Medical data formatting to improve physician interpretation speed in the Military Healthcare System.

Objective: The purpose of this project was to improve ease and speed of physician comprehension when interpreting daily laboratory data for patients admitted within the Military Healthcare System (MHS). Materials and Methods: A JavaScript program was created to convert the laboratory data obtained via the outpatient electronic medical record (EMR) into a "fishbone diagram" format that is familiar to most physicians. Using a balanced crossover design, 35 internal medicine trainees and staff at Naval Medical Center Portsmouth were asked to complete timed comprehension tests for laboratory data sets formatted in the outpatient EMR's format and in fishbone diagram format. The number of responses per second and error rate per response were measured for each format. Participants were asked to rate relative ease of use for each format and indicate which format they preferred. Results: Comprehension speed increased 37% (6.28 seconds per interpretation) with the fishbone diagram format with no observed increase in errors. Using a Likert scale of 1-5 (1 being hard, 5 easy), participants indicated the new format was easier to use (4.14 for fishbone vs 2.14 for table) with 89% expressing preference for the new format. Discussion: The publically available web application that converts tabular lab data to fishbone diagram format is currently used 10 000-12 000 times per month across the MHS, delivering significant benefit to the enterprise in terms of time saved and improved physician experience. Conclusions: This study supports the use of fishbone diagram formatting for laboratory data for inpatients within the MHS.

Elevated Detection of Dual Antibody B Cells Identifies Lupus Patients With B Cell-Reactive VH4-34 Autoantibodies.

About 5% of B cells in healthy mice and humans are allelically or isotypically included and hence co-express two different antibodies. In mice, dual antibody B cells (B2R) expand with systemic autoimmunity, co-express autoreactive and non-autoreactive antibodies, and participate in immune responses, but this phenomenon is strain dependent. This study was developed with two goals: 1) to establish the contribution of TLR and IFN receptor signaling to the development of germinal center B cells that express two antibodies in MRL/lpr mice; and 2) to determine whether B2R B cells are increased and particularly activated in a subset of adult patients diagnosed with systemic lupus erythematosus (SLE). Results from the MRL/lpr studies indicate that the enhanced differentiation of dual-κ B cells into germinal center B cells is due to a heightened response to TLR7 and TLR9 signaling, further fueled by an increased response to type II IFN. To understand the clinical and translational implications of our observations in mouse B2R B cells, cohorts of SLE patients and healthy controls were recruited and evaluated for expression of dual BCRs. Results from flow cytometry and microscopy revealed supraphysiological frequencies of κ+λ+ B2R cells in one fourth of the SLE patients. Abnormal numbers of κ+λ+ B cells correlated with higher frequencies of activated naïve B cells and age-associated B cells, and a lower proportion of "B cells that are naïve IgD+" (BND). However, results from single cell V(D)J sequencing demonstrated that these high κ+λ+ SLE patients harbored normal frequencies of κ+λ+ and other B2R B cells. and we further show that their B cells were instead decorated by κ and λ VH4-34 autoantibodies. Thus, our findings indicate that elevated flow cytometric detection of isotypically-included B cells can identify patients with high titers of B cell-reactive VH4-34 autoantibodies and abnormal distribution of B cell subsets relevant to autoimmunity.

Incidence of Fever Associated With Dexmedetomidine in the Adult Intensive Care Unit.

BACKGROUND: Published literature has described the temporal relationship of dexmedetomidine with elevated temperatures, but there is limited data to quantify the incidence of fever in ICU patients receiving dexmedetomidine. OBJECTIVE: The primary objective of this study was to estimate the incidence of temperature greater than or equal to 38.5°C in ICU patients receiving dexmedetomidine. METHODS: This was a retrospective cohort study of ICU patients who received dexmedetomidine with a propensity-matched subgroup analysis comparing dexmedetomidine fever patients to non-fever patients. Patients 18 years of age and older admitted between November 2017 and August 2018 who received continuous dexmedetomidine for 6 or more hours were eligible for inclusion. Included patients with a temperature of great than or equal to 38.5°C while receiving dexmedetomidine were established as having dexmedetomidine-related fever. RESULTS: Of 882 eligible ICU patients, 404 dexmedetomidine patients were included in the study. Sixty-one patients (15.1%) met the definition for the primary endpoint. Forty-two patients who received dexmedetomidine but experienced no fever were matched for multivariate analysis. The fever group received a higher mean maximum infusion rate (0.98 µg/kg/h ± 0.43 vs. 0.68 µg/kg/h ± 0.42, P < 0.001) and a longer median duration of dexmedetomidine (43.0 hours [range 7-711] vs. 24.3 hours [6-148], P = 0.001) compared to the non-fever group. CONCLUSION: Fever greater than 38.5°C was observed in 15.1% of ICU patients while receiving dexmedetomidine. Prospective studies are warranted to validate these findings.

Woody encroachment of grasslands: Near-surface thermal implications assessed through the lens of an astronomical event.

Temperature has long been understood as a fundamental condition that influences ecological patterns and processes. Heterogeneity in landscapes that is structured by ultimate (climate) and proximate (vegetation, topography, disturbance events, and land use) forces serve to shape thermal patterns across multiple spatio-temporal scales. Thermal landscapes of grasslands are likely shifting as woody encroachment fragments these ecosystems and studies quantifying thermal fragmentation in grassland systems resulting from woody encroachment are lacking. We utilized the August 21st, 2017, solar eclipse to mimic a rapid sunrise/sunset event across a landscape characterized as a grassland to experimentally manipulate levels of solar radiation in the system. We then quantified changes in near-surface temperatures resulting from changes in solar radiation levels during the eclipse. Temperatures were monitored across three grassland pastures in central Oklahoma that were characterized by different densities (low, medium, and high) of Juniperus virginiana to understand the impact of woody encroachment on diurnal temperature patterns and thermal heterogeneity in a grassland's thermal landscape. The largest temperature range across sites that occurred during the eclipse was in the mixed grass vegetation. Similarly, the largest change in thermal heterogeneity occurred in the grassland with the lowest amount of woody encroachment. Thermal heterogeneity was lowest in the highly encroached grassland, which also experienced the lowest overall change in thermal heterogeneity during the eclipse. Time series models suggested that solar radiation was the most influential factor in predicting changes in thermal heterogeneity as opposed to ambient temperature alone. These results suggest that highly encroached grasslands may experience lower diurnal variability of temperatures at the cost of a decrease in the overall thermal heterogeneity of that landscape. It appears that fine-scale spatio-temporal thermal variation is largely driven by solar radiation, which can be influenced by vegetation heterogeneity inherent within a landscape.

Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice.

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.

Gaseous Iodine Sorbents: A Comparison between Ag-Loaded Aerogel and Xerogel Scaffolds.

Silver-exchanged aluminosilicate aerogels and xerogels were investigated as gaseous iodine [I2(g)] sorbents. The structures, morphologies, compositions, and porosities of aerogels (as-made and heat-treated at 350 °C) and xerogels are compared by using powder X-ray diffraction (PXRD), scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, and specific surface area (SSA) as well as pore size analyses. The as-made aerogels, xerogels, and heat-treated aerogels were ion exchanged with Ag in AgNO3 solutions of deionized water and methanol (5:1 by volume), and PXRD patterns showed the presence of nanocrystalline Ag0 after the Ag exchange. Gravimetric iodine loadings of Ag-aerogels and Ag-xerogels were 0.33-0.41 g g-1. The Ag-aerogels without heat treatment showed an ∼8 mass % higher iodine loading than Ag-impregnated xerogels and ∼3 mass % higher than heat-treated Ag-impregnated aerogels. All gels after iodine uptake showed the presence of AgI, indicating chemisorption of iodine to silver. The SSA values of the as-made gels were 420-600 m2 g-1 but decreased significantly to 34-120 m2 g-1 after Ag impregnation and iodine uptake. Overall, changes in physical and chemical properties of aerogels and xerogels after iodine uptake were similar and the differences in iodine loading capacities of the aerogels and xerogels were minimal, providing a driver for using xerogels due to their less complex synthesis process as compared to aerogels.

Evaluation of Getter Metals in Na-Al-Si-O Aerogels and Xerogels for the Capture of Iodine Gas.

In this paper, sodium aluminosilicate aerogels and xerogels were evaluated as scaffolds for a variety of different getters including Ag+, Cs+, Cu2+, Fe3+, K+, Li+, Rb+, Sb3+, Sn2+, and Sn4+ for the capture of gaseous iodine coming from nuclear facilities. The exchange capacities varied widely from a near complete exchange in the case of Ag+ to much lower exchange levels for some of the Sn compounds [i.e., colloidal SnO2, Sn(II) acetate, and Sn(IV) acetate]. Several of the additives showed great promise at allowing for high iodine loadings in the base materials including the following: AgNO3, colloidal SnO2, Sn(II) acetate, Sn(IV) acetate, Cu(NO3)2, and CuSO4. From the standpoint of iodine uptake as a function of getter loading, Sn4+ was the most promising with a getter utilization (mass of iodine divided by mass of Sn, in atomic %) of 8.4, a chemical uptake of 60.7 mass % (oxygen excluded), and an mI ms-1 (mass of iodine per mass of sorbent) value of 0.881; these are some of the highest values reported to date for inorganic iodine sorbents.

Syntheses, crystal structures, and comparisons of rare-earth oxyapatites Ca2 RE 8(SiO4)6O2 (RE = La, Nd, Sm, Eu, or Yb) and NaLa9(SiO4)6O2.

Six different rare-earth oxyapatites, including Ca2 RE 8(SiO4)6O2 (RE = La, Nd, Sm, Eu, or Yb) and NaLa9(SiO4)6O2, were synthesized using solution-based processes followed by cold pressing and sinter-ing. The crystal structures of the synthesized oxyapatites were determined from powder X-ray diffraction (P-XRD) and their chemistries verified with electron probe microanalysis (EPMA). All the oxyapatites were isostructural within the hexa-gonal space group P63/m and showed similar unit-cell parameters. The isolated [SiO4]4- tetra-hedra in each crystal are linked by the cations at the 4f and 6h sites occupied by RE 3+ and Ca2+ in Ca2 RE 8(SiO4)6O2 or La3+ and Na+ in NaLa9(SiO4)6O2. The lattice parameters, cell volumes, and densities of the synthesized oxyapatites fit well to the trendlines calculated from literature values.

Active PI3K abrogates central tolerance in high-avidity autoreactive B cells.

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell-mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell-intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

Corrigendum: Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance.

[This corrects the article DOI: 10.3389/fimmu.2018.00707.].

Innate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus.

Autoreactive B cells have a major function in autoimmunity. A small subset of B cells expressing two distinct B-cell-antigen-receptors (B2R cells) is elevated in many patients with systematic lupus erythematosus (SLE) and in the MRL(/lpr) mouse model of lupus, and is often autoreactive. Here we show, using RNAseq and in vitro and in vivo analyses, signals that are required for promoting B2R cell numbers and effector function in autoimmune mice. Compared with conventional B cells, B2R cells are more responsive to Toll-like receptor 7/9 and type I/II interferon treatment, display higher levels of MHCII and co-receptors, and depend on IL-21 for their homeostasis; moreover they expand better upon T cell-dependent antigen stimulation, and mount a more robust memory response, which are characteristics essential for enhanced (auto)immune responses. Our findings thus provide insights on the stimuli for the expansion of an autoreactive B cell subset that may contribute to the etiology of SLE.

Activation of the MEK-ERK Pathway Is Necessary but Not Sufficient for Breaking Central B Cell Tolerance.

Newly generated bone marrow B cells are positively selected into the peripheral lymphoid tissue only when they express a B cell receptor (BCR) that is nonautoreactive or one that binds self-antigen with only minimal avidity. This positive selection process, moreover, is critically contingent on the ligand-independent tonic signals transduced by the BCR. We have previously shown that when autoreactive B cells express an active form of the rat sarcoma (RAS) oncogene, they upregulate the receptor for the B cell activating factor (BAFFR) and undergo differentiation in vitro and positive selection into the spleen in vivo, overcoming central tolerance. Based on the in vitro use of pharmacologic inhibitors, we further showed that this cell differentiation process is critically dependent on the activation of the mitogen-activated protein kinase kinase pathway MEK (MAPKK)-extracellular signal-regulated kinase (ERK), which is downstream of RAS. Here, we next investigated if activation of ERK is not only necessary but also sufficient to break central B cell tolerance and induce differentiation of autoreactive B cells in vitro and in vivo. Our results demonstrate that activation of ERK is critical for upregulating BAFFR and overcoming suboptimal levels of tonic BCR signals or low amounts of antigen-induced BCR signals during in vitro B cell differentiation. However, direct activation of ERK does not lead high avidity autoreactive B cells to increase BAFFR levels and undergo positive selection and differentiation in vivo. B cell-specific MEK-ERK activation in mice is also unable to lead to autoantibody secretion, and this in spite of a general increase of serum immunoglobulin levels. These findings indicate that additional pathways downstream of RAS are required for high avidity autoreactive B cells to break central and/or peripheral tolerance.

Silver-Loaded Aluminosilicate Aerogels As Iodine Sorbents.

In this paper, aluminosilicate aerogels were used as scaffolds for silver nanoparticles to capture I2(g). The starting materials for these scaffolds included Na-Al-Si-O and Al-Si-O aerogels, both synthesized from metal alkoxides. The Ag0 particles were added by soaking the aerogels in aqueous AgNO3 solutions followed by drying and Ag+ reduction under H2/Ar to form Ag0 crystallites within the aerogel matrix. In some cases, aerogels were thiolated with 3-(mercaptopropyl)trimethoxysilane as an alternative method for binding Ag+. During the Ag+-impregnation steps, for the Na-Al-Si-O aerogels, Na was replaced with Ag, and for the Al-Si-O aerogels, Si was replaced with Ag. The Ag-loading of thiolated versus nonthiolated Na-Al-Si-O aerogels was comparable at ∼35 atomic %, whereas the Ag-loading in unthiolated Al-Si-O aerogels was significantly lower at ∼7 atomic % after identical treatment. Iodine loadings in both thiolated and unthiolated Ag0-functionalized Na-Al-Si-O aerogels were >0.5 mI ms-1 (denoting the mass of iodine captured per starting mass of the sorbent) showing almost complete utilization of the Ag through chemisorption to form AgI. Iodine loading in the thiolated and Ag0-functionalized Al-Si-O aerogel was 0.31 mI ms-1. The control of Ag uptake over solution residence time and [Ag] demonstrates the ability to customize the Ag-loading in the base sorbent to regulate the loading capacity of iodine.

Ensembles in medial and lateral orbitofrontal cortex construct cognitive maps emphasizing different features of the behavioral landscape.

The orbitofrontal cortex (OFC) has long been implicated in the ability to use the current value of expected outcomes to guide behavior. More recently, this specific role has been conceptualized as a special case of a more general function that OFC plays in constructing a "cognitive map" of the behavioral task space by labeling the current task state and learning relationships among task states. Here, we have used single unit recording data from 2 prior studies to examine whether and how information relating different states within and across trials is represented in medial versus lateral OFC in rats. Using a hierarchical clustering analysis, we examined how neurons from each area represented information about differently valued trial types, defined by the cue-outcome pairings, versus how those same neurons represented information about similar epochs between these different trial types, such as the stimulus sample, delay, and reward consumption epochs. This analysis revealed that ensembles in the lateral OFC (lOFC) group states according to trial epoch, whereas those in the medial OFC (mOFC) organize the same states by trial type. These results suggest that the lOFC and mOFC construct cognitive maps that emphasize different features of the behavioral landscape, with lOFC tracking events based on local similarities, irrespective of their values and mOFC tracking more distal or higher order relationships relevant to value. (PsycINFO Database Record

Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice.

Hematopoietic humanized mice (hu-mice) have been developed to study the human immune system in an experimental in vivo model, and experiments to improve its performance are ongoing. Previous studies have suggested that the impaired maturation of human B cells observed in hu-mice might be in part due to inefficient interaction of the human B-cell-activating factor (hBAFF) receptor with mouse B-cell-activating factor (mBAFF), as this cytokine is an important homeostatic and differentiation factor for B lymphocytes both in mice and humans. To investigate this hypothesis, we created a genetically engineered mouse strain in which a complementary DNA (cDNA) encoding full-length hBAFF replaces the mBAFF-encoding gene. Expression of hBAFF in the endogenous mouse locus did not lead to higher numbers of mature and effector human B cells in hu-mice. Instead, B cells from hBAFF knock-in (hBAFFKI) hu-mice were in proportion more immature than those of hu-mice expressing mBAFF. Memory B cells, plasmablasts, and plasma cells were also significantly reduced, a phenotype that associated with diminished levels of immunoglobulin G and T-cell-independent antibody responses. Although the reasons for these findings are still unclear, our data suggest that the inefficient B-cell maturation in hu-mice is not due to suboptimal bioactivity of mBAFF on human B cells.

Medial Orbitofrontal Neurons Preferentially Signal Cues Predicting Changes in Reward during Unblocking.

UNLABELLED: The orbitofrontal cortex (OFC) has been broadly implicated in the ability to use the current value of expected outcomes to guide behavior. Although value correlates have been prominently reported in lateral OFC, they are more often associated with more medial areas. Further, recent studies in primates have suggested a dissociation in which the lateral OFC is involved in credit assignment and representation of reward identity and more medial areas are critical to representing value. Previously, we used unblocking to test more specifically what information about outcomes is represented by OFC neurons in rats; consistent with the proposed dichotomy between the lateral and medial OFC, we found relatively little linear value coding in the lateral OFC (Lopatina et al., 2015). Here we have repeated this experiment, recording in the medial OFC, to test whether such value signals might be found there. Neurons were recorded in an unblocking task as rats learned about cues that signaled either more, less, or the same amount of reward. We found that medial OFC neurons acquired responses to these cues; however, these responses did not signal different reward values across cues. Surprisingly, we found that cells developed responses to cues predicting a change, particularly a decrease, in reward value. This is consistent with a special role for medial OFC in representing current value to support devaluation/revaluation sensitive changes in behavior. SIGNIFICANCE STATEMENT: This study uniquely examines encoding in rodent mOFC at the single-unit level in response to cues that predict more, less, or no change in reward in rats during training in a Pavlovian unblocking task, finding more cells responding to change-predictive cues and stronger activity in response to cues predictive of less reward.