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Respiratory syncytial virus (RSV) commonly causes severe respiratory tract infections in infants, peaking between 2 and 6 months of age; an age at which direct vaccination is unlikely to be effective. Maternal immunization can deliver high levels of antibodies to newborns, providing immediate protection. Following natural infection, antibodies targeting the prefusion conformation of RSV F protein (PreF) have the greatest neutralizing capacity and thus, may provide infants with a high degree of RSV protection when acquired through maternal vaccination. However, the influence of anti-PreF maternal antibodies on infant immunity following RSV exposure has not been elucidated. To address this knowledge gap, offspring born to dams immunized with a RSV PreF vaccine formulation were challenged with RSV and their immune responses were analyzed over time. These studies demonstrated safety and efficacy for RSV-challenged, maternally-immunized offspring but high and waning maternal antibody levels were associated with differential innate and T cell immunity.

Real-Time Hybrid Simulation (RTHS) is an experimental framework that allows the testing of components or substructures under realistic, dynamic boundary conditions, by imposing the reactions calculated from a model of the rest of the assembly through one or more actuators. In the context of rapid prototyping of mechanical components, RTHS could be used to explore the design space of a device while at the same time physically validating its interaction with other components of the final assembly from the early stages of the design-to-production cycle. In this work, RTHS was applied for the first time to the investigation of aerodynamic gust loading alleviation devices in a highly flexible strut-braced wing. The model wing was taken as the physical substructure and tested in a low-speed wind tunnel equipped with gust generators. The load alleviation device was simulated through a real-time feedforward-feedback controller, and its response imposed via an electro-mechanical linear actuator, in contrast with the hydraulic actuators more commonly used in standard RTHS. The controller-actuator subsystem was studied in detail to assess and minimise errors at the physical interface with the wing. The behaviour of the electromechanical subsystem showed a strong dependence on the characteristics of the numerical substructure and the frequency of excitation, and resulted in a significant discrepancy between the simulated and real displacements at the interface between the actuator and the wing. A narrow-band feedforward displacement control scheme based on a model of this subsystem alone was therefore developed and shown to significantly reduce synchronisation errors at the interface.

This paper presents a novel method for gust loads alleviation in a truss-braced wing in which an inerter-based device located in the truss-structure is used to reduce peak-loads during a discrete “1-cosine” gust. Three candidate layouts are considered, and the device parameters are optimized to target the response of the first three structural modes. It is demonstrated that either a single damper or a combination of inerter-based devices can be used to achieve a reduction of approximately 4% for spanwise locations inboard of the strut attachment point and that this reduction is consistent across the full range of gust gradients. Furthermore, it is noted that the inerter-based device has a significantly smaller damping coefficient than the case where just a damper is used and that the device parameter values are viable within the scope of an aerospace application.

Background Coronary artery disease (CAD) is an under-recognized complication of intense arterial inflammation in Takayasu arteritis (TAK). While pericoronary adipose tissue (PCAT) density is associated with arterial inflammation in CAD patients, this relationship has not previously been studied in TAK patients, nor directly compared with coronary arterial inflammation measured by 68Ga-DOTATATE positron emission tomography (PET). Purpose To compare PCAT density with clinical, biochemical and molecular imaging markers of inflammation in TAK and CAD patients. Methods PCAT density was quantified from computed tomography coronary angiography (CTCA) around each of the 17 coronary segments in patients with: (1) TAK and CAD, (2) atherosclerotic CAD, and (3) age and gender-matched healthy controls, using semi-automated software (Autoplaque). In TAK patients, PCAT density was compared to the Indian Takayasu Clinical Activity Score (ITAS) and high-sensitivity C-reactive protein (CRP). In CAD patients, PCAT density was compared to local arterial inflammation measured by coronary motion-frozen 68Ga-DOTATATE PET using image registration software (FusionQuant), and systemic (aortic) inflammation using 18F-fluorodeoxyglucose (FDG) PET. Data was acquired either during routine clinical care or prior research that established 68Ga-DOTATATE as an experimental marker of arterial inflammation that binds macrophage somatostatin receptor-2 in atherosclerotic plaques (NCT02021188). Results 60 patients were included (TAK, n=20; CAD, n=20; healthy, n=20). Non-calcified plaque burden (TAK: 95.2%; CAD: 90.4%, p PCAT density varied significantly among the three groups (median [IQR] TAK: −72.9 [−81.2 to -66.1] Hounsfield unit [HU]; CAD: −79.9 [−88.0 to −72.2]; healthy: −83.8 [−90.1 to −75.8] HU, p PCAT density was significantly associated with ITAS (r=0.61, p=0.004) and CRP (r=0.43, p=0.03) in TAK patients, and coronary 68Ga-DOTATATE maximum tissue-to-blood ratio (r=0.31, p Conclusion PCAT density measured by CTCA is greater in TAK than CAD patients, and is associated with clinical and biochemical markers of disease activity in TAK, and coronary arterial inflammation measured by 68Ga-DOTATATE PET in CAD. PCAT could be a useful, easy to measure marker of coronary inflammation and disease activity in both TAK and CAD. PCAT density is greater in TAK than CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Wellcome Trust

Purpose Assess feasibility and interexaminer reliability of a new test of contrast sensitivity (CS) for pediatric populations. Methods The Double Happy (DH) measures CS using a method similar to the Teller Acuity Cards. The schematic DH face is 16 degrees in diameter with features of 0.3 c/d and a channel frequency of 0.8 c/d. DH log10 CS is in 0.15 log unit steps, 0.05 to 2.1. Participants were 43 unselected patients, ages 2 to 18 years: 23 were diagnosed with ocular disorders only; 20 were diagnosed with cerebral visual impairment (CVI). Two examiners measured DH log10 CS. Visual acuity (VA) was also measured. Results All 43 participants were tested for binocular DH log10CS. Cohen's kappa values for interexaminer reliability were fair. The between examiner ICC was +0.92 (P < 0.001). The mean difference between examiners was near zero, and the 95% CI was -0.44 to 0.45 log10CS. DH log10CS was near normal in the ocular disorder group and reduced in the CVI group. VA was reduced in both groups. DH log10 CS and VA were correlated (r = -0.65). DH log10 CS was a marginally better predictor of diagnosis than VA. Conclusions DH log10CS test was successful in a diverse pediatric population diagnosed with ocular disorders or CVI. Interexaminer reliability was comparable to that of adults tested previously using the same stimuli and methods. Both CS and VA are reduced in CVI. Translational Relevance CS and VA both should be tested in pediatric clinical populations, especially in those at risk of CVI.

As a result of longitudinal chromatic aberration (LCA), longer wavelengths are blurred when shorter wavelengths are in focus, and vice versa. As a result, LCA affects the color and temporal aspects of the retinal image with hyperopic defocus. In this experiment, we investigated how the sensitivity to temporal color contrast affects emmetropization. Ten-day-old chicks were exposed for three days to sinusoidal color modulation. The modulation was either blue/yellow flicker (BY) (n = 57) or red/green flicker (RG) (n = 60) simulating hyperopic defocus with and without a blue light component. The color contrasts tested were 0.1, 0.2, 0.3, 0.4, 0.6, and 0.8 Michelson contrast. The mean illuminance of all stimuli was 680 lux. Temporal modulation was either of a high (10 Hz) or low (0.2 Hz) temporal frequency. To test the role of short- and double-cone stimulation, an additional condition silenced these cones in RG_0.4 (D-) and was compared with RG_0.4 (D+) (n = 14). Changes in ocular components and refractive error were measured using Lenstar and a photorefractometer. With high temporal frequency BY representing an in-focus condition for shorter-wavelengths, we found that high temporal frequency BY contrast was positively correlated with vitreous expansion (R2 = 0.87, p

Fracture liaison services (FLS) address the treatment gap for those with osteoporosis (OP) who fracture and are not treated. Given the limited human resources in FLS, screening high volumes of radiology reports for fractures with Natural Language Processing (NLP) could identify patients that have not been recognized or treated. This study is an analytical and clinical validation of X-Ray Artificial Intelligence Tool software (XRAIT) at its development site (a tertiary hospital) and external validation in an adjudicated cohort from the Dubbo Osteoporosis Epidemiology Study (DOES).Methods: XRAIT uses NLP to perform a Boolean search of radiology reports for fracture and related terms. It can be trained for site-specific reporting styles and use rules to refine identification (e.g. age>50y; bone involved; etc). At the development site, XRAIT was used to search the emergency patient presentations of people over 50 years of age and compared to referrals to FLS (usual care) during the same 3-month period. XRAIT analyzed all plain radiographs and CT scans (n = 5089) while n = 224 were referred to FLS for usual care. External validation: XRAIT was used to analyze digitally readable radiology reports in an untrained cohort from DOES (n = 327) to calculate sensitivity and specificity.Results: XRAIT identified a 5-fold higher number of potential significant fractures (349/5089) compared to manual case finding (70/224). 339/349 were confirmed fractures (97.1%). Only 29% of those eligible were started or recommended anti-resorptive therapy, including those seen by the fracture liaison service. XRAIT unadjusted for the local radiology reporting styles in DOES had a sensitivity of 69.6% and specificity of 95%. Conclusion: XRAIT identifies clinically significant fractures efficiently with minimal additional human resources. Its high specificity in an untrained cohort suggests it could be used at other sites. Automated methods of patient identification may assist fracture liaison services to identify fractures that still remain largely untreated.

Rapid technological advances in noninvasive imaging, combined with their increased availability in health systems around the world, have helped transform clinical management in Takayasu arteritis (TA) and minimized the need for intra-arterial angiography. TA, a rare autoimmune granulomatous

Chicks respond to two signals from longitudinal chromatic aberration (LCA): a wavelength defocus signal and a chromatic signal. Wavelength defocus predicts reduced axial eye growth in monochromatic short-wavelength light, compared to monochromatic long-wavelength light. Wavelength defocus may also influence growth in broadband light. In contrast, a chromatic signal predicts increased growth when short-wavelength contrast > long-wavelength contrast, but only when light is broadband. We aimed to investigate the influence of blue light, temporal frequency and contrast on these signals under broadband conditions. Starting at 12 to 13 days-old, 587 chicks were exposed to the experimental illumination conditions for three days for 8h/day and spent the remainder of their day in the dark. The stimuli were flickering lights, with a temporal frequency of 0.2 or 10 Hz, low (30%) or high contrast (80%), and a variety of ratios of cone contrast simulating the effects of defocus with LCA. There were two color conditions, with blue contrast (bPlus) and without (bMinus). Stimuli in the “bPlus” condition varied the amounts of long- (L-), middle- (M-) and double- (D-) cone contrast, relative to short- (S-) and ultraviolet (UV-) cone contrast, to simulate defocus. Stimuli in the “bMinus” condition only varied the relative modulations of the L+D vs. M cones. In all cases, the average of the stimuli was white, with an illuminance of 777 lux, with cone contrast created through temporal modulation. A Lenstar LS 900 and a Hartinger refractometer were used to measure ocular components and refraction. Wavelength defocus signals with relatively high S-cone contrast resulted in reduced axial growth, and more hyperopic refractions, under low-frequency conditions (p = 0.002), in response to the myopic defocus of blue light. Chromatic signals with relatively high S-cone contrast resulted in increased axial growth and more myopic refractions, under high frequency, low contrast, conditions (p < 0.001). We conclude that the chromatic signals from LCA are dependent on the temporal frequency, phase, and relative contrast of S-cone temporal modulation, and recommend broadband spectral and temporal environments, such as the outdoor environment, to optimize the signals-for-defocus in chick.

A previous experiment showed that blue light (as a component of white light) protected against low temporal frequency dependent eye growth. This experiment investigated the role of temporal contrast. White leghorn chicks were exposed to white (with blue) or yellow (without blue) LED lighting modulated at either low (0.2 Hz) or high (10 Hz) temporal frequencies. Four cone contrast conditions were used: low (16%), medium (32%), medium-high (60%) and very-high (80%). Chicks were exposed to the lighting condition for 3 days (mean 680 lux). Exposure to high temporal frequencies, with very high temporal contrast, reduced eye growth, regardless of spectral content. However, at low temporal frequencies, eye growth was dependent on the illuminant. At lower temporal contrast levels, eye growth increased regardless of temporal or spectral characteristics. To conclude, very high temporal contrast, white light, provides a “stop” signal for eye growth that overrides temporal cues for growth that manifest in yellow light.

Purpose Longitudinal chromatic aberration can provide luminance and chromatic signals for emmetropization. A previous experiment examined the role of temporal sensitivity to luminance flicker in the emmetropization response. In the current experiment, we investigate the role of temporal sensitivity to color flicker. Methods Five-day-old chicks were exposed to sinusoidal color modulation of blue/yellow (N = 73) or red/green LEDs (N = 84) at 80% contrast for 3 days. The modulation frequencies used were as follows: 0, 0.2, 1, 2, 5, and 10 Hz. There were 5 to 16 chicks per condition. Mean illumination was 680 lux. Changes in ocular components were measured using Lenstar, and refraction was measured with a Hartinger refractometer. Results Eyes grew less when exposed to high temporal frequencies and more at low temporal frequencies. With blue/yellow modulation, the temporal variation was small; eyes grew 268 ± 15 μm at 0 Hz and 224 ± 12 μm at 10 Hz, representing a 16.4% growth reduction. With red/green modulation, eyes grew 336 ± 31 μm at 0 Hz and 218 ± 20 μm at 10 Hz, representing a 35% growth reduction. Choroidal and anterior chamber changes compensated for eye growth, reducing refractive effects; blue/yellow refraction changes ranged from -0.63 to 1.04 diopters. Conclusions At high temporal frequencies, color is not a factor, but at low temporal frequencies, red/green modulation produced maximal growth. The pattern of changes observed in each ocular component with changes in the temporal frequency and/or the color of the stimulus was consistent with the idea that the natural sunlight spectrum may be optimal for emmetropization.

Background Inadequate ankle syndesmotic reduction is a common and important cause of poor outcome after surgery. It is not clear what magnitude or planes of displacement impact most. Many computerised tomography (CT) measurement techniques rely on landmarks that are difficult to reproduce, and none measure all types of mal-positioning in a single protocol. The purpose of this study was to design and validate a protocol for measuring the distal tibio-fibular relationship. Methods We devised a method for measuring fibular diastasis, antero-posterior translation (APT) and fibular length on CT images. CTs of sixteen un-injured ankles were examined using our protocol and that of an established alternative method for comparison. The measurements were recorded by two independent observers and repeated for inter- and intra-observer agreement scores. Results Our method showed inter- and intra-observer agreement of r =0.994 and r =0.999, demonstrating strong agreement. This compared to r =0.218 and r =0.820 respectively for the comparative protocol. Conclusion This ankle CT measurement protocol is accurate, reproducible and simple to use. Its aim is to be a useful tool for clinicians to quantify post-operative mal-positioning of the distal fibula in comparison to the un-injured ankle. We believe that routine, bilateral, post-operative CT imaging will lead to improvements in the understanding and outcomes of the treatment of complex ankle fractures. To our knowledge no other validated measurement of fibular length on CT images exists in the literature.

The neural circuits responsible for behavior remain largely unknown. Previous efforts have reconstructed the complete circuits of small animals, with hundreds of neurons, and selected circuits for larger animals. Here we (the FlyEM project at Janelia and collaborators at Google) summarize new methods and present the complete circuitry of a large fraction of the brain of a much more complex animal, the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses, and proofread such large data sets; new methods that define cell types based on connectivity in addition to morphology; and new methods to simplify access to a large and evolving data set. From the resulting data we derive a better definition of computational compartments and their connections; an exhaustive atlas of cell examples and types, many of them novel; detailed circuits for most of the central brain; and exploration of the statistics and structure of different brain compartments, and the brain as a whole. We make the data public, with a web site and resources specifically designed to make it easy to explore, for all levels of expertise from the expert to the merely curious. The public availability of these data, and the simplified means to access it, dramatically reduces the effort needed to answer typical circuit questions, such as the identity of upstream and downstream neural partners, the circuitry of brain regions, and to link the neurons defined by our analysis with genetic reagents that can be used to study their functions.Note: In the next few weeks, we will release a series of papers with more involved discussions. One paper will detail the hemibrain reconstruction with more extensive analysis and interpretation made possible by this dense connectome. Another paper will explore the central complex, a brain region involved in navigation, motor control, and sleep. A final paper will present insights from the mushroom body, a center of multimodal associative learning in the fly brain.

BACKGROUND Registry data from the Human Fertilisation and Embryology Authority (HFEA) show an increase of 40% in IUI and 377% in IVF cases using donor sperm between 2006 and 2016. OBJECTIVE AND RATIONALE The objective of this study was to establish whether pregnancies conceived using donor sperm are at higher risk of obstetric and perinatal complications than those conceived with partner sperm. As more treatments are being carried out using donor sperm, attention is being given to obstetric and perinatal outcomes, as events in utero and at delivery have implications for long-term health. There is a need to know if there is any difference in the outcomes of pregnancies between those conceived using donor versus partner sperm in order to adequately inform and counsel couples. SEARCH METHODS We performed a systematic review and meta-analysis of the outcomes of pregnancies conceived using donor sperm compared with partner sperm. Searches were performed in the OVID MEDLINE, OVID Embase, CENTRAL and CINAHL databases, including all studies published before 11 February 2019. The search strategy involved search terms for pregnancy, infant, donor sperm, heterologous artificial insemination, donor gametes, pregnancy outcomes and perinatal outcomes. Studies were included if they assessed pregnancies conceived by any method using, or infants born from, donor sperm compared with partner sperm and described early pregnancy, obstetric or perinatal outcomes. The Downs and Black tool was used for quality and bias assessment of studies. OUTCOMES Of 3391 studies identified from the search, 37 studies were included in the review and 36 were included in the meta-analysis. For pregnancies conceived with donor sperm, versus partner sperm, there was an increase in the relative risk (RR) (95% CI) of combined hypertensive disorders of pregnancy: 1.44 (1.17–1.78), pre-eclampsia: 1.49 (1.05–2.09) and small for gestational age (SGA): 1.42 (1.17–1.79) but a reduced risk of ectopic pregnancy: 0.69 (0.48–0.98). There was no difference in the overall RR (95% CI) of miscarriage: 0.94 (0.80–1.11), gestational diabetes: 1.49 (0.62–3.59), pregnancy-induced hypertension (PIH): 1.24 (0.87–1.76), placental abruption: 0.65 (0.04–10.37), placenta praevia: 1.19 (0.64–2.21), preterm birth: 0.98 (0.88–1.08), low birth weight: 0.97 (0.82–1.15), high birthweight: 1.28 (0.94–1.73): large for gestational age (LGA): 1.01 (0.84–1.22), stillbirth: 1.23 (0.97–1.57), neonatal death: 0.79 (0.36–1.73) and congenital anomaly: 1.15 (0.86–1.53). WIDER IMPLICATIONS The majority of our findings are reassuring, except for the mild increased risk of hypertensive disorders of pregnancy and SGA in pregnancies resulting from donor sperm. However, the evidence for this is limited and should be interpreted with caution because the evidence was based on observational studies which varied in their quality and risk of bias. Further high-quality population-based studies reporting obstetric outcomes in detail are required to confirm these findings.

Hammersmith Hospital transplants around 200 kidneys per year and follows up around 300 transplant patients per week in the outpatient department. Upon discharge from hospital, the immediate postoperative period as an outpatient is crucial as clinicians make key decisions regarding management in

Melatonin is involved in regulation of a variety of physiologic functions, including circadian rhythm, reproduction, mood, and immune function. Exogenous melatonin has demonstrated many clinical effects. Numerous clinical studies have documented improved sleep quality following administration of exogenous melatonin. Recent studies also demonstrate the analgesic, anxiolytic, antiinflammatory, and antioxidative effects of melatonin. This article reviews the principal properties of melatonin and how these could find clinical applications in care of the critically ill patients.

In broadband light, longitudinal chromatic aberration (LCA) provides emmetropization signals from both wavelength defocus and the resulting chromatic cues. Indoor illuminants vary in their spectral output, potentially limiting the signals from LCA. Our aim is to investigate the effect that artificial illuminants with different spectral outputs have on chick emmetropization with and without low temporal frequency modulation. In Experiment 1, two-week-old chicks were exposed to 0.2 Hz, square-wave luminance modulation for 3 days. There were 4 spectral conditions: LED strips that simulated General Electric (GE) LED "Soft" (n = 13), GE LED "Daylight" (n = 12), a novel "Equal" condition (n = 12), and a novel "High S" condition (n = 10). These conditions were all tested at a mean level of 985 lux. In Experiment 2, the effect of intensity on the "Equal" condition was tested at two other light levels (70 lux: n = 10; 680 lux: n = 7). In Experiment 3, the effect of temporal modulation on the "Equal" condition was tested by comparing the 0.2 Hz condition with 0 Hz (steady). Significant differences were found in axial growth across lighting conditions. At 985 lux, birds exposed to the "Equal" condition showed a greater reduction in axial growth (both p 0.01) and a greater hyperopic shift compared to "Soft" and "Daylight" (both p 0.01). The "High S" birds experienced more axial growth compared to "Equal" (p 0.01) but less than in "Soft" and "Daylight" (p 0.01). Axial changes in "Equal" were only observed at 985 lux with 0.2 Hz temporal modulation, and not with lower light levels or steady light. We conclude that axial growth and refraction were dependent on the lighting condition in a manner predicted by wavelength defocus signals arising from LCA.

Introduction:. Hydroxyurea (HU) is a drug that targets the underlying pathophysiology of sickle cell disease (SCD); however, it continues to be an underutilized treatment for adults. Previous research suggests that HU treatment can result in fewer hospital contacts for acute vaso-occlusive pain crises (VOC). Hydroxyurea's impact on non-VOC pain, however, is not well established. Objectives:. This study examined whether HU moderated patterns of static and dynamic pain processing and clinical pain in SCD individuals. Methods:. Fifty-eight patients with SCD (N taking HU = 17) underwent quantitative sensory testing (QST) and completed twice daily symptom diaries for 12 weeks. Quantitative sensory testing established thermal threshold and tolerance, mechanical thresholds, and thermal and mechanical temporal summation of pain. Results:. Groups did not differ in age, sex, or opioid use. After controlling for morphine use, QST results showed that participants taking HU had higher heat and mechanical pain thresholds (static QST measures) but not thermal and mechanical temporal summation (dynamic QST measures). Participants taking HU also reported lower VOC pain compared with SCD participants not taking HU; however, HU did not moderate non-VOC clinical pain ratings. Conclusion:. Findings cautiously suggest that HU acts on pain hypersensitivity and VOC pain, rather than inhibiting pain facilitation and non-VOC pain. These differences may reflect HU's influence on peripheral rather than central sensitization. Future research is warranted to replicate these findings in a larger sample and determine whether early HU administration can prevent peripheral sensitization in SCD individuals.

Background: Sedative agents used during cardiac surgery can influence the patient’s time to extubation, intensive care unit (ICU) and hospital length of stay, and incidence of delirium. Objective: This study evaluates the effects of the intraoperative and postoperative use of dexmedetomidine versus propofol infusions. Methods: This 19-month retrospective observational study at an academic medical center included 278 patients 18 years of age or older who underwent coronary artery bypass grafting (CABG), valve replacement surgery, or combined CABG plus valve surgery, who received either a dexmedetomidine or propofol infusion in addition to general anesthesia intraoperatively. The primary outcome was time to extubation. The secondary outcomes were ICU and hospital length of stay and incidence of delirium. Results: Use of dexmedetomidine (n = 69) as an intraoperative and postoperative sedative as opposed to propofol (n = 209) was significantly associated with increased likelihood of extubation (ie, shorter time to extubation; hazard ratio = 1.63, 95% CI = 1.21-2.19, P = 0.001). There was no significant association between use of dexmedetomidine and ICU discharge ( P = 0.99), hospital discharge ( P = 0.52), and incidence of delirium ( P = 0.27) after adjusting for other covariates. Conclusion and Relevance: Dexmedetomidine increased the likelihood of extubation when compared with propofol, with no increase in ICU or hospital length of stay or incidence of delirium. Our study is unique in that there was no crossover between patients who received dexmedetomidine and propofol infusions intraoperatively and postoperatively Dexmedetomidine-based regimens could serve as a suitable alternative to propofol-based regimens for fast-track extubation.

Background: cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. Methods: we conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. Results: we analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12–4.02; PConclusions: a significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.

Blur is a useful cue for depth. Natural images contain objects at a range of depths whose depth can be signaled by their perceived blur. Here, to evaluate the usefulness of blur as a depth cue, we estimate the number blur levels that observers can perceive simultaneously. To estimate this value, observers discriminated and classified dead leaves patterns that contained a controlled distribution of blur levels but are more complex or naturalistic than stimuli typically used in blur research. We used a 2-IFC discrimination task, in which observers reported the interval that contained more blur levels and a classification task, in which observers reported the number of perceived blur levels. In both tasks, observers could not discriminate or classify more than four levels of blur in the stimulus reliably. In isolation from other cues, blur may provide only a coarse cue to depth and add limited depth information when present in natural scenes with complex distributions of blur and multiple depth cues.

Obesity and insulin resistance are primary risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is generally exhibited by non-progressive simple steatosis. However, a significant subset of patient's progress to nonalcoholic steatohepatitis (NASH) that is defined by the presence of steatosis, inflammation and hepatocyte injury with fibrosis. Unfortunately, there are no approved therapies for NAFLD or NASH and therefore therapeutic approaches are urgently needed. Niclosamide is an U.S. Food and Drug Administration (FDA)-approved anthelmintic drug that mediates its effect by uncoupling oxidative phosphorylation. Niclosamide and its salt forms, Niclosamide Ethanolamine (NEN), and Niclosamide Piperazine (NPP) have shown efficacy in murine models of diet induced obesity characterized by attenuation of the prominent fatty liver disease phenotype and improved glucose metabolism. While the exact mechanism(s) underlying these changes remains unclear, the ability to uncouple oxidative phosphorylation leading to increased energy expenditure and lipid metabolism or attenuation of PKA mediated glucagon signaling in the liver have been proposed. Unfortunately, niclosamide has very poor water solubility, leading to low oral bioavailability. This, in addition to mitochondrial uncoupling activity and potential genotoxicity have reduced enthusiasm for its clinical use. More recently, salt forms of niclosamide, NEN and NPP, have demonstrated improved oral bioavailability while retaining activity. This suggests that development of safer more effective niclosamide derivatives for the treatment of NAFLD and Type 2 Diabetes may be possible. Herein we explored the ability of a series of N-substituted phenylbenzamide derivatives of the niclosamide salicylanilide chemotype to attenuate hepatic steatosis using a novel phenotypic in vitro model of fatty liver and the high fat diet-fed mouse model of diet induced obesity. These studies identified novel compounds with improved pre-clinical properties that attenuate hepatic steatosis in vitro and in vivo. These compounds with improved drug properties may be useful in alleviating symptoms and protection against disease progression in patients with metabolic syndrome and NAFLD.

To evaluate the Spot Vision Screener in detecting targeted vision disorders compared to cycloplegic retinoscopy in children3 years of age.Children, ages 6 months to 36 months underwent vision screening using the Spot Vision Screener. Results were compared to results of comprehensive eye examinations. Validity of the Spot was evaluated by calculating the area under the curve (AUC); the receiver operating characteristics (ROC) were used to determine optimal sensitivity and specificity for detection of targeted vision disorders.A total of 249 children were included. The AUC for detecting targeted vision disorders as defined by the study specific criteria using the Spot was 0.790. Compared to cycloplegic retinoscopy, the Spot underestimated hyperopia by 1.02 D (95% CI, 0.86-1.17 D). For hyperopia ≥4.5 D spherical equivalent (n = 10), the mean difference between the Spot and cycloplegic retinoscopy was 3.46 D (95% CI, 1.95-4.98 D). In contrast, the Spot overestimated astigmatism compared to cycloplegic retinoscopy (-1.00 D vs -0.48 D; P 0.001) by -0.52 D (95% CI, 0.43-0.62 D).The Spot Vision Screener showed good overall validity in detecting targeted vision disorders. It was within 0.5 D and 1 D of cycloplegic retinoscopy with regard to low hyperopia and astigmatism. Higher hyperopic spherical equivalent refractive errors showed larger differences in mean values between the Spot and cycloplegic retinoscopy.

Echinocandins are a first-line therapy for candidemia and invasive candidiasis. They are generally safe with few drug interactions, but the stability and pharmacokinetic properties of currently approved echinocandins are such that each was developed for daily intravenous infusion. We sought to discover a novel echinocandin with properties that would enable more flexible dosing regimens, alternate routes of delivery, and expanded utility. Derivatives of known echinocandin scaffolds were generated, and an iterative process of design and screening led to the discovery of CD101, a novel echinocandin that has since demonstrated improved chemical stability and pharmacokinetics. Here, we report the structure-activity relationships (including preclinical efficacy and pharmacokinetic data) for the series of echinocandin analogs from which CD101 was selected. In a mouse model of disseminated candidiasis, the test compounds displayed clear dose responses and were generally associated with lower fungal burdens than that of anidulafungin. Single-dose pharmacokinetic studies in beagle dogs revealed a wide disparity in the half-lives and volumes of distribution, with one compound (now known as CD101) displaying a half-life that is nearly 5-fold longer than that of anidulafungin (53.1 h versus 11.6 h, respectively). In vitro activity data against panels of Candida spp. and Aspergillus spp. demonstrated that CD101 behaved similarly to approved echinocandins in terms of potency and spectrum of activity, suggesting that the improved efficacy observed in vivo for CD101 is a result of features beyond the antifungal potency inherent to the molecule. Factors that potentially contribute to the improved in vivo efficacy of CD101 are discussed.

Objectives Sickle cell disease (SCD) is associated with high healthcare utilization rates and poor outcomes in a subset of patients, although the underlying factors that predict this phenotype are poorly understood. Prior studies suggest that comorbid avascular necrosis (AVN) contributes to high healthcare utilization. We sought to clarify whether AVN independently predicts acute care utilization in adults with SCD and to identify characteristics of those with AVN that predict higher utilization. Methods We reviewed the medical records of 87 patients with SCD with symptomatic AVN and compared acute care utilization and clinical characteristics with 87 sex- and age-matched patients with SCD without symptomatic AVN. Patients with ≥2 years of follow-up were included. Outcomes were compared using bivariate analysis and multivariate regression. Results Our study included 1381 follow-up years, with a median of 7 years per patient. The AVN cohort had greater median rates of urgent care visits (3.2/year vs 1.3/year; P = 0.0155), admissions (1.3/year vs 0.4/year; P = 0.0002), and admission days (5.1 days/year vs 1.8 days/year; P = 0.0007). History of high utilization (odds ratio [OR] 4.28; P = 0.001), acute chest syndrome (OR 3.12; P = 0.005), pneumonia (OR 3.20; P = 0.023), hydroxyurea therapy (OR 2.23; P = 0.0136), and long-term transfusion (OR 2.33; P = 0.014) were associated with AVN. In a median regression model, AVN, acute chest syndrome, and pneumonia were independently associated with greater urgent care visits and admissions. Conclusions Symptomatic AVN was found to be an independent risk factor for acute care utilization in patients with SCD. Because this is a potentially modifiable factor, further studies are urgently needed to determine whether AVN prevention/early treatment interventions will alter utilization and improve outcomes for patients with SCD.

Gifted girls and gifted boys are more alike than they are different, although researchers remain fascinated with sex differences. Small differences between gifted boys and girls in achievements, interests, careers, and relationships can become exaggerated through gendered educational practices. Kindergarten “red-shirting'' of boys and the denial of early admission to girls can cause gifted children to be out of step throughout their academic careers. When gifted children are not actively encouraged to participate in talent searches and after-school and summer programs, whether because of overprotection of girls or the insistence on athletic activities at the expense of academic activities for boys, they lose the opportunity for challenge, friendships, and community. When boys are not supported in their interests in creative careers and girls are not supported in their interests in science, technology, engineering, and mathematics careers, they may enter occupations that will not offer them the sense of purpose and meaning they might have otherwise had. It is in the area of gender relations, however, that long-term consequences of gendered practices are most apparent for gifted individuals because both gifted boys and girls need to plan for balancing family and career. © 2012 Wiley Periodicals, Inc.

Background: The management of pain in adults with sickle cell disease (SCD) is complex, with the intermingling of both acute vaso-occlusive events and chronic daily pain. Sixty percent of adults with SCD suffer with every day chronic pain. In patients with frequent acute visits we use aggressive disease modifying therapy to decrease the risk of VOC yet there remains a subset of patients who continue to have frequent acute visits for pain. In addition, there are patients maintained on high doses of oral opioids as outpatients who continue to have high levels of daily pain. There is little data that escalating doses of opioids is associated with benefit, yet significant data to support that higher doses are associated with harms. We consider these to be cases of opioid failure. Identifying therapies for these patients that improve quality of life is essential. Buprenorphine is a partial mu opioid receptor agonist and kappa antagonist, and has a very high affinity for the mu receptors, with an elimination half-life of 28-37 hours for the sublingual administration. The reduced risk of overdose, lower risk for misuse, diminished withdrawal symptoms, and blunting of opioid craving make it an appealing alternative to full opioid agonists in a subset of patients with SCD who continue to have significant pain or are unable to wean off of ineffective opioid therapy. The purpose of this report is to describe our experience converting patients with SCD and chronic pain from chronic opioid therapy to buprenorphine. Methods: Routine clinical care in our clinic includes offering buprenorphine transition to patients on chronic opioid therapy with numerous acute care visits despite the use of disease modifying therapy; or patients on chronic opioid therapy reporting significant ongoing pain. Patients are typically weaned to lower opioid doses (goal 90 oral morphine equivalents) prior to the planned induction with buprenorphine. Once patients are at the goal dose, they are asked to hold opioids for 12-24 hours prior to presentation so that they are in at least mild opioid withdrawal prior to their first dose of buprenorphine to avoid precipitated withdrawal. The patient is assessed with the Clinical Opiate Withdrawal Scale (COWs) and if their score is 5 or higher they are administered their first dose of sublingual buprenorphine. If COWs scores are less than 5, buprenorphine is not initiated and the subject is asked to return the following day or earlier if withdrawal symptoms begin. Patients are reassessed with the COWs and dosed with buprenorphine hourly until withdrawal has ceased. The dose needed to minimize withdrawal is considered the working total daily dose. Patients are sent home and return the next day to start their once daily dose of buprenorphine. Urine toxicology testing is done the day of planned induction. Data on acute visits 6 months prior and 6 months post induction and on complications associated with induction were pulled from the electronic health record. Results: 21 patients have been converted from full agonist opioids to buprenorphine from 3/2015-6/1/2018. The average age of the patients at the time of induction was 36.1 years (SD 9.1), 62% were female. Sixteen (76 %) of the patients had sickle cell anemia, the remainder had variant genotypes. The mean dose (in morphine equivalents) of full agonist opioid that patients were on prior to weaning of opioids was 196.8 mg (SD 222.7) and just prior to induction was 85 mg (SD 70 mg) with a range of 11.4 to 315 mg. Seventeen patients tolerated the induction without any complications, 2 patients had abdominal cramps but were successfully converted, 2 patients has adverse reactions (1 had numbness of tongue and 1 with worsening of asthma) and buprenorphine was stopped. Of the 19 patients successfully converted, two chose to stop buprenorphine and resume taking full opioid agonists. For the 13 patients with 6 months of follow-up post induction, the median number of acute care visits prior to induction was 12.5 and post was 4.0 (Figure). Conclusions: Adults with sickle cell disease on chronic full agonist opioid therapy can be safely converted to buprenorphine. Acute care utilization has dropped significantly for patients post induction. Assessment of patient reported outcomes such as quality of life and pain interference are being collected. Buprenorphine appears to be a safe and effective medication in the management of pain in adults with SCD. Figure. Figure. Disclosures Lanzkron: PCORI: Research Funding; GBT: Research Funding; Prolong: Research Funding; Pfizer: Research Funding; selexys: Research Funding; NHLBI: Research Funding; HRSA: Research Funding; Ironwood: Research Funding.

This report is an update of the 2013 Market Research Survey1-3 of field-deployable commercial off-the-shelf (COTS) mass spectrometry instruments for safeguards application.

SummaryDiscriminating the direction of motion of a low-contrast pattern becomes easier with increasing stimulus area. However, increasing the size of a high-contrast pattern makes it more difficult for observers to discriminate motion. This surprising result, termed spatial suppression, is thought to be mediated by a form of center-surround suppression found throughout the visual pathway. Here, we examine the counterintuitive hypothesis that aging alters such center-surround interactions in ways that improve performance in some tasks. We found that older observers required briefer stimulus durations than did younger observers to extract information about stimulus direction in conditions using large, high-contrast patterns. We suggest that this age-related improvement in motion discrimination may be linked to reduced GABAergic functioning in the senescent brain, which reduces center-surround suppression in motion-selective neurons.

The standard model of early vision claims that orientation and spatial frequency are encoded with multiple, quasi-independent channels that have fixed spatial frequency and orientation bandwidths. The standard model was developed using detection and discrimination data collected from experiments that used deterministic patterns such as Gabor patches and gratings used as stimuli. However, detection data from experiments using noise as a stimulus suggests that the visual system may use adjustable-bandwidth, rather than fixed-bandwidth, channels. In our previous work, we used classification images as a key piece of evidence against the hypothesis that pattern detection is based on the responses of channels with an adjustable spatial frequency bandwidth. Here we tested the hypothesis that channels with adjustable orientation bandwidths are used to detect two-dimensional, filtered noise targets that varied in orientation bandwidth and were presented in white noise. Consistent with our previous work that examined spatial frequency bandwidth, we found that detection thresholds were consistent with the hypothesis that observers sum information across a broad range of orientations nearly optimally: absolute efficiency for stimulus detection was 20-30% and approximately constant across a wide range of orientation bandwidths. Unlike what we found with spatial frequency bandwidth, the results of our classification image experiment were consistent with the hypothesis that the orientation bandwidth of internal filters were adjustable. Thus, for orientation summation, both detection thresholds and classification images support the adjustable channels hypothesis. Classification images also revealed hallmarks of inhibition or suppression from uninformative spatial frequencies and/or orientations. This work highlights the limitations of the standard model of summation for orientation. The standard model of orientation summation and tuning was chiefly developed with narrow-band stimuli that were not presented in noise, stimuli that are arguably less naturalistic than the variable bandwidth stimuli presented in noise used in our experiments. Finally, the disagreement between the results from our experiments on spatial frequency summation with the data presented in this paper suggests that orientation may be encoded more flexibly than spatial frequency channels.

• PURPOSE: To assess whether brimonidine 0.15% alters retinal vascular autoregulation and short-term visual function in normal tension glaucoma patients who demonstrate retinal vascular dysregulation. • DESIGN: Nonrandomized clinical trial. • METHODS: In this prospective study, 46 normal tension glaucoma patients not previously treated with brimonidine underwent retinal vascular autoregulation testing and visual function assessment using frequency doubling technology perimetry and equivalent noise motion sensitivity testing. We measured blood flow in a major temporal retinal artery with subjects seated and then while reclined for 30 minutes. Patients having a change in retinal blood flow with posture change outside the range previously found in healthy subjects were classified as having retinal vascular dysregulation. They were treated with brimonidine 0.15% for 8 weeks and designated for retesting. • RESULTS: Twenty-three patients demonstrated retinal vascular dysregulation at the initial visit. Younger age (P = .050) and diabetes (P = .055) were marginally significant risk factors for retinal vascular dysregulation. After the 8-week course with brimonidine, 14 of the 17 patients who completed the study showed a return of posture-induced retinal blood flow changes to levels consistent with normal retinal vascular autoregulation (P < .0001). We found no significant changes in frequency doubling technology perimetry or in motion detection parameters following treatment with brimondine (P > .09 for all tests performed). • CONCLUSIONS: Brimonidine significantly improved impaired retinal vascular autoregulation in normal tension glaucoma patients, but short-term alteration in visual function could not be demonstrated.

While recent work in lyric theory has put the generic category of the lyric into radical question, less attention has been paid to how lyric poets employ the instabilities of figuration and reference to critical, and ultimately social, ends. Taking as a test case the most popular poet of a regionally authentic American lyric, Robert Frost, I argue that Frost uses techniques of lyric voicing to critique the very means by which persons appear as familiar individuals, of a sociality or place, and therefore worthy of certain liberties and property claims. I draw upon Frost’s early New England poems, his relationship with Edward Thomas, as well as his final public lecture, “On Extravagance” to show how he links “drifts” in reference and cumulative “shifts” in sound or sense to the lived experience of transience, particularly within the context of rural economies. Frost allies the vocation of poetry and lyric form not with a rugged isolationism but a more conditional notion of freedom, one that forms across a variety of egoisms, boundaries, and moral or ethical values.

Kersten [Vision Res. 27, 1029 (1987)] reported that absolute efficiency for the detection of static, one-dimensional bandpass noise was high and approximately constant for stimulus bandwidths ranging from 1 to 6 octaves. This result implies that human observers integrated information efficiently across a wide range of spatial frequency. One interpretation of this result--and similar results obtained with auditory stimuli [J. Acoust. Soc. Am. 32, 121 (1960)]--is that human observers, like ideal observers, can detect stimuli using an internal filter that has an adjustable bandwidth. The current experiments replicate Kersten's findings, extend them to the case where observers are uncertain about stimulus bandwidth, and use the classification image technique to estimate the filter used to detect noise stimuli that differ in bandwidth. Our results suggest that observers do not adjust channel bandwidth to match the stimulus and that detection thresholds are consistent with the predictions of a multiple-channel model.

Introduction: Sickle cell disease (SCD) is linked to high healthcare utilization, with a small subpopulation of patients accounting for a disproportionate share of healthcare use. Examination of the high utilizer population shows an association with avascular necrosis (AVN). To develop interventions to mitigate hospital utilization, we aimed to clarify this relationship. By comparing utilization rates and the clinical characteristics of SCD patients with and without AVN, our goals were to test the hypothesis that AVN would serve as an independent risk factor for utilization, and identify characteristics of those with AVN that predict higher hospital utilization. Methods: We reviewed medical records at the Johns Hopkins Sickle Cell Center for Adults to identify a sample of 87 SCD (all genotypes) patients that had been diagnosed with symptomatic AVN (femoral or humeral head) who were then individually sex- and age-matched (±5 years as of 1/31/2014) with 87 SCD patients without a symptomatic AVN diagnosis. All patients were ≥18 years old. Positive AVN diagnosis was confirmed through clinical documentation and radiographic imaging. For those with AVN, baseline was defined as the date of AVN diagnosis, and if unknown, the date of established care. For those without AVN, baseline was defined as the date of established care. All patients had ≥2 years of follow up; years without encounters were excluded. From baseline to 1/31/2014 or date of death, we collected data on the frequency of hospitalizations and acute visits to the emergency department (ED) and Sickle Cell Infusion Center (SCIC). Additionally, we recorded steady-state outpatient laboratory and clinical markers associated with AVN and/or high hospital utilization. Utilization rates per patient were calculated as ED and SCIC visits (acute care) per year of follow up and admissions per year of follow up. Student's t-tests, Wilcoxon signed-rank tests, and Mantel-Haenszel pooled odds ratios were used for bivariate analyses. Variables from significant bivariate tests (p≤0.05) and traditional AVN comorbidities were then used in a median regression risk factor model for acute care and inpatient utilization. Results: The sample was 59.7% female, with a mean match age of 41 years (24 – 71 years, as of 1/31/2014). The study included 1,381 follow up years, with a median of 7 years per patient (IQR: 5 – 10 years). Patients with SS (HbSS or HbSβ0-thalassemia) constituted 72.4% of the sample, and had a lower mean match age of 39 years compared to 45 years for patients with variant genotypes (p=0.0059). The mean age at AVN diagnosis was also lower for SS patients than for those with variant genotypes. Genotype and follow-up period distributions were comparable for both cohorts. In bivariate analysis, the AVN cohort had significantly greater rates of acute visits and admissions (Figure 1). Additionally, history of high utilization (≥4 hospital visits/yr), acute chest syndrome (ACS), pneumonia (PNA), and hydroxyurea therapy were all significantly associated with a greater prevalence of AVN (Table 1). Of note, we did not find meaningful differences in laboratory values between cohorts. In a regression model controlling for comorbidities and genotype, AVN, ACS, and PNA were independently associated with a greater number of acute visits and admissions per year (Table 2). Conclusion: AVN is an independent risk factor for acute care utilization in patients with SCD. Because this is a potentially modifiable risk factor, further investigation of AVN in SCD is urgently needed. Hospital utilization increases with disease severity, and accordingly, treating or preventing complications such as AVN may have a great impact. Figure 1 Figure 1. Disclosures Haywood: NHLBI: Research Funding. Lanzkron:NHLBI: Research Funding.

Purpose: In contrast to the dominant medical liquid crystal display (LCD) technology, organic light-emitting diode (OLED) monitors control the display luminance via separate light-emitting diodes for each pixel and are therefore supposed to overcome many previously documented temporal artifacts of medical LCDs. We assessed the temporal and luminance characteristics of the only currently available OLED monitor designed for use in the medical treatment field (SONY PVM2551MD) and checked the authors’ main findings with another SONY OLED device (PVM2541). Methods: Temporal properties of the photometric output were measured with an optical transient recorder. Luminances of the three color primaries and white for all 256 digital driving levels (DDLs) were measured with a spectroradiometer. Between the luminances of neighboring DDLs, just noticeable differences were calculated according to a perceptual model developed for medical displays. Luminances of full screen (FS) stimuli were compared to luminances of smaller stimuli with identical DDLs. Results: All measured luminance transition times were below 300 μs. Luminances were independent of the luminance in the preceding frame. However, for the single color primaries, up to 50.5% of the luminances of neighboring DDLs were not perceptually distinguishable. If two color primaries were active simultaneously, between 36.7% and 55.1% of neighboring luminances for increasing DDLs of the third primary were even decreasing. Moreover, luminance saturation effects were observed when too many pixels were active simultaneously. This effect was strongest for white; a small white patch was close to 400 cd/m2, but in FS the luminance of white saturated at 162 cd/m2. Due to different saturation levels, the luminance of FS green and FS yellow could exceed the luminance of FS white for identical DDLs. Conclusions: The OLED temporal characteristics are excellent and superior to those of LCDs. However, the OLEDs revealed severe perceptually relevant artifacts with implications for applicability to medical imaging.