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The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-vs-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and non-relapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n=1604) was divided into two cohorts: historical (2006–2015, n=702) and current (2015–2017, n=902) with similar non-relapse mortality, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16% and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3α. We conducted a multicenter proof-of-concept “preemptive” treatment trial of α-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.

The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.

Background: A major cause of mortality in patients receiving hematopoietic stem cell transplantation (HCT) is acute graft-versus-host disease (GVHD), a multiorgan disorder that includes the skin, liver and gastrointestinal tract. We have previously identified elafin, a protease inhibitor overexpressed in inflamed epidermis, as a diagnostic biomarker of GVHD in the skin, the most commonly involved GVHD organ. However, our initial study was limited to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT patients is GI GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have since been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker of acute GVHD in the general population of previously unstudied acute GVHD patients, and to compare it to ST2 and REG3α. Study Design: 526 patients who received systemic corticosteroid treatment for skin GVHD were analyzed from the Mount Sinai Acute GVHD International Consortium (MAGIC), which includes patients from 25 HCT centers. We used ELISA to measure serum concentrations of elafin, ST2 and REG3α. Patients were divided randomly into equal training and validation sets; and we developed a competing risk regression model for 6-month NRM using elafin concentration in the training set. We developed additional models for 6-month NRM using concentrations of ST2 and REG3α, or the combination of all three biomarkers as predictors. We then constructed ROC curves to evaluate the predictive accuracy of each model and to analyze the ability of each model to stratify patients into high- and low-risk groups. We analyzed the cumulative incidence of 6-month NRM and overall survival in each model and compared the accuracy of each model in the validation set. Results: The area under the receiver operating curve (AUROC) for elafin alone was 0.55 whereas it was 0.75 and statistically superior (P = 0.02) for the combination of ST2 and REG3α. The combination of 3 biomarkers produced an AUROC of 0.76 that was not significantly better than the two biomarker model (P = 0.10). Elafin concentrations, either alone or in combination with ST2 and REG3α, did not produce higher hazard ratios of NRM (data not shown). Patients in the low-risk elafin group paradoxically demonstrated a higher incidence of 6-month NRM, although this difference was not statistically significant (17% vs. 11%, P=0.19), and both overall survival at 6 months (68% vs. 68%, P>0.99) and four-week response (78% vs. 78%, P=0.98) were similar in the low- and high-risk elafin groups (Figure 1). As demonstrated in previous data sets, the combination of ST2 and REG3α divided patients into two groups with a nearly five-fold difference in NRM (6.7% vs. 31%, P Conclusion: We demonstrated that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD in a multicenter population of patients treated systemically for acute GVHD do not predict 6-month NRM, overall survival, or treatment response. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD. Figure 1. Cumulative incidence of nonrelapse mortality and overall survival in high and low risk groups Six-month cumulative incidences of nonrelapse mortality (NRM) in high (solid line) and low (dotted line) risk groups defined by optimized biomarker thresholds (upper panels) and six-month overall survival estimated using the Kaplan-Meier method (lower panels). (A) Cumulative incidence of NRM (14%) and overall survival (75%) in the total validation set (N=263). (B) Cumulative incidence of NRM in the low (N=150) and high (N=113) elafin group (17% vs. 11%, P=0.19). Overall survival in the low and high elafin group (68% vs. 68%, P > 0.99). (C) Cumulative incidence of NRM in the low (N=175) and high (N=88) ST2 + REG3a group (6.7 vs. 31%, P < 0.001). Overall survival in the low and high ST2 + REG3a group (77% vs. 51%, P < 0.001). (D) Cumulative incidence of NRM in the low (N=180) and high (N=83) elafin + ST2 + REG3a group (7.0 vs. 30%, P < 0.001). Overall survival in the low and high elafin + ST2 + REG3a group (79% vs. 64%, P < 0.001). Figure 1 Figure 1. Disclosures Ozbek: Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor. DeFilipp: Omeros, Corp.: Consultancy; Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Syndax Pharmaceuticals, Inc: Consultancy. Grupp: Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tmunity Therapeutics: Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Kitko: Co-investigator on two NIH grants as part of the cGVHD consortium: Research Funding; Vanderbilt University Medical Center: Current Employment; PER: Other: PER - CME educational talks about GVHD; Horizon: Membership on an entity's Board of Directors or advisory committees. Qayed: Novartis: Honoraria; Mesoblast: Honoraria; Medexus: Honoraria. Reshef: ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; Gilead and Novartis: Honoraria; BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy. Levine: Incyte: Consultancy, Research Funding; Viracor: Patents & Royalties: GVHD biomarker patent with royalties from Viracor; Mesoblast: Consultancy, Research Funding; Equillium Bio: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Talaris Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Symbio: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Kamada: Research Funding. Ferrara: Eurofins Viracor: Consultancy, Other: Royalties. Chen: Incyte: Consultancy; Gamida: Consultancy.

Entidad financiadora : Indian National Science Academy, New Delhi, India under the INSA Honorary Scientist Scheme

A two-dimensional version of a chaotic thermostat is investigated. Its structure follows the concept previously introduced by the author [G. J. Morales, Phys. Rev. E 97, 032203 (2018)2470-004510.1103/PhysRevE.97.032203] to generate a one-dimensional chaotic thermostat, namely, the usual friction force of a deterministic thermostat is supplemented with a self-consistent fluctuating force that depends on the drag coefficient associated with coupling to the heat bath. Azimuthal symmetry requires the thermostat to have two internal degrees of freedom, thus the Martyna-Klein-Tuckerman [G. J. Martyna et al., J. Chem. Phys. 97, 2635 (1992)JCPSA60021-960610.1063/1.463940] model is chosen for the heat bath. The unmagnetized system exhibits two-dimensional diffusive behavior, achieves symmetric Maxwellian velocity distributions in the absence of an external potential, and satisfies the Einstein relation when an external force is applied. The velocity fluctuations display the characteristic exponential frequency spectrum associated with chaotic systems. The model is used to explore the diffusive motion of a thermalized charge in a weak magnetic field and the associated Hall and Pedersen mobilities. Over a range of magnetic field strengths the charge exhibits absolute negative mobility.

A numerical investigation is made of the response of a thermalized charge in contact with a chaotic thermostat to an externally applied, oscillating electric field, with and without a confining magnetic field. This study is based on the recent theoretical development of a chaotic thermostat [G. J. Morales, Phys. Rev. E 99, 062218 (2019)] for which the static properties of a thermalized charge (spatial diffusion and mobilities) were previously established. It is found here that in the unmagnetized case, to extract significant power from the oscillating electric field requires that the oscillatory velocity be larger than the thermal velocity. The spatial diffusion caused by the self-consistent, chaotic fluctuations is shown to be reduced, and even suppressed, by the coherent oscillations. The frequency-dependent mobilities, including cyclotron resonance, are determined, and the nonlinear modifications produced by large electric fields are explored. The value of the mobilities and the modifications to the diffusion coefficient exhibit non-monotonic dependencies on the control parameters.

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight, 2017; Major- Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment.

The concept of transport mediated through the dynamics of ``jumping'' particles is used to develop an iterative method for obtaining steady-state solutions to the nonlocal transport equation in two dimensions. The technique is self-adjoint and capable of correctly treating spatially nonuniform, asymmetric systems. An appropriate reduced version of the iteration method is used to compare with results obtained with a self-adjoint one-dimensional transport matrix approach [Maggs and Morales, Phys. Rev. E 94, 053302 (2016)]. The transport ``jump'' probability distribution functions are based on L\'evy \ensuremath{\alpha}-stable distributions. The technique can handle the entire L\'evy \ensuremath{\alpha}-parameter range from one (Lorentz distributions) to two (Gaussian distributions). Cases with $\ensuremath{\alpha}=2$ (standard diffusion) are used to establish the validity of the iterative method. The capabilities of the iterative method are demonstrated by presenting examples from systems with various source configurations, boundary shapes, boundary conditions, and spatial variations in parameters.

An experiment is performed on a large plasma device operated by the Basic Plasma Science Facility at the University of California, Los Angeles, in which an electrically floating structure is placed near the end of the 18-m magnetized plasma column. The structure consists of a flat carbon plate that acts as a mask for a smaller, ring-shaped LaB6 emissive surface whose temperature can be externally controlled. This configuration has been previously used to study electron heat transport and pressure-driven avalanches [B. Van Compernolle and G. J. Morales, Phys. Plasmas 24, 112302 (2017)] by biasing the LaB6 ring-cathode with respect to a distant anode in a cold afterglow plasma. In contrast, the present study is performed during the active portion of the steady-state discharge in which the nominal plasma parameters are determined by the injection of an electron beam from a BaO cathode at the opposite end. It is found that, even without an applied bias on the LaB6 cathode, the self-consistent potential and current profiles are modified near the end plate as the LaB6 temperature is increased, resulting in density increases on the field lines in contact with the ring-cathode. In the absence of enhanced ionization, at the largest cathode temperatures, the ambient density can be doubled. A theoretical model is presented that provides a quantitative explanation for the experimental observations.An experiment is performed on a large plasma device operated by the Basic Plasma Science Facility at the University of California, Los Angeles, in which an electrically floating structure is placed near the end of the 18-m magnetized plasma column. The structure consists of a flat carbon plate that acts as a mask for a smaller, ring-shaped LaB6 emissive surface whose temperature can be externally controlled. This configuration has been previously used to study electron heat transport and pressure-driven avalanches [B. Van Compernolle and G. J. Morales, Phys. Plasmas 24, 112302 (2017)] by biasing the LaB6 ring-cathode with respect to a distant anode in a cold afterglow plasma. In contrast, the present study is performed during the active portion of the steady-state discharge in which the nominal plasma parameters are determined by the injection of an electron beam from a BaO cathode at the opposite end. It is found that, even without an applied bias on the LaB6 cathode, the self-consistent potential and cu...

This analytical and numerical study explores, from a deterministic perspective, the response of a particle in contact with a heat bath to an external force that varies sinusoidally in time. The heat bath is represented as a deterministic Nose-Hoover thermostat. Such an idealized model encompasses features found in a variety of physical problems in which the coherent influence of an external agent competes against the thermalization tendencies of the surrounding medium, e.g., a charged particle in a thermal plasma that is acted on by a powerful electromagnetic wave. It is found that, independently of the coupling strength to the thermostat, average power can only be extracted from the sinusoidal force when the oscillatory velocity exceeds the thermal velocity. It follows from this property that a candidate heat bath whose temperature is raised solely through the application of a sinusoidal force (e.g., radio-frequency heating), reaches, in a finite time, a unique final temperature determined by the force parameters. The transition boundary separating the two domains of power transfer is shown to be dominated by chaotic behavior. The combined response to a sinusoidal force and a dc force are also considered and the relevant regions of power transfer are delineated.

A numerical study is presented of a free particle interacting with a deterministic thermostat in which the usual friction force is supplemented with a fluctuating force that depends on the self-consistent damping coefficient associated with coupling to the heat bath. It is found that this addition results in a chaotic environment in which a particle self-heats from rest and moves in positive and negative directions, exhibiting a characteristic diffusive behavior. The frequency power spectrum of the dynamical quantities displays the exponential frequency dependence ubiquitous to chaotic dynamics. The velocity distribution function approximates a Maxwellian distribution, but it does show departures from perfect thermal equilibrium, while the distribution function for the damping coefficient shows a closer fit. The behavior for the classic Nosé-Hoover (NH) thermostat is compared to that of the enlarged Martyna-Klein-Tuckerman (MKT) model. Over a narrow amplitude range, the application of a constant external force results quantitatively in the Einstein relation for the NH thermostat, and for the MKT model it differs by a factor of 2.

Acute GVHD biomarkers predict long-term outcomes after GVHD diagnosis. Our group has validated the MAGIC algorithm which uses the concentrations of 2 GVHD biomarkers, ST2+REG3a, to predict lethal GVHD (defined as death from GVHD without relapse) [Hartwell 2017]. Other published biomarker combinations that predict GVHD outcomes include ST2+ REG3a+TNFR1 [Levine 2015], ST2+TIM3 [Abu Zaid 2017], ST2+TNFR1 [McDonald 2015], TIM3+TNFR1+IL6 [McDonald 2015], as well as AREG alone [Holtan 2018]. It is not clear which biomarker combination best predicts lethal GVHD because these algorithms were developed using different patient cohorts with different endpoints. To answer this question, we compared the predictive accuracy of different biomarker combinations as well as these six specific combinations in the same patient cohort. We studied 522 patients with serum samples at GVHD diagnosis who were transplanted at 19 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 1, 2004 and April 30, 2017. Patients were divided into training (n = 253) and validation (n = 269) sets; validation patients were transplanted after November 1, 2015 and had not previously been used to generate an algorithm. Biomarkers were measured by ELISA and log-transformed values were used to predict 1-year lethal GVHD by competing risk regression. Four of the 6 biomarkers (ST2, REG3a, TNFR1, and TIM3) independently predicted lethal GVHD in the training set. We then developed algorithms that predicted lethal GVHD using all possible combinations of these 4 biomarkers as well as the published combination of TIM3+TNFR1+IL6 and AREG alone. The best algorithms of 1-4 biomarkers for predicting lethal GVHD were REG3a alone, ST2+REG3a, ST2+REG3a+TNFR1, and ST2+REG3a+TNFR1+TIM3. While ST2+REG3a was the most accurate combination based on the lowest Akaike Information Criterion (AIC), the other published biomarker combinations produced similar AICs. Therefore, we used the independent validation set to compare all six published algorithms. We generated area under the receiver operating characteristic curves (AUC) for each algorithm (FIG 1). We next determined the threshold that maximized sensitivity and specificity for each algorithm and calculated the cumulative incidence of lethal GVHD in the resulting high and low risk strata (FIG 2). Highly similar results were obtained when the cumulative incidence of non-relapse mortality was used as the endpoint. In a validation set of previously unanalyzed patients, several biomarker combinations reproducibly stratified patients with GVHD for risk of death. The best 4 algorithms, all of which included ST2, produced comparable outcomes. Adding TNFR1 to ST2+ REG3a did not improve accuracy. The ST2+REG3a algorithm best identifies patients at onset of GVHD for high risk of lethal GVHD and NRM, and thus remains a standard for biomarker-based risk prediction.

The Nonlinear Wave and Chaos Workshop 2017 (NWCW17); San Diego, California, 20–24 March 2017

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n = 309) and validation set (n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

Systemic glucocorticoids are the principal treatment for acute graft-versus-host disease (GVHD), which remains the major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). However, there are no validated biomarkers that measure a patient's response to glucocorticoid therapy, and thus response is evaluated by the change in clinical symptom severity. A major weakness in the predictive power of clinical responses is that changes to all organs are weighted equally even though the major driver of NRM is irreversible damage to the crypts of the GI tract. Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP has been considered a "liquid biopsy" that estimates the damage caused by GVHD to crypts throughout the lower GI tract (Hartwell et al., JCI Insight, 2017; Major-Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker for GVHD and might compare favorably to the change in clinical symptoms that measures response to GVHD treatment, which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We measured the serum concentrations of REG3α and ST2 before and after systemic therapy for acute GVHD and computed MAPs, the changes in MAPs, and clinical responses for each patient. MAPs of patients who experienced 6 month NRM showed significantly greater increases than MAPs of patients who survived (p=0.0004). In patients whose MAPs at the start of treatment were low (Ann Arbor 1, MAP < 0.141) or intermediate (Ann Arbor 2, 0.141 ≤ MAP ≤ 0.290), 6 month NRM clustered among those who had the greatest increases in MAP after 28 days (Fig 1A,B). In patients with high MAPs at the start of treatment (Ann Arbor 3, MAP > 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). These changes in MAP suggested crossing a single threshold could predict risk of mortality. We found that patients whose MAPs rose above a threshold MAP of 0.290 (5% of Ann Arbor 1, 27% of Ann Arbor 2) had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold (66% of Ann Arbor 3) had a large increases in mortality (Fig 2). When measured at day 28, the MAP was significantly more accurate in predicting NRM than the gold standard of the clinical response, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first validated laboratory test to serve as response biomarker for the treatment for acute GVHD and a more accurate predictor of survival than clinical response after four weeks of treatment. The MAP may serve as a novel endpoint and an important complement to changes in clinical symptom severity in future trials of GVHD treatment. Disclosures Srinagesh: National Institutes of Health: Research Funding. Ozbek:Viracor: Patents & Royalties: Biomarker Patent. Ayuk:Novartis: Honoraria, Other: Advisory Board, Research Funding. Aziz:Doris Duke Charitable Foundation: Research Funding. Defilipp:Incyte: Research Funding. Grupp:Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; CBMG: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy; Humanigen: Consultancy. Hexner:novartis: Research Funding. Kitko:Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Mielke:EBMT/EHA: Other: Travel support; ISCT: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau. Merli:Sobi: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Bellicum: Consultancy. Pulsipher:Amgen: Other: Lecture; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Honoraria. Qayed:Bristol-Myers Squibb: Honoraria. Reshef:Pfizer: Consultancy; Magenta: Consultancy; Kite: Consultancy, Research Funding; Atara: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Shire: Research Funding. Levine:Incyte: Consultancy, Research Funding; Biogen: Other: non-financial support; Viracor: Patents & Royalties: biomarker patent; Ironwood: Honoraria; bluebird bio: Consultancy; National Cancer Institute: Research Funding; Novartis: Honoraria; Kamada: Research Funding. Ferrara:National Institutes of Health: Research Funding; ViraCor: Consultancy; Incyte: Consultancy; Kamada: Consultancy; Mallinckrodt: Consultancy; Enlivex: Consultancy; Xenikos: Consultancy; CSL Behring: Consultancy.

A recently developed model of nonlocal transport in two dimensions (2D), the “iterative method” [J. E. Maggs and G. J. Morales, Phys. Rev. E 99, 013307 (2019)], is applied to the published results of ECRH experiments [Takahashi et al. AIP Conf. Proc. 1580, 145 (2014)] performed in the Large Helical Device. It is found from the temperature profiles obtained from the 2D model that the sharply peaked electron temperature profiles observed in such experiments, and previously associated with local transport and “internal transport barriers” or Core Electron-Root Confinement, are also consistent with nonlocal transport. It is shown that the iterative method is suited to handling both scenarios.A recently developed model of nonlocal transport in two dimensions (2D), the “iterative method” [J. E. Maggs and G. J. Morales, Phys. Rev. E 99, 013307 (2019)], is applied to the published results of ECRH experiments [Takahashi et al. AIP Conf. Proc. 1580, 145 (2014)] performed in the Large Helical Device. It is found from the temperature profiles obtained from the 2D model that the sharply peaked electron temperature profiles observed in such experiments, and previously associated with local transport and “internal transport barriers” or Core Electron-Root Confinement, are also consistent with nonlocal transport. It is shown that the iterative method is suited to handling both scenarios.

Introduction aGVHD affects 40% to 60% of hematopoietic cellular transplant (HCT) patients, targeting the skin, liver, and gastrointestinal tract with a median onset approximately 1 month after transplant. In 2017, an interpretive algorithm based on serum ST2 and REG3α levels was clinically validated (JCI Insight 2017;2(3):e89798). Objectives This report details validation, inter-lab correlation and initial results from clinical analysis. Methods ST2 and REG3α levels were analyzed in serum using enzyme immunoassays. ST2 and REG3α values are analyzed through an equation to provide an index value that can be used for predicting non-relapse mortality and aGVHD risk for pre-symptomatic (low/high risk), symptomatic onset (low/medium/high risk) and post treatment (low/high risk) HCT patients. Results were compared with the research lab where the equation was established (Mount Sinai Medical Center, MSMC). Results The inter-assay precision ranged from 12 to 26 %CV for ST2 and REG3a, while those for the calculated indices ranged from 17 to 18%. Accuracy was compared against biomarker values and indices reported by MSMC for 106 serum samples. Among samples with biomarker concentrations within the assays' measuring range, the relative error was Conclusions The aGVHD index and its component input assays, ST2 and REG3a, were validated for clinical use. Notably, excellent concordance was observed on a large sample set (106 sera) with MSMC. In addition, initial results indicate that the aGVHD index may prove useful for risk-stratifying HCT patients.

A LaB6 thermionic emitter of annular shape is used in the Large Plasma Device at the University of California, Los Angeles to create off-axis heating conditions for various transport studies. Since the emitter is biased relative to a distant anode, which is many collision lengths away, the entire magnetized plasma develops a self-consistent, potential structure that simultaneously generates transverse and axial flows with shear. This study uses swept Langmuir probe techniques and Mach probes to map the flow patterns and their dependence on bias and plasma parameters. By implementing additional biasing configurations, it is possible to control the magnitude of the flows and their shear strength. The experimental measurements, including the self-consistent currents, are compared to predictions of a model that incorporates the boundary conditions associated with thermionic injection, combined with a Braginskii transport code for the electron temperature.

An integral operator is developed to describe nonlocal transport in a one-dimensional system bounded on both ends by material walls. The "jump" distributions associated with nonlocal transport are taken to be Lévy α-stable distributions, which become naturally truncated by the bounding walls. The truncation process results in the operator containing a self-consistent, convective inward transport term (pinch). The properties of the integral operator as functions of the Lévy distribution parameter set [α,γ] and the wall conductivity are presented. The integral operator continuously recovers the features of local transport when α=2. The self-adjoint formulation allows for an accurate description of spatial variation in the Lévy parameters in the nonlocal system. Spatial variation in the Lévy parameters is shown to result in internally generated flows. Examples of cold-pulse propagation in nonlocal systems illustrate the capabilities of the methodology.

Results are presented from basic heat transport experiments and gyrokinetic simulations of multiple magnetized electron temperature filaments in close proximity. This arrangement samples cross-field transport from nonlinear drift-Alfven waves and large scale convective cells. Experiments are performed in the Large Plasma Device (LAPD) at UCLA. A biased LaB6 cathode injects low energy electrons (below ionization energy) along a strong magnetic field into a pre-existing large and cold plasma forming an electron temperature filament embedded in a colder plasma, and far from the machine walls. A car bon masking plate with several holes (each 1cm diameter, 1.5 cm apart) is used to create 3 electron temperature filaments. By covering two holes in the mask drift-Alfven and thermal waves from a single filament have been characterized and compared to previous studies with a different electron beam source1. The observed eigenmode structures also compares favor ably with recent 3D gyrokinetic simulations2. The 3-filament case exhibits a complex wave pattern and enhanced cross-field transport. Detailed mode analysis and comparison with non linear simulations is reported.

Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz: Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wölfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

This is the final report of a panel set up by the U.S. Department of Energy (DOE) Fusion Energy Sciences Advisory Committee (FESAC) in response to a charge letter from Dr. Raymond Orbach (Appendix A), asking FESAC to “addressed the issue of workforce development in the U.S. fusion program.” This report, submitted to FESAC March 29, 2004 and subsequently approved by them (Appendix B), presents FESAC's response to that charge.

A broad experimental survey is made of the properties of spontaneously generated magnetic fluctuations in a large linear device in which the plasma density has different cross-field gradient scales. It includes steep gradients at the plasma–wall edge as well as at an interior plasma–plasma interface, thus phenomena of interest to magnetic fusion research as well as to space plasma physics is illustrated. Fluctuations in uniformly magnetized columns and plasmas with an axial gradient in the confining magnetic field are studied. Some of the highlights include the identification of a universal spectrum for drift-Alfven turbulence and the role of partial reflections in shaping the spectra.

The results are presented for a basic heat transport experiment involving an off-axis heat source in which avalanche events occur. The configuration consists of a long, hollow, cylindrical region of elevated electron temperature embedded in a colder plasma, and far from the device walls [Van Compernolle et al. Phys. Rev. E 91, 031102(R) (2015)]. The avalanche events are identified as sudden rearrangements of the pressure profile following the growth of fluctuations from ambient noise. The intermittent collapses of the plasma pressure profile are associated with unstable drift-Alfven waves and exhibit both radial and poloidal dynamics. After each collapse, the plasma enters a quiescent phase in which the pressure profile slowly recovers and steepens until a threshold is exceeded, and the process repeats. The use of reference probes as time markers allows for the visualization of the 2D spatio-temporal evolution of the avalanche events. Avalanches are observed only for a limited combination of heating power...

It is demonstrated that a novel heating configuration applied to a large and cold magnetized plasma allows the study of avalanche phenomena under controlled conditions. Intermittent collapses of the plasma pressure profile, associated with unstable drift-Alfven waves, exhibit a two-slope power-law spectrum with exponents near -1 at lower frequencies and in the range of -2 to -4 at higher frequencies. A detailed mapping of the spatiotemporal evolution of a single avalanche event is presented.

The project expanded and developed mathematical descriptions, and corresponding numerical modeling, of non-diffusive transport to incorporate new perspectives derived from basic transport experiments performed in the LAPD device at UCLA, and at fusion devices throughout the world. By non-diffusive it is meant that the transport of fundamental macroscopic parameters of a system, such as temperature and density, does not follow the standard diffusive behavior predicted by a classical Fokker-Planck equation. The appearance of non-diffusive behavior is often related to underlying microscopic processes that cause the value of a system parameter, at one spatial position, to be linked to distant events, i.e., non-locality. In the LAPD experiments the underlying process was traced to large amplitude, coherent drift-waves that give rise to chaotic trajectories. Significant advances were made in this project. The results have lead to a new perspective about the fundamentals of edge transport in magnetically confined plasmas; the insight has important consequences for worldwide studies in fusion devices. Progress was also made in advancing the mathematical techniques used to describe fractional diffusion.

This panel was set up by the U.S. Department of Energy's Fusion Energy Sciences Advisory Committee in response to a request from the department to prepare a strategy for the study of burning fusion plasmas. Experimental study of a burning plasma has long been a goal of the U.S. science-based fusion energy program. There is an overwhelming consensus among fusion scientists that we are now ready scientifically, and have the full technical capability, to embark on this step. The fusion community is prepared to construct a facility that will allow us to produce this new plasma state in the laboratory, uncover the new physics associated with the fusion burn, and develop and test new technology essential for fusion power. Given this background, the panel has produced a strategy to enable the United States to proceed with this crucial next step in fusion energy science. The strategy was constructed with awareness that the burning plasma program is only one major component in a comprehensive development plan for fusion energy. A strong core science and technology program focused on fundamental understanding, confinement configuration optimization, and the development of plasma and fusion technologies essential to the realization of fusion energy. The core program will also be essential to the successful guidance and exploitation of the burning plasma program, providing the necessary knowledge base and scientific workforce.

A systematic study is made of the spontaneous growth of fluctuations in temperature, density, and magnetic field in a narrow (on the order of the electron skin depth) field-aligned temperature filament embedded in a large magnetized plasma. Two broad classes of fluctuation (“low” and “high” frequency modes) have been identified and studied in detail. A high-frequency drift-Alfven mode grows at frequencies about one tenth the ion gyrofrequency in the region of the filament where the temperature gradient is large. The measured radial profiles of the density and magnetic field fluctuations associated with this mode agree well with theoretical predictions. The high-frequency mode has been observed to exhibit several interesting nonlinear features, including steepening wave form, progression in azimuthal mode number, coupling to the low frequency mode with subsequent sideband generation, and eventually a transition to broad band turbulence. The nature of the low-frequency mode which has frequencies about one f...

This experiment illustrates the spatiotemporal pattern of the fluctuations that spontaneously develop in a magnetized temperature filament whose transverse scale is comparable to the electron skin depth. A high-frequency mode exhibits a striking spiral structure and is identified as a drift-Alfv\'en eigenmode. A low-frequency mode is found to be localized near the center of the filament. It is documented that the fluctuations significantly increase the transport of heat beyond the prediction of classical theory based on Coulomb collisions.

A systematic study is made of the axial and transverse heat transport that arises when a microscopic temperature filament is generated, under controlled conditions, in a magnetized plasma of large dimensions. For early times and relatively small temperature gradients the study conclusively demonstrates the two-dimensional pattern characteristic of the classical theory based on Coulomb collisions. The full nonlinear dependence of the transverse and axial electron heat conductivities is sampled through temperature changes in the range δTe/Te∼1–10. The dependence on the confining magnetic field is explored over a factor of 3 (∼ factor of 10 in transverse conductivity). It is found that under quiescent conditions, the observed behavior agrees with classical theory within the experimental uncertainties. However, over long times and/or for steep temperature gradients, fluctuations develop spontaneously and cause a significant departure from the predictions of the classical theory.

This analytical and numerical study illustrates the linear stability properties of low frequency electromagnetic eigenmodes driven by field-aligned pressure striations whose scale transverse to the confining magnetic field is on the order of the electron skin-depth. A full electromagnetic formulation is given in terms of the coupling of the fluctuating axial fields (Ẽz,Bz) and incorporates shear and compressional Alfven waves, drift waves, and ion acoustic waves. The kinetic response of the electrons includes pitch-angle scattering (Lorentz model) and the ions are treated as a magnetized, cold fluid. Detailed quantitative comparisons of the theoretical predictions are made with laboratory observations of fluctuations generated in controlled pressure depletions [J. E. Maggs and G. J. Morales, Phys. Plasmas 4, 290 (1997)] and in narrow temperature plumes [A. T. Burke, J. E. Maggs, and G. J. Morales, Phys. Rev. Lett. 81, 3659 (1998)].

A systematic laboratory study of controlled density and temperature filaments having transverse scale length comparable to the electron skin-depth has been performed in the large plasma device (LAPD) at UCLA. It is found that large amplitude shear Alfven waves develop spontaneously and are localized within the filaments. As the plasma conditions change (e.g., lowering the plasma beta parameter or increasing the heating power) the highly coherent eigenmodes develop into broad band Alfvenic turbulence. A kinetic description that includes the effect of coulomb collisions has been developed to understand the linear properties of the modes. Excellent agreement with the measured eigenfunctions is found for the density filaments in the higher beta regime in which the modes remain strongly coherent. The similarity between the broad band fluctuation spectra generated in a variety of plasma configurations suggest the possibility of a universal process involving filamentary structures and spontaneously generated Alfvenic turbulence.

In this analytical and computer simulation study we explore the dynamics of a narrow electron stream embedded in a magnetized plasma. The transverse dimension of the stream is envisioned to be on the order of the electron skin depth, as is appropriate to several problems of current interest (e.g., auroral beams, reconnection). Within the layer the drift velocity exceeds the thermal velocity, and thus the Buneman instability is excited. The method of matched asymptotic expansions is used to describe the linear stage of the instability for a nonuniform drift profile. It predicts a lowering of the growth rate and a rapid decrease in wave amplitude at the spatial location where the beam mode resonance is encountered. A particle-in-cell (PIC) simulation is used to verify the predictions of the analysis and to illustrate the important nonlinear behavior. It is found that the rapid flash of the Buneman instability excites a lower-hybrid wave, causes strong perpendicular ion acceleration, and results in a region ...

The transport of heat deposited by a small low-voltage electron beam in a strongly magnetized plasma is studied for a time interval in excess of two thousand ion-gyro periods. Electron temperatures are observed to evolve along and across the magnetic field at the classically predicted rates up to times approaching one thousand gyro periods. At later times the onset of low-frequency fluctuations (below one-tenth the ion gyrofrequency) coincides with departures from classical behavior.

We have investigated an effect that is inherent to weakly stable plasmas: an enhanced large-velocity interaction. This behavior is not unique to two dimensions, but is quite similar to the higher-order terms in a three-dimensional dominant approximation expansion, as shown in the studies of Ware2 and of Tidman and Eviatar.3 The increased level of fluctuations generated by fast electrons is quite similar in both two and three dimensions. However, because both the emission and absorption of fluctuations by fast electrons is retained by the two-dimensional Fokker-Planck theory to lowest order (no dominant approximation is needed), these electrons interact at a significantly higher level than predicted by an extrapolation based on the usual three-dimensional dominant calculation. Small-angle collisions do not dominate in two dimensions, and the soft core of the logarithmic potential implies that any enhanced fluctuations affect the transport significantly. In three dimensions, a substantial tail would be necessary before a corresponding effect is observed.4,5 These results are essential to a complete understanding of two-dimensional particle simulations, especially those of weakly stable plasmas.

Magnetic field-aligned structures in current, density, and temperature are common features of the auroral ionospheric plasma. These structures both generate and transform low frequency waves in the plasma. The results of laboratory studies of two processes involving magnetic field-aligned density depletions (striations) that play a role in auroral plasma dynamics are presented. The first process involves the spontaneous generation of density and magnetic fluctuations at the striation edge. The nature of the fluctuations depends upon the electron plasma beta. At high beta (greater than the electron to ion mass ratio, m/M) the drift Alfven wave is excited. At lower beta the density and magnetic field fluctuations separate and the shear Alfven wave dominates. This process creates an environment conducive to electron acceleration along the magnetic field when the striation size is on the order of the electron skin depth because the shear Alfven wave then has a substantial field-aligned electric field. The sec...

Density and magnetic fluctuations arising spontaneously in a narrow field-aligned density striation in a magnetized discharge He plasma are found to exhibit a radial eigenmode structure. The nature of the fluctuations depends upon the electron plasma beta, βe. For βe greater than the electron to ion mass ratio (βe>m/M) the frequency spectrum exhibits sharply peaked eigenfrequencies with the density and magnetic fluctuations strongly coupled so that the growing mode is identified as the drift-Alfven wave. For βe less than the mass ratio (βe

The high‐frequency electromagnetic field generated by a density‐modulated, helical electron beam propagating in a magnetized plasma is calculated. The magnetic fluctuations are found to exhibit spatially localized (evanescent) resonances at harmonics of the electron‐cyclotron frequency, whose width is determined by the pitch angle of the beam, and whose existence is a consequence of the helical geometry. In addition, electrostatic modes are radiated near the hybrid frequencies, and electromagnetic modes are radiated above the upper‐hybrid frequency. The predicted frequency spectrum and mode structure in configuration space are in good agreement with experimental observations of discrete emission lines at the electron‐cyclotron harmonics [Phys. Fluids B 5, 3789 (1993)].

A basic process capable of explaining observations of fast perpendicular ions in a wide range of plasma environments is described. Spatial symmetry breaking perpendicular to the confining magnetic field is shown to cause irreversible energy gain for ions gyrating through an electric field having a nonuniform amplitude. The efficiency depends on the ratio of the ion Larmor radius to the scale length of the amplitude gradient, and on the scaled frequency ν≡ω/Ωi. A Landau resonance is not required, and there is no lower threshold on the electric field, because the mechanism is active in the linear regime. Theory, numerics, and particle‐in‐cell simulations are used to illustrate the interaction for electrostatic fields in the lower‐hybrid range of frequencies, but the process does not depend on a particular type of mode.

In a laboratory experiment modeling conditions in the auroral ionosphere, magnetic and density fluctuations are observed to grow spontaneously within a field aligned density depletion. The plasma has both cross-field pressure gradients and magnetically field-aligned currents. The magnetic fluctuations, identified as shear Alfven waves, are coupled with the density fluctuations depending upon the plasma beta, β. The fluctuations exhibit a coherent eigenmode structure at higher β and evolve towards broadband Alfven turbulence as β is lowered. We identify the cross field pressure gradient as the dominant driving source for the fluctuations.