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.

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.

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.

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.

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.

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.

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.

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.

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.

An integrated web application for decision support and automation of EHR workflow: a case study of current challenges to standards-based messaging and scalability from the EMBED trial.

Computerized clinical decision support (CDS) faces challenges to interoperability and scalability. Centralized, web-based solutions offer a mechanism to share the cost of CDS development, maintenance, and implementation across practices. Data standards have emerged to facilitate interoperability and rapid integration of such third-party CDS. This case report describes the challenges to implementation and scalability of an integrated, web-based CDS intervention for EMergency department-initiated BuprenorphinE for opioid use Disorder which will soon be evaluated in a trial across 20 sites in five healthcare systems. Due to limitations of current standards, security concerns, and the need for resource-intensive local customization, barriers persist related to centralized CDS at this scale. These challenges demonstrate the need and importance for future standards to support two-way messaging (read and write) between electronic health records and web applications, thus allowing for more robust sharing across health systems and decreasing redundant, resource-intensive CDS development at individual sites.