed evacuation of the epidural abscess with a small residual collection. Six days after the procedure, she experienced worsening headaches and MRV showed a nonocclusive thrombus in the superior sagittal sinus, which was treated with anticoagulation therapy. Upon follow-up, the patient showed improvement of the sinusitis, abscess and thrombus. CONCLUSION: This specific case encourages clinicians to be aware of complications, though rare, and to diagnose and treat sinusitis cases quickly. It is also important to be aware of any risk factors for thrombus formation, including an inflammatory and hypercoagulable state. In the patient's case, it was perceived that the CSVT was provoked due to the patient's Covid-19 infection, abscess, and sinus disease.
Subject(s)
Brain Abscess , COVID-19 , Epidural Abscess , Sinusitis , Thrombosis , Female , Humans , Child , Superior Sagittal Sinus , COVID-19/complications , Sinusitis/complications , Brain Abscess/complications , Headache , Thrombosis/complicationsABSTRACT
Syncope is a common reason for children and adolescents to seek care in the emergency department. Often syncopal episodes are benign and most commonly due to a vasovagal event. Occasionally an underlying cardiac arrhythmia is responsible. We present a case report of a 17-year-old male who collapsed during an emotional event and went into cardiac arrest. Emergency department evaluation including imaging, laboratory studies, and EKG indicated the cause of cardiac arrest was likely a primary cardiac arrhythmia. An initial clinical diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was made based on symptom onset during an emotional event, family history of sudden cardiac death, patient age, past episodes of chest pain and palpitations, absence of structural heart defect, and lack of EKG changes after the return of spontaneous circulation (ROSC). The diagnosis was later confirmed with genetic testing. The patient was started on a beta-blocker and a subcutaneous implantable cardioverter-defibrillator (S-ICD, Boston Scientific, Marlborough, MA) was placed. Given the rarity of this condition, this diagnosis is often missed, which contributes to increased mortality rates. In children and young adults presenting with syncope without clear etiology in the presence of high-risk features, further evaluation should be performed including referral to cardiology to rule out chronic cardiac arrhythmias.