Diagnostic Identification of Acute Brain Dysfunction in Pediatric Sepsis and Septic Shock in the Electronic Health Record: A Comparison of Four Definitions in a Reference Dataset.

OBJECTIVES: Acute brain dysfunction (ABD) in pediatric sepsis has a prevalence of 20%, but can be difficult to identify. Our previously validated ABD computational phenotype (CP ABD ) used variables obtained from the electronic health record indicative of clinician concern for acute neurologic or behavioral change. We tested whether the CP ABD has better diagnostic performance to identify confirmed ABD than other definitions using the Glasgow Coma Scale or delirium scores. DESIGN: Diagnostic testing in a curated cohort of pediatric sepsis/septic shock patients. SETTING: Quaternary freestanding children's hospital. SUBJECTS: The test dataset comprised 527 children with sepsis/septic shock managed between 2011 and 2021 with a prevalence (pretest probability) of confirmed ABD of 30% (159/527). MEASUREMENTS AND MAIN RESULTS: CP ABD was based on use of neuroimaging, electroencephalogram, and/or administration of new antipsychotic medication. We compared the performance of the CP ABD with three GCS/delirium-based definitions of ABD-Proulx et al, International Pediatric Sepsis Consensus Conference, and Pediatric Organ Dysfunction Information Update Mandate. The posttest probability of identifying ABD was highest in CP ABD (0.84) compared with other definitions. CP ABD also had the highest sensitivity (83%; 95% CI, 76-89%) and specificity (93%; 95% CI, 90-96%). The false discovery rate was lowest in CP ABD (1-in-6) as was the false omission rate (1-in-14). Finally, the prevalence threshold for the definitions varied, with the CP ABD being the definition closest to 20%. CONCLUSIONS: In our curated dataset of pediatric sepsis/septic shock, CP ABD had favorable characteristics to identify confirmed ABD compared with GCS/delirium-based definitions. The CP ABD can be used to further study the impact of ABD in studies using large electronic health datasets.

Validation of a Computational Phenotype to Identify Acute Brain Dysfunction in Pediatric Sepsis.

OBJECTIVES: To validate a computational phenotype that identifies acute brain dysfunction (ABD) based on clinician concern for neurologic or behavioral changes in pediatric sepsis. DESIGN: Retrospective observational study. SETTING: Single academic children's hospital. PATIENTS: Four thousand two hundred eighty-nine index sepsis episodes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An existing computational phenotype of ABD was optimized to include routinely collected variables indicative of clinician concern for acute neurologic or behavioral change (completion of CT or MRI, electroencephalogram, or new antipsychotic administration). First, the computational phenotype was compared with an ABD reference standard established from chart review of 527 random sepsis episodes to determine criterion validity. Next, the computational phenotype was compared with a separate validation cohort of 3,762 index sepsis episodes to determine content and construct validity. Criterion validity for the final phenotype had sensitivity 83% (95% CI, 76-89%), specificity 93% (90-95%), positive predictive value 84% (77-89%), and negative predictive value 93% (90-96%). In the validation cohort, the computational phenotype identified ABD in 35% (95% CI 33-36%). Content validity was demonstrated as those with the ABD computational phenotype were more likely to have characteristics of neurologic dysfunction and severe illness than those without the ABD phenotype, including nonreactive pupils (15% vs 1%; p < 0.001), Glasgow Coma Scale less than 5 (44% vs 12%; p < 0.001), greater than or equal to two nonneurologic organ dysfunctions (50% vs 25%; p < 0.001), and need for intensive care (81% vs 65%; p < 0.001). Construct validity was demonstrated by higher odds for mortality (odds ratio [OR], 6.9; 95% CI, 5.3-9.1) and discharge to rehabilitation (OR, 11.4; 95% CI 7.4-17.5) in patients with, versus without, the ABD computational phenotype. CONCLUSIONS: A computational phenotype of ABD indicative of clinician concern for new neurologic or behavioral change offers a valid retrospective measure to identify episodes of sepsis that involved ABD. This computational phenotype provides a feasible and efficient way to study risk factors for and outcomes from ABD using routinely collected clinical data.

Intracranial Hypertension in Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is characterized by fever and multiorgan system dysfunction. Neurologic complications of MIS-C are not well described. We present 4 patients with MIS-C who had intracranial hypertension and discuss the unique management considerations when this occurs concurrently with significant myocardial dysfunction.

eIF5A-Independent Role of DHPS in p21CIP1 and Cell Fate Regulation.

Deoxyhypusine synthase (DHPS) catalyzes the first step of hypusination of the elongation translation factor 5A (eIF5A), and these two proteins have an exclusive enzyme-substrate relationship. Here we demonstrate that DHPS has a role independent of eIF5A hypusination in A375 and SK-MEL-28 human melanoma cells, in which the extracellular signal regulated kinase 1/2 (ERK1/2) pathway is deregulated. We found that RNA interference of DHPS induces G0/G1 cell cycle arrest in association with increased p21CIP1 expression in these cells whereas eIF5A knockdown induces cell death without increasing p21CIP1 expression. Interestingly, p21CIP1 knockdown switched DHPS knockdown-induced growth arrest to cell death in these cells, suggesting a specific relation between DHPS and p21CIP1 in determining cell fate. Surprisingly, ectopic expression of DHPS-K329R mutant that cannot hypusinate eIF5A abrogated DHPS knockdown-induced p21CIP1 expression in these cells, suggesting a non-canonical role of DHPS underlying the contrasting effects of DHPS and eIF5A knockdowns. We also show that DHPS knockdown induces p21CIP1 expression in these cells by increasing CDKN1A transcription through TP53 and SP1 in an ERK1/2-dependent manner. These data suggest that DHPS has a role independent of its ability to hypusinate eIF5A in cells, which appears to be important for regulating p21CIP1 expression and cell fate.

Advances in Point-of-Care Ultrasound in Pediatric Acute Care Medicine.

Pediatric point-of-care ultrasonography (POCUS) has grown in utilization and is now an integral part of pediatric acute care. Applications within the pediatric critical care, neonatology and pediatric emergency were once limited to evaluation of undifferentiated shock states, abdominal free fluid assessments in trauma resuscitation and procedural guidance. The body of pediatric POCUS literature is ever expanding and recently published international consensus guidelines are available to guide implementation into clinical practice. The authors present a review of emerging applications and controversies within thoracic, hemodynamic, neurologic, and ocular POCUS in pediatric acute care medicine.

ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity.

This study explores a non-kinase effect of extracellular regulated kinases 1/2 (ERK1/2) on the interaction between deoxyhypusine synthase (DHPS) and its substrate, eukaryotic translation initiation factor 5A (eIF5A). We report that Raf/MEK/ERK activation decreases the DHPS-ERK1/2 interaction while increasing DHPS-eIF5A association in cells. We determined the cryoelectron microscopy (cryo-EM) structure of the DHPS-ERK2 complex at 3.5 Å to show that ERK2 hinders substrate entrance to the DHPS active site, subsequently inhibiting deoxyhypusination in vitro. In cells, impairing the ERK2 activation loop, but not the catalytic site, prolongs the DHPS-ERK2 interaction irrespective of Raf/MEK signaling. The ERK2 Ser-Pro-Ser motif, but not the common docking or F-site recognition sites, also regulates this complex. These data suggest that ERK1/2 dynamically regulate the DHPS-eIF5A interaction in response to Raf/MEK activity, regardless of its kinase function. In contrast, ERK1/2 kinase activity is necessary to regulate the expression of DHPS and eIF5A. These findings highlight an ERK1/2-mediated dual kinase-dependent and -independent regulation of deoxyhypusination.

Sepsis-Related Brain MRI Abnormalities Are Associated With Mortality and Poor Neurological Outcome in Pediatric Sepsis.

BACKGROUND: It is not known whether brain magnetic resonance imaging (MRI) abnormalities in pediatric sepsis are associated with clinical outcomes. Study objectives were to (1) determine the prevalence and type of sepsis-related neuroimaging abnormalities evident on clinically indicated brain MRI in children with sepsis and (2) test the association of these abnormalities with mortality, new disability, length of stay (LOS), and MRI indication. METHODS: Retrospective cohort study of 140 pediatric patients with sepsis and a clinically indicated brain MRI obtained within 60 days of sepsis onset at a single, large academic pediatric intensive care unit (PICU). Two radiologists systematically reviewed the first post-sepsis brain MRI and determined which abnormalities were sepsis-related. Outcomes compared in patients with versus without sepsis-related MRI abnormalities. RESULTS: PICU mortality was 7%. Thirty patients had one or more sepsis-related MRI abnormality, yielding a prevalence of 21% (95% confidence interval 15%, 28%). Among those, 53% (16 of 30) had sepsis-related white matter signal abnormalities; 53% (16 of 30) sepsis-related ischemia, infarction, or thrombosis; and 27% (eight of 30) sepsis-related posterior reversible encephalopathy. Patients with one or more sepsis-related MRI abnormality had increased mortality (17% vs 5%; P = 0.04), new neurological disability at PICU discharge (32% vs 11%; P = 0.03), and longer PICU LOS (median 18 vs 11 days; P = 0.04) compared with patients without. CONCLUSIONS: In children with sepsis and a clinically indicated brain MRI, 21% had a sepsis-related MRI abnormality. Sepsis-related MRI abnormalities were associated with increased mortality, new neurological disability, and longer PICU LOS.

Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability.

Mortalin [also known as heat shock protein family A (HSP70) member 9 (HSPA9) or glucose-regulated protein 75 (GRP75)] is a mitochondrial molecular chaperone that is often up-regulated and mislocalized in tumors with abnormal activation of the kinases MEK and ERK. Here, we found that mortalin depletion was selectively lethal to tumor and immortalized normal cells expressing the mutant kinase B-RafV600E or the chimeric protein ΔRaf-1:ER and that MEK-ERK-sensitive regulation of the peptide-binding domain in mortalin was critical to cell survival or death. Proteomics screening identified adenine nucleotide translocase 3 (ANT3) as a previously unknown mortalin substrate and cell survival/death effector. Mechanistically, increased MEK-ERK signaling activity and mortalin function converged opposingly on the regulation of mitochondrial permeability. Specifically, whereas MEK-ERK activity increased mitochondrial permeability by promoting the interaction between ANT3 and the peptidyl-prolyl isomerase cyclophilin D (CypD), mortalin decreased mitochondrial permeability by inhibiting this interaction. Hence, mortalin depletion increased mitochondrial permeability in MEK-ERK-deregulated cells to an extent that triggered cell death. HSP70 inhibitor derivatives that effectively inhibited mortalin suppressed the proliferation of B-RafV600E tumor cells in culture and in vivo, including their B-Raf inhibitor-resistant progenies. These findings suggest that targeting mortalin has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors.

Ataxia with Vitamin E Deficiency May Present with Cervical Dystonia.

BACKGROUND: Ataxia with vitamin E deficiency (AVED) is an autosomal recessive disorder that usually presents with ataxia, areflexia, and proprioceptive and vibratory sensory loss. Dystonia has been reported rarely. CASE REPORT: An 11-year-old female presented with dystonic head tremor and cervical and bilateral arm dystonia. Her 14-year-old older brother had dystonic head tremor and generalized dystonia. One year later, the brother developed dysarthria, limb dysmetria, and gait ataxia. Compound heterozygous mutations in TTPA were detected, confirming the diagnosis of AVED. DISCUSSION: AVED may present with dystonia rather than ataxia, and should be considered in the differential diagnosis of progressive dystonia.

Pancreatic ductal adenocarcinoma: risk factors, screening, and early detection.

Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with over 38000 deaths in 2013. The opportunity to detect pancreatic cancer while it is still curable is dependent on our ability to identify and screen high-risk populations before their symptoms arise. Risk factors for developing pancreatic cancer include multiple genetic syndromes as well as modifiable risk factors. Genetic conditions include hereditary breast and ovarian cancer syndrome, Lynch Syndrome, familial adenomatous polyposis, Peutz-Jeghers Syndrome, familial atypical multiple mole melanoma syndrome, hereditary pancreatitis, cystic fibrosis, and ataxia-telangiectasia; having a genetic predisposition can raise the risk of developing pancreatic cancer up to 132-fold over the general population. Modifiable risk factors, which include tobacco exposure, alcohol use, chronic pancreatitis, diet, obesity, diabetes mellitus, as well as certain abdominal surgeries and infections, have also been shown to increase the risk of pancreatic cancer development. Several large-volume centers have initiated such screening protocols, and consensus-based guidelines for screening high-risk groups have recently been published. The focus of this review will be both the genetic and modifiable risk factors implicated in pancreatic cancer, as well as a review of screening strategies and their diagnostic yields.