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PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 μm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 μm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

Background Accelerated idioventricular rhythm (AIVR) is an uncommon and typically benign dysrhythmia with similarities to more malignant forms of ventricular tachycardia (VT). It is often seen in adults after myocardial infarctions, although it also arises in the newborn period, as well as in children with and without congenital heart disease. Case Report We describe a presentation of AIVR in an otherwise healthy 13-year-old girl, discovered on arrival to the pediatric emergency department in the setting of post-tonsillectomy bleeding. The case reviews the diagnostic criteria of AIVR, associated symptoms, the pathophysiologic origin of AIVR, and potential treatment strategies. Why Should an Emergency Physician Be Aware of This? Given its morphologic similarities to life-threatening forms of VT, AIVR can be misdiagnosed in the emergency department or primary care settings. With an understanding of the dysrhythmia's unique features, emergency physicians can avoid unnecessary interventions and provide the correct diagnosis, workup, and management of AIVR for pediatric patients.

Histone arginine methylation is a prevalent posttranslational modification (PTM) in eukaryotic cells and contributes to the histone codes for epigenetic regulation of gene transcription. In this study, we determined how local changes on adjacent residues in the histone H4 substrate regulate arginine asymmetric dimethylation and symmetric dimethylation catalysed by the major protein arginine methyltransferase (PRMT) enzymes PRMT1 and PRMT5, respectively. We found that phosphorylation at histone H4 Ser-1 site (H4S1) was inhibitory to activities of PRMT1 and PRMT5 in both monomethylating and dimethylating H4R3. Also, a positively charged H4K5 was important for PRMT1 catalysis because acetylation of H4K5 or the loss of the H4K5 ��-amine had a similar effect in reducing the catalytic efficiency of asymmetric dimethylation of H4R3. An opposite effect was observed in that acetylation of H4K5 or the loss of the H4K5 ��-amine enhanced PRMT5-mediated symmetric dimethylation of H4R3. Furthermore, we observed that N-terminal acetylation of H4 modestly decreased asymmetric dimethylation of H4R3 by PRMT1 and symmetric dimethylation of H4R3 by PRMT5. This work highlights the significance of local chemical changes in the substrate to regulating PRMT activity and unravels the pattern complexities and subtleties of histone codes.

Purpose Pterygium is characterized by the development of wing-shaped fibrovascular tissue from the bulbar conjunctiva across the limbus onto the cornea. The purpose of this study was to quantify the discrepancy of the pterygium size between the fibrous area and the vascularized area. Methods Color photographs of 146 eyes with pterygia obtained with a single-lens reflex camera system were analyzed by 2 independent graders for width (vertical dimension), length (horizontal dimension), and surface area of the pterygium head using 2 methods: the fibrous method, which measures any fibrovascular tissue crossing the corneal limbus, and the vascular method, which measures only tissue with discernible active blood flow, without any avascular tissue or opacity. Statistics of intraclass correlation coefficients for intergrader and intragrader reproducibility were calculated, and the paired t test between methods was used. Results Both intergrader and intragrader intraclass correlation coefficients for both methods were above 0.85. The vascular measurement was significantly larger in width (vertical dimension, fibrous 3.97 ± 1.02 mm vs. vascular 4.49 ± 1.33 mm, P = 0.01), whereas the fibrous measurement was significantly larger in length (horizontal dimension, fibrous 2.41 ± 1.16 mm vs. vascular 2.23 ± 1.05 mm, P = 0.04). No significant difference was found in the surface area (fibrous 7.27 ± 4.65 mm vs. vascular 7.40 ± 5.13 mm, P = 0.67). Conclusions With both methods, reproducibility of the size of the pterygium head was high. Significant differences were shown between the two methods in quantification of the width and length but not in the surface area. Such methods can be used to standardize the evaluation of pterygia in clinical research and clinical trials.

Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

Traumatic brain injury (TBI) is a leading cause of death and disability, with injuries classified as mild in severity being the most frequently sustained. While the majority of patients recover within 3 months post-injury, many individuals continue to experience debilitating emotional sequelae several months after the injury. While spiritual well-being has been shown to carry protective benefits against both depression and anxiety in the general population, it has not been investigated as a protective factor in this population. The aim of this study was to investigate whether spiritual well-being leads to a reduction in anxious and depressive symptomatology following mild TBI (mTBI). The Beck Anxiety Inventory, Beck Depression Inventory-II, and Spiritual Well-Being Scale were administered to a sample of 83 litigating examinees who had undergone neuropsychological testing to assess their present functioning secondary to mTBI. The existential well-being (EWB) subscale significantly predicted depressive symptomatology. These findings support the role of EWB as contributory factor related to depressive symptomatology following mTBI. Rehabilitation practitioners should consider treatment paradigms that address EWB as a primary contributor to reduce depressive symptomatology, which may ultimately lead to improved functional ability.

Diabetes mellitus has become a major public health issue that has almost reached epidemic proportions worldwide. Injectable insulin has been typically utilized for the management of this chronic disease. However, lack of patient compliance with injectable formulations has spurred the development of oral insulin formulations, which although appealing, face several delivery challenges. We have developed novel mucoadhesive intestinal patches, several hundred micrometers in dimension (micropatches) that address the challenges of oral insulin delivery. The micropatches adhere to the intestinal mucosa, release their drug load rapidly within 30 min and are effective in lowering blood glucose levels in vivo. When insulin-loaded micropatches were administered with a permeation enhancer and protease inhibitor, a peak efficacy of 34% drop in blood glucose levels was observed within 3 h. Efficacy further improved to 41% when micropatches were administered in multiple doses. Here, we describe the design of micropatches as an oral insulin formulation and report their in vivo efficacy.

The present study combines the theory and the experimental data to predict the changes on intestinal bacterial populations during ingestion of beneficial probiotic bacteria. Our proposed model is a modified version of the Lotka-Volterra model, which takes the probiotic administration into account. Using the linear stability analysis of the model, the conditions for coexistence of the probiotics with other bacteria are established. Using the model fitted to the data of C. coccoides species and Bifidobacterium species, the effects of oral probiotics on autochthonous bacterial cultures is investigated. The estimated parameter values suggest that C. coccoides and Bifidobacterium facilitate each other during the probiotics administration, whereas they compete in the absence of the probiotics administration. This may suggest the beneficial effect of probiotic administration as it promotes the growth of C. coccoides species. The results also confirm prior studies showing that once probiotic supplementation is discontinued, the probiotic population and the promoting effect within the digestive tract will diminish.

Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies. This study has been partially supported by grants from Instituto de Salud Carlos III (PI13/00292 and PI17/0054), Spanish ResearchNetwork on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014),Fundación Mutua Madrileña. The Ministry of Economy and Competitiveness of Spain (SAF2017-84267-R). The European Union program FEDER and the European Regional Development Fund–ERDF, MADIA project No. 732678 to FC. Furthermore, F. Campos (CP14/00154) recipients a research contract from Miguel Servet Program of Instituto de Salud Carlos III. National Science Foundation Graduate Research Fellowship under Grant DGE-1745303 SI

The focus of this paper is to provide an update on the use of psychotherapy as a treatment in sport psychiatry, and the use of this approach to address common psychiatric issues encountered with this population. Specifically, family therapy, individual therapy, and group psychotherapy prescribed alone, or in combination with medication, will be examined as methods to manage issues/disorders often associated with athletes. These include obsessive-compulsive rituals and perfectionism, and aggressive and risky behaviours, such as gambling, infidelity, substance use, and suicidal ideation, narcissism, and aggression in the context of individual and team competitive sports.

The inclusion of plant meals in diets of farmed Atlantic salmon can elicit inflammatory responses in the distal intestine (DI). For the present work, fish were fed a standard fish meal (FM) diet or a diet with partial replacement of FM with solvent-extracted camelina meal (CM) (8, 16, or 24 % CM inclusion) during a 16-week feeding trial. A significant decrease in growth performance was seen in fish fed all CM inclusion diets (Hixson et al. in Aquacult Nutr 22:615–630, 2016). A 4x44K oligonucleotide microarray experiment was carried out and significance analysis of microarrays (SAM) and rank products (RP) methods were used to identify differentially expressed genes between the DIs of fish fed the 24 % CM diet and those fed the FM diet. Twelve features representing six known transcripts and two unknowns were identified as CM responsive by both SAM and RP. The six known transcripts (including thioredoxin and ependymin), in addition to tgfb, mmp13, and GILT, were studied using qPCR with RNA templates from all four experimental diet groups. All six microarray-identified genes were confirmed to be CM responsive, as was tgfb and mmp13. Histopathological analyses identified signs of inflammation in the DI of salmon fed CM-containing diets, including lamina propria and sub-epithelial mucosa thickening, infiltration of eosinophilic granule cells, increased goblet cells and decreased enterocyte vacuolization. All of these were significantly altered in 24 % CM compared to all other diets, with the latter two also altered in 16 % CM compared with 8 % CM and control diet groups. Significant correlation was seen between histological parameters as well as between five of the qPCR analyzed genes and histological parameters. These molecular biomarkers of inflammation arising from long-term dietary CM exposure will be useful in the development of CM-containing diets that do not have deleterious effects on salmon growth or physiology. Electronic supplementary material The online version of this article (doi:10.1007/s10126-016-9704-x) contains supplementary material, which is available to authorized users.

Digoxin use has been associated with lower interstage mortality in infants with HLHS and variants. The NEONATE score was developed to risk stratify patients for interstage mortality or transplantation; risk factors included type of stage 1 palliation (S1P)—Norwood with BT or Sano shunt vs. Hybrid

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3–10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Objective: Since April 2010, our institution has repaired complete atrioventricular septal defects (CAVSDs) with a two-patch technique utilizing CorMatrix extracellular material. This material is potentially an attractive patch because of its theorized eventual integration with the host tissue. We sought to analyze initial outcomes of CAVSD repair with CorMatrix. Methods: Data were collected on consecutive pediatric (age Results: Fifteen patients were identified. The average age at operation was 205 days, with mean follow-up time at 1,364 days. Echocardiograms revealed the following: 12 (80%) patients showed either improved or stable left AV valve performance remaining at “mild” or less insufficiency, while two (13%) declined from “none” to mild and one (7%) from mild to “severe,” which required reoperation. There was no residual shunting or LVOT obstruction at follow-up. The single (7%) reoperation was performed after three years due to left AV valve zone of apposition dehiscence. No permanent pacemakers were needed, and no deaths were reported. Conclusion: Our initial experience with CorMatrix in the repair of CAVSD in children has resulted in good initial and midterm outcomes. The CorMatrix patch remained stable through midterm follow-up, thus may be efficacious for use in CAVSD repair.

Background In vitro three-dimensional neural spheroid models have an in vivo -like cell density, and have the potential to reduce animal usage and increase experimental throughput. The aim of this study was to establish a spheroid model to study the formation of capillary-like networks in a three-dimensional environment that incorporates both neuronal and glial cell types, and does not require exogenous vasculogenic growth factors. New method We created self-assembled, scaffold-free cellular spheroids using primary-derived postnatal rodent cortex as a cell source. The interactions between relevant neural cell types, basement membrane proteins, and endothelial cells were characterized by immunohistochemistry. Transmission electron microscopy was used to determine if endothelial network structures had lumens. Results Endothelial cells within cortical spheroids assembled into capillary-like networks with lumens. Networks were surrounded by basement membrane proteins, including laminin, fibronectin and collagen IV, as well as key neurovascular cell types. Comparison with existing method(s) Existing in vitro models of the cortical neurovascular environment study monolayers of endothelial cells, either on transwell inserts or coating cellular spheroids. These models are not well suited to study vasculogenesis, a process hallmarked by endothelial cell cord formation and subsequent lumenization. Conclusions The neural spheroid is a new model to study the formation of endothelial cell capillary-like structures in vitro within a high cell density three-dimensional environment that contains both neuronal and glial populations. This model can be applied to investigate vascular assembly in healthy or disease states, such as stroke, traumatic brain injury, or neurodegenerative disorders.

Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resection of primary brain tumors and metastases. We conducted a systematic review of the literature to further understand the role of 5-ALA in neurosurgery. Our goal was to identify the utility of 5-ALA during resection by evaluating its sensitivity and specificity for different tumor types, as well as the extent of tumor resection achieved while using 5-ALA. A search of the literature was conducted using the PubMed database for the period January 1990 through May 2014. Surgical series in which 5-ALA was used for brain neoplasm resections were evaluated for tumor histology, sensitivity, specificity, extent of resection, complications, and outcomes. Twenty-two series, involving 1163 patients, were included in our review. 5-ALA sensitivity was highest in high-grade gliomas (85 %) and meningiomas (81 %). 5-ALA specificity was high in meningiomas (100 %), as well as metastases (84 %) and high-grade gliomas (82 %). Gross total resection (GTR) was achieved using 5-ALA in 66.2 % of all gliomas and 69.6 % of meningiomas, regardless of histological subtype. 5-ALA may be a useful tool in increasing the extent of resection and achieving GTR in intracranial tumors. The resection of tumors for which 5-ALA has high sensitivity and specificity, such as high-grade gliomas, may lead to an increase in extent of resection when compared to operations using only standard white light. Further evidence for the use of 5-ALA in meningiomas and certain subtypes of metastases may be needed to qualify its efficacy.