Recovery of Visual Function in a Patient with an Onodi Cell Mucocele Compressive Optic Neuropathy Who Had a 5-Week Interval between Onset and Surgical Intervention: A Case Report

Purpose. To report on a patient with compressive optic neuropathy secondary to an Onodi cell mucocele, who fully recovered visual function following surgery. Method. Case report. Results. A 28-year-old male was admitted with a right visual acuity of 20/100 following treatment for an initial diagnosis of optic neuritis. Subsequent examination suggested compressive optic neuropathy, and neuroimaging confirmed the presence of an Onodi mucocele compressing the optic nerve. The patient underwent a right endonasal sphenoethmoidectomy with decompression 5 weeks after the initial onset of symptoms. Three weeks following surgery, the visual acuity was 20/20, and there was complete resolution of the visual field defect, which has remained stable at 1 year. Conclusion. Onodi cell mucocele should be included in the differential diagnosis of a young patient with compressive optic neuropathy. Surgical decompression should be considered even when symptoms have been present for over a month

How good are Global Newton methods? Part 2

Newton's method applied to certain problems with a discontinuous derivative operator is shown to be effective. A global Newton method in this setting is exhibited and its computational complexity is estimated. As an application a method is proposed to solve problems of linear inequalities (linear programming, phase 1). Using an example of the Klee-Minty type due to Blair, it was found that the simplex method (used in super-lindo) required over 2,000 iterations, while the method above required an average of 8 iterations (Newton steps) over 15 random starting values.Naval Surface Weapons Center, Dahlgren, VAhttp://archive.org/details/howgoodareglobal00goldO&MN Direct FundingApproved for public release; distribution is unlimited

Evaluating Opioid Dispensing Rates among Pediatrics and Young Adults based on CURES Data Reporting in California from 2015–2019

Background Receipt of opioid prescriptions in pediatric and young adult patients may be a risk factor for future opioid misuse. Data from prescription drug monitoring programs provide insight on outpatient opioid use. In our study, we analyzed the opioid dispensing rates for pediatrics and young adults in California. Methods A secondary analysis was performed from 2015–2019 using Controlled Utilization Review and Evaluation System data. This database provides dispensing data of controlled substances in California. Patients younger than 25 years who were prescribed opiates were analyzed by county. We further divided them into two groups (children: ≤14 years; adolescents and young adult: 15–24 years). Descriptive statistics and heat maps were used to illustrate the trends in opioid usage among different age groups. Results The overall percentages for the number of opioids being dispensed to patients aged \u3c25 years have decreased over the past four years. In 2015, 6 out of 58 counties in California were considered “high-rate” with \u3e2.9% of opioids dispensed to patients younger than 25 years old; in 2019, this number reduced to zero. Patients 25 and older received a higher proportion of opioids compared to younger populations; in 2019, 35.91% of opioids were dispensed to patients 45–64, and 8.92% to patients younger than 25. Conclusion Pediatric opioid prescriptions have declined over the recent years. However, a high degree of variability of prescription rates between demographic counties was noted. More studies are warranted in order to understand this discrepancy in opioid prescribing among pediatric and young adult patients

Racial and Ethnic Disparities in Opioid Use for Adolescents at US Emergency Departments

Background Racial/ethnic disparities in the use of opioids to treat pain disorders have been previously reported in the emergency department (ED). Further research is needed to better evaluate the impact race/ethnicity may have on the use of opioids in adolescents for the management of pain disorders in the ED. Methods This was a cross-sectional study using data from the National Hospital Ambulatory Medical Care Survey from 2006 to 2016. Multivariate models were used to evaluate the role of race/ethnicity in the receipt of opioid agonists while in the ED. All ED visits with patients aged 11–21 years old were analyzed. Races/ethnicities were stratified as non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. In addition to race, statistical analysis included the following covariates: pain score, pain diagnosis, age, region, sex, and payment method. Results There was a weighted total of 189,256,419 ED visits. Those visits involved 109,826,315 (58%) non-Hispanic Whites, 46,314,977 (24%) non-Hispanic Blacks, and 33,115,127 (18%) Hispanics, with 21.6% (95% CI, 21.1%-22.1), 15.2% (95% CI, 14.6–15.9%), and 17.4% (95% CI, 16.5–18.2%) of those visits reporting use of opioids, respectively. Regardless of age, sex, and region, non-Hispanic Whites received opioids at a higher rate than non-Hispanic Blacks and Hispanics. Based on diagnosis, non-Hispanic Whites received opioids at a higher rate in multiple pain diagnoses. Additionally, non-Hispanic Blacks and Hispanics were less likely to receive an opioid when reporting moderate pain (aOR = 0.738, 95% CI 0.601–0.906, aOR = 0.739, 95% CI 0.578–0.945, respectively) and severe pain (aOR = 0.580, 95% CI 0.500–0.672, aOR = 0.807, 95% CI 0.685–0.951, respectively) compared to non-Hispanic Whites. Conclusions Differences in the receipt of opioid agonists in EDs among the races/ethnicities exist, with more non-Hispanic Whites receiving opioids than their minority counterparts. Non-Hispanic Black women may be an especially marginalized population. Further investigation into sex-based and regional differences are needed

Case Report Recovery of Visual Function in a Patient with an Onodi Cell Mucocele Compressive Optic Neuropathy Who Had a 5-Week Interval between Onset and Surgical Intervention: A Case Report

. Purpose. To report on a patient with compressive optic neuropathy secondary to an Onodi cell mucocele, who fully recovered visual function following surgery. Method. Case report. Results. A 28-year-old male was admitted with a right visual acuity of 20/100 following treatment for an initial diagnosis of optic neuritis. Subsequent examination suggested compressive optic neuropathy, and neuroimaging confirmed the presence of an Onodi mucocele compressing the optic nerve. The patient underwent a right endonasal sphenoethmoidectomy with decompression 5 weeks after the initial onset of symptoms. Three weeks following surgery, the visual acuity was 20/20, and there was complete resolution of the visual field defect, which has remained stable at 1 year. Conclusion. Onodi cell mucocele should be included in the differential diagnosis of a young patient with compressive optic neuropathy. Surgical decompression should be considered even when symptoms have been present for over a month

Evaluating the 0–10 Point Pain Scale on Adolescent Opioid Use in US Emergency Departments

Objective: To evaluate trends in national emergency department (ED) adolescent opioid use in relation to reported pain scores. Methods: A retrospective, cross-sectional analysis on National Hospital Ambulatory Medical Care Survey (NHAMCS) data was conducted on ED visits involving patients aged 11–21 from 2008–2017. Crude observational counts were extrapolated to weighted estimates matching total population counts. Multivariate models were used to evaluate the role of a pain score in the reported use of opioids. Anchors for pain scores were 0 (no pain) and 10 (worst pain imaginable). Results: 31,355 observations were captured, which were extrapolated by the NHAMCS to represent 162,515,943 visits nationwide. Overall, patients with a score of 10 were 1.35 times more likely to receive an opioid than patients scoring a 9, 41.7% (CI95 39.7–43.8%) and 31.0% (CI95 28.8–33.3%), respectively. Opioid use was significantly different between traditional pain score cutoffs of mild (1–3) and moderate pain (4–6), where scores of 4 were 1.76 times more likely to receive an opioid than scores of 3, 15.5% (CI95 13.7–17.3%) and 8.8% (CI95 7.1–10.6%), respectively. Scores of 7 were 1.33 times more likely to receive opioids than scores of 6, 24.7% (CI95 23.0–26.3%) and 18.5% (CI95 16.9–20.0%), respectively. Fractures had the highest likelihood of receiving an opioid, as 49.2% of adolescents with a fracture received an opioid (CI95 46.4–51.9%). Within this subgroup, only adolescents reporting a fracture pain score of 10 had significantly higher opioid use than adjacent pain scores, where fracture patients scoring a 10 were 1.4 times more likely to use opioids than those scoring 9, 82.2% (CI95 76.1–88.4%) and 59.8% (CI95 49.0–70.5%), respectively. Conclusions: While some guidelines in the adult population have revised cut-offs and groupings of the traditional tiers on a 0–10 point pain scale, the adolescent population may also require further examination to potentially warrant a similar adjustment

Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury.

Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells

KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Non-Canonical Activin Pathway

BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A in PDAC development. METHODS: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed Bru-seq analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1a(Cre); LSL-Kras(G12D); Trp53(R172H/+); Kdm6a(fl/fl or fl/Y), Ptf1a(Cre); Kdm6a(fl/fl or fl/Y), and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bru-seq analysis revealed upregulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient of KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata demonstrated accelerated PDAC progression, developed a more aggressive undifferentiated type PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared to wild-type pancreata. CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a non-canonical p38-dependant activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be utilized as a therapeutic target for KDM6A-deficient PDACs