Novel Application of Hydrodissection in Laparoscopic Cholecystectomy for Gangrenous Gallbladders.

INTRODUCTION: Laparoscopic cholecystectomy (LC) for gangrenous gallbladders (GGBs) can be challenging and represent a significant number of LC cases, necessitating more efficacious surgical techniques. Currently, the standard treatment for GGBs is blunt dissection which can have high iatrogenic complication rates. To our knowledge, this is the first large retrospective study conducted on the novel application of hydrodissection (HD) in LCs for GGBs. METHODS: In this retrospective study of 386 LCs, data were collected for patient demographics, medical comorbidities, operating time (OT), anesthesia time (AT), length of stay (LOS), estimated blood loss, conversion to open procedures, 30-day readmissions, and mortality. Patients were categorized into four groups: (1) Vyas employing HD for GGBs (VHG), (2) non-Vyas group of five surgeons not employing HD for GGBs (NVG), (3) Vyas treating non-GGBs, and (4) non-Vyas group of five surgeons treating non-GGBs. Control groups were age-matched and sex-matched. Statistical analysis used descriptive statistics, Mann-Whitney U testing, and chi-squared testing (α = 0.05). RESULTS: This study demonstrated significantly decreased (P < 0.05) OT (P = 0.001), AT (P < 0.001), LOS (P = 0.015), and conversion to open procedures (P = 0.047) between the VHG and NVG groups, with HD reducing OT by 35.5% compared to blunt dissection. This study did not demonstrate significantly decreased (P > 0.05) estimated blood loss (P = 0.185) and 30-day readmissions (P = 0.531) between the VHG and NVG groups, but they were trending toward significant. There were no mortalities in this study. CONCLUSIONS: HD is associated with improved surgical outcomes of LCs for GGBs demonstrated by reduced OT, AT, LOS, and conversion to open procedures. Further multi-institutional studies are needed to validate HD implementation and further dissemination.

In-patient comorbidities in inclusion body myositis: a United States national in-patient sample-based study.

OBJECTIVES: Inclusion body myositis (IBM) is the most common idiopathic inflammatory myopathy (IIM) above the age of 50 with a distinct clinical phenotype of progressive, painless, asymmetric weakness predominantly involving the long finger flexors and quadriceps. In this study, we compared comorbidities in IBM with other IIMs (i.e., dermatomyositis (DM) and polymyositis (PM)) from the United States National Inpatient Sample Database. METHODS: We identified patients with a primary diagnosis of IBM or IIM from the National Inpatient Sample (NIS) from 2012 to 2018. We then compared the rate of common inpatient comorbidities between the IBM and IIM. RESULTS: There were 18,819 admissions for patients with either IBM or IIM. IBM patients were older (72.9±10.7 years vs. 59.3±18.4 years for IIM, p<0.001), predominantly men (65.0% vs. 31.2% for IIM, p<0.001), and White Caucasians (82.5% vs. 58.4% for IIM, p<0.001). IBM patients had significantly more frequent events of aspiration pneumonia, atrial fibrillation, falls, and sepsis. The rate of PEG tube placement was also significantly higher. When performing multivariable logistic regression, we found that IBM is a risk factor for aspiration pneumonia (OR 3.03), PEG tube placement (OR 2.91), falls (OR 2.05), and sepsis (OR 1.30) but not for significant cardiovascular events. CONCLUSIONS: IBM increases a patient's risk for dysphagia, falls, and infection as compared to other IIM patients. Further population-based studies are warranted to better elucidate the impact of these comorbidities in patients with IBM.

Diverse GPCRs exhibit conserved water networks for stabilization and activation.

G protein-coupled receptors (GPCRs) have evolved to recognize incredibly diverse extracellular ligands while sharing a common architecture and structurally conserved intracellular signaling partners. It remains unclear how binding of diverse ligands brings about GPCR activation, the common structural change that enables intracellular signaling. Here, we identify highly conserved networks of water-mediated interactions that play a central role in activation. Using atomic-level simulations of diverse GPCRs, we show that most of the water molecules in GPCR crystal structures are highly mobile. Several water molecules near the G protein-coupling interface, however, are stable. These water molecules form two kinds of polar networks that are conserved across diverse GPCRs: (i) a network that is maintained across the inactive and the active states and (ii) a network that rearranges upon activation. Comparative analysis of GPCR crystal structures independently confirms the striking conservation of water-mediated interaction networks. These conserved water-mediated interactions near the G protein-coupling region, along with diverse water-mediated interactions with extracellular ligands, have direct implications for structure-based drug design and GPCR engineering.

Early B cell tolerance defects in neuromyelitis optica favour anti-AQP4 autoantibody production.

Neuromyelitis optica spectrum disorders (NMOSD) constitute rare autoimmune disorders of the CNS that are primarily characterized by severe inflammation of the spinal cord and optic nerve. Approximately 75% of NMOSD patients harbour circulating pathogenic autoantibodies targeting the aquaporin-4 water channel (AQP4). The source of these autoantibodies remains unclear, but parallels between NMOSD and other autoantibody-mediated diseases posit compromised B cell tolerance checkpoints as common underlying and contributing factors. Using a well established assay, we assessed tolerance fidelity by creating recombinant antibodies from B cell populations directly downstream of each checkpoint and testing them for polyreactivity and autoreactivity. We examined a total of 863 recombinant antibodies. Those derived from three anti-AQP4-IgG seropositive NMOSD patients (n = 130) were compared to 733 antibodies from 15 healthy donors. We found significantly higher frequencies of poly- and autoreactive new emigrant/transitional and mature naïve B cells in NMOSD patients compared to healthy donors (P-values < 0.003), thereby identifying defects in both central and peripheral B cell tolerance checkpoints in these patients. We next explored whether pathogenic NMOSD anti-AQP4 autoantibodies can originate from the pool of poly- and autoreactive clones that populate the naïve B cell compartment of NMOSD patients. Six human anti-AQP4 autoantibodies that acquired somatic mutations were reverted back to their unmutated germline precursors, which were tested for both binding to AQP4 and poly- or autoreactivity. While the affinity of mature autoantibodies against AQP4 ranged from modest to strong (Kd 15.2-559 nM), none of the germline revertants displayed any detectable binding to AQP4, revealing that somatic hypermutation is required for the generation of anti-AQP4 autoantibodies. However, two (33.3%) germline autoantibody revertants were polyreactive and four (66.7%) were autoreactive, suggesting that pathogenic anti-AQP4 autoantibodies can originate from the pool of autoreactive naïve B cells, which develops as a consequence of impaired early B cell tolerance checkpoints in NMOSD patients.

An Epidemiological Analysis and Comparison of Single Site and Multiple Site Fracture Repair: An NSQIP Analysis.

We aimed to utilize the 2010 to 2017 National Surgical Quality Improvement Program to evaluate the epidemiology and efficacy of facial fracture repairs, specifically comparing multiple fracture site repairs (MFR) compared to single fracture site repairs (SFR). Of 4739 patients, 718 (15.2%) were found to have undergone MFR. A total of 577 (80.4%) of the MFRs involved the midface only. A total of 2114 (52.6%) of the SFRs were mid-face fractures, while 1825 (45.4%) involved the lower-face and only 82 (2.0%) involved the upper-face. The most frequent MFR was combined orbital and malar/zygoma repair (230 cases [32.0%]). When comparing MFR and SFR of the mid-face, MFR patients were more commonly male, White, operated on by plastic surgeons, presented with contaminated wounds, and active smokers. While MFRs were associated with a longer operative time (P < 0.001) and a longer postoperative hospital stay (P < 0.001), there were no differences in reoperation or readmission. Overall, complication rates were low, but slightly higher in the mid-face MFR group (1.4% in mid-face SFR and 3.0% in mid-face MFR; P = 0.019). Sub-analysis of mid-face only MFRs and middle-lower-face MFRs revealed no difference in postoperative complication rates (3.0% and 7.0%, respectively; P = 0.071). The data presented suggests that MFR are a relatively common occurrence. Although plastic surgeons perform MFRs more frequently, it is currently unclear whether the underlying reason is a product of differences in training, coding patterns, or referral patterns. Though MFRs require more hospital resources, complications rates are low. This will help manage patient expectations and guide patient counseling before surgery, as well as help to plan postoperative care.

Epidemiology, outcomes, and prognostic factors of orbital lymphoma in the United States.

PURPOSE: We performed an epidemiological study of orbital lymphoma in the United States to determine how histological subtypes confer differing prognosis, and understand other factors associated with survival. METHODS: All patients in the Surveillance, Epidemiology and End Results database diagnosed with a histologically confirmed orbital lymphoma between 1973 and 2014 were included. Exclusion criteria included diagnosis at autopsy and the presence of other malignancies. Measures included patient demographic information, histological subtype and treatment modalities. Outcomes included overall and disease specific survival. RESULTS: Of the 1504 cases identified, 702 were male (46.7%, mean age: 64.4 years, standard deviation [SD]: 15.3) and 802 were female (53.3%, mean age: 67.5 years, SD: 14.3). Mucosal associated lymphoid tissue (MALT) (49.5%) and diffuse large B cell lymphoma (DLBCL) (19.5%) were the two most common histologic subtypes. MALT lymphoma conferred the best prognosis (10-year cancer specific survival [CSS] 90.2%, 95% Confidence Interval [CI] 87.4% - 93.1%) and DLBCL conferred the worst prognosis (10-year CSS 68.6%, 95% CI 62.5% - 75.3%) (p < .001, log-rank test). Older age (Hazard Ratio [HR]: 3.71, 95% Confidence Interval [CI]: 2.94-4.66, p < .001), male sex (HR: 1.22, 95% CI: 1.039-1.441, p = .015), no radiation (HR: 1.72, 95% CI: 1.46-2.02, p < .001) and DLBCL histology were significant predictors of worse overall survival. CONCLUSIONS: DLBCL histology confers the worst outcomes whereas MALT lymphoma confers the best outcome in orbital lymphoma. Age, gender, and radiation treatment also influence survival. These epidemiological results can be used clinically to communicate outcomes on the basis of patient characteristics and disease histology.

Teaching Tracheostomy Tube Changes: Comparison of Operant Learning Versus Traditional Demonstration.

Objective: Tracheostomy tube change is a multistep skill that must be performed rapidly and precisely. Despite the critical importance of this skill, there is wide variation in teaching protocols. Methods: An innovative operant conditioning teaching methodology was employed and compared to traditional educational techniques. Medical student volunteers at a tertiary care academic institution (Albert Einstein College of Medicine) were recruited and randomly distributed into 2 groups: operant vs traditional (control). Following the educational session, each group was provided with practice time and then asked to perform 10 tracheostomy tube changes. Performance was recorded and scored by blinded raters using deidentified video recordings. Results: The operant learning group (OLG) demonstrated greater accuracy in performing a tracheostomy tube change than the traditional demonstration group. Twelve of 13 operant learners performed the skill accurately each time compared to 3 of 13 in the traditional group (P = 0.002). The median lesson time was longer for the OLG (535 seconds) than for the traditional group, (200 seconds P < 0.001). The average time per tracheostomy change was not significantly different between the 2 groups (operant learners mean 7.1 seconds, traditional learners mean 7.5 seconds, P = 0.427). Discussion: Although the operant conditioning methodology necessarily requires a greater time to teach, the results support this methodology over traditional learning modalities as it enhances accuracy in the acquired skill. Operant learning methodology is under consideration for other skills and education sessions in our program. Future steps include the application and adaptation of this education model to students and residents in other settings and fields. Implications for Practice: Operant learning is effective for teaching multistep skills such as tracheostomy tube changes with decreased error rates.

Plasmapheresis Versus Intravenous Immunoglobulin in Patients With Autoimmune Neuromuscular and Neuro-immunological Conditions.

OBJECTIVES: Plasmapheresis (PLEX) and intravenous immunoglobulin (IVIg) are commonly used to treat autoimmune neuromuscular disorders, including myasthenia gravis, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, and other autoimmune neurological disorders. The side effect profiles of these therapies vary, and concern has been raised regarding the safety of PLEX in the elderly population. In this study, we have examined the pattern of PLEX and IVIg use for autoimmune neurological disorders at a single facility and in a national database, focusing on the complications in elderly patients. METHODS: We performed a retrospective chart review of adult patients at our institution receiving PLEX or IVIg for any autoimmune neuromuscular or neuro-immunological disease. Next, we analyzed the National Inpatient Sample database to confirm the trend in IVIg and PLEX use from 2012 to 2018 for a set of neuromuscular and neuro-immunological primary diagnoses. RESULTS: IVIg was overall favored over PLEX. The adverse effects were similar among elderly patients (age ≥65 years) compared with younger patients (<65 years) in our institution, even after adequate matching of patients based on age, sex, and medical history. We examined the National Inpatient Sample dataset and noted increasingly higher frequency of IVIg use, consistent with the findings from our institution or facility. CONCLUSIONS: Both PLEX and IVIg are safe therapeutic choices in adult patients with autoimmune neuromuscular disorders and other neuro-immunological diseases and can be safely administered in the appropriate clinical setting.

Choroidal Changes in Rhesus Macaques in Aging and Age-Related Drusen.

Purpose: Choroidal vascular changes occur with normal aging and age-related macular degeneration (AMD). Here, we evaluate choroidal thickness and vascularity in aged rhesus macaques to better understand the choroid's role in this nonhuman primate model of AMD. Methods: We analyzed optical coherence tomography (OCT) images of 244 eyes from 122 rhesus macaques (aged 4-32 years) to measure choroidal thickness (CT) and choroidal vascularity index (CVI). Drusen number, size, and volume were measured by semiautomated annotation and segmentation of OCT images. We performed regression analyses to determine any association of CT or CVI with age, sex, and axial length and to determine if the presence and volume of soft drusen impacted these choroidal parameters. Results: In rhesus macaques, subfoveal CT decreased with age at 3.2 µm/y (R2 = 0.481, P < 0.001), while CVI decreased at 0.66% per year (R2 = 0.257, P < 0.001). Eyes with soft drusen exhibited thicker choroid (179.9 ± 17.5 µm vs. 162.0 ± 27.9 µm, P < 0.001) and higher CVI (0.612 ± 0.051 vs. 0.577 ± 0.093, P = 0.005) than age-matched control animals. Neither CT or CVI appeared to be associated with drusen number, size, or volume in this cohort. However, some drusen in macaques were associated with underlying choroidal vessel enlargement resembling pachydrusen in human patients with AMD. Conclusions: Changes in the choroidal vasculature in rhesus macaques resemble choroidal changes in human aging, but eyes with drusen exhibit choroidal thickening, increased vascularity, and phenotypic characteristics of pachydrusen observed in some patients with AMD.

Telmisartan Tablets Repackaged into Dose Administration Aids: Physicochemical Stability under Tropical Conditions.

Dose administration aids (DAAs) are commonly used to assist patients with chronic disease to manage multiple medications and thus improve adherence. Several brands of telmisartan, commonly prescribed for hypertension, are available in Australia. Manufacturer's storage advice is to leave tablets in the blister strip until administered to patients. This study aimed to investigate the stability of telmisartan tablets when repackaged and stored in DAAs, to identify a brand, which is sufficiently stable to be repackaged. All available brands of telmisartan tablets in Australia, which contain different excipients, were repackaged into DAAs and stored at 30 °C, 75% RH for 28 days before screening, using visual inspection and physical testing. A candidate brand was then selected for physicochemical and photostability testing using pharmacopoeial methods. Repackaged Mizart® tablets were shown to be sufficiently stable, when repackaged and stored under tropical conditions (30 °C, 75% RH) for 28 days. Several of the other brands were deemed inappropriate for repackaging, due to physical instability, highlighting the importance of considering not only the drug, but also excipients to ensure the stability of repackaged medicines. Although the repackaging of telmisartan tablets is not advised, this study provides evidence to support the Mizart® brand as an option for pharmacists to recommend for repackaging.

Impact of iStent Micro-Bypass Shunt on Medicare Part B Glaucoma Surgical Expenditure.

PURPOSE: To examine the impact of the iStent (Glaukos) on the recent glaucoma surgical expenditure for Medicare Part B beneficiaries. DESIGN: Retrospective, observational, population-based analysis. PARTICIPANTS: All applicable cases in the Centers for Medicare and Medicaid Services Part B Summary Data Files. METHODS: The Part B National Summary Data Files from 2007 to 2017 were obtained through the Centers for Medicare and Medicaid Services. Glaucoma surgical procedures, including trabeculectomy, glaucoma drainage implants (GDIs), and select minimally invasive glaucoma surgeries (MIGS) including the iStent, were queried from the database using Current Procedural Terminology (CPT) codes. We used Chow's test to confirm significant changes in expenditure trajectories. We built a mixed-effects regression model to examine the effect of demographic factors on each state's iStent adoption speed. MAIN OUTCOME MEASURES: Proportion of iStent in total glaucoma surgical spending for individual states for each year. RESULTS: Total Medicare part B payment for the selected glaucoma procedures increased from $52.0 million in 2007 to $179.9 million in 2017. The percentage for trabeculectomy and GDIs decreased from 92.3% to 21.2%. Conversely, the iStent, approved by the Food and Drug Administration in 2012, increased to represent 57.9% of total payment by 2017. There were significant changes in the slope of glaucoma surgical Medicare payment (P < 0.00001) and iStent payment (P < 0.0001) trajectories in 2012. Mixed-effect regression analysis showed a wide range among the states' rates of increase in iStent proportion between 2012 and 2017 (range, 5.12%-14.54% per year). Higher male proportion in the population was associated with faster increases in iStent proportions (12.4% per 5% increase in male proportion, 95% confidence interval [CI], 4.3-20.5, P = 0.003). Higher median age of the population was associated with slower increases (-3.6% per 1-year increase in median age, 95% CI, -0.4 to -6.8, P = 0.026). CONCLUSIONS: Increasing payment for the iStent represents the majority of the increase in glaucoma surgical spending in the recent decade. Male gender and age significantly affect the state-wise speed of adoption for the iStent. The impact of the iStent on the comprehensive glaucoma Medicare expenditure in the same time period warrants further study.

Specific Denitrifying and Dissimilatory Nitrate Reduction to Ammonium Bacteria Assisted the Recovery of Anammox Community From Nitrite Inhibition.

The anaerobic ammonium oxidation (anammox) by autotrophic anaerobic ammonia-oxidizing bacteria (AnAOB) is a biological process used to remove reactive nitrogen from wastewater. It has been repeatedly reported that elevated nitrite concentrations can severely inhibit the growth of AnAOB, which renders the anammox process challenging for industrial-scale applications. Both denitrifying (DN) and dissimilatory nitrate reduction to ammonium (DNRA) bacteria can potentially consume excess nitrite in an anammox system to prevent its inhibitory effect on AnAOB. However, metabolic interactions among DN, DNRA, and AnAOB bacteria under elevated nitrite conditions remain to be elucidated at metabolic resolutions. In this study, a laboratory-scale anammox bioreactor was used to conduct an investigation of the microbial shift and functional interactions of AnAOB, DN, and DNRA bacteria during a long-term nitrite inhibition to eventual self-recovery episode. The relative abundance of AnAOB first decreased due to high nitrite concentration, which lowered the system's nitrogen removal efficiency, but then recovered automatically without any external interference. Based on the relative abundance variations of genomes in the inhibition, adaptation, and recovery periods, we found that DN and DNRA bacteria could be divided into three niche groups: type I (types Ia and Ib) that includes mainly DN bacteria and type II and type III that include primarily DNRA bacteria. Type Ia and type II bacteria outcompeted other bacteria in the inhibition and adaptation periods, respectively. They were recognized as potential nitrite scavengers at high nitrite concentrations, contributing to stabilizing the nitrite concentration and the eventual recovery of the anammox system. These findings shed light on the potential engineering solutions to maintain a robust and efficient industrial-scale anammox process.

Outpatient Versus Inpatient Anterior Lumbar Spine Surgery: A Multisite, Comparative Analysis of Patient Safety Measures.

BACKGROUND: The frequency and complexity of spinal surgery performed in an ambulatory surgery center (ASC) is increasing. However, safety and efficacy data of most spinal procedures adapted to the ASC are sparse and have focused on anterior cervical surgery. The purpose of this study was to compare the 90-day complication and readmission rates of anterior lumbar spine surgery performed in an ASC or inpatient setting. METHODS: We performed a retrospective comparative analysis of 226 consecutive anterior lumbar surgeries (283 levels treated) completed in an ASC (n = 124) or in an inpatient tertiary care hospital (n = 102) over a 3-year period. These included anterior lumbar interbody fusion (ALIF), artificial disc replacement (ADR), and hybrids. Patients undergoing simultaneous or staged posterior procedures within 3 months were excluded. Patient demographics and surgical parameters between the two surgical settings were compared. Ninety-day medical complications and readmission rates were assessed. One-way analysis of variance and Chi-square analysis were used. A P value of less than .05 was considered statistically significant. RESULTS: The two study groups had similar baseline characteristics. While there was a trend toward fewer complications, reoperations, and readmissions for the ASC cohort, the differences were not statistically significant. There were 7 intraoperative complications (5.6% minor vascular injury) in the inpatient cohort and 0 in the ASC cohort. The overall 90-day postoperative complication rate was 5.6% for the inpatient cohort and 0.9% for the ASC cohort. The 90-day readmission rate was 1.9% in the ASC cohort and 1.6% in the inpatient cohort. The 90-day reoperation rate was 0.8% for the inpatient cohort and 0% in the ASC cohort. The average hospital stay was 2.3 ± 1.5 days for the inpatient cohort. CONCLUSION: The 90-day readmission rates were lower for outpatients than for inpatients, while the complication and reoperation rates were similar. Our results demonstrate that anterior lumbar procedures, including single-level and multilevel ALIF, ADR, and hybrid procedures, can be performed safely in an ASC. This has significant cost savings implications for the ASC setting.

GlaucoMap - Distribution of Glaucoma Surgical Procedures in the United States.

PURPOSE: To understand the distribution of trabeculectomies, glaucoma drainage implants (GDI) and micro-invasive glaucoma surgeries (MIGS) performed in the United States through geospatial mapping. METHODS: We performed an observational cohort study to evaluate glaucoma surgeries in patients age ≥65. The most recently released data from Centers for Medicare Part B Carrier Summary Files were queried to determine the number of glaucoma surgeries performed per state during the year of 2017. We created choropleth maps, titled "GlaucoMap", to characterize the rates of various surgeries performed across the United States, defined as the number of procedures performed per 10,000 individuals. A chi-squared analysis was further used to evaluate differences in surgical preferences across geographic region. Standardized residuals (SR) were calculated to determine regional influences on surgical distribution. RESULTS: There were 174,788 glaucoma surgeries performed: 22,862 trabeculectomies (13.1%), 19,991 GDI (11.4%) and 131,935 (75.5%) MIGS. The Northeast had the highest trabeculectomy rate, GDI was highest in the Southeast and MIGS were highest in the Southwest. There was a statistically significant difference in proportional use of conventional surgeries versus MIGS across various regions in the United States (p < 0.0001). Given the high trabeculectomy and GDI rates and relatively low MIGS adoption in the Southeast, we observed a +7.03 SR for conventional surgeries and -4.01 SR for MIGS. The Southwest and Western states had the highest MIGS rate and contributed +3.29 and +3.24 SR toward disproportional MIGS preference, respectively. The preference for conventional surgeries in the Northeast (SR = +2.93) and MIGS in the Midwest (SR = +0.99) also contribute to the overall differences in glaucoma surgeries across the United States. CONCLUSION: GlaucoMap is useful for visualizing the distribution of glaucoma surgeries in the United States. The heterogeneity in surgical preferences points to regional differences in glaucoma management.

Tumor Location and Treatment Modality are Associated with Overall Survival in Adult Medulloblastoma.

Introduction Medulloblastoma (MB) is an aggressive brain tumor most commonly found in children. Although prognostic factors are well studied in children, factors affecting survival in adults with medulloblastoma are unclear. Methods We queried the 1973-2015 United States Surveillance, Epidemiology, and End Results (SEER) registry to identify all adult cases of medulloblastoma, and performed multivariate survival analyses to assess the relationships amongst various clinical variables, including age, sex, race, tumor location, treatment modalities, and overall survival. Results A total of 857 patients, 20 years of age and older, with MB were identified in the SEER registry. Adult cases presented most frequently in the cerebellum (91.6%) compared to other less common regions (brain stem 3.2%, brain 2.2%, ventricle 1.8%). The overall median survival for adult MB is 60 months (SD = 94.3) and survival time is related to tumor location and course of treatment (P < 0.001). Multivariate Cox proportional hazard models showed that lesions found outside the cerebellum corresponded to worse median survival times (37 months) than those in the cerebellum (63 months) (hazard ratio 1.69, 95% CI 1.321-2.158, P = 0.001). Patients who were assigned chemotherapy had shorter survival (54 months) than those who were not (67 months) (HR 1.4515, 95% CI 1.26-1.671, P < 0.001), but receiving radiation therapy was associated with better overall survival (66 months) relative to not receiving radiation (25 months) (HR 0.581, 95% CI 0.48-0.70, P < 0.001). Conclusions Tumor location appears to be a significant prognostic factor for survival in adult MB. Recommended treatment regimes, likely reflective of the underlying aggressiveness of the tumor, also seem to impact survival.

Regulation of MIF Enzymatic Activity by an Allosteric Site at the Central Solvent Channel.

In proteins with multiple functions, such as macrophage migration inhibitory factor (MIF), the study of its intramolecular dynamic network can offer a unique opportunity to understand how a single protein is able to carry out several nonoverlapping functions. A dynamic mechanism that controls the MIF-induced activation of CD74 was recently discovered. In this study, the regulation of tautomerase activity was explored. The catalytic base Pro1 is found to form dynamic communications with the same allosteric node that regulates CD74 activation. Signal transmission between the allosteric and catalytic sites take place through intramolecular aromatic interactions and a hydrogen bond network that involves residues and water molecules of the MIF solvent channel. Once thought to be a consequence of trimerization, a regulatory function for the solvent channel is now defined. These results provide mechanistic insights into the regulation of catalytic activity and the role of solvent channel water molecules in MIF catalysis.

In Situ Simulation to Assess Pediatric Tracheostomy Care Safety: A Novel Multicenter Quality Improvement Program.

OBJECTIVES: Our objectives were (1) to use in situ simulation to assess the clinical environment and identify latent safety threats (LSTs) related to the management of pediatric tracheostomy patients and (2) to analyze the effects of systems interventions and team factors on LSTs and simulation performance. METHODS: A multicenter, prospective study to assess LSTs related to pediatric tracheostomy care management was conducted in emergency departments (EDs) and intensive care units (ICUs). LSTs were identified through equipment checklists and in situ simulations via structured debriefs and blinded ratings of team performance. The research team and unit champions developed action plans with interventions to address each LST. Reassessment by equipment checklists and in situ simulations was repeated after 6 to 9 months. RESULTS: Forty-one LSTs were identified over 21 simulations, 24 in the preintervention group and 17 in the postintervention group. These included LSTs in access to equipment (ie, availability of suction catheters, lack of awareness of the location of tracheostomy tubes) and clinical knowledge gaps. Mean equipment checklist scores improved from 76% to 87%. Twenty-one unique teams (65 participants) participated in the simulations. The average simulation score was 6.19 out of 16 points. DISCUSSION: In situ simulation is feasible and effective as an assessment tool to identify latent safety threats and thus measure the system-level performance of a clinical care environment. IMPLICATIONS FOR PRACTICE: In situ simulation can be used to identify and reassess latent safety threats related to pediatric tracheostomy management and thereby support quality improvement and educational initiatives.

Improved Measurement of Proteins Using a Solid-State Nanopore Coupled with a Hydrogel.

Although resistive pulse sensing using solid-state nanopores is capable of single-molecule sensitivity, previous work has shown that nanoparticles, such as proteins, pass through nanopores too quickly for accurate detection with typical measurement apparatus. As a result, nanopore measurements of these particles significantly deviate from theoretically estimated current amplitudes and detection rates. Here, we show that a hydrogel placed on the distal side of a nanopore can increase the residence time of nanoparticles within the nanopore, significantly increasing the detection rate and allowing improved resolution of blockage currents. The method is simple and inexpensive to implement while being label-free and applicable to a wide range of nanoparticle targets. Using hydrogel-backed nanopores, we detected the protein IgG with event frequencies several orders of magnitude higher than those in the absence of the hydrogel and with larger measured currents that agree well with theoretical models. We also show that the improved measurement also enables discrimination of IgG and bovine serum albumin in a mixed solution. Finally, we show that measurements of IgG with the hydrogel-backed nanopores can also yield current amplitude distributions that can be analyzed to infer its approximate shape.

High-throughput investigation of molecular and cellular biomarkers in NMOSD.

OBJECTIVE: To identify candidate biomarkers associated with neuromyelitis optica spectrum disorder (NMOSD) using high-throughput technologies that broadly assay the concentrations of serum analytes and frequencies of immune cell subsets. METHODS: Sera, peripheral blood mononuclear cells (PBMCs), and matched clinical data from participants with NMOSD and healthy controls (HCs) were obtained from the Collaborative International Research in Clinical and Longitudinal Experience Study NMOSD biorepository. Flow cytometry panels were used to measure the frequencies of 39 T-cell, B-cell, regulatory T-cell, monocyte, natural killer (NK) cell, and dendritic cell subsets in unstimulated PBMCs. In parallel, multiplex proteomics assays were used to measure 46 serum cytokines and chemokines in 2 independent NMOSD and HC cohorts. Multivariable regression models were used to assess molecular and cellular profiles in NMOSD compared with HC. RESULTS: NMOSD samples had a lower frequency of CD16+CD56+ NK cells. Both serum cohorts and multivariable logistic regression revealed increased levels of B-cell activating factor associated with NMOSD. Interleukin 6, CCL22, and CCL3 were also elevated in 1 NMOSD cohort of the 2 analyzed. Multivariable linear regression of serum analyte levels revealed a correlation between CX3CL1 (fractalkine) levels and the number of days since most recent disease relapse. CONCLUSIONS: Integrative analyses of cytokines, chemokines, and immune cells in participants with NMOSD and HCs provide congruence with previously identified biomarkers of NMOSD and highlight CD16+CD56+ NK cells and CX3CL1 as potential novel biomarker candidates.

Clinical and economic burden of neurofibromatosis type 2 in the United States.

OBJECTIVES: We aimed to investigate the prevalence and cost-associated risk factors for hospital stays for Neurofibromatosis Type 2 (NF2) patients in the past decade. PATIENTS AND METHODS: A multi-year cross-sectional study was performed using the National Inpatient Sample. Patients with a diagnosis code of NF2 according to the International Classification of Diseases, 9th Revision, Clinical Modification coding system were queried from 2006-2014. Sampling discharge weights were used to calculate trend estimates for national demographics, hospital characteristics, comorbidities, and surgical interventions. Regression analysis was performed to determine significant independent associations between comorbidities and admission cost. RESULTS: From 2006-2014, there were 5,078 discharges for patients diagnosed with NF2. Patient demographics, comorbidities, and procedures performed were overall consistent over time. The most common admission diagnoses were hearing loss (28.2 %), acoustic schwannoma (14.3 %), cranial meningioma (11.8 %) and epilepsy (10.8 %). The most common procedures performed were craniotomy and meningioma resection (10.2 %) and acoustic neuroma open resection (7.9 %). The median inflation-adjusted cost of admission did not change over time, with an admission cost value of $12,387 [6,042 - 26,051]. On regression analysis, obstructive hydrocephalus, craniotomy and meningioma resection, acoustic neuroma open resection, and spine tumor resection were all independent predictors of increased cost. CONCLUSION: The care for NF2 patients continues to evolve over time. We report the prevalence of patient demographics, comorbidities, and treatments in the NF2 inpatient population. Further studies are warranted to better understand the risk factors for higher costs, so that patients with NF2 may continue to receive life-long quality care in a cost-effective manner.