High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma.

INTRODUCTION: Severe traumatic injury with shock can lead to direct and indirect organ injury; however, tissue-specific biomarkers are limited in clinical panels. We used proteomic and metabolomic databases to identify organ injury patterns after severe injury in humans. METHODS: Plasma samples (times 0, 24, and 72 hours after arrival to trauma center) from injured patients enrolled in two randomized prehospital trials were subjected to multiplexed proteomics (SomaLogic Inc., Boulder, CO). Patients were categorized by outcome: nonresolvers (died >72 hours or required ≥7 days of critical care), resolvers (survived to 30 days and required <7 days of critical care), and low Injury Severity Score (ISS) controls. Established tissue-specific biomarkers were identified through a literature review and cross-referenced with tissue specificity from the Human Protein Atlas. Untargeted plasma metabolomics (Metabolon Inc., Durham, NC), inflammatory mediators, and endothelial damage markers were correlated with injury biomarkers. Kruskal-Wallis/Mann-Whitney U tests with false discovery rate correction assessed differences in biomarker expression across outcome groups (significance; p < 0.1). RESULTS: Of 142 patients, 78 were nonresolvers (median ISS, 30), 34 were resolvers (median ISS, 22), and 30 were low ISS controls (median ISS, 1). A broad release of tissue-specific damage markers was observed at admission; this was greater in nonresolvers. By 72 hours, nine cardiac, three liver, eight neurologic, and three pulmonary proteins remained significantly elevated in nonresolvers compared with resolvers. Cardiac damage biomarkers showed the greatest elevations at 72 hours in nonresolvers and had significant positive correlations with proinflammatory mediators and endothelial damage markers. Nonresolvers had lower concentrations of fatty acid metabolites compared with resolvers, particularly acyl carnitines and cholines. CONCLUSION: We identified an immediate release of tissue-specific biomarkers with sustained elevation in the liver, pulmonary, neurologic, and especially cardiac injury biomarkers in patients with complex clinical courses after severe injury. The persistent myocardial injury in nonresolvers may be due to a combination of factors including metabolic stress, inflammation, and endotheliopathy.

Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients.

Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights.

The Use of Multiplexing to Identify Cytokine and Chemokine Networks in the Immune-Inflammatory Response to Trauma.

Significance: The immunoinflammatory responses that follow trauma contribute to clinical trajectory and patient outcomes. While remarkable advances have been made in trauma services and injury management, clarity on how the immune system in humans responds to trauma is lagging. Recent Advances: Multiplexing platforms have transformed our ability to analyze comprehensive immune mediator responses in human trauma. In parallel, with the establishment of large data sets, computational methods have been adapted to yield new insights based on mediator patterns. These efforts have added an important data layer to the emerging multiomic characterization of the human response to injury. Critical Issues: Outcome after trauma is greatly affected by the host immunoinflammatory response. Excessive or sustained responses can contribute to organ damage. Hence, understanding the pathophysiology behind traumatic injury is of vital importance. Future Directions: This review summarizes our work in the study of circulating immune mediators in trauma patients. Our foundational studies into dynamic patterns of inflammatory mediators represent an important contribution to the concepts and computational challenges that these large data sets present. We hope to see further integration and understanding of multiomics strategies in the field of trauma that can aid in patient endotyping and in potentially identifiying certain therapeutic targets in the future. Antioxid. Redox Signal. 35, 1393-1406.

Association of Parental Consanguinity With Papillary Thyroid Carcinoma: A Case-Control Study.

CONTEXT: Papillary thyroid carcinoma (PTC) is the most common type of nonmedullary thyroid carcinoma. Uncommonly, PTC is associated with multiple genetic alterations and chromosomal abnormalities and displays familial patterns of inheritance. Parental consanguinity increases susceptibility to many genetic disorders. OBJECTIVE: This work aimed to investigate the association of parental consanguinity with PTC. METHODS: This case-control study of PTC patients compared with healthy controls took place in a tertiary referral hospital. We recruited 200 PTC patients who were managed at the endocrinology outpatient clinics of the Jordan University Hospital, and we recruited 515 healthy controls from a nonclinical setting. We interviewed all participants and collected sociodemographic data. We reviewed the family pedigrees of each participant four generations back and excluded any participant who was related. We established whether the parents of each participant were first cousins, first cousins once removed, second cousins, or unrelated. We then used binary logistic regression to assess the association of parental consanguinity with PTC adjusted for age, sex, smoking status, body mass index, and parental education. RESULTS: We recruited 715 participants. The numbers of PTC patients and healthy controls were 200 (28.0%) and 515 (72.0%), respectively. The rate of parental consanguinity was 25.5% in PTC patients and 12.2% in healthy controls. Parental consanguinity was significantly associated with PTC (adjusted odds ratio, 2.60; 95% CI, 1.63-4.17; P < .001). CONCLUSION: Parental consanguinity is a risk factor for PTC. Our findings should be considered during familial risk assessment and genetic counseling, especially in populations with high rates of consanguinity.

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses.

Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.

The association between levels of inflammatory markers in autistic children compared to their unaffected siblings and unrelated healthy controls

Background/aim: Autism spectrum disorder (ASD) describes a range of neurodevelopmental disabilities that impair behavior and communication. Although it is relatively prevalent, the pathophysiology is still subject to speculation and debate. The aim of this study is to identify a possible association between interleukin-6, -8, -9, and -10 and tumor necrosis factor alpha (TNF-α) in autism among Jordanian children by comparing the plasma levels of these cytokines in autistic children with those of their unaffected siblings and unrelated healthy controls. Materials and methods: In this study, 80 Jordanian children under the age of 12 with diagnosed autism were selected. For comparison, 51 unaffected siblings and 86 unrelated healthy controls were also recruited. Venous blood was collected and interleukin levels in all three groups were investigated. Results: Interleukin-6 was found to be significantly higher in the plasma of both autistic children and their siblings compared with the unrelated healthy control group (P < 0.05). As for interleukin-8 and TNF-α, plasma levels were significantly higher exclusively in autistic children compared to their siblings and unaffected control subjects (P < 0.001, P < 0.001). There was no significant difference between plasma levels of the previously mentioned cytokines in the siblings and the unrelated control group. As for interleukin-9 and interleukin-10, no significant differences were found between all three groups (P = 0.15, P = 0.35). Conclusion: We found that interleukin-8 and TNF-α were exclusively elevated in autistic Jordanian children, while interleukin-6 was elevated in both autistic children and their siblings, potentially dismissing its significance. These results may lead to a better understanding of the disorder's pathophysiology, early testing, and diagnosis.

Ulnar nerve palsy as a complication of closed both-bone forearm fracture in a pediatric patient: a case report.

Background: Fractures of both the ulna and radius, known as both-bone forearm fractures are common among the pediatric population. However, ulnar nerve palsy is a rare complication. Nerve damage can be due to multiple factors. Identification of the type of nerve damage is vital for proper management of this complication. Here, we present a case of ulnar nerve palsy complicating a closed both-bone forearm fracture in a pediatric patient. Furthermore, we explored how to best manage such cases and decrease permanent nerve damage through a literature review. Case presentation: A 10-year-old boy presented to the emergency department (ED) 1 day after sustaining a closed right forearm fracture due to a fall. Examination at our ED revealed intact vascularity and nerve function. Reduction and casting were performed. On follow-up 7 days later, signs of ulnar nerve palsy in the form of decreased sensation in the little finger and weak abduction and adduction of the fingers were present. The patient was admitted and underwent closed reduction with percutaneous elastic stable intramedullary nailing. We found 14 case reports in the literature with similar case presentations. These fractures are commonly managed conservatively by closed reduction, casting, and rehabilitation. However, in both-bone forearm fractures, management began with observation, with surgical exploration being reserved for non-improving patients. Conclusion: The uncommon occurrence of ulnar nerve palsy after closed forearm fractures in children should alert physicians to maintain a high index of suspicion and to thoroughly evaluate nerve function in children both before and after reduction of forearm fractures. Surgical exploration is recommended in cases of delayed recovery of nerve function.

Prolonged Rupture of Membranes, Neonatal Outcomes and Management Guidelines.

BACKGROUND: Prolonged rupture of membranes (PROM) is a risk factor for early-onset neonatal sepsis (EOS). In the absence of early specific and sensitive diagnostic tools, management of asymptomatic infants is difficult. This study was conducted to investigate clinical outcomes of newborns born to mothers with PROM. METHODS: A retrospective study of neonates ≥ 34 weeks admitted due to PROM was conducted. Medical charts were reviewed. Neonates were classified into three categories based on their status at birth: ill appearing, well, and equivocal. Sepsis risk calculator was retrospectively applied. RESULTS: A total of 176 neonates were included. All mothers had unknown group B streptococcus (GBS) status. Of them, 74.4% were asymptomatic. Nine infants (5%) had positive cultures, and 23 infants (13%) had culture-negative sepsis. The newborns with sepsis fit into the "ill appearing" category with a significantly higher proportion (12.5% vs. 0.0%, P value < 0.0). CONCLUSIONS: Reliable early diagnostic tools for neonatal sepsis are lacking. Adopting a protocol that utilizes multiple methods and follow-up for the clinical condition of these infants are the key factors to avoid missing neonates with true sepsis and decreasing the use of antibiotics in those without infection.

Association of MicroRNAs with the Clinicopathologic Characteristics of Ependymoma.

The current management of ependymoma is wrought with limitations. Molecular classification is a promising development. MicroRNA (miRNA) deregulation is associated with human cancer and may be a means of molecular classification. The aim of our study is to investigate the association of miRNA expression with the clinicopathologic characteristics of ependymoma. Twenty-two samples were clinically annotated. Histologic features were reassessed and the expression of Ki-67, cyclin D1, and nestin was examined. The expression of 84 stem cell-related miRNAs was profiled. The ΔΔCT method and a Student's t test were used to compute fold changes and P values, respectively. Our analysis revealed 24 statistically significant associations. We identified seven site-specific miRNAs. The pattern of expression was variable in each anatomic site. In addition, we identified six candidate recurrence biomarkers, all of which were overexpressed in recurrent cases. All three grade-related miRNAs were underexpressed in anaplastic samples. Two miRNAs each were underexpressed in samples immunoreactive to Ki-67 and cyclin D1. No miRNAs were differentially expressed between nestin-negative and nestin-positive samples. In conclusion, molecular alterations in ependymoma involve miRNAs. In our report, we review the level of evidence for the biomarker candidacy of identified miRNAs. Confirmatory studies are necessary to establish robust biomarkers for the clinical management of ependymoma. Proteins regulated by differentially expressed miRNAs are additional candidate biomarkers and may offer targets for novel therapeutic interventions.