An empirically observed pitch-angle diffusion eigenmode in the Earth\u27s electron belt near L* = 5.0

Abstract Using data from NASA\u27s Van Allen Probes, we have identified a synchronized exponential decay of electron flux in the outer zone, near L* = 5.0. Exponential decays strongly indicate the presence of a pure eigenmode of a diffusion operator acting in the synchronized dimension(s). The decay has a time scale of about 4 days with no dependence on pitch angle. While flux at nearby energies and L* is also decaying exponentially, the decay time varies in those dimensions. This suggests the primary decay mechanism is elastic pitch angle scattering, which itself depends on energy and L *. We invert the shape of the observed eigenmode to obtain an approximate shape of the pitch angle diffusion coefficient and show excellent agreement with diffusion by plasmaspheric hiss. Our results suggest that empirically derived eigenmodes provide a powerful diagnostic of the dynamic processes behind exponential decays

Radiofrequency Ablation in Combination With Cd73 Inhibitor Ab680 Reduces Tumor Growth and Enhances Anti-tumor Immunity in a Syngeneic Model of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma presents a 5-year overall survival rate of 11%, placing an imperative need for the discovery and application of innovative treatments. Radiofrequency ablation represents a promising therapy for PDA, as studies show it induces coagulative necrosis and a host adaptive immune response. In this work we evaluated the effects of RFA treatment in vivo by establishing a syngeneic mouse model of PDA and performing tumor ablation in one flank. Our studies revealed RFA acutely impaired PDA tumor growth; however, such effects were not sustained one week after treatment. Adenosine (ADO) pathway represents a strong immunosuppressive mechanism that was shown to play a role in PDA progression and preliminary data from ongoing clinical studies suggest ADO pathway inhibition may improve therapeutic outcomes. Thus, to investigate whether ADO generation may be involved in tumor growth relapse after RFA, we evaluated adenosine-monophosphate (AMP), ADO and inosine (INO) levels by HPLC and found they were acutely increased after treatment. Thus, we evaluated an in vivo CD73 inhibition in combination with RFA to study ADO pathway implication in RFA response. Results showed combination therapy of RFA and a CD73 small molecule inhibitor (AB680) in vivo promoted sustained tumor growth impairment up to 10 days after treatment as evidenced by increased necrosis and anti-tumor immunity, suggesting RFA in combination with CD73 inhibitors may improve PDA patient response

A Composite Metric for Benchmarking Site Performance in TAVR: Results from the STS/ACC TVT Registry

Background: Transcatheter aortic valve replacement (TAVR) is a transformative therapy for aortic stenosis. Despite rapid improvements in technology and techniques, serious complications remain relatively common and are not well described by single outcome measures. The purpose of this study was to determine if there is site-level variation in TAVR outcomes in the United States using a novel 30-day composite measure. Methods: We performed a retrospective cohort study using data from the STS/ACC TVT Registry to develop a novel ranked composite performance measure that incorporates mortality and serious complications. The selection and rank order of the complications for the composite was determined by their adjusted association with 1-year outcomes. Sites whose risk-adjusted outcomes were significantly more or less frequent than the national average based on a 95% probability interval were classified as performing worse or better than expected. Results: The development cohort consisted of 52,561 patients who underwent TAVR between January 1, 2015 and December 31, 2017. Based on the associations with 1-year risk-adjusted mortality and health status, we identified four periprocedural complications to include in the composite risk model in addition to mortality. Ranked empirically according to severity, these included stroke, major, life-threatening or disabling bleeding, stage III acute kidney injury, and moderate or severe peri-valvular regurgitation. Based on these ranked outcomes, we found that there was significant site-level variation in quality of care in TAVR in the United States. Overall, better than expected site performance was observed in 25/301 (8%) of sites; performance as expected was observed in 242/301 sites (80%); and worse than expected performance was observed in 34/301 (11%) of sites. Thirty-day mortality, stroke, major, life-threatening or disabling bleeding, and moderate or severe peri-valvular leak were each substantially more common in sites with worse than expected performance as compared with other sites. There was good aggregate reliability of the model. Conclusions: There are substantial variations in the quality of TAVR care received in the United States, and 11% of sites were identified as providing care below the average level of performance. Further study is necessary to determine structural, process-related, and technical factors associated with high- and low-performing sites

ERK2 alone drives inflammatory pain but cooperates with ERK1 in sensory neuron survival

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP-mediated deletion of ERK2 in Na(v)1.8(+) sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Na(v)1.8(+) sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons. SIGNIFICANCE STATEMENT ERK1/2 signaling affects sensory neuron function and survival. However, it was not clear whether ERK isoform-specific roles exist in these processes postnatally. Previous work from our laboratory suggested either functional redundancy of ERK isoforms or a predominant role for ERK2 in pain; however, the tools to discriminate between these possibilities were not available at the time. In the present study, we use new genetic knock-out lines to demonstrate that ERK2 in sensory neurons is necessary for development of inflammatory pain and for postnatal maintenance of peptidergic epidermal innervation. Interestingly, postnatal loss of both ERK isoforms leads to a profound loss of sensory neurons. Therefore, ERK1 and ERK2 display both functionally distinct and redundant roles in sensory neurons

A Phase 2 Study of Nivolumab Combined With Ibrutinib in Patients With Diffuse Large B-Cell Richter Transformation of CLL

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912

Fuel lifecycle and long term fire behavior responses to fuel treatments in southeastern US pine ecosystems

We completed an investigation of the long term legacies of fuels treatments in longleaf pine sandhills at Eglin Air Force Base in the panhandle of Florida. From 1994-1999, The Nature Conservancy conducted a large-scale, long-term study at Eglin Air Force Base to compare the effectiveness of midstory reduction treatments, including herbicide, growing season fire, and mechanical clearing on the restoration of longleaf sandhill pine forests. The study plots have been monitored continuously since the completion of the original study and information still exists for all experimental sites, which have been burned as part of the prescribed fire program at Eglin AFB since the study concluded. We examined the legacy of these treatments on fire behavior 15+ years later in these plots. We measured multiple aspects of fuels and fire behavior in a subset of the original plots using a combination spatially explicit fuel sampling, high resolution visual and thermal imagery, wide and narrow field of view radiometers, thermocouples and thermopiles to collect data on fuel type, fuel loading, radiant and convective heat fluxes. We collected data in nine large operational prescribed fires that included the treatment plots in 2011. Preliminary data analyses showed that the impact of the treatments was not detectable in our measurements. The occurrence of frequent low intensity fires in the treatments appeared to have driven a convergence of fuel characteristics in plots with and without management interventions in as little as 16 years. Within stand variation in overstory derived fuels appeared to be more important in explaining fire behavior than the original treatments. We also completed an investigation of heat transfer in midstory oak stems. While these results are still being analyzed we found that in species with rough bark, heat transfer is much more complex and necessitates the consideration of three-dimensional information on bark topography and surface heating to develop accurate tissue damage models. The data we have collected will allow us to make those improvements. We also have developed a promising means (photogrammetry coupled with IR imagery) to rapidly capture the fine scale surface topography and heating of stems useful for improving such models

Fire Managers Field Guide: Hazardous Fuels Management in Subtropical Pine Flatwoods and Tropical Pine Rocklands

Preface This document, The Fire Managers Field Guide: Hazardous Fuels Management in Sub-tropical Pine Flatwoods and Tropical Pine Rocklands is intended to provide an overview of techniques and tactics under actual use for addressing hazardous fuels in tropical and subtropical pine forests found in Florida, the Bahamas and elsewhere in the Caribbean. The information presented here was distilled from peer reviewed literature, technical reports, and the experiences of on-theground fire managers. Managing fuels is complex and idiosyncratic. This guide is intended to provide only a broad introduction to currently available techniques; some well known and others newer and untested. The goal is to give the fuel manager options and food for thought, not to provide exact prescriptions for dealing with a specific fuel problem. A fire manager must always attend appropriate training and seek out guidance from colleagues and other experts before applying an unfamiliar treatment or experimenting with a new, untested combination of techniques

A Tumor Necrosis Factor-α-Inducible Promoter Variant of Interferon-γ Accelerates CD4+ T Cell Depletion in Human Immunodeficiency Virus-1-Infected Individuals

A polymorphism,—179G/T, in the promoter of the interferon (IFN)-γ gene (IFNG) confers differential tumor necrosis factor-α (TNF-α) inducibility to the IFNG =romoter. The rarer allele, −179T, but not −179G, is inducible by TNF-α.We investigated the effects of IFNG −179G/T on AIDS pathogenesis. In 298 African American human immunodeficiency virus (HIV)-1 seroconverters, the IFNG −179G/T genotype was associated with accelerated progression to CD4\u3c200 and AIDS-1993, a finding suggesting that IFNG −179T is a risk factor for AIDS progression, as measured by CD4 cell count. It is possible that increased IFN-γ production induced by TNF-α when −179T is present causes CD4 cell depletion by apoptosis