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Mars Atmosphere and Volatile EvolutioN (MAVEN) has observed oscillations in the density, velocity, and temperature of ionospheric plasma on Mars. Atmospheric gravity waves can be an underlying mechanism. We propose a linearized wave–electron interaction model adopting a Wentzel–Kramers–Brillouin approximation to explore the electron density variations in the Martian day-side ionosphere for two regions, which are dominated by crustal magnetic fields and horizontal draped interplanetary magnetic fields. Our model results reveal that the electron density fluctuations associated with the crustal magnetic fields and the draped magnetic fields range from ∼ 40 per cent to ∼ 83 per cent and ∼ 29 per cent to ∼ 125 per cent, respectively. The wave-induced vertical electron flux peaks occur in a region ranging from ∼ 115 km to ∼ 179 km altitude. These results are comparable to the satellite observations. We further investigate the effect of the Martian magnetic topology on the wave-induced electron fluxes and demonstrate that the electron motions associated with the propagating gravity waves can be significantly influenced by the magnetic field orientations. The wave-induced variations in the electron temperature, ion density, and magnetic field combined with a comprehensive gravity wave model will be studied in further work.

Graphical representation of cell types identified in CODEX analysis in image data from respective patients.

Heatmap depicting cell states from monocytes and macrophages identified using Ecotyper NMF analysis, annotated by condition and genes with highest fold change in each state. Data from seven mCRCs, five paired normal liver tissue and two paired PBMCs.

To coordinate Medicare and Medicaid benefits, multiple states are creating opportunities for dual-eligible beneficiaries to join Medicare Advantage Dual-Eligible Special Needs Plans (D-SNPs) and Medicaid plans operated by the same insurer. Tennessee implemented this approach by requiring insurers who offered Medicaid plans to also offer a D-SNP by 2015. Tennessee’s aligned D-SNP participation increased from 7% to 24% of dual-eligible beneficiaries aged 65 years and above between 2011 and 2017. Within a county, a 10-percentage-point increase in aligned D-SNP participation was associated with 0.3 fewer inpatient admissions ( p = .048), 13.9 fewer prescription drugs per month ( p = .048), and 0.3 fewer nursing home users ( p = .06) per 100 dual-eligible beneficiaries aged 65 years and older. Increased aligned plan participation was associated with 0.2 more inpatient admissions ( p = .004) per 100 dual-eligible beneficiaries younger than 65 years. For some dual-eligible beneficiaries, increasing Medicare and Medicaid managed plan alignment has the potential to promote more efficient service use.

(A) UMAP representation of dimensionally reduced data following batch-corrected graph-based clustering of all tumor epithelial cells annotated by sample. (B) Heatmap depicting expression of five highest significantly expressed genes (adjusted p-value

(A-C) Comparisons with Pearson correlation between (A) proportions of cell lineages in five samples with both scRNA-seq and CODEX data. (B) Average expression of LGALS3 and CD68 in macrophages across all 15 patients. (C) Average expression of COL4A1 and ACTA2 in CAFs across all 15 patients.

Purpose: The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME).Experimental Design:We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.Results:We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients.Conclusions:We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.

(A) UMAP representation of dimensionally reduced data following batch-corrected graph-based clustering of all lymphocyte lineage cells annotated by cell types. (B) Heatmap depicting average expression of selected genes for each cell type. (C) UMAP representation annotated by condition. (D) Heatmap depicting cell states from CD8 T cells identified using EcoTyper NMF analysis, annotated by condition. (A-D) Data from seven mCRCs, five paired normal liver tissue and two paired PBMCs. (E) Violin plot depicting the expression of cytotoxicity gene signature in normal and tumor CD8 T cells with T-test p-value. Data from seven mCRCs, five paired normal liver tissue.

(A) Dot plot depicting expression levels of respective ligands and receptors together with the percentage of cells expressing them. (B) Top 10 percent of interactions inferred between cell types in the TME. Edge weights are proportional to the number of interactions, circle sizes are proportional to the number of cells in each group, edge color represents the cell type as sender. For scale, autocrine interactions in CAFs are 68. (A-B) Data from seven mCRCs and five paired normal liver tissue.

Supplemental Table 1: Antibodies, reporters, imaging order and exposure times used in CODEX imaging. EPCAM, SPP1, CD163 were excluded from downstream analysis due to non-specific staining; Supplemental Table 2: Sequencing metrics for scRNA-seq; Supplemental Table 3: Absolute number of cells detected from each sample per cell lineage; Supplemental Table 4: Differentially expressed genes belonging to respective macrophage clusters compared by site of sample origin. pct.1, pct.2 indicate percentage of cells expressing given gene in the cluster of interest and all other comparison clusters respectively; Supplemental Table 5: Enriched reactome pathways in differentially expressed genes in tumor macrophages; Supplemental Table 6: Gene signatures for Foam cells (Fernandez et.al., 2020, PMID 31591603) and scar-associated macrophages (Ramachandran et. al., 2020, PMID 31597160); Supplemental Table 7: Annotation of differentially expressed genes in CAFs with the components of the matrisome expression program; Supplemental Table 8: Spatial proximity analysis examining whether fibroblasts are more proximal to macrophages than any other cell type.

Cell senescence deters the activation of various oncogenes. Induction of senescence is therefore a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells, which concurred with cell cycle arrest in the G1/S phase. S1PR1 deletion enhanced cisplatin-induced ovarian cancer cell senescence. Treatment of ovarian cancer cells with sphingosine-1-phosphate (S1P) led to increased expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased expression of large tumor suppressor 1/2 (LATS1/2), and increased activity of the yes-associated protein (YAP). Opposite results were obtained in S1PR1-knockout or pharmacological inhibition in ovarian cancer cells. LATS1/2 inactivation caused by S1PR1 deletion increased YAP expression, inhibited senescence, and lead to increased S1PR1 expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.

PURPOSE. Genomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of population-wide LS genomic screening versus family history-based screening alone in an unselected U.S. population. METHODS. We developed a decision-analytic Markov model including health states for pre-cancer, stage-specific CRC, and death, and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. RESULTS. Screening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR]: 35 to 63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR: 123 to 260) gained at an incremental cost of $24.6 million (95% CR: $20.3 million to $29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. CONCLUSIONS. Population LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to be highly cost-effective.

Purpose: The liver is the most frequent metastatic site for colorectal cancer. Its microenvironment is modified to provide a niche that is conducive for colorectal cancer cell growth. This study focused on characterizing the cellular changes in the metastatic colorectal cancer (mCRC) liver tumor microenvironment (TME). Experimental Design: We analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue, and peripheral blood mononuclear cells using single-cell RNA sequencing (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution. Results: We identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics, and increased activity in extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand–receptor pairs with the potential to mutually influence their gene-expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, which is a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene-expression data. An increased proportion of TME fibroblasts was associated with the worst prognosis in these patients. Conclusions: We demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports colorectal cancer growth in the immunosuppressed metastatic niche in the liver. These features can be used to target immune-checkpoint–resistant MSS tumors.

Analyzing the effects of space weather on aviation is a new and developing topic. It has been commonly accepted that the flight time of the polar flights may increase during solar proton events because the flights have to change their route to avoid the high-energy particles. However, apart from such phenomenon, researches related to the flight time during space weather events is very rare. Based on the analyses of 39 representative international air routes around westerlies, it is found that 97.44% (94.87%) of the commercial airplanes on the westbound (eastbound) air routes reveal shorter (longer) flight time during solar proton events compared to those during quiet periods, and the averaged magnitude of change in flight time is ~10 min or 0.21%-4.17% of the total flight durations. Comparative investigations reassure the certainty of such phenomenon that the directional differences in flight time are still incontrovertible regardless of over-land routes (China-Europe) or over-sea routes (China-Western America). Further analyses suggest that the solar proton events associated atmospheric heating will change the flight durations by weakening certain atmospheric circulations, such as the polar jet stream. While the polar jet stream will not be obviously altered during solar flares so that the directional differences in flight time are not found. Besides the conventional space weather effects already known, this paper is the first report that indicates a distinct new scenario of how the solar proton events affect flight time. These analyses are also important for aviation since our discoveries could help the airways optimize the air routes to save passenger time costs, reduce fuel costs and even contribute to the global warming issues., submitted to Scientific Reports

The EXperiment for Cryogenic Large-Aperture Intensity Mapping (EXCLAIM) is a balloon-borne cryogenic telescope that will survey the spectrum of diffuse emission from both the Milky Way and the cosmic web to probe star formation, the interstellar medium, and galaxy evolution across cosmic time. EXCLAIM's primary extragalactic science survey maps 305 deg$^2$ along the celestial equator with an R=512 spectrometer over the frequency range \nu=420-540 GHz, targeting emission of the [CII] line over redshifts 2.5, Comment: 19 pages, 14 figures, will submit to MNRAS

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

The two-fluid generalized Ohm's law (GOL) is based on the assumption that plasma is composed of only protons and electrons. The three-fluid GOL is obtained theoretically for the three-fluid plasma consisting of heavy ions, light ions, and electrons, which prevails in planetary ionospheres and magnetospheres. Three inertial lengths corresponding to the three-scale diffusion region in the three-fluid magnetic reconnection are derived. The ion inertial lengths and reconnection rate as well as the Hall magnetic and electric fields are modified due to the two-step decoupling process of ions. Our results provide a framework to extend the reconnection theory for even more ion species.

Solar wind dynamic pressure pulses (DPPs) are small-scale plasma structures with abrupt and large-amplitude plasma dynamic pressure changes on timescales of seconds to several minutes. Overwhelming majority of DPP events (around 79.13%) reside in large-scale solar wind transients, i.e., coronal mass ejections, stream interaction regions, and complex ejecta. In this study, the intermittency, which is a typical feature of solar wind turbulence, is determined and compared during the time intervals in the undisturbed solar wind and in large-scale solar wind transients with clustered DPP events, respectively, as well as in the undisturbed solar wind without DPPs. The probability distribution functions (PDFs) of the fluctuations of proton density increments normalized to the standard deviation at different time lags in the three types of distinct regions are calculated. The PDFs in the undisturbed solar wind without DPPs are near-Gaussian distributions. However, the PDFs in the solar wind with clustered DPPs are obviously non-Gaussian distributions, and the intermittency is much stronger in the large-scale solar wind transients than that in the undisturbed solar wind. The major components of the DPPs are tangential discontinuities (TDs) and rotational discontinuities (RDs), which are suggested to be formed by compressive magnetohydrodynamic (MHD) turbulence. There are far more TD-type DPPs than RD-type DPPs both in the undisturbed solar wind and large-scale solar wind transients. The results imply that the formation of solar wind DPPs could be associated with solar wind turbulence, and much stronger intermittency may be responsible for the high occurrence rate of DPPs in the large-scale solar wind transients.

When Mercury moves in its high-eccentricity orbit around the Sun, the background solar wind conditions are significantly changed. We investigated the effects of heliocentric distance and interplanetary magnetic field (IMF) orientation on the shape and location of Mercury’s bow shock. We fit empirical models to the bow shock crossings obtained from the MErcury Surface, Space ENvironment, GEochemistry, and Ranging magnetometer observations under different conditions. Our results demonstrate that the bow shock moves antiplanetward when Mercury moves from perihelion to aphelion. However, this difference is not as significant as that of magnetopause due to the thickness variation of the magnetosheath. The IMF orientations show a weak influence on the bow shock shape and location, which implies that the southward magnetic field component is not the determinant factor that drives reconnection at the low-β magnetopause of Mercury.

We discuss tradeoffs and errors associated with approaches to modeling health economic decisions. Through an application in pharmacogenomic (PGx) testing to guide drug selection for individuals with a genetic variant, we assessed model accuracy, optimal decisions and computation time for an identical decision scenario modeled four ways: using (1) coupled-time differential equations [DEQ]; (2) a cohort-based discrete-time state transition model [MARKOV]; (3) an individual discrete-time state transition microsimulation model [MICROSIM]; and (4) discrete event simulation [DES]. Relative to DEQ, the Net Monetary Benefit for PGx testing (vs. a reference strategy of no testing) based on MARKOV with rate-to-probability conversions using commonly used formulas resulted in different optimal decisions. MARKOV was nearly identical to DEQ when transition probabilities were embedded using a transition intensity matrix. Among stochastic models, DES model outputs converged to DEQ with substantially fewer simulated patients (1 million) vs. MICROSIM (1 billion). Overall, properly embedded Markov models provided the most favorable mix of accuracy and run-time, but introduced additional complexity for calculating cost and quality-adjusted life year outcomes due to the inclusion of “jumpover” states after proper embedding of transition probabilities. Among stochastic models, DES offered the most favorable mix of accuracy, reliability, and speed.

Supplemental material, sj-pdf-1-mdm-10.1177_0272989X21995805 for Comparison of Decision Modeling Approaches for Health Technology and Policy Evaluation by John Graves, Shawn Garbett, Zilu Zhou, Jonathan S. Schildcrout and Josh Peterson in Medical Decision Making

Using the data from the Advanced Composition Explorer (ACE) and Wind spacecraft, we statistically studied the Parker spiral angle (PSA) of the solar wind magnetic field from 1998 to 2019 at 1 au. The PSA occurrences over both a Carrington rotation (CR) and a year can be well fitted by a Gaussian distribution. However, large-scale magnetic structures, such as interplanetary coronal mass ejections (ICMEs), can significantly deviate the PSA distribution of a CR from the Gaussian distribution. The PSA distributions of each CR and each year are affected by the solar activity: They are more concentrated at a relatively higher average PSA at solar maximum. There is also a weak anticorrelation between the yearly solar wind speed (v sw) and the average PSA. MESSENGER, Venus Express, and ACE observations at different heliocentric distances within 1 au show that the dominating polarities of the heliospheric magnetic field change greatly from year to year even when the solar activity is on the same level. Our results suggest that the PSA distribution in addition to the sunspot number can provide some new information on the magnetic field variation of the Sun.

The influences of the interplanetary magnetic field (IMF) on the induced magnetosphere of Venus are investigated using a global multispecies magnetohydrodynamics (MHD) model. The simulation results show that the induced magnetosphere is controlled by the IMF components perpendicular to the solar wind velocity (B Y and B Z in the Venus Solar Orbital coordinate), rather than the IMF magnitude (∣B∣). With the increase of ( B Y 2 + B Z 2 ) 1 2 , the induced magnetosphere becomes stronger in field strength and thicker in spatial scale, and the bow shock locates farther from the planet. The parallel IMF component (B X ) has relatively small impacts on the magnetic barrier and the magnetotail, regardless of the various IMF magnitudes and orientations caused by different B X . The responses of the Venusian induced magnetosphere to the change of upstream IMF are also studied. The time-dependent MHD calculations show that the dayside magnetosphere responds quickly with a timescale of 10 s–10 minutes, depending on the considered magnetospheric region. For comparison, the timescale required for the adjustment of magnetotail as driven by an IMF rotation is derived to be ∼10–20 minutes.

PurposeThe liver is the most frequent metastatic site for colorectal cancer (CRC). Its microenvironment is modified to provide a niche that allows CRC cell growth. This study focused on characterizing the cellular changes in the metastatic CRC (mCRC) liver tumor microenvironment (TME).Experimental DesignWe analyzed a series of microsatellite stable (MSS) mCRCs to the liver, paired normal liver tissue and peripheral blood mononuclear cells using single cell RNA-seq (scRNA-seq). We validated our findings using multiplexed spatial imaging and bulk gene expression with cell deconvolution.ResultsWe identified TME-specific SPP1-expressing macrophages with altered metabolism features, foam cell characteristics and increased activity for extracellular matrix (ECM) organization. SPP1+ macrophages and fibroblasts expressed complementary ligand receptor pairs with the potential to mutually influence their gene expression programs. TME lacked dysfunctional CD8 T cells and contained regulatory T cells, indicative of immunosuppression. Spatial imaging validated these cell states in the TME. Moreover, TME macrophages and fibroblasts had close spatial proximity, a requirement for intercellular communication and networking. In an independent cohort of mCRCs in the liver, we confirmed the presence of SPP1+ macrophages and fibroblasts using gene expression data. An increased proportion of TME fibroblasts was associated with worst prognosis in these patients.ConclusionsWe demonstrated that mCRC in the liver is characterized by transcriptional alterations of macrophages in the TME. Intercellular networking between macrophages and fibroblasts supports CRC growth in the immunosuppressed metastatic niche in the liver. These features can be used to target these immune checkpoint resistant MSS tumors.TRANSLATIONAL RELEVANCEThe liver is the commonest site for metastatic colorectal cancer (mCRC). Alterations in the tumor microenvironment (TME) allow metastatic cells to seed the distant liver site and grow. Leveraging single-cell RNA sequencing, we discovered a distinct SPP1+ macrophage cell state with pro-fibrogenic gene expression and altered metabolism. These SPP1+ macrophages communicated with fibroblasts, mutually influencing each other’s gene expression program. Using spatial imaging, we confirmed proximal colocalization between macrophages and fibroblasts in the mCRC TME, which is required for intercellular communication. These states and intercellular communication promoted immunosuppression in the TME, with a lack of dysfunctional anti-tumor CD8 T cells and prevalence of regulatory T cells. Increased fibroblasts were associated with worst prognosis in an independent patient cohort. Our results identified novel TME features that result in reshaping of the metastatic niche that allows progression of mCRC. These features can be potential targets for mCRC treatment, which is microsatellite stable and resistant to immune checkpoint blockade.

Plasma heating at thin current sheets in the solar wind is examined using magnetic field and plasma data obtained by the WIND spacecraft in the past 17 years from 2004 to 2019. In this study, a thin current sheet is defined by an abrupt rotation (larger than 45°) of the magnetic field direction in 3 s. A total of 57,814 current sheets have been identified, among which 25,018 current sheets are located in the slow wind and 19,842 current sheets are located in the fast wind. Significant plasma heating is found at current sheets in both slow and fast wind. Proton temperature increases more significantly at current sheets in the fast wind than in the slow wind, while the enhancement in electron temperature is less remarkable at current sheets in the fast wind. The results reveal that plasma heating commonly exists at thin current sheets in the solar wind regardless of the wind speed, but the underlying heating mechanisms might be different.

Recent improvements in the production of artificial single-crystal diamonds have made it possible to produce commercial radiation detectors. However, the availability of diamond detectors for high-temperature and high-shock applications is limited. We have developed a compact solid-state diamond detector for high-temperature applications which require compact size, stable performance, and extreme ruggedness. It is used as a fast neutron detector for monitoring the output of a pulsed neutron generator in oil well-logging tools. The sensor consists of a high-purity monocrystalline diamond wafer with metallized electrodes on both faces. One of the metallized surfaces is mounted on a metallic plate resting on a ceramic substrate. The metallized diamond assembly is mounted in a TO-257 metal housing, which has pins connected to the two electrodes on the two faces of the diamond. The detector package, consisting of the diamond sensor and the electronics assembly, has been qualified for operation in the harsh downhole environment of oil fields. This includes high temperature and repeated shocks and vibration. Units have been tested for up to 150 h at 200 °C with no degradation in signal or count rate accuracy. The count rate accuracy with a simple detection threshold regulation scheme can reach ±1% over the range from 25 °C to 200 °C. However, this detector has applications beyond well logging, wherever there is a need for a compact, reliable detector for fast neutrons in an environment where ruggedness, exposure to high temperature, compactness, and radiation hardness are essential.

We perform a statistical study on the intermittency and the associated local heating in the front boundary layers (BLs) of 74 magnetic clouds (MCs). The intermittent structures are identified by the partial variance of increments (PVI) method. The probability distribution function of PVI-values reveals that the BLs are more intermittent than adjacent sheath regions, and they contain a greater concentration of strong intermittencies. These strong intermittencies are accompanied by local enhancement of the proton temperature, while the enhancement is not prominent at weaker intermittencies inside the BLs. Since the strong intermittencies are associated with magnetic reconnection (MR) processes according to previous studies, these results indicate that MR processes may account for the local heating in the MCBLs to a large extent.

Time History of Events and Macroscale Interactions during Substorms (THEMIS) data are used to investigate the magnetic field structures in the vicinity of the magnetopause. Generally, the tendency that the farther away from the Earth, the weaker the detected magnetic field is expected inside the dayside magnetopause. Here we show two cases which conflict with the expectation that the magnetic field gradient direction reverses from inward to outward in a short time interval. After a further analysis, it is found that the THEMIS probes encountered a magnetopause indentation moving along the magnetopause towards the dawn in one case, and for the other case, they crossed an evolutive indented magnetopause that was produced locally and then recovered to its normal state. These two magnetopause indentation may be related with the fast magnetosheath flow. Accordingly, we suppose that the fast magnetic gradient direction reverse is caused by the abnormal magnetic field distribution adjacent to the deformed magnetopause.

We discuss a decision-theoretic approach to building a panel-based, preemptive genotyping program. The method is based on findings that a large percentage of patients are prescribed medications that are known to have pharmacogenetic associations, and over time, a substantial proportion are prescribed additional such medication. Preemptive genotyping facilitates genotype-guided therapy at the time medications are prescribed; panel-based testing allows providers to reuse previously collected genetic data when a new indication arises. Because it is cost-prohibitive to conduct panel-based genotyping on all patients, we describe a three-step approach to identify patients with the highest anticipated benefit. First, we construct prediction models to estimate the risk of being prescribed one of the target medications using readily available clinical data. Second, we use literature-based estimates of adverse event rates, variant allele frequencies, secular death rates, and costs to construct a discrete event simulation that estimates the expected benefit of having an individual’s genetic data in the electronic health record after an indication has occurred. Finally, we combine medication prescription risk with expected benefit of genotyping once a medication is indicated to calculate the expected benefit of preemptive genotyping. For each patient-clinic visit, we calculate this expected benefit across a range of medications and select patients with the highest expected benefit overall. We build a proof of concept implementation using a cohort of patients from a single academic medical center observed from July 2010 through December 2012. We then apply the results of our modeling strategy to show the extent to which we can improve clinical and economic outcomes in a cohort observed from January 2013 through December 2015.