Landscape context is integral to population ecology, affecting a range of life history parameters, yet very little is known about how landscape structure influences many taxa. We sampled wetlands at ...531 sites across 16 states in the eastern U.S. to examine the influence of landscape heterogeneity and anthropogenic land use on the relative abundance of freshwater turtles, one of the most endangered vertebrate clades in the world. Specifically, we aimed to understand how two components of landscape structure — compositional heterogeneity (wetland diversity) and configurational heterogeneity (wetland aggregation) — influence turtles with varying life history traits. Our results suggest that wetland configuration can modulate the relationship between relative abundance and anthropogenic land use. For example, spotted turtle (Clemmys guttata) was negatively associated with hay/pasture cover when wetlands were less aggregated, but this relationship subsided as aggregation increased. Notably, the way wetland aggregation modulated land use relationships varied across species. These results suggest that some anthropogenic cover types are not strictly positive or negative for certain species, but are instead context-dependent. Relative abundance also generally increased with higher wetland diversity, indicating the potential importance of landscape supplementation for turtles. We report a range of responses to roads that did not strictly correspond with well-established predictions related to body size and terrestrial activity patterns, including positive associations for certain species. Overall, our study supports the use of context-driven approaches to land use-related conservation and management decisions rather than blanket prescriptions, and further emphasizes that effective conservation of freshwater systems requires a landscape-level perspective.
•Wetland configuration modulates the effect of land use on relative abundance.•Most turtle species displayed positive relationships with wetland diversity.•Effect of roads varied by species, with positive, negative, neutral relationships.
Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly ...vulnerable to TBI. The alpha7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of alpha7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in na#239;ve animals and healthy human subjects. Therefore, we hypothesized that targeting the alpha7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the alpha7 nAChR may be a novel therapeutic to improve cognition after TBI.
Xeno‐free, chemically defined poly(ethylene glycol) (PEG)‐based hydrogels are being increasingly used for in vitro culture and differentiation of human induced pluripotent stem cells (hiPSCs). These ...synthetic matrices provide tunable gelation and adaptable material properties crucial for guiding stem cell fate. Here, sequential norbornene‐click chemistries are integrated to form synthetic, dynamically tunable PEG–peptide hydrogels for hiPSCs culture and differentiation. Specifically, hiPSCs are photoencapsulated in thiol–norbornene hydrogels crosslinked by multiarm PEG–norbornene (PEG–NB) and proteaselabile crosslinkers. These matrices are used to evaluate hiPSC growth under the influence of extracellular matrix properties. Tetrazine–norbornene (Tz–NB) click reaction is then employed to dynamically stiffen the cell‐laden hydrogels. Fast reactive Tz and its stable derivative methyltetrazine (mTz) are tethered to multiarm PEG, yielding mono‐functionalized PEG‐Tz, PEG‐mTz, and dualfunctionalized PEG‐Tz/mTz that react with PEG–NB to form additional crosslinks in the cell‐laden hydrogels. The versatility of Tz‐NB stiffening is demonstrated with different Tz‐modified macromers or by intermittent incubation of PEG‐Tz for temporal stiffening. Finally, the Tz–NB‐mediated dynamic stiffening is explored for 4D culture and definitive endoderm differentiation of hiPSCs. Overall, this dynamic hydrogel platform affords exquisite controls of hydrogel crosslinking for serving as a xeno‐free and dynamic stem cell niche.
Dynamic cell‐laden hydrogels based on sequential thiol–norbornene (thiol–NB) photoclick and norbornene–tetrazine (NB–Tz) inverse electron‐demand Diels–Alder (iEDDA) reactions are developed for guiding proliferation and differentiation of induced‐pluripotent stem cell (iPSC). Pluripotency of iPSCs is maintained in a soft thiol–NB hydrogel, while dynamic stiffening via NB–Tz reaction alters the gel crosslinking density and enhances definitive endoderm differentiation of the encapsulated iPSCs.
Introduction. Cytokine release syndrome (CRS) and neurotoxicity (NT)(also known as immune effector cell-associated neurotoxicity syndrome or ICANS) are commonly observed after chimeric antigen ...receptor (CAR) T-cell therapy. While the clinical features of CRS have been extensively described, limited data exists for NT. Here, we report clinical and radiological features of NT after standard of care (SOC) axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (LBCL).
Methods. Pts with r/r LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 and 04/2019 were included in the study. All pts received anti-seizure prophylaxis with levetiracetam starting on the day of axi-cel infusion for 30 days. CRS and NT were prospectively graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018).
Association between continuous variables were assessed using the bivariate Pearson correlation.
Results. Ninety-five pts were included in the study, 72 (76%) with diffuse LBCL, 17 (18%) with transformed follicular lymphoma, and 6 (6%) with primary mediastinal LBCL. Median age was 60 (range, 18-85), 71 (75%) were male. Median number of previous therapies was 4 (range, 2-15), 26 (27%) had a previous autologous stem cell transplant (SCT), and 1 (1%) a previous allogeneic SCT. Eight (8%) pts had prior central nervous system lymphomatous involvement (parenchymal in 5), and 39 (41%) had prior neurological and/or psychiatric medical history. After axi-cel infusion, NT of any grade was observed in 65 (68%) pts, grade ³3 in 46 (48%)(Table). No significant association was observed between above outlined baseline characteristics and development of NT. Median time from axi-cel infusion to NT onset was 5 days (range, 0-25 days) and median duration was 6 days (range, 1-52 days); no new onset/recurrent NT was observed beyond day 30.
Among the 65 pts who developed NT, a CT head without contrast was performed in 48, and was not evaluable in 2 because of motion artifacts. Among the 46 evaluable scans, 1 (4%) was abnormal as compared to baseline, and showed new onset cortical edema (non-diffuse but symmetrical). An MRI brain with contrast was performed in 36 pts, but was not evaluable in 10 because of lack of baseline, motion artifacts or differences in imaging sequences. Among the 26 evaluable scans, 15 (58%) showed abnormal findings, including autoimmune encephalitis-like, characterized by symmetric white matter changes of the pons and hippocampus (6; Fig. A), stroke-like (4; Fig. B), LMD-like (3; Fig. C) and PRES-like (2; Fig. D), with concomitant cortical edema in 5. EEGs were performed in 52 pts (>1/pt, for a total of 116 EEGs) and were abnormal in 47 (90%). Focal and/or diffuse slowing was the most common abnormality (isolated finding in 35 73% pts), while epileptiform discharges and/or non-convulsive status epilepticus (NCSE) were observed 12 (27%) pts. A lumbar puncture was performed in 12 pts: median white blood cell count was 2 cells/µL (range, 0-6), median protein 47 mg/dL (range, 13-600), median glucose 69 mg/dL (range, 30-111), and cytology was positive for malignant cells in 2 (7%) pts. Convulsive seizure was observed in 4 (6%) pts and 10 (15%) received additional anti-seizure therapy for convulsive or non-convulsive seizures. Among the 65 pts with NT, dexamethasone up to 20 mg IV Q6H was given to 42 (65%) pts, methylprednisolone 1000 mg IV daily to 12 (18%), and tocilizumab to 64 (98%; during CRS or CRS with concurrent NT).
Overall, 93 (98%) pts developed CRS, grade >3 in 27 (28%). A significantly higher rate of NT of any grade (96% vs 57%, p<0.001) or grade >3 (81% vs 35%, p<0.001) was observed among pts with grade >3 CRS.
After a median follow-up of 4 months, 6-month progression-free (PFS) and overall survival (OS) rates were 60% and 65%, respectively. Significantly shorter 6-month PFS (46% vs 80%, p=0.02) and OS rates (56% vs 83%, p=0.01) were observed among pts developing NT of any grade.
Conclusions. Our results suggest that multiple radiological patterns of NT after axi-cel are possible in r/r LBCL pts, MRI being more sensitive than CT scan for their detection. NCSE is a common event, supporting the use of seizure prophylaxis and EEGs for evaluation of these pts. Pts with NT experience a worse outcome, and additional clinical and biological predictors of NT will be analyzed and presented at the meeting.
Display omitted
Nastoupil:Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria. Westin:47 Inc: Research Funding; Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Pinnix:Merck: Research Funding. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Neelapu:Precision Biosciences: Consultancy; Novartis: Consultancy; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy. Chi:Kite, A Gilead Company: Consultancy, Honoraria, Other: Kite Patient Management Advisory Board.
In response to the global shortage of Helium-3 gas, various alternative technologies have been developed for the detection of neutrons. Boron-10 (B-10) lined proportional counters represent one ...alternative that has been developed by GE Reuter-Stokes and deployed in applications such as Radiation Portal Monitors. The formulation of the B-10 coating used in these detectors was designed to maximize the content of B-10 in the coating, and the thickness of the coating was initially optimized to maximize the sensitivity of an individual detector in a thermal neutron field. Further study has indicated the optimal coating thickness for an assembly of detectors differs from that of an individual detector. Here, we report on the results of optimization of B-10 coating thickness for systems containing various numbers of detectors in various moderator configurations. In this work, the relationship between coating thickness, number of detectors, and moderator design is investigated using MCNP modeling and experimental data. The effectiveness of optimizing coating thickness at the system level is demonstrated experimentally for a commercially available radiation portal monitor neutron detection module.
Despite evidence from randomized trials that, compared with early thrombolysis, primary percutaneous transluminal coronary angioplasty (PTCA) after acute myocardial infarction (AMI) reduces mortality ...in middle-aged adults, whether elderly patients with AMI are more likely to benefit from PTCA or early thrombolysis is not known.
To determine survival after primary PTCA vs thrombolysis in elderly patients.
The Cooperative Cardiovascular Project, a retrospective cohort study using data from medical charts and administrative files.
Acute care hospitals in the United States.
A total of 20683 Medicare beneficiaries, who arrived within 12 hours of the onset of symptoms, were admitted between January 1994 and February 1996 with a principal discharge diagnosis of AMI, and were eligible for reperfusion therapy.
Thirty-day and 1-year survival.
A total of 80356 eligible patients had an AMI at hospital arrival and met the inclusion criteria, of whom 23.2% received thrombolysis and 2.5% underwent primary PTCA within 6 hours of hospital arrival. Patients undergoing primary PTCA had lower 30-day (8.7% vs 11.9%, P=.001) and 1-year mortality (14.4% vs 17.6%, P=.001). After adjusting for baseline cardiac risk factors and admission and hospital characteristics, primary PTCA was associated with improved 30-day (hazard ratio HR of death, 0.74; 95% confidence interval CI, 0.63-0.88) and 1-year (HR, 0.88; 95% CI, 0.73-0.94) survival. The benefits of primary coronary angioplasty persisted when stratified by hospitals' AMI volume and the presence of on-site angiography. In patients classified as ideal for reperfusion therapy, the mortality benefit of primary PTCA was not significant at 1-year follow-up (HR, 0.92; 95% CI, 0.78-1.08).
In elderly patients who present with AMI, primary PTCA is associated with modestly lower short- and long-term mortality rates. In the subgroup of patients who were classified as ideal for reperfusion therapy, the observed benefit of primary PTCA was no longer significant.
A unique how-to guide for spine surgeons on state-of-the-art computer-assisted navigation and robotic surgery techniques
The past decade has seen major advances in image-guided spine surgery ...techniques, with robotically assisted approaches emerging in the last five years. While early adopters of this technology paved the way for more widespread use of navigated and robotic systems, barriers still exist. Navigation and Robotics in Spine Surgery by master spine surgeon Alexander Vaccaro and esteemed co-editors Jaykar Panchmatia, I. David Kaye, and Srinivas Prasad addresses existing issues such as the perception of increased upfront costs, intrusion on current workflow, and a lack of understanding about the potential ways these technologies can enhance the surgical experience and improve patient outcomes.
Organized into six sections, the book starts with evidence-based fundamentals of navigated spine surgery and robotics including discussion of instrumentation and mechanics. Sections 2-5 serve as a surgical handbook for spine surgeons who wish to introduce these technologies into practice or augment their current repertoire with more complex techniques. Topics range from more routine procedures such as navigated and robotic minimally invasive TLIF to complex approaches like intraoperative ultrasound guided intradural spinal tumor resection. The final section looks at future directions and potential new applications for these technologies.
Key Highlights
*An impressive group of international spine surgeons who pioneered navigation and robotic surgery techniques share invaluable tricks of the trade
*Discussion of fluoroscopy- and intraoperative CT-based platforms, applications for intraoperative sonography, and radiation exposure and minimization strategies
*Special topics include OR set-up and workflow, surmounting the learning curve, artificial intelligence, and lessons learned from other industries
*Procedural videos demonstrate the benefits of computer-assisted navigation and robotic techniques
This book is essential reading for orthopaedic surgery and neurosurgery residents and spine fellows who wish to learn about and incorporate these technologies into practice. Seasoned spine surgeons seeking to expand the scope of their navigated/robotic practice will benefit from chapters detailing advanced approaches.
This book includes complimentary access to a digital copy on https://medone.thieme.com.
This dissertation is concerned with several problems of instrumentation and data analysis encountered by the Apache Point Observatory Lunar Laser-ranging Operation. Chapter 2 considers crosstalk ...between elements of a single-photon avalanche photodiode detector. Experimental and analytic methods were developed to determine crosstalk rates, and empirical findings are presented. Chapter 3 details electronics developments that have improved the quality of data collected by detectors of the same type. Chapter 4 explores the challenges of estimating gravitational parameters on the basis of ranging data collected by this and other experiments and presents resampling techniques for the derivation of standard errors for estimates of such parameters determined by the Planetary Ephemeris Program (PEP), a solar-system model and data-fitting code. Possible directions for future work are discussed in Chapter 5. A manual of instructions for working with PEP is presented as an appendix.
Abstract 3645
PI3Kδ drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kδ that has shown considerable monotherapy activity when ...given at dose levels of ≥100 mg BID in patients with heavily pretreated indolent non-Hodgkins lymphoma (iNHL).
This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 with rituximab and/or bendamustine in patients with previously treated iNHL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles (GS-1101/BR regimen). Initial cohorts received a GS-1101 dose of 100 mg/dose BID. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays.ParameterRegimenGS-1101/R N=30GS-1101/B N=33GS-1101/BR N=13Age, median range, years65 40–8459 38–8159 48–76Histology, %Follicular lymphoma707677Small lymphocytic lymphoma231815Marginal zone lymphoma768Patients with bulky* adenopathy, % (evaluable N)50 (30)53 (32)31 (13)Prior therapiesMedian range, n3 1–93 1–103 1–8Patients with prior R/B, %93/37100/21100/31Patients with refractory disease, %373946GS-1101 dosesPatients at 100 mg/dose BID, n87n/aPatients at 150 mg/dose BID, n222613GS-1101 median follow-up, weeks41 4–5228 4–5748 5–51Patients with grade ≥3 adverse eventsNeutropenia, %435246Anemia, %10158Thrombocytopenia, %7158Febrile neutropenia, %0120Infections, %7158Pneumonia/pneumonitis, %7330Rash, %10623Diarrhea, %10315Hepatic transaminase elevation, %13240Patients with decrease in adenopathy, % (evaluable N)97 (30)97 (32)100 (11)Maximum adenopathy change, median range, %(evaluable N)−74 −100 to 0 (30)−79 −100 to 58 (32)−88 −97 to −21 (11)Best on-treatment response rate, CR/PR/SD/PD/NE, % (total N)13/64/16/4/3 (30)16/69/9/3/3 (33)30/47/8/0/15 (13)Intent-to-Treat ORR, %7785771-Year PFS, %829078*≥1 node of ≥5 cm diameter
The study enrolled 76 patients with iNHL. Patient characteristics, histological sub-typing, safety, and efficacy results are depicted in the table.
The majority of patients were >60 years of age and had undergone extensive prior therapy. Grade ≥3 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid and all evaluable patients had reductions in lymphadenopathy, resulting in overall response rates (ORR) of 77%, 85%, and 77% for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens, respectively. Complete responses (with bone marrow confirmation) were observed in 13%, 16%, and 30% of patients. With median follow-up duration ranging from 28 to 48 weeks, 1-year progression- free survival (PFS) rates were >75% in all treatment groups. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment.
A lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with iNHL. GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy. All 3 regimens provide durable tumor control. The data from this trial support the development of Phase 3 combination trials of GS-1101 with rituximab- and/or bendamustine-containing regimens in patients with iNHL.
Fowler:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Phase I trial of GS-1101, a PI3K delta inhibitor, in B cell malignancies. de Vos:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Schreeder:Gilead Sciences: Research Funding. Leonard:Gilead: Consultancy. Coutre:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Sharman:Gilead: Honoraria, Research Funding. Boccia:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Jahn:Gilead: Employment. Miller:Gilead: Employment. Godfrey:Gilead Sciences: Employment.
PDF
