Prognostic Factors Associated with Ocriplasmin Efficacy for the Treatment of Symptomatic Vitreomacular Adhesion and Full-thickness Macular Hole: Analysis from Four Studies

Purpose: To assess the effect of patient baseline characteristics on the efficacy of ocriplasmin treatment for symptomatic vitreomacular adhesion (VMA) with full-thickness macular hole (FTMH) from phase 3/4 studies. Methods: Patients with symptomatic VMA and FTMH at baseline and receiving ocriplasmin treatment 12

Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice

The radiation environment in deep space includes the galactic cosmic radiation with different proportions of all naturally occurring ions from protons to uranium. Most experimental animal studies for assessing the biological effects of charged particles have involved acute dose delivery for single ions and/or fractionated exposure protocols. Here, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice 2 months following rapidly delivered, sequential irradiation with protons (1 GeV, 60%), 16O (250 MeV/n, 20%), and 28Si (263 MeV/n, 20%) at 0, 25, 50, or 200 cGy at 4–6 months of age. Cortical BDNF, CD68, and MAP-2 levels were analyzed 3 months after irradiation or sham irradiation. During the dark period, male mice irradiated with 50 cGy showed higher activity levels in the home cage than sham-irradiated mice. Mice irradiated with 50 cGy also showed increased depressive behavior in the forced swim test. When cognitive performance was assessed, sham-irradiated mice of both sexes and mice irradiated with 25 cGy showed normal responses to object recognition and novel object exploration. However, object recognition was impaired in female and male mice irradiated with 50 or 200 cGy. For cortical levels of the neurotrophic factor BDNF and the marker of microglial activation CD68, there were sex × radiation interactions. In females, but not males, there were increased CD68 levels following irradiation. In males, but not females, there were reduced BDNF levels following irradiation. A significant positive correlation between BDNF and CD68 levels was observed, suggesting a role for activated microglia in the alterations in BDNF levels. Finally, sequential beam irradiation impacted the diversity and composition of the gut microbiome. These included dose-dependent impacts and alterations to the relative abundance of several gut genera, such as Butyricicoccus and Lachnospiraceae. Thus, exposure to rapidly delivered sequential proton, 16O ion, and 28Si ion irradiation significantly affects behavioral and cognitive performance, cortical levels of CD68 and BDNF in a sex-dependent fashion, and the gut microbiome

Effects of climate change on grassland biodiversity and productivity: the need for a diversity of models

There is increasing evidence that the impact of climate change on the productivity of grasslands will at least partly depend on their biodiversity. A high level of biodiversity may confer stability to grassland ecosystems against environmental change, but there are also direct effects of biodiversity on the quantity and quality of grassland productivity. To explain the manifold interactions, and to predict future climatic responses, models may be used. However, models designed for studying the interaction between biodiversity and productivity tend to be structurally different from models for studying the effects of climatic impacts. Here we review the literature on the impacts of climate change on biodiversity and productivity of grasslands. We first discuss the availability of data for model development. Then we analyse strengths and weaknesses of three types of model: ecological, process-based and integrated. We discuss the merits of this model diversity and the scope for merging different model types

Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model.

BACKGROUND: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. RESULTS: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). MATERIALS AND METHODS: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. CONCLUSIONS: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation

Weaving Academic Grace into the Fabric of Online Courses and Faculty Training: First-Year Engineering Student Advice for Online Faculty During the COVID-19 Pandemic and Faculty Responses

Background: In the spring of 2020, COVID-19 forced the majority of higher education online, resulting in a wave of new online students uniquely positioned to offer fresh perspectives and advice to faculty. Purpose: This study investigated the advice offered to online faculty by first-year engineering (FYE) students who were forced online during the pandemic and faculty ideas to address the student advice. Methods: This multi-methods study included qualitative data from 233 FYE students (in 67 teams across four class offerings) who provided advice for online faculty through an end-of-year team assignment, leveraging analytic induction methods for analysis. The Quality Matters Online Instructor Skill Set was used as the theoretical framework for viewing the student results (Quality Matters, 2016). After being presented with the student results, 41 faculty participants within two workshops brainstormed ways to respond to FYEs’ advice. Faculty workshop participants organized their own brainstorming/discussion results by themes within community documents. Results: Students forced online expressed the following needs/desires: instructional design practices appropriate for the online environment; understanding, flexibility, and patience from their faculty (which we defined as Academic Grace); instructor social presence; appropriate pedagogy for online learning environments; effective assessment; technologically capable instructors; and instructor understanding of their institutional context. Faculty advised responding to online students with more Academic Grace. Conclusions: This work reveals a new competency missing from traditional online instructor skills, that of Academic Grace. To embed Academic Grace within online courses, we propose that faculty consider a flexible bichronous model for online courses, in which students can choose to attend synchronous live lectures/classes or cover the material asynchronously at their own convenience. In this model, lecture/class recordings and supplemental asynchronous materials should be provided to foster fluid student movement between the learning modes. We also recommend online faculty training efforts include the components of Academic Grace: understanding, flexibility, and patience

Expression of aberrant forms of CD22 on B lymphocytes in Cd22a lupus-prone mice affects ligand binding

CD22 functions primarily as a negative regulator of B-cell receptor signaling. The Cd22a allele has been proposed as a candidate allele for murine systemic lupus erythematosus. In this study, we explored the possible expression of aberrant forms of CD22, which differ in the N-terminal sequences constituting the ligand-binding site due to synthesis of abnormally processed Cd22 mRNA, in several Cd22a mouse strains, including C57BL/6 Cd22 congenic mice. The staining pattern of splenic B cells obtained with CY34 anti-CD22 mAb, which was expected to bind poorly to the aberrant CD22, was more heterogeneous in Cd22a mice than in Cd22b mice. Moreover, CD22 detected on B cells of Cd22a mice was expressed more weakly and as a smaller-sized protein, compared with Cd22b mice. Significantly, analysis with a synthetic CD22 ligand demonstrated that Cd22a mice carried a larger proportion of CD22 that was not bound by cis ligands on the B-cell surface than Cd22b mice. Finally, the study of C57BL/6 Cd22 congenic mice revealed that Cd22a B cells displayed a phenotype reminiscent of constitutively activated B cells (reduced surface IgM expression and augmented MHC class II expression), as reported for B cells expressing a mutant CD22 lacking the ligand-binding domain. Our demonstration that Cd22a B cells express aberrant forms of CD22, which can potentially deregulate B-cell signaling because of their decreased ligand-binding capacity, provides further support for Cd22a as a potential candidate allele for murine systemic lupus erythematosu

TCT-4 Efficacy and Safety of Concurrent Administration of Clopidogrel-loading (600mg) and Prasugrel-loading (60mg) in Patients with Acute ST-Segment Elevation Myocardial Infarction

Background: Current STEMI guideline recommendations limit the use of prasugrel to clopidogrel-naïve patients. However, in daily clinical practice a considerable proportion of STEMI patients undergoing primary PCI are preloaded with clopidogrel. Whether the use of prasugrel in clopidogrel pretreated STEMI patients is safe remains unknown. Similarly, the efficacy of a combined loading dose regimen has not been evaluated. Methods: Between 1 September 2009 and 15 October 2012, a total of 1,157 STEMI patients were included in the randomized COMFORTABLE AMI trial (NCT 00962416) and 891 STEMI patients in the SPUM ACS registry (NCT 01000701) at 12 centers. Patients were divided into three groups according to type of peri-procedural antiplatelet loading: (1) Clopidogrel and subsequent Prasugrel loading dose [CP], (2) Prasugrel loading dose alone [P] (3) Clopidogrel loading dose alone [C]; 23 patients were excluded because they were not exposed to Clopidogrel and Prasugrel. The primary safety endpoint was the rate of BARC type 3, 4 and 5 bleeding at 30 days. The primary efficacy endpoint was the composite of cardiac death, nonfatal MI and nonfatal stroke at 30 days. Outcomes were analyzed using Cox's Regressions (crude) and multinomial ITPW weighted Cox's Regressions. Results: A total of 2,025 patients were analysed of whom 428 (21.1%) had received CP, 447 (22.1%) patients P alone, and 1,150 (56.8%) patients C alone. The primary safety endpoint was observed among 1.2% of CP, 1.6% of P, and 1.5% of C patients (CP vs C ad. HR 0.99 (0.36-2.72), PC vs P ad. HR 0.73 (0.22-2.41). The primary safety endpoint occurred less frequently among CP (1.9%) compared with C patients (5.0%, adjusted HR 0.47 (0.22-1.00), but with similar frequency among P and C patients (2.9% vs 5.0%, ad. HR 0.68 (0.27-1.73). The net clinical benefit outcome parameter tended to be lower among CP (2.8%) compared with C patients (6.3%, ad. HR 0.56 (0.30-1.05), whereas no significant difference was observed between P and C patients (3.8% vs 6.3%, ad. HR 0.85 (0.39-1.86). Conclusions: Among STEMI patients preloaded with Clopidogrel, the concurrent administration of a Prasugrel loading dose appears safe and potentially more effective than Clopiogrel alone

Swallowing dysfunction in cancer patients

Purpose Dysphagia (swallowing dysfunction) is a debilitating, depressing, and potentially life-threatening complication in cancer patients that is likely underreported. The present paper is aimed to review relevant dysphagia literature between 1990 and 2010 with a focus on assessment tools, prevalence, complications, and impact on quality of life in patients with a variety of different cancers, particularly in those treated with curative chemoradiation for head and neck cancer. Methods The literature search was limited to the English language and included both MEDLINE/PubMed and EMBASE. The search focused on papers reporting dysphagia as a side effect of cancer and cancer therapy. We identified relevant literature through the primary literature search and by articles identified in references. Results A wide range of assessment tools for dysphagia was identified. Dysphagia is related to a number of factors such as direct impact of the tumor, cancer resection, chemotherapy, and radiotherapy and to newer therapies such as epidermal growth factor receptor inhibitors. Concomitant oral complications such as xerostomia may exacerbate subjective dysphagia. Most literature focuses on head and neck cancer, but dysphagia is also common in other types of cancer. Conclusions Swallowing impairment is a clinically relevant acute and long-term complication in patients with a wide variety of cancers. More prospective studies on the course of dysphagia and impact on quality of life from baseline to long-term follow-up after various treatment modalities, including targeted therapies, are needed

Defining optimal DEM resolutions and point densities for modelling hydrologically sensitive areas in agricultural catchments dominated by microtopography

AbstractDefining critical source areas (CSAs) of diffuse pollution in agricultural catchments depends upon the accurate delineation of hydrologically sensitive areas (HSAs) at highest risk of generating surface runoff pathways. In topographically complex landscapes, this delineation is constrained by digital elevation model (DEM) resolution and the influence of microtopographic features. To address this, optimal DEM resolutions and point densities for spatially modelling HSAs were investigated, for onward use in delineating CSAs. The surface runoff framework was modelled using the Topographic Wetness Index (TWI) and maps were derived from 0.25m LiDAR DEMs (40 bare-earth points m−2), resampled 1m and 2m LiDAR DEMs, and a radar generated 5m DEM. Furthermore, the resampled 1m and 2m LiDAR DEMs were regenerated with reduced bare-earth point densities (5, 2, 1, 0.5, 0.25 and 0.125 points m−2) to analyse effects on elevation accuracy and important microtopographic features. Results were compared to surface runoff field observations in two 10km2 agricultural catchments for evaluation. Analysis showed that the accuracy of modelled HSAs using different thresholds (5%, 10% and 15% of the catchment area with the highest TWI values) was much higher using LiDAR data compared to the 5m DEM (70–100% and 10–84%, respectively). This was attributed to the DEM capturing microtopographic features such as hedgerow banks, roads, tramlines and open agricultural drains, which acted as topographic barriers or channels that diverted runoff away from the hillslope scale flow direction. Furthermore, the identification of ‘breakthrough’ and ‘delivery’ points along runoff pathways where runoff and mobilised pollutants could be potentially transported between fields or delivered to the drainage channel network was much higher using LiDAR data compared to the 5m DEM (75–100% and 0–100%, respectively). Optimal DEM resolutions of 1–2m were identified for modelling HSAs, which balanced the need for microtopographic detail as well as surface generalisations required to model the natural hillslope scale movement of flow. Little loss of vertical accuracy was observed in 1–2m LiDAR DEMs with reduced bare-earth point densities of 2–5 points m−2, even at hedgerows. Further improvements in HSA models could be achieved if soil hydrological properties and the effects of flow sinks (filtered out in TWI models) on hydrological connectivity are also considered