Comparison and Utility of Intravenous Iodinated Contrast in Chest, Abdomen, Pelvis Computerized Tomography for Trauma Patients With Blunt Mechanism of Injury Before and After the May 9, 2022 Global Contrast Shortage at a Level II Trauma Center.

Background: Intravenous (IV) contrast improves the sensitivity and specificity of injury detection in computerized tomography (CT). Its use is recommended in the workup of trauma patients by the American College of Surgeons and American College of Radiology. On May 9, 2022, the Food and Drug Administration declared a shortage of iodinated contrast due to the COVID-19 pandemic. Although the shortage has ended, the temporary lack of IV contrast forced physicians to be prudent in ordering CT scans with IV contrast. We sought to determine if there was a change in the percentage of CT contrast studies performed during the contrast shortage and if this change affected patient outcomes.Methods: Retrospective chart review was performed on all adult tier 2 trauma patients at a 619-bed community-based level II trauma center who received CT chest, abdomen, and pelvis imaging as initial workup for blunt trauma from 5/9/2021-6/30/2021 (pre-shortage) and 5/9/2022-6/30/2022 (during shortage).Results: Patients were predominantly male with median age of 31-52 and of White or Hispanic ethnicity. Before the contrast shortage, all 110 trauma patients were scanned with contrast. During the shortage, 29 of 114 patients were scanned with contrast (P < 0.001). Injuries were identified in 59% of patients scanned with contrast (P < 0.001). There were no significant differences in blood transfusion needs, repeat CT, disposition, or mortality when comparing pre-shortage to during shortage or when comparing between non-contrast and contrast studies during the shortage.Discussion: There was a decrease in the percentage of CT contrast studies performed during the shortage. A higher percentage of injuries were identified in the patients scanned with contrast. However, there were no significant differences in patient outcomes. Certain trauma patients may be safely scanned without contrast.

Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease.

Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach. Dose proportionality was determined using the power model. Two- and 3-compartment linear PK models were tested for the characterization of the PK of ANAVEX3-71 and its M8 metabolite. The PK of ANAVEX3-71 is linear, dose proportional, and time invariant. The drug is rapidly eliminated with a mean (standard deviation) apparent terminal elimination half-life of 3.56 (4.09) hours, while the M8 metabolite was eliminated with a mean (standard deviation) apparent terminal elimination half-life of 6.59 (1.64) hours. The population PK model was used to investigate the effects of covariates on the PK of ANAVEX3-71 and M8. Age, weight, and creatinine clearance were not explanatory of the variability in apparent clearance and apparent volume of the central compartment of ANAVEX3-71. Food had no effect on the PK of ANAVEX3-71 and its M8 metabolite.

Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration-QTcF relationship was small and slightly negative: -0.017 ms per µg/L, with a small treatment effect-specific intercept of -0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58 µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

Severity of traumatic adrenal injury does not meaningfully affect clinical outcomes.

PURPOSE: There are limited data comparing the severity of traumatic adrenal injury (TAI) and the need for interventions, such as transfusions, hospitalization, or incidence of adrenal insufficiency (AI) and other clinical outcomes. The aim of this study was to analyze the relationship between the grade of TAI and the need for subsequent intervention and clinical outcomes following the injury. METHODS: After obtaining Institutional Review Board approval, our trauma registry was queried for patients with TAI between 2009 and 2017. Contrast-enhanced computed tomography (CT) examinations of the abdomen and pelvis were evaluated by a board-certified radiologist with subspecialty expertise in abdominal and trauma imaging, and adrenal injuries were classified as either low grade (American Association for the Surgery of Trauma (AAST) grade I-III) or high grade (AAST grade IV-V). Patients without initial contrast-enhanced CT imaging and those with indeterminate imaging findings on initial CT were excluded. RESULTS: A total of 129 patients with 149 TAI were included. Eight-six patients demonstrated low-grade injuries and 43 high grade. Age, gender, and Injury Severity Score (ISS) were not statistically different between the groups. There was an increased number of major vascular injuries in the low-grade vs. high-grade group (23% vs. 5%, p < 0.01). No patient required transfusions or laparotomy for control of adrenal hemorrhage. There was no statistical difference in hospital length of stay (LOS), ventilator days, or mortality. Low-grade adrenal injuries were, however, associated with shorter ICU LOS (10 days vs. 16 days, p = 0.03). CONCLUSION: The need for interventions and clinical outcomes between the low-grade and high-grade groups was similar. These results suggest that, regardless of the TAI grade, treatment should be based on a holistic clinical assessment and less focused on specific interventions directed at addressing the adrenal injury.

A Boy with Rash and Joint Pain Diagnosed with Scurvy: A Case Report.

While rare, scurvy is a disease the emergency physician should continue to consider in the differential of bruising and joint pain. Although these symptoms are nonspecific, the astute physician should remain open-minded even when scurvy is not likely to be seen in an economically stable country. Contrary to this, we report a case of a young boy in the United States with scurvy who presented with a rash and limp. The diagnosis of scurvy can be made alone by a thorough history, but radiologic studies and pertinent labs also helped. Early diagnosis resulted in adequate vitamin supplementation and quick recovery of symptoms thereby avoiding unnecessary testing and lowering the cost of care. Topics: Scurvy, pediatric, vitamin C deficiency, nutritional deficiencies.

Sevoflurane-Induced Thrombocytopenia in Post-Robotic-Assisted Paraesophageal Hernia Repair.

BACKGROUND: Transient transaminitis is an expected outcome from liver retraction after foregut surgeries. However, severe thrombocytopenia is usually not a sequela of that. We present a case in which sevoflurane is suspected of inducing thrombocytopenia as it was the only newly introduced medication to the patient during the hospital course. Thrombocytopenia may present in a variety of settings in hospitalized patients. However, managing this occurrence requires deep exploration of pathophysiology that can cause decreased platelets, which may be a challenging task in certain circumstances. The liver plays an important role in thrombopoiesis by releasing megakaryocyte growth factors. Therefore, liver dysfunction can present as thrombocytopenia or other platelet dysfunctions. OBJECTIVE: To describe a presentation of thrombocytopenia possibly associated with anesthesia-induced transaminitis after a robotic paraesophageal hernia repair with mesh and fundoplasty with intraoperative esophagogastroduodenoscopy (EGD). METHODS: A 55-year-old presented to the ED with abdominal pain and was found to have a large type IV paraesophageal hernia that was surgically treated with a robotic paraesophageal hernia repair with mesh. However, on the first postoperative day (POD) (#1), the patient developed new onset thrombocytopenia with transaminitis. Workup for thrombocytopenia failed to determine an etiology. With platelet transfusion, platelet count showed an upward trend. The patient was then evaluated and cleared for discharge by POD#5. RESULTS: The patient's POD#1 daily labs showed elevated values for liver function tests and a low platelet count of 10,000 platelets per microliter with an international normalized value (INR) of 1.3. She had received two doses of intravenous acetaminophen just prior to surgery. Her platelet count responded to two units of platelets but decreased again immediately after. She continued to have transaminitis with down-trending liver enzymes. Peripheral smear on review showed no evidence of schistocytes. A heparin-induced thrombocytopenia (HIT) screening was negative. The patient was regularly evaluated, and the platelets stabilized and slowly started to trend up. The patient recovered by the morning of her POD#5 and was cleared for discharge. CONCLUSION: We are reporting on a case of acute postoperative thrombocytopenia that was associated with transaminitis and elevated liver enzymes. We are linking the role of the liver dysfunction in noncirrhotic patients with surgical abdominal procedures. Although liver retraction transaminitis possibly played a role in the laboratory findings in the patient, the acute drop in her platelet count could be closely related to the use of sevoflurane anesthetic considering its potential hepatotoxic side effects. We also cannot rule out the sevoflurane directly affecting the platelet count.

Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses.

Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.

Amyloid Beta and MicroRNAs in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive mental illness characterized by memory loss and multiple cognitive impairments. In the last several decades, significant progress has been made in understanding basic biology, molecular mechanisms, and development of biomarkers and therapeutic drugs. Multiple cellular changes are implicated in the disease process including amyloid beta and phosphorylation of tau synaptic damage and mitochondrial dysfunction in AD. Among these, amyloid beta is considered a major player in the disease process. Recent advancements in molecular biology revealed that microRNAs (miRNAs) are considered potential biomarkers in AD with a focus on amyloid beta. In this article we discussed several aspects of AD including its prevalence, classifications, risk factors, and amyloid species and their accumulation in subcellular compartments. This article also discusses the discovery and biogenesis of miRNAs and their relevance to AD. Today's research continues to add to the wealth of miRNA data that has been accumulated, however, there still lacks clear-cut understanding of the physiological relevance of miRNAs to AD. MiRNAs appear to regulate translation of gene products in AD and other human diseases. However, the mechanism of how many of these miRNAs regulate both the 5' and 3'UTR of amyloid precursor protein (APP) processing is still being extrapolated. Hence, we still need more research on miRNAs and APP/amyloid beta formation in the progression and pathogenesis of AD.

Effects of Environmental Water Absorption by Solution-Deposited Al2O3 Gate Dielectrics on Thin Film Transistor Performance and Mobility.

In recent years, many solution-processed oxide transistors have been reported with mobility rivaling or exceeding their vacuum-deposited counterparts. Here, we show that water absorption from the environment by solution-processed dielectric materialsexplains this enhanced mobility. By monitoring the water content of Al2O3, ZrO2, and bilayer dielectric materials, we demonstrate how water absorption by the dielectric affects electrical characteristics in solution-processed metal oxide transistors. These effects, including capacitance-frequency dispersion, counterclockwise hysteresis in transfer curves, and high channel mobility, are elucidated by electron transfer between the gate/channel and trap states within the band gap of the dielectric created by the water.

HIV blocks Type I IFN signaling through disruption of STAT1 phosphorylation.

This study investigates the modulation of Type I IFN induction of an antiviral state by HIV. IFNs, including IFN-α, are key innate immune cytokines that activate the JAK/STAT pathway leading to the expression of IFN-stimulated genes. IFN-stimulated gene expression establishes the antiviral state, limiting viral infection in IFN-α-stimulated microenvironments. Our previous studies have shown that HIV proteins disrupt the induction of IFN-α by degradation of IFN-ß promoter stimulator-1, an adaptor protein for the up-regulation and release of IFN-α into the local microenvironment via the retinoic acid-inducible gene 1-like receptor signaling pathway. However, IFN-α is still released from other sources such as plasmacytoid dendritic cells via TLR-dependent recognition of HIV. Here we report that the activation of the JAK/STAT pathway by IFN-α stimulation is disrupted by HIV proteins Vpu and Nef, which both reduce IFN-α induction of STAT1 phosphorylation. Thus, HIV would still be able to avoid antiviral protection induced by IFN-α in the local microenvironment. These findings show that HIV blocks multiple signaling points that would lead to the up-regulation of IFN-stimulated genes, allowing more effective replication in IFN-α-rich environments.

Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome.

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.

Genome-Wide DNA Methylation Analysis Reveals Epigenetic Dysregulation of MicroRNA-34A in TP53-Associated Cancer Susceptibility.

PURPOSE: Although the link between mutant TP53 and human cancer is unequivocal, a significant knowledge gap exists in clinically actionable molecular targets in Li-Fraumeni syndrome (LFS), a highly penetrant cancer predisposition syndrome associated with germline mutations in TP53. This study surveyed the epigenome to identify functionally and clinically relevant novel genes implicated in LFS. PATIENTS AND METHODS: We performed genome-wide methylation analyses of peripheral blood leukocyte DNA in germline TP53 mutation carriers (n = 72) and individuals with TP53 wild type in whom histologically comparable malignancies developed (n = 111). Targeted bisulfite pyrosequencing was performed on a validation cohort of 30 TP53 mutation carriers and 46 patients with TP53 wild type, and candidate sites were evaluated in primary tumors from patients with LFS across multiple histologic tumor types. RESULTS: In 183 patients, distinct DNA methylation signatures were associated with deleterious TP53 mutations in peripheral blood leukocytes. TP53-associated DNA methylation marks occurred in genomic regions that harbored p53 binding sites and in genes encoding p53 pathway proteins. Moreover, loss-of-function TP53 mutations were significantly associated with differential methylation at the locus encoding microRNA miR-34A, a key component of the p53 regulatory network (adjusted P < .001), and validated in an independent patient cohort (n = 76, P < .001). Targeted bisulfite pyrosequencing demonstrated that miR-34A was inactivated by hypermethylation across many histologic types of primary tumors from patients with LFS. Moreover, miR-34A tumor hypermethylation was associated with decreased overall survival in a cohort of 29 patients with choroid plexus carcinomas, a characteristic LFS tumor (P < .05). CONCLUSION: Epigenetic dysregulation of miR-34A may comprise an important path in TP53-associated cancer predisposition and represents a therapeutically actionable target with potential clinical relevance.

Super-Transactivation TP53 Variant in the Germline of a Family with Li-Fraumeni Syndrome.

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic TP53 variants detected in patients with a suspected diagnosis of LFS. Most intriguing was the discovery of a "super-transactivation" variant within Exon 10 of TP53 (c.1079G>T/p.G360V). Functional analysis of this novel variant revealed a paradoxical "super-transactivation" effect on tp53 response elements and a corresponding tumor suppressive effect on colony formation and apoptosis. While unlikely to be disease-causing, we propose that this variant may represent a novel tp53 polymorphism and potential phenotypic modifier in LFS. In the future, the enhanced transactivation effects of p.G360V-tp53 may also prove useful in designing more efficacious tp53-based gene therapies.