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Background and aims In 2017, the U.S. Food and Drug Administration (FDA) proposed to reduce nicotine in cigarettes to minimally or non-addictive levels. This study qualitatively explored perceptions of nicotine and addiction, both independently and in response to messages communicating about nicotine reduction. Design Qualitative study using focus groups. Participants described their perceptions of nicotine and addiction and their responses to messages about the nicotine reduction. Setting Atlanta, GA and San Francisco, CA, USA. Semi-structured focus groups were conducted virtually in Spring 2020. Participants Exclusive smokers (n=27), dual users (of cigarettes and electronic cigarettes) (n=25), former smokers (n=32), and young adult non-smokers (n=31). Measurement Inductive thematic analysis of transcripts was conducted, and results were compared across smoking status groups. Findings Participants across all smoking status groups associated nicotine with tobacco products, but consistently misperceived that nicotine caused disease. Perceptions of addiction were largely negative and varied by smoking status. Experienced smokers (exclusive smokers, former smokers, and dual users) differentiated tobacco use from other addictions and minimized their own experiences of addiction. Perceptions of addiction across experienced smokers included not only the chemical properties of nicotine, but also the behavioral aspects of tobacco use, including oral fixation, having a smoking routine, and response to internal and external cues. In response to messages, many believed that removing the nicotine would not make cigarettes less addictive because of the multi-factorial nature of smoking addiction that includes nonpharmacological cues. Conclusions Perceptions of nicotine and addiction among nonsmokers, former smokers, exclusive smokers and dual users of cigarettes and e-cigarettes vary based on smoking status, but there is a common tendency to believe that nicotine is addictive, that addiction results from more than just nicotine, and that very low nicotine cigarettes will not necessarily reduce the addictiveness of cigarettes.

There is a lack of normative data for children tested with the electronic Early Treatment for Diabetic Retinopathy Study (E-ETDRS) protocol. In the current cross-sectional study, the mean best-corrected normal and 95% lower tolerance limit for E-ETDRS visual acuity by year in children 7-12 years of age was measured. Our objective was to provide a large normative data set for E-ETDRS visual acuity in children for use in clinical management and clinical trials.

Depression in older adults is associated with decreased physical, cognitive, and social functioning, which in turn, are associated with increased mortality. Research has found that robust social networks can protect against depression, yet it is unclear whether the relationship between social ties and depression is reciprocal. Moreover, links between network connections at different social layers are not well understood. This study uses a representative sample with panel data collected between 2005 and 2016 to identify the influence of social network composition on subsequent depression and explore how various layers of human relationships (e.g., community vs. interpersonal level) influence one another. Results demonstrate multiple links between social connection and depression, and that the evolution of social networks in older adults is complex, with distinct mechanisms leading to positive and negative outcomes. Specifically, community involvement showed consistent benefits in reducing depression. In contrast, intimate partnerships appear to increase susceptibility to depression among older adults through exposure to the severe outcomes of partner loss. In addition, intimate partnerships reduce future interpersonal connections, whereas community involvement increases future interpersonal connections for older adults. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Significance We sought to identify baseline and clinical factors that were predictive of the response to amblyopia treatment. We report that binocular amblyopia treatment may be especially effective for moderate amblyopia in orthotropic children. Purpose We previously reported results from the primary cohort (n = 28) enrolled in a randomized clinical trial (NCT02365090), which found that binocular amblyopia treatment was more effective than patching. Enrollment of an additional 20 children was pre-planned to provide the opportunity to examine factors that may be predictive of response to amblyopia treatment. Methods Forty-eight children (4 to 10 years old) were enrolled, with 24 randomized to contrast-rebalanced binocular game treatment (1 hour a day, 5 days a week) and 24 to patching treatment (2 hours a day, 7 days a week). The primary outcome was change in amblyopic eye best-corrected visual acuity at the 2-week visit. Baseline factors examined were age at enrollment, visual acuity, stereoacuity, and suppression. Clinical factors were etiology, age at diagnosis, prior treatment, and ocular alignment. Results At 2 weeks, visual acuity improvement was significantly greater with the binocular game than patching. Children with moderate amblyopia and orthotropia had more visual acuity improvement with binocular game play than did those with severe amblyopia. In addition, children who spent more time playing the binocular game had more improvement. We were not able to confidently identify any baseline or clinical factors that were associated with response to patching treatment. Conclusions Binocular amblyopia treatment was more effective among orthotropic children with moderate amblyopia than among children with microtropia or severe amblyopia.

Hydrologists and water managers increasingly face challenges associated with extreme climatic events. At the same time, historic datasets for modeling contemporary and future hydrologic conditions are increasingly inadequate. Machine learning is one promising technological tool for navigating the challenges of understanding and managing contemporary hydrological systems. However, in addition to the technical challenges associated with effectively leveraging ML for understanding subsurface hydrological processes, practitioner skepticism and hesitancy surrounding ML presents a significant barrier to adoption of ML technologies among practitioners. In this paper, we discuss an educational application we have developed—Sandtank-ML—to be used as a training and educational tool aimed at building user confidence and supporting adoption of ML technologies among water managers. We argue that supporting the adoption of ML methods and technologies for subsurface hydrological investigations and management requires not only the development of robust technologic tools and approaches, but educational strategies and tools capable of building confidence among diverse users.

Structure-based docking screens of large compound libraries have become common in early drug and probe discovery. As computer efficiency has improved and compound libraries have grown, the ability to screen hundreds of millions, and even billions, of compounds has become feasible for modest-sized computer clusters. This allows the rapid and cost-effective exploration and categorization of vast chemical space into a subset enriched with potential hits for a given target. To accomplish this goal at speed, approximations are used that result in undersampling of possible configurations and inaccurate predictions of absolute binding energies. Accordingly, it is important to establish controls, as are common in other fields, to enhance the likelihood of success in spite of these challenges. Here we outline best practices and control docking calculations that help evaluate docking parameters for a given target prior to undertaking a large-scale prospective screen, with exemplification in one particular target, the melatonin receptor, where following this procedure led to direct docking hits with activities in the subnanomolar range. Additional controls are suggested to ensure specific activity for experimentally validated hit compounds. These guidelines should be useful regardless of the docking software used. Docking software described in the outlined protocol (DOCK3.7) is made freely available for academic research to explore new hits for a range of targets.

The ability of natural resource agencies to act before, during, and after outbreaks of conifer bark beetles (Coleoptera: Curculionidae) is important to ensure the continued provision of ecosystem services. Adaptive capacity refers to the capability of an agent or system to adapt to change, regardless of whether it is examined as an independent social or ecological entity, or as a coupled social–ecological system. Understanding the components of a disturbance and the associated effects to ecosystem services, social systems, and natural resource management increases the ability to adapt to change and ensure continued resilience. This paper presents a definition and conceptual framework of adaptive capacity relevant to bark beetle disturbances that was developed through an interdisciplinary workshop held in 2016. The intent is to assist natural resource managers and policy-makers in identifying important adaptation characteristics to effectively address bark beetle disturbances. The current state of knowledge regarding institutional, social, and environmental factors that influence adaptive capacity are identified. The mountain pine beetle (Dendroctonus ponderosae) in the western USA is used as a specific example to discuss several factors that influence adaptive capacity for increasing resilience. We hope that our proposed framework serves as a model for future collaborations among both social and physical scientists and land managers to better address landscape-level disturbances that are being exacerbated by climate change.

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Historically, medical students have received little training about working with patients with disability, but there is now a greater recognition of the need to educate medical students in this domain. The aims of this review were to define the body of literature and to determine effective strategies for teaching medical students about disability. A systematic search protocol executed across six databases identified journal articles reporting interventions implemented to teach disability to medical students. Seventy-seven articles spanning 1960-2018 met inclusion criteria. Most articles reported objectives related to increasing knowledge and skills or changing attitudes. However, only half included evaluations for all of their stated objectives in those domains. In addition, few articles used longitudinal evaluations, resulting in most articles basing conclusions on immediate posttest evaluations. Overall, the reported interventions exhibit a high risk of potential bias, with only 10% of the articles receiving a global quality rating of "good." Thus, although several articles have reported educational interventions to teach medical students about disability, the high risk of bias, incomplete reporting, and limitations of the evaluations prevent evidence-based determinations of effective strategies for teaching medical students about disability. The findings highlight ways to improve future studies in this domain.

Current point cloud processing algorithms do not have the capability to automatically extract semantic information from the observed scenes, except in very specialized cases. Furthermore, existing mesh analysis paradigms cannot be directly employed to automatically perform typical shape analysis tasks directly on point cloud models. We present a potent framework for shape analysis, similarity, and segmentation of noisy point cloud models for real objects of engineering interest, models that may be incomplete. The proposed framework relies on spectral methods and the heat diffusion kernel to construct compact shape signatures, and we show that the framework supports a variety of clustering techniques that have traditionally been applied only on mesh models. We developed and implemented one practical and convergent estimate of the Laplace-Beltrami operator for point clouds as well as a number of clustering techniques adapted to work directly on point clouds to produce geometric features of engineering interest. The key advantage of this framework is that it supports practical shape analysis capabilities that operate directly on point cloud models of objects without requiring surface reconstruction or global meshing. We show that the proposed technique is robust against typical noise present in possibly incomplete point clouds, and segment point clouds scanned by depth cameras (e.g. Kinect) into semantically-meaningful sub-shapes., 21 pages, 20 figures. To appear in The Journal of Computer Aided Geometric Design's Special Issue on Heat Diffusion Equation and Optimal Transport in Geometry Processing and Computer Graphics

Background Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. Methods A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. Results A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference –0.20, 95 per cent confidence interval (C.I.) –2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference –4.5 (C.I. –8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. Conclusion The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

Background Binocular neural architecture may be preserved in children with deprivation amblyopia due to unilateral cataract. The purpose of this study was to investigate whether a contrast-rebalanced binocular treatment, recently used with success to treat the interocular suppression and amblyopia in strabismic and anisometropic children, can contribute to rehabilitation of visual acuity in children with deprivation amblyopia secondary to monocular cataract. Methods In a pilot randomized trial, 15 children (4-13 years of age) were enrolled and randomized to continue with their current treatment only (n = 7) or to continue with their current treatment and add contrast-rebalanced binocular iPad game play 5 hours/week for 4 weeks (n = 8). The primary outcome was change in visual acuity at 4 weeks. Results Although 10 of 15 participants were patching, there was little change in visual acuity during the 3 months prior to enrollment. At the 4-week primary outcome visit, the mean improvement in visual acuity for the binocular game group was significantly greater than that for the current-treatment group (0.08 ± 0.10 logMAR vs −0.03 ± 0.05 logMAR [t10.2 = 2.53, P = 0.03]). None of the children who had dense congenital cataract achieved improved visual acuity with binocular treatment. Conclusions In this study cohort, visual acuity improved over 8 weeks in children with unilateral deprivation amblyopia who played a binocular contrast-rebalanced binocular iPad game.

A present goal of the Conservation Reserve Program (CRP) is to manage land in agricultural landscapes to increase pollinator abundance and diversity. CP42, or the pollinator seed mix, is planted and managed to support foraging pollinators with blooming flowers present at all points in the foraging season. This high-quality habitat provides an excellent opportunity to study honey bee nutrition and determine whether honey bees located near CRP sites use known resources included in planting seed mixes. This study aims to highlight the primary sources of honey bee forage in the northern Midwest as well as to assess honey bee utilization of the floral resources provided by the pollinator seed mix used for CRP plantings. We received pollen samples collected using pollen traps by beekeepers in Ohio, South Dakota, Indiana, Illinois, and Michigan. Metabarcoding methods were used to identify and quantify pollen collected at different points in the season. The results indicate that honey bees frequently used major mass flowering resources such as Glycine, Trifolium, and Symphiotrichum throughout the season. In addition, flowers included in the CRP pollinator seed mix were used modestly. These results have implications for pollinator seed mix design.

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

The Integrated Groundwater Modeling Center is a small research center with a focus on hydrological research and a mission to develop and promote education and outreach in our community. We believe that students of all ages learn better when learning is fun, social, and hands-on. We strive to develop games that will immerse and educate users in geoscience concepts by collaborating closely with computer scientists and software engineers. For the work presented here, we have partnered with the University of Arizona and Kitware, Inc., blending technologies and expertise to develop a game to teach hydrogeology concepts.We have developed an interactive computer simulation of a physical teaching model for students. This computer simulation has a game-like web browser-based interface but builds upon open source software components developed by Kitware (e.g. ParaView and SimPut) executing the integrated hydrology model ParFlow, using a framework built upon the widely used Python scripting language. Students run the simulation using a familiar web-app like interface with sliders and buttons yet are learning real hydrologic concepts and can compare to the physical model. Here, we will present this interactive toolkit and the physical sand tank aquifer model on which it’s based.

BACKGROUND: Use of a microsensor has been suggested to monitor patching adherence. Application has been limited because the microsensor’s small size makes it easy to lose and a swallowing risk. We designed the Eye Patch Assistant (EPA) to hold the small microsensor in place and reduce the risk of loss or swallowing. This study reports the accuracy, precision, ease of use, and comfort for patching with EPA (patch+EPA) to monitor adherence. METHODS: Adults (N = 13) wore an adhesive patch alone or a patch+EPA for 2 hours each, recorded wear time, and completed an ease of use/comfort questionnaire; 30 children wore a patch or patch+EPA and completed the questionnaire. Sensor sampling interval was every 5 minutes or every 1 minute. Sensor accuracy and precision were evaluated by Bland-Altman analysis and 95% limits of agreement, and questionnaire scores compared by Wilcoxon tests. RESULTS: With 5-minute sampling, we found excellent accuracy for adults (mean actual vs recorded time difference, 1.4 minutes) and children (mean difference, −0.9 min). We found high precision for both adults and children (95% limits of agreement half widths of 6.4 minutes and 1.9 minutes, respectively). In adults, the ease of use score for the patch+EPA was lower than the patch (P < 0.01), but the comfort score for the patch+EPA was higher (P < 0.01). For children, scores did not differ significantly. The patch+EPA functioned well between 45° and 82°F. CONCLUSIONS: The patch+EPA was well accepted and monitored adherence accurately and precisely.

Background Reading relies on ocular motor function, requiring sequential eye movements (forward and regressive saccades). Binocularly discordant input from a dense congenital or infantile cataract is associated with ocular motor dysfunction and may affect the development of reading ability. The purpose of this study was to assess silent, binocular reading in children treated for unilateral congenital or infantile cataract. Methods Twenty school-age children (age range, 7-13 years) treated for unilateral congenital (n = 9) or infantile (n = 11) cataract and 49 age-similar control children silently read a grade-appropriate paragraph during binocular viewing. Reading rate (words/min) and the number of forward and regressive saccades (per 100 words) were recorded using the ReadAlyzer. Results Reading rate in children treated for a unilateral cataract did not differ significantly from controls (174 ± 59 words/min vs 195 ± 54 words/min; P = 0.1). However, they did have significantly more forward saccades (101 ± 33 saccades/100 words vs 87 ± 21 saccades/100 words; P = 0.03) but not regressive saccades (21 ± 14 saccades/100 words vs 16 ± 8 saccades/100 words; P = 0.1) compared with controls. Reading rate was not related to cataract type (congenital vs infantile), visual acuity outcome (poor vs good), or sensory fusion (fail vs pass; all P ≥ 0.1). Conclusions Reading rate of children treated for a dense unilateral cataract did not differ from that of controls. Increased forward saccades during reading may be due to fixation instability associated with fusion maldevelopment nystagmus prevalent in children following cataract extraction.

The HydroFrame project is a community platform designed to facilitate integrated hydrologic modeling across the US. As a part of HydroFrame, we seek to design innovative workflow solutions that create pathways to enable hydrologic analysis for three target user groups: the modeler, the analyzer, and the domain science educator. We present the initial progress on the HydroFrame community platform using an automated Kepler workflow. This workflow performs end-to-end hydrology simulations involving data ingestion, preprocessing, analysis, modeling, and visualization. We demonstrate how different modules of the workflow can be reused and repurposed for the three target user groups. The Kepler workflow ensures complete reproducibility through a built-in provenance framework that collects workflow specific parameters, software versions, and hardware system configuration. In addition, we aim to optimize the utilization of large-scale computational resources to adjust to the needs of all three user groups. Towards this goal, we present a design that leverages provenance data and machine learning techniques to predict performance and forecast failures using an automatic performance collection component of the pipeline.

This article examines the distribution and correlates of mass attitudes toward the privatization of US military operations. Relying on insights from principal–agent theory, we form predictions abou...

In western Micronesia, sea levels are rising at three to four times the global average, saltwater intrusion is impacting freshwater supplies and food production, and local cultures are being forced to respond. Yap State, Federated States of Micronesia (9.5N, 138E), consists of a cluster of four main islands (MI) and 14 coral atolls and smaller outer islands (OI) spread over 400,000 km2 of ocean. This paper examines three aspects of Yap State’s adaptive capacity to climate change impacts: 1) differences in environmental conditions between the MI and OI; 2) relevant features of the MI’s cultural heritage; and 3) relevant features of OI’s cultural heritage, including values and practices surrounding the sawei system relationship. Cultural support networks in both the MI and OI will almost certainly be relied upon to lessen the severity of climate change impacts, perhaps especially as more OI residents relocate to the MI. More research is needed to document how features of intangible cultural heritage that create and maintain social resilience in Yap State will shape residents’ adaptive capacity to climate change.

Treatment guidelines for Clostridium difficile infection (CDI) are limited by a lack of widely accepted clinical prediction tools (CPTs). Two published CPTs, the Velazquez-Gomez Severity Score Index (VGSSI) and ATLAS scores, were evaluated, and variables showing the greatest correlation with mortality in patients with CDI were identified to further develop an objective, mortality-based CPT. A retrospective review of the charts of 271 hospitalized patients with CDI was performed. VGSSI and ATLAS scores were assigned. Means and correlations of these scores with mortality were evaluated. Multivariate logistic regression analysis was performed on 32 known potential mortality predictor variables. Mortality was overall strongly associated with VGSSI and ATLAS scores with poor correlation within the intermediate ranges. Mean scores for nonsurvivors indicated poor calibration. The variables most associated with mortality were Age, vasopressors, steroids, creatinine level, and albumin. Although both CPTs revealed the ability to discriminate patients at greater risk for mortality, precision and overall calibration were lacking. Five variables were identified which had the greatest correlation with mortality. Utilization of these variables to enhance or modify the existing CPTs is suggested as the next step in the development of a useful and accurate mortality-based CPT for the treatment of CDI.

We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin ≥2 weeks before leukapheresis and continue for ≥3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with and without concurrent ibrutinib, respectively (P = .91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with low CRS severity, and led to high rates of MRD-negative response by IGH sequencing.

Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. We report efficacy and long-term follow-up of 21 patients with relapsed/refractory (R/R) FL (n = 8) and tFL (n = 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 × 106 CD19-directed chimeric antigen receptor–modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ≥3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617.

BACKGROUND: Binocular amblyopia treatments promote visual acuity recovery and binocularity by rebalancing the signal strength of dichoptic images. Most require active participation by the amblyopic child to play a game or perform a repetitive visual task. The purpose of this study was to investigate a passive form of binocular treatment with contrast-rebalanced dichoptic movies. METHODS: A total of 27 amblyopic children, 4–10 years of age, wore polarized glasses to watch 6 contrast-rebalanced dichoptic movies on a passive 3D display during a 2-week period. Amblyopic eye contrast was 100%; fellow eye contrast was initially set to a lower level (20%−60%), which allowed the child to overcome suppression and use binocular vision. Fellow eye contrast was incremented by 10% for each subsequent movie. Best-corrected visual acuity, random dot stereoacuity, and interocular suppression were measured at baseline and at 2 weeks. RESULTS: Amblyopic eye best-corrected visual acuity improved from 0.57 ± 0.22 at baseline to 0.42 ± 0.23 logMAR (t(26) = 8.09; P < 0.0001; 95% CI for improvement, 0.11–0.19 logMAR). Children aged 3–6 years had more improvement (0.21 ± 0.11 logMAR) than children aged 7–10 years (0.11 ± 0.06 logMAR; t(25) = 3.05; P = 0.005). Children with severe amblyopia (≥0.7 logMAR) at baseline experienced greater improvement (0.24 ± 0.12 logMAR) than children with moderate amblyopia at baseline (0.12 ± 0.06 logMAR; t(25) = 3.49; P = 0.002). CONCLUSIONS: In this cohort, passive viewing of contrast-rebalanced dichoptic movies effectively improved visual acuity in amblyopic subjects. The degree of improvement observed was similar to that previously reported for 2 weeks of binocular games treatment and with 3–4 months of occlusion therapy.

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Annual allocations of bilateral and multilateral humanitarian assistance to conflict-affected states total billions of dollars each year. Humanitarian assistance plays a vital role in sustaining vulnerable populations. However, inflows of such aid may also exacerbate violence by both threatening insurgents and creating incentives for these groups to extend or deepen control over the areas in which aid is concentrated. Insurgent efforts to ameliorate threats and co-opt resources ultimately raise the risk of conflict between insurgent and counterinsurgent forces. We use recently constructed geo-located data on both aid commitments and conflict events in a sample of twenty sub-Saharan African countries during the post–Cold War era to evaluate the impact of aid on violence. Even after accounting for the non-random assignment of aid within conflict zones, we find that humanitarian aid increases the frequency of subsequent violent engagements between rebel and government forces in the areas in which aid is concentrated. Importantly, however, we find no evidence that other forms of foreign development aid exacerbate or prolong violence in the areas in which they are allocated.

Summary Objectives: To review the history of clinical information systems over the past twenty-five years and project anticipated changes to those systems over the next twenty-five years. Methods: Over 250 Medline references about clinical information systems, quality of patient care, and patient safety were reviewed. Books, Web resources, and the author’s personal experience with developing the HELP system were also used. Results: There have been dramatic improvements in the use and acceptance of clinical computing systems and Electronic Health Records (EHRs), especially in the United States. Although there are still challenges with the implementation of such systems, the rate of progress has been remarkable. Over the next twenty-five years, there will remain many important opportunities and challenges. These opportunities include understanding complex clinical computing issues that must be studied, understood and optimized. Dramatic improvements in quality of care and patient safety must be anticipated as a result of the use of clinical information systems. These improvements will result from a closer involvement of clinical informaticians in the optimization of patient care processes. Conclusions: Clinical information systems and computerized clinical decision support have made contributions to medicine in the past. Therefore, by using better medical knowledge, optimized clinical information systems, and computerized clinical decision, we will enable dramatic improvements in both the quality and safety of patient care in the next twenty-five years.

Natural disasters often cause significant human suffering. They may also provide incentives for states to escalate repression against their citizens. We argue that state authorities escalate repression in the wake of natural disasters because the combination of increased grievances and declining state control produced by disasters creates windows of opportunity for dissident mobilization and challenges to state authority. We also investigate the impact of the post-disaster humanitarian aid on this relationship. Specifically, we argue that inflows of aid in the immediate aftermath of disasters are likely to dampen the impact of disasters on repression. However, we expect that this effect is greater when aid flows to more democratic states. We examine these interrelated hypotheses using cross-national data on immediate-onset natural disasters and state violations of physical integrity rights between 1977 and 2009 as well as newly collected foreign aid data disaggregated by sector. The results provide support for both our general argument and the corollary hypotheses.

Purpose To determine the specificity of the Pediatric Vision Scanner, a binocular retinal birefringence scanner, in its intended setting, a pediatric primary care office. Methods A total of 102 preschool children (age 2-6 years) were screened during a well-child pediatric visit using the Pediatric Vision Scanner and the SureSight Autorefractor and completed a masked comprehensive pediatric ophthalmic examination (gold standard examination). Results Based on the gold standard examination, one child had anisometropic amblyopia, and the remaining 101 had no amblyopia or strabismus. Specificity of the Pediatric Vision Scanner was 90% (95% CI, 82%-95%) while specificity of the SureSight was 87% (95%CI, 79-93%). Combining these results with the sensitivity of the devices determined in our previous study conducted in a pediatric ophthalmology office setting, the positive likelihood ratio for the Pediatric Vision Scanner was 10.2; for the SureSight, 5.0. The negative likelihood ratio for the Pediatric Vision Scanner was 0.03; for the SureSight, 0.42, a significant difference. Conclusions The Pediatric Vision Scanner had high specificity (90%) in screening for amblyopia and strabismus as part of a pediatric well-child visit. Likelihood ratio analysis suggests that affected children have a high probability of being correctly identified by the Pediatric Vision Scanner. The high level of confidence conferred by Pediatric Vision Scanner screening may remove an important barrier to vision screening in pediatric primary care.

Background Recent evidence suggests that amblyopia results in fixation instability and atypical saccades. Reading is a vision-reliant ability that requires sequential eye movements, including forward and regressive saccades. This study investigated reading and associated eye movements in school-age amblyopic children. Methods Amblyopic children with strabismus and/or anisometropia (n = 29) were compared to nonamblyopic children treated for strabismus (n = 23) and normal control children (n = 21). While fitted with the ReadAlyzer, an eye movement recording system, children silently read a grade-level paragraph of text during binocular viewing. Reading rate, number of forward and regressive saccades per 100 words, and fixation duration were determined. Comprehension was evaluated with a 10-item quiz; only data from children with at least 80% correct responses were included. Results Amblyopic children read more slowly and had more saccades compared with nonamblyopic children with treated strabismus and normal controls. Fixation duration did not differ significantly for amblyopic children versus normal controls. Treated strabismic children without amblyopia did not differ significantly from normal controls on any reading measure. Amblyopic eye visual acuity was not correlated with any reading measure. Conclusions Amblyopia was associated with slower reading speed in school-age children. Treatment for monocular amblyopia visual acuity impairment could improve reading speed and efficiency.

BACKGROUND: Most clinical trials of contrast-rebalanced binocular amblyopia treatment used a contrast increment protocol of 10% daily with successful play. Paired with a definition of success requiring only 15–30 min/day of gameplay, this increment protocol could allow children to reach 100% fellow eye contrast in 3–9 hours; however, this may not provide adequate therapeutic time with reduced fellow eye contrast. The purpose of this study was to compare the original protocol against three alternative contrast increment protocols designed to increase the number of treatment hours. METHODS: In this prospective study, 63 amblyopic children (4–10 years; amblyopic eye visual acuity, 20/40-125) were randomly assigned one of four daily contrast increment protocols for 4 weeks, all starting with 20% fellow eye contrast: 10%, 5%, 0%, or 10% for first 4 weeks then reset to 20% and repeat 10% increment for the final 4 weeks. Children played contrast-rebalanced games for 1 hour/day, 5 days/week. Best-corrected visual acuity, stereoacuity, and suppression were assessed at baseline and every 2 weeks until the 8-week outcome visit. RESULTS: At baseline, mean amblyopic eye best-corrected visual acuity was 0.47 ± 0.14 logMAR (20/60), improving overall 0.14 ± 0.08 logMAR (1.4 lines; P < 0.0001) at 8 weeks. All four protocols resulted in similar improvement in visual acuity (0.13–0.16 logMAR; all Ps < 0.0002). Stereoacuity and suppression also improved (all Ps < 0.05). CONCLUSIONS: None of the new protocols resulted in less improvement than the original 10% contrast increment protocol. Contrast-rebalanced binocular games yielded significant improvements in visual acuity, stereoacuity, and suppression with or without daily contrast increments.

Highlights • Studied the role of social distancing in mental health during the COVID-19 pandemic. • Stay-at-home orders associated with depression, GAD, insomnia, and acute stress. • Distancing behavior associated with depression, GAD, intrusive thoughts, and stress. • Depression and GAD symptoms increased between February and March 2020. • Symptom increases were associated with individuals’ social distancing behavior., Social distancing is the most visible public health response to the COVID-19 pandemic, but its implications for mental health are unknown. In a nationwide online sample of 435 U.S. adults, conducted in March 2020 as the pandemic accelerated and states implemented stay-at-home orders, we examined whether stay-at-home orders and individuals’ personal distancing behavior were associated with symptoms of depression, generalized anxiety disorder (GAD), intrusive thoughts, insomnia, and acute stress. Stay-at-home order status and personal distancing were independently associated with higher symptoms, beyond protective effects of available social resources (social support and social network size). A subsample of 118 participants who had completed symptom measures earlier in the outbreak (February 2020) showed increases in depression and GAD between February and March, and personal distancing behavior was associated with these increases. Findings suggest that there are negative mental health correlates of social distancing, which should be addressed in research, policy, and clinical approaches to the COVID-19 pandemic.

Background Little is known about the availability and technical quality of online information related to the medical care of people with disability, despite the potential of this information to alter clinical interactions and treatment decisions. Objectives This review examines the utility of internet search engines for finding information related to medical care for people with disability, identifies common sources of this online information, and assesses the presence of technical attributes which allow for its critical evaluation. Methods Exhaustive systematic searches were conducted on two popular search engines (Google and Yahoo) using six search phrases. Resources were coded to categorize presenting organization, format, and technical quality. Results Only 8.9% of results included information related to medical care for people with disability. Analyzed resources were most often from non-profit organizations (31.7%) in website format (60.2%). The composite technical quality score for all included resources had a median and mode of three on a scale of six. Conclusions Online information related to medical care for people with disability is not only difficult to locate, but has generally low technical quality. These findings have implications for health information professionals, patients, care providers, and information developers.

Li-ion batteries currently dominate electrochemical energy storage for grid-scale applications, but there are promising aqueous battery technologies on the path to commercial adoption. Though aqueous batteries are considered lower risk, they can still undergo problematic degradation processes. This perspective details the degradation that aqueous batteries can experience during normal and abusive operation, and how these processes can even lead to cascading failure. We outline methods for studying these phenomena at the material and single-cell level. Considering reliability and safety studies early in technology development will facilitate translation of emerging aqueous batteries from the lab to the field.

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795

Background CD19 CAR T immunotherapy has been successful in achieving durable remissions in some patients with relapsed/refractory B cell lymphomas, but disease progression and loss of CAR T cell persistence remains problematic. Interleukin 15 (IL-15) is known to support T cell proliferation and survival, and therefore may enhance CAR T cell efficacy, however, utilizing native IL-15 is challenging due to its short half-life and poor tolerability in the clinical setting. NKTR-255 is a polymer-conjugated IL-15 that retains binding affinity to IL15Rα and exhibits reduced clearance, providing sustained pharmacodynamic responses. We investigated the effects of NKTR-255 on human CD19 CAR T cells both in vitro and in an in vivo xenogeneic B cell lymphoma model and found improved survival of lymphoma bearing mice receiving NKTR-255 and CAR T cells compared to CAR T cells alone. Here, we extend upon these findings to further characterize CAR T cells in vivo and examine potential mechanisms underlying improved anti-tumor efficacy. Methods CD19 CAR T cells incorporating 4-1BB co-stimulation were generated from CD8 and CD4 T cells isolated from healthy donors. For in vitro studies, CAR T cells were incubated with NKTR-255 or native IL-15 with and without CD19 antigen. STAT5 phosphorylation, CAR T cell phenotype and CFSE dilution were assessed by flow cytometry and cytokine production by Luminex. For in vivo studies, NSG mice received 5x105 Raji lymphoma cells IV on day (D)-7 and a subtherapeutic dose (0.8x106) of CAR T cells (1:1 CD4:CD8) on D0. To determine optimal start date of NKTR-255, mice were treated weekly starting on D-1, 7, or 14 post CAR T cell infusion. Tumors were assessed by bioluminescence imaging. Tumor-free mice were re-challenged with Raji cells. For necropsy studies mice received NKTR-255 every 7 days following CAR T cell infusion and were euthanized at various timepoints post CAR T cell infusion. Results Treatment of CD8 and CD4 CAR T cells in vitro with NKTR-255 resulted in dose dependent STAT5 phosphorylation and antigen independent proliferation. Co-culture of CD8 CAR T cells with CD19 positive targets and NKTR-255 led to enhanced proliferation, expansion and TNFα and IFNγ production, particularly at lower effector to target ratios. Further studies showed that treatment of CD8 CAR T cells with NKTR-255 led to decreased expression of activated caspase 3 and increased expression of bcl-2. In Raji lymphoma bearing NSG mice, administration of NKTR-255 in combination with CAR T cells increased peak CAR T cell numbers, Ki-67 expression and persistence in the bone marrow compared to mice receiving CAR T cells alone. There was a higher percentage of EMRA like (CD45RA+CCR7-) CD4 and CD8 CAR T cells in NKTR-255 treated mice compared to mice treated with CAR T cells alone and persistent CAR T cells in mice treated with NKTR-255 were able to reject re-challenge of Raji tumor cells. Additionally, starting NKTR-255 on D7 post T cell infusion resulted in superior tumor control and survival compared to starting NKTR-255 on D-1 or D14. Conclusion Administration of NKTR-255 in combination with CD19 CAR T cells leads to improved anti-tumor efficacy making NKTR-255 an attractive candidate for enhancing CAR T cell therapy in the clinic. Disclosures Chou: Nektar Therapeutics: Other: Travel grant. Fraessle:Technical University of Munich: Patents & Royalties. Busch:Juno Therapeutics/Celgene: Consultancy, Equity Ownership, Research Funding; Kite Pharma: Equity Ownership; Technical University of Munich: Patents & Royalties. Miyazaki:Nektar Therapeutics: Employment, Equity Ownership. Marcondes:Nektar Therapeutics: Employment, Equity Ownership. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; Lyell Immunopharma: Equity Ownership, Patents & Royalties, Research Funding. Turtle:Allogene: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member.

Background CD19-targeted chimeric antigen receptor-engineered (CD19 CAR)-T cell immunotherapy has shown promising efficacy in patients with relapsed or refractory (R/R) B-cell malignancies. The potential benefits of repeat infusions of CD19 CAR-T cells are unknown, and the factors associated with response, CAR-T cell in vivo expansion, and progression-free survival (PFS) after repeat infusion of CD19 CAR-T cells have not been investigated. Methods We analyzed the outcomes of patients with R/R B-cell malignancies after a second infusion of CD19 CAR-T cells (CART2) on a phase 1/2 trial (NCT01865617) at our institution. Responses after CAR-T cell therapy were evaluated around day 28 after infusion and defined according to the 2018 NCCN guidelines for acute lymphoblastic leukemia (ALL), 2018 iwCLL for chronic lymphocytic leukemia (CLL), and the Lugano criteria for non-Hodgkin lymphoma (NHL). Logistic, Cox and linear regression were used for multivariable analyses of response, progression-free survival and peak CD8+ CAR-T in blood, respectively. Bayesian model averaging was performed for variable selection. Results Forty-four patients evaluable for response (ALL, n=14; CLL, n=11; NHL, n=19) were included in this study. The median age at the time of CART2 was 58 (range, 23-73). Patients were heavily pre-treated (median prior therapies, 6; range, 2-13), and 16 patients (36%) had bulky (≥ 5cm) nodal or extramedullary disease. The median time from the first CAR-T infusion (CART1) to CART2 was 70 days (range, 28-712). Twenty-eight patients (64%) had received a CART1 dose ≥ 2x106 CAR-T cells/kg. Fifteen patients (32%) had not responded to CART1, 22 (50%) relapsed or progressed after having initially responded (complete response [CR], n=15; partial response [PR], n=7) to CART1; 7 (16%) received CART2 in PR after CART1. All characteristics are shown in the Table. We observed responses in all disease types, including 3 of 14 ALL patients (21%; all CR/CRi), 4 of 11 CLL patients (36%; CR/CRi, n=3; partial response [PR], n=1), and 9 of 19 NHL patients (47%; CR, n=2; PR, n=7). After a median follow-up of 43 months (range, 16-66) in alive and responding patients, the estimated 4-year PFS probability in responders was 23% (95% CI, 9-59%). The 4-year overall survival probability in responders was 36% (95% CI 19-71%) compared to 24% (95% CI, 12-47) in non-responders. Multivariable logistic regression modeling identified predictors of response after CART2: CART1 lymphodepletion (high-intensity cyclophosphamide and fludarabine [CyFlu] vs no CyFlu, OR=12.19, 95% CI, 1.10-1689.85, p=0.04), and peak of in vivo CAR-T cell expansion after CART2 (OR=2.31 per log10 CD8+ CAR-T cell/µL increase, 95% CI, 1.17-5.29, p=0.01). In a multivariable Cox model, a higher peak of CD8+ CAR-T cells after CART2 (HR=0.47 per log10 CD8+ CAR-T cell/µL increase, 95%CI, 0.33-0.68, p CART1 cell dose was associated with longer PFS (HR=0.36, 95% CI, 0.16-0.86, p=0.02). This suggested that CD8+ CAR-T cell peak after CART2 and factors increasing CART2 peak (e.g. prevention of immune rejection or increase in the infused cell dose) are key elements associated with outcomes of CART2. Hence, we looked at factors associated with higher CD8+ CART2 peak. In multivariable linear regression, CART1 CyFlu predicted a higher peak of CD8+ CAR-T cells after CART2 (high-intensity CyFlu vs no CyFlu, p CyFlu being the most commonly used lymphodepletion prior to CAR-T cell therapy, we evaluated the impact of CART1 CyFlu lymphodepletion intensity by comparing high-intensity to low-intensity CyFlu in our multivariable models. Logistic regression suggested higher probabilities of response to CART2 in patients who received high-intensity compared to low-intensity CyFlu prior to CART1 (OR=3.83, 95%CI, 0.85-21.83, p=0.08). In multivariable analysis, CART1 high-intensity CyFlu was associated with higher CD8+ CAR-T cell numbers at day 60 after CART2 compared to low-intensity CyFlu (p=0.01) after adjusting for disease type and total CD19+ cell count in the blood. Conclusion Our findings suggest outcomes after second infusions of CD19 CAR-T cells might be improved with high-intensity CyFlu lymphodepletion prior to CART1 and by increasing the CAR-T cell dose at the time of CART2. Table Disclosures Hirayama: DAVA Oncology: Honoraria. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Rocket Pharma: Consultancy, Equity Ownership; Homology Medicines: Consultancy, Equity Ownership; CSL Behring: Consultancy; Magenta Therapeutics: Consultancy. Shadman:Mustang Biopharma: Research Funding; Gilead: Research Funding; Bigene: Research Funding; AstraZeneca: Consultancy; Merck: Research Funding; Atara: Consultancy; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; TG Therapeutics: Research Funding; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; Lyell Immunopharma: Equity Ownership, Patents & Royalties, Research Funding. Maloney:BioLine RX, Gilead,Genentech,Novartis: Honoraria; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; Celgene,Kite Pharma: Honoraria, Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Allogene: Other: Ad hoc advisory board member; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; T-CURX: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member.

Purpose Strabismus or anisometropia disrupts binocularity and results in fixation instability, which is increased with amblyopia. Fixation instability has typically been assessed for each eye individually. Recently, vergence instability was reported in exotropic adults and monkeys during binocular viewing. We evaluated fixation instability during binocular viewing in children treated for anisometropia and/or strabismus. Methods 160 children age 4–12 years with treated esotropia and/or anisometropia (98 amblyopic, 62 nonamblyopic) were compared to 46 age-similar controls. Fixation instability was recorded during binocular fixation of a 0.3 deg diameter dot for 20 s using a 500 Hz remote video binocular eye tracker (EyeLink 1000; SR Research). The bivariate contour ellipse area (BCEA; log deg2) for fixation instability was calculated for each eye (nonpreferred, preferred) and for vergence instability (left eye position – right eye position). Best-corrected visual acuity, Randot Preschool stereoacuity, and extent of suppression scotoma (Worth 4-Dot) were also obtained. Results When binocularly viewing, both amblyopic and nonamblyopic children treated for anisometropia and/or strabismus had larger fixation instability and vergence instability than controls. Amblyopia primarily added to the instability of the nonpreferred eye. Anisometropic children had less nonpreferred eye instability and vergence instability than those with strabismus or combined mechanism. Nonpreferred eye instability and vergence instability were related to poorer stereoacuity and a larger suppression scotoma. Preferred eye instability was not related to any visual outcome measure. No relationships were found with visual acuity. Conclusions Fixation instability and vergence instability during binocular viewing suggests that discordant binocular visual experience during childhood, especially strabismus, interferes with ocular motor development. Amblyopia adds to instability of the nonpreferred eye. Vergence instability may limit potential for recovery of binocular vision in these children.

Green chemistry principles will be discussed, and examples will be given of the use of Molecular Recognition Technology (MRT) to selectively separate specialty metals such as cobalt, nickel, bismuth, rhenium, molybdenum, indium and germanium from various primary and secondary feed streams. Recovery of these metals has numerous advantages including (i) conservation of valuable resources, (ii) prevention of environmental damage, and (iii) elimination of capital and operating expenses due to re-processing or disposal of metal-bearing streams.

Introduction CD19 chimeric antigen receptor (CAR)-T cell therapy has shown efficacy in Non-Hodgkin lymphoma (NHL), but the factors associated with durable remission have not been identified. Objectives We report multivariate analyses of factors impacting progression-free survival (PFS) in NHL patients (pts) treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion (LD) and CD19 CAR-T cells. Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of a defined composition of CD19 CAR-T cells after LD in pts with R/R CD19+ B-cell malignancies. PFS was defined as the time from CAR-T cell infusion until disease progression or death. Multivariate models using elastic net were performed for analysis of response and PFS. Results Characteristics of the 57 pts in the study are shown in Tbl 1. Thirty-six (63%) received high-intensity (HI) Cy/Flu and 21 (37%) received low-intensity (LI) Cy/Flu LD (Tbl 1). All pts received 2 × 106 CD19 CAR-T cells/kg. The best overall response (OR) rate was 57%, with 48% complete remission (CR). Pts who achieved CR had a median PFS not reached (median follow-up [fu] 20.2 months; mo), with only 1 relapse beyond 12 mo after CAR-T cell infusion (Fig. 1). Eight of 9 pts with indolent NHL achieved CR (89%) and none relapsed (median fu 14.5 mo). For the 47 pts with aggressive NHL, the best OR rate was 51%, with 40% CR. The median PFS of aggressive NHL pts achieving CR was 20.0 mo (median fu 26.9 mo), and 24-mo probabilities of PFS and OS were 46% and 72%, respectively. In aggressive NHL, multivariate analysis showed that the probability of CR was associated with lower pre-LD serum LDH and greater increase in serum MCP-1 concentration from LD to the day of CAR-T cell infusion. HI LD was associated with more CAR-T cells in blood, but there was no difference in response in pts who received HI (CR 14/31, 45%) compared to LI LD (CR 5/16, 31%; P = .53). Multivariate analysis in aggressive NHL showed that lower pre-LD serum LDH and higher day 0 MCP-1 and peak IL-7 after CAR-T cell infusion were associated with better PFS. The IL-7 peak after CAR-T cell infusion (median day 4) correlated with day 0 IL-7, consistent with an effect of LD. MCP-1 and IL-7 increased after LD, independent of prior bridging therapy, and their concentrations correlated with Cy/Flu LD intensity. However, LD intensity was not independently associated with CR or PFS. Independent of LD intensity, a subset of pts had a robust increase in day 0 MCP-1 and peak IL-7 after LD and achieved better responses (CR 10/16, 63%) compared to those with limited cytokine increase (CR 9/30, 30%; P = .06). Conclusion Multivariate analyses show that cytokines associated with effective LD are, unlike the intensity of Cy/Flu LD, independently associated with CR and PFS. Strategies to augment biological LD efficacy could be tested in studies of CD19 CAR-T cells for aggressive NHL.

Background In relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) who had previously failed ibrutinib, we observed durable responses after CD19 chimeric antigen receptor-modified T-cell immunotherapy (Turtle CJ et al, JCO, 2017; NCT01865617). The combination of CD19 CAR-T cells with ibrutinib might improve response and decrease toxicity. Objectives To evaluate the efficacy and toxicity of CD19 CAR-T cell immunotherapy alone or in combination with ibrutinib for R/R CLL. Methods Our phase 1/2 study of CD19 CAR-T cell immunotherapy established a preferred regimen for R/R CLL pts of cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2 × 106 CD19 CAR-T cells/kg (Turtle, JCO, 2017). We then compared outcomes of these pts (No-ibr cohort) with a subsequent cohort receiving Cy/Flu with 2 × 106/kg JCAR014 CAR-T cells with concurrent ibrutinib (420 mg/d) from at least 2 weeks prior to leukapheresis until at least 3 months after JCAR014 infusion (Ibr cohort). Results We treated 19 and 17 pts in the No-Ibr and Ibr cohorts, respectively. Pt characteristics were comparable (Table 1). Median follow-up in responders was 764 and 98 days in the No-ibr and Ibr cohorts, respectively. Administration of ibrutinib with Cy/Flu and CD19 CAR-T cells was well tolerated in most pts; ibrutinib was reduced or discontinued in 6 pts (35%) at a median of 21 days after JCAR014 infusion. In the Ibr cohort 1 pt with grade 2 CRS (Lee, Blood, 2014) developed fatal presumed cardiac arrhythmia and 1 pt developed a subdural hematoma in the setting of trauma and thrombocytopenia. Although the proportions of pts with grade ≥1 CRS were similar between cohorts (76% vs 89%, P = 0.39), the severity of CRS (grade ≥3 CRS: Ibr, 0%; No-Ibr, 26%; P = 0.05) and serum peak IL-8 (P = 0.04), IL-15 (P = 0.003) and MCP-1 (P = 0.004) concentrations were lower in the Ibr cohort. However, we found higher peak CD4+ CAR-T cell counts (P = 0.06) and comparable peak CD8+ CAR-T cell counts (P = 0.29) in blood in the Ibr compared to the No-Ibr cohort. Sixteen pts (94%) and 18 pts (95%) in the Ibr and No-ibr cohorts, respectively, were evaluable for response. We observed a higher proportion of responders (complete response and partial response) by 2008 IWCLL criteria in the Ibr compared to the No-ibr cohort (88% vs 56%, respectively, P = 0.06). In pts with no disease by BM flow cytometry after treatment (N = 23), a higher proportion of pts in the Ibr cohort had no malignant IgH sequences at 4 weeks (83% vs 60%, P = 0.35). Using multivariable logistic regression (Table 2), treatment in the Ibr cohort and a lower pre-treatment SUVmax were associated with a higher probability of response (Ibr cohort, OR = 14.02, P = 0.05; SUVmax, OR = 1.31 per SUV unit decrease, P Conclusion The combination of ibrutinib with CD19 CAR-T cell immunotherapy was well tolerated in most pts, and might decrease the incidence of severe CRS and improve responses in pts with R/R CLL.

Hydrology is an integrative discipline linking the broad array of water-related research with physical, ecological, and social sciences. The increasing breadth of hydrological research, often where subdisciplines of hydrology partner with related sciences, reflects the central importance of water to environmental science, while highlighting the fractured nature of the discipline itself. This lack of coordination among hydrologic subdisciplines has hindered the development of hydrologic theory and integrated models capable of predicting hydrologic partitioning across time and space. The recent development of the concept of the critical zone (CZ), an open system extending from the top of the canopy to the base of groundwater, brings together multiple hydrological subdisciplines with related physical and ecological sciences. Observations obtained by CZ researchers provide a diverse range of complementary process and structural data to evaluate both conceptual and numerical models. Consequently, a cross-site focus on “critical zone hydrology” has potential to advance the discipline of hydrology and to facilitate the transition of CZ observatories into a research network with immediate societal relevance. Here we review recent work in catchment hydrology and hydrochemistry, hydrogeology, and ecohydrology that highlights a common knowledge gap in how precipitation is partitioned in the critical zone: “how is the amount, routing, and residence time of water in the subsurface related to the biogeophysical structure of the CZ?” Addressing this question will require coordination among hydrologic subdisciplines and interfacing sciences, and catalyze rapid progress in understanding current CZ structure and predicting how climate and land cover changes will affect hydrologic partitioning. This article is protected by copyright. All rights reserved.

Many of the scientific and societal challenges in understanding and preparing for global environmental change rest upon our ability to understand and predict the water cycle change at large river basin, continent, and global scales. However, current large-scale models, such as the land components of Earth System Models (ESMs), do not yet represent the terrestrial water cycle in a fully integrated manner or resolve the finer-scale processes that can dominate large-scale water budgets. This paper reviews the current representation of hydrologic processes in ESMs and identifies the key opportunities for improvement. This review suggests that (1) the development of ESMs has not kept pace with modeling advances in hydrology, both through neglecting key processes (e.g., groundwater) and neglecting key aspects of spatial variability and hydrologic connectivity; and (2) many modeling advances in hydrology can readily be incorporated into ESMs and substantially improve predictions of the water cycle. Accelerating modeling advances in ESMs requires comprehensive hydrologic benchmarking activities, in order to systematically evaluate competing modeling alternatives, understand model weaknesses, and prioritize model development needs. This demands stronger collaboration, both through greater engagement of hydrologists in ESM development and through more detailed evaluation of ESM processes in research watersheds. Advances in themore » representation of hydrologic process in ESMs can substantially improve energy, carbon and nutrient cycle prediction capabilities through the fundamental role the water cycle plays in regulating these cycles.« less

Humanitarian assistance is intended to ameliorate the human costs of war by providing relief to vulnerable populations. Yet the introduction of aid resources into conflict zones may influence subsequent violence patterns and expose intended recipients to new risks. Here we investigate the potential negative externalities associated with humanitarian aid. We argue that aid can create incentives for armed actors to intentionally target civilians for violence. Aid encourages rebel violence by providing opportunities for looting and presenting challenges to rebel authority. It potentially encourages state violence where it augments rebel capabilities or provides rebels a resource base. We evaluate both arguments using spatially disaggregated data on aid and conflict violence for a sample of nearly two dozen post–Cold War African countries. The results of multiple statistical analyses provide strong support for the argument that humanitarian aid is associated with increased rebel violence but less support for ...

In the Bay Area of California, a collection of utilities must determine how to allocate a shared resource during drought. If they choose to use market principles, the market price for water will be determined by the total demand for water, which is dependent on the elasticity of demand for water for each utility. The elasticity of demand for water has proved a difficult metric to estimate, involving considerable uncertainty. This work, rather than trying to use a single estimate of elasticity for each utility, uses Monte Carlo simulation to evaluate a market using a range of elasticity values. The use of a market is shown to reduce economic losses by at least 25%, compared with the current nonmarket allocation. The robustness of the benefits shown by the market, even with the inherent uncertainty in elasticity values, may inspire confidence in policymakers to adopt more market-based allocation strategies.