Intraspecific variation and directional casque asymmetry in adult southern cassowaries (Casuarius casuarius).

The cranial casques of modern cassowaries (Casuarius) have long intrigued researchers; however, in-depth studies regarding their morphological variation are scarce. Through visual inspection, it has been recognized that casque variability exists between conspecifics. Understanding casque variation has both evolutionary and ecological importance. Although hypothesized to be targeted by selection, intraspecific casque variation has not been quantified previously. Through a large sample of C. casuarius (n = 103), we compared casque shape (lateral and rostral views) between sexes and between individuals from non-overlapping geographical regions using two-dimensional (2D) geometric morphometrics. We found no statistically significant differences between the casque shape of females and males and few substantial shape differences between individuals from different geographic areas. Much of the intraspecific variation within C. casuarius is due to casque asymmetries (77.5% rightward deviating, 20.7% leftward deviating, and 1.8% non-deviating from the midline; n = 111), which explain the high variability of southern cassowary casque shape, particularly from the rostral aspect. Finally, we discuss how our non-significant findings implicate social selection theory, and we identify the benefits of quantifying such variation for further elucidating casque function(s) and the social biology of cassowaries.

Validation of the traditional Chinese version of the Sinus and Nasal Quality of Life Survey (SN-5) for children.

BACKGROUND: Persistent sinonasal symptoms are common in children with chronic rhinosinusitis. The Sinus and Nasal Quality of Life (QoL) Survey (SN-5) was the first validated questionnaire measuring sinonasal-related QoL in populations aged 2-12 years. No norm has been established for Chinese-speaking countries. We translated the SN-5 into traditional Chinese and evaluated validity and reliability. METHODS: From December 2016 to December 2017, healthy volunteers and children with persistent sinonasal symptoms were enrolled. Guardians of the participants completed the SN-5, a visual analog scale (VAS) of nasal symptoms, and the Obstructive Sleep Apnea-18 (OSA-18); the responses were used to assess internal consistency, discriminant validity, and treatment responsiveness. A nontreatment group was administered the SN-5 1 week later to assess test-retest reliability. RESULTS: We recruited 31 healthy volunteers and 85 children with rhinosinusitis, 50 and 35 in the treatment and nontreatment groups, respectively. The SN-5 demonstrated good internal consistency (Cronbach's α = 0.86) and test-retest reliability (0.74, p < 0.01). It exhibited good discriminant validity between the healthy and rhinosinusitis groups (p < 0.001). The SN-5 scores were correlated with the VAS scores (0.63, p < 0.001). The effect size of the SN-5 scores was 0.51. The total SN-5 and OSA-18 scores changed significantly after 4-week treatment (p < 0.05) and demonstrated good responsiveness. The SN-5 and OSA-18 scores were significantly and positively correlated (r2 = 0.53, p < 0.001). CONCLUSION: Our traditional Chinese version of the SN-5 is reliable and valid for measuring sinonasal-related QoL in children in Chinese-speaking countries. TRIAL REGISTRATION NUMBER: NCT04836403.

Fixation Principles in Minimal Incision Hallux Valgus Surgery.

Minimal incision surgical principals rely on the soft tissue envelope to maintain stability that is supplemented by a variety of clinically recommended fixation methods. The extended distal first metatarsal osteotomy has renewed interest because of the ability to laterally translate, angulate, and rotate the metatarsal head in proper alignment with the sesamoids to a neutral alignment. The soft tissue envelope of capsule, ligaments, and tendons will re-align once the bone deformity is corrected. The periosteum is maintained to provide a biologic scaffold for new bone formation and must be minimally disrupted during the intervention."

Rate and risk factors for post-adenotonsillectomy complications in children under 24 months and 24 to 36 months old.

PURPOSE: The primary purpose of this study was to assess the overall rate of postoperative complications after adenotonsillectomy in children under 24 months old relative to children 24-36 months old. Our secondary goal focused on quantifying specific preoperative risk factors that predispose children to postoperative complications. METHODS: We retrospectively reviewed 248 patients who underwent adenotonsillectomy at our ENT office from 2006 to 2011. We stratified these patients into two groups: under 2 years old; and 2-3 years old. We identified 42 preoperative risk factors and 22 postoperative complications for each age group and conducted tests of statistical significance. RESULTS: We found that children under 24 months old had a statistically significant higher postoperative complication rate of 38% compared to 22.3% in children 2-3 years old (p = 0.0320, chi-squared test). For specific complications, younger children had a higher rate of respiratory distress within 24 h (p = 0.0355), endotracheal re-intubation (p = 0.0281), and retractions (p = 0.0281). The only identified risk factors aside from age demonstrating statistical significance were nasal steroid sprays used preoperatively in children under 24 months (p = 0.005) and concurrent tympanostomy tube placement in children 24-36 months (p = 0.026). CONCLUSION: Our data demonstrates that children under 2 years of age have an overall increased rate of postoperative complications after adenotonsillectomy when compared to children between 2 and 3 years old, with a significantly higher rates of early respiratory distress, endotracheal re-intubation, and retractions. This study is one of the largest that compares postoperative complication rates and risk factors after adenotonsillectomy in this age group.

Chaste: Cancer, Heart and Soft Tissue Environment.

Chaste (Cancer, Heart And Soft Tissue Environment) is an open source simulation package for the numerical solution of mathematical models arising in physiology and biology. To date, Chaste development has been driven primarily by applications that include continuum modelling of cardiac electrophysiology ('Cardiac Chaste'), discrete cell-based modelling of soft tissues ('Cell-based Chaste'), and modelling of ventilation in lungs ('Lung Chaste'). Cardiac Chaste addresses the need for a high-performance, generic, and verified simulation framework for cardiac electrophysiology that is freely available to the scientific community. Cardiac chaste provides a software package capable of realistic heart simulations that is efficient, rigorously tested, and runs on HPC platforms. Cell-based Chaste addresses the need for efficient and verified implementations of cell-based modelling frameworks, providing a set of extensible tools for simulating biological tissues. Computational modelling, along with live imaging techniques, plays an important role in understanding the processes of tissue growth and repair. A wide range of cell-based modelling frameworks have been developed that have each been successfully applied in a range of biological applications. Cell-based Chaste includes implementations of the cellular automaton model, the cellular Potts model, cell-centre models with cell representations as overlapping spheres or Voronoi tessellations, and the vertex model. Lung Chaste addresses the need for a novel, generic and efficient lung modelling software package that is both tested and verified. It aims to couple biophysically-detailed models of airway mechanics with organ-scale ventilation models in a package that is freely available to the scientific community. Chaste is designed to be modular and extensible, providing libraries for common scientific computing infrastructure such as linear algebra operations, finite element meshes, and ordinary and partial differential equation solvers. This infrastructure is used by libraries for specific applications, such as continuum mechanics, cardiac models, and cell-based models. The software engineering techniques used to develop Chaste are intended to ensure code quality, re-usability and reliability. Primary applications of the software include cardiac and respiratory physiology, cancer and developmental biology.

Lung Computational Models and the Role of the Small Airways in Asthma.

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique-derived resistance at 5 Hz (R5) - resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date.Objectives: To validate the use of forced oscillation R5 - R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma.Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 - R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137).Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 - R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 - R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%.Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 - R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics.

Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

Functional CT imaging for identification of the spatial determinants of small-airways disease in adults with asthma.

BACKGROUND: Asthma is a disease characterized by ventilation heterogeneity (VH). A number of studies have demonstrated that VH markers derived by using impulse oscillometry (IOS) or multiple-breath washout (MBW) are associated with key asthmatic patient-related outcome measures and airways hyperresponsiveness. However, the topographical mechanisms of VH in the lung remain poorly understood. OBJECTIVES: We hypothesized that specific regionalization of topographical small-airway disease would best account for IOS- and MBW-measured indices in patients. METHODS: We evaluated the results of paired expiratory/inspiratory computed tomography in a cohort of asthmatic (n = 41) and healthy (n = 11) volunteers to understand the determinants of clinical VH indices commonly reported by using IOS and MBW. Parametric response mapping (PRM) was used to calculate the functional small-airways disease marker PRMfSAD and Hounsfield unit (HU)-based density changes from total lung capacity to functional residual capacity (ΔHU); gradients of ΔHU in gravitationally perpendicular (parallel) inferior-superior (anterior-posterior) axes were quantified. RESULTS: The ΔHU gradient in the inferior-superior axis provided the highest level of discrimination of both acinar VH (measured by using phase 3 slope analysis of multiple-breath washout data) and resistance at 5 Hz minus resistance at 20 Hz measured by using impulse oscillometry (R5-R20) values. Patients with a high inferior-superior ΔHU gradient demonstrated evidence of reduced specific ventilation in the lower lobes of the lungs and high levels of PRMfSAD. A computational small-airway tree model confirmed that constriction of gravitationally dependent, lower-zone, small-airway branches would promote the largest increases in R5-R20 values. Ventilation gradients correlated with asthma control and quality of life but not with exacerbation frequency. CONCLUSIONS: Lower lobe-predominant small-airways disease is a major driver of clinically measured VH in adults with asthma.

Faecal indicator organism inputs to watercourses from streamside pastures grazed by cattle: Before and after implementation of streambank fencing.

Faecal indicator organisms (FIOs) are major pollutants in many catchments world-wide, with streamside pastures on livestock farms being potentially significant sources. Hitherto, few empirical studies have quantified FIO fluxes from such areas or investigated streambank fencing (SBF) and other possible mitigation measures. The aim of this two-phase (before/after intervention) study of the effectiveness of SBF was to generate an empirical evidence-base to enable regulatory authorities to make better-informed decisions concerning the implementation of this measure. It was undertaken during the summer bathing season along a 271 m stream reach in the River Tamar catchment, SW England. The study included: cattle distribution surveys; monitoring of changes in E. coli (EC) and intestinal enterococci (IE) concentrations and fluxes down the reach and of concentrations in ditch flow and surface runoff; phage tracer studies of surface runoff from pasture land; and experimental streambed trampling to investigate streambed FIO sources. The results show that cattle spend a disproportionately large amount of time in the watercourse/riparian zone along unfenced streams; identify direct defecation to the stream by wading livestock and the release/mobilisation of FIOs from cowpats by surface runoff from the adjacent pastures at times of high flow as key transmission routes; and demonstrate that FIOs become incorporated within streambed sediments, from which they may subsequently be released by trampling. Partial exclusion of cattle through SBF with a drinking bay greatly reduces the time cattle spend in streams. Total exclusion SBF, with provision of an alternative drinking supply, considerably reduces FIO load inputs to the stream reach, e.g. at times of high flow, which are critical in terms of pollutant fluxes to coastal waters, the mean EC and IE input loads to the reach fell by 0.842 and 2.206 log10, respectively.

Modelling the effect of gravity on inert-gas washout outputs.

Multiple-breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the "Slinky" effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient-specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs.

Within-day variability in microbial concentrations at a UK designated bathing water: Implications for regulatory monitoring and the application of predictive modelling based on historical compliance data.

Prediction of bathing water quality is recommended by the World Health Organization (WHO), the European Union (EU) and the United States Environmental Protection Agency (USEPA) and is an established element in bathing water management designed to protect public health. Most commonly, historical regulatory compliance data are used for model calibration and provide the dependent variable for modelling. Independent (or predictor) variables (e.g. rainfall, river flow and received irradiance) measured over some antecedent period are used to deliver prediction of the faecal indicator concentration measured on the day of the regulatory sample collection. The implied linked assumptions of this approach are, therefore, that; (i) the independent variables accurately predict the bathing-day water quality; which is (ii) accurately characterized by the single regulatory sample. Assumption (ii) will not be the case where significant within-day variability in water quality is evident. This study built a detailed record of water quality change through 60 days at a UK coastal bathing water in 2011 using half-hourly samples each subjected to triplicate filtration designed to enhance enumeration precision. On average, the mean daily variation in FIO concentrations exceeded 1 log10 order, with the largest daily variations exceeding 2 log10 orders. Significant diurnality was observed at this bathing water, which would determine its EU Directive compliance category if the regulatory samples were collected at the same time each day. A sampling programme of this intensity has not been reported elsewhere to date and, if this pattern is proven to be characteristic of other bathing waters world-wide, it has significance for: (a) the design of regulatory sampling programmes; (b) the use of historical data to assess compliance, which often comprises a single sample taken at the compliance point on a regular, often weekly, basis; and (c) the use of regulatory compliance data to build predictive models of water quality.

Cross-sectional study of the provision of interventional oncology services in the UK.

OBJECTIVE: To map out the current provision of interventional oncology (IO) services in the UK. DESIGN: Cross-sectional multicentre study. SETTING: All National Health Service (NHS) trusts in England and Scottish, Welsh and Northern Ireland health boards. PARTICIPANTS: Interventional radiology (IR) departments in all NHS trusts/health boards in the UK. RESULTS: A total of 179 NHS trusts/health boards were contacted. We received a 100% response rate. Only 19 (11%) institutions had an IO lead. 144 trusts (80%) provided IO services or had a formal pathway of referral in place for patients to a recipient trust. 21 trusts (12%) had plans to provide an IO service or formal referral pathway in the next 12 months only. 14 trusts (8%) did not have a pathway of referral and no plans to implement one. 70 trusts (39%) offered supportive and disease-modifying procedures. One trust had a formal referral pathway for supportive procedures. 73 trusts (41%) provided only supportive procedures (diagnostic or therapeutic). Of these, 43 (59%) had a referral pathway for disease-modifying IO procedures, either from a regional cancer network or through IR networks and 30 trusts (41%) did not have a referral pathway for disease-modifying procedures. CONCLUSION: The provision of IO services in the UK is promising; however, collaborative networks are necessary to ensure disease-modifying IO procedures are made accessible to all patients and to facilitate larger registry data for research with commissioning of new services.

Local Government Capacity to Respond to Environmental Change: Insights from Towns in New York State.

Local governments attempting to respond to environmental change face an array of challenges. To better understand policy responses and factors influencing local government capacity to respond to environmental change, we studied three environmental issues affecting rural or peri-urban towns in different regions of New York State: climate change in the Adirondacks (n = 63 towns), loss of open space due to residential/commercial development in the Hudson Valley (n = 50), and natural gas development in the Southern Tier (n = 62). Our analysis focused on towns' progression through three key stages of the environmental policy process (issue awareness and salience, common goals and agenda setting, policy development and implementation) and the factors that affect this progression and overall capacity for environmental governance. We found that-when compared to towns addressing open space development and natural gas development-towns confronted with climate change were at a much earlier stage in the policy process and were generally less likely to display the essential resources, social support, and political legitimacy needed for an effective policy response. Social capital cultivated through collaboration and networking was strongly associated with towns' policy response across all regions and could help municipalities overcome omnipresent resource constraints. By comparing and contrasting municipal responses to each issue, this study highlights the processes and factors influencing local government capacity to address a range of environmental changes across diverse management contexts.

A computational comparison of the multiple-breath washout and forced oscillation technique as markers of bronchoconstriction.

Many types of lung disease lead to constriction of airways within the conducting zone, causing increases in airway resistance and ventilation heterogeneity (VH). The multiple-breath washout (MBW) and forced oscillation technique (FOT) are two clinical measures of small airway bronchoconstriction. Within this study computational modelling of the MBW and FOT was applied to the analysis of thousands of bronchoconstriction scenarios in the conducting zone of the lungs. The simulations show that MBW indices primarily respond to the severity of constriction, while FOT indices may be able to distinguish between constrictions at differing airway depths. Following this, we show the potential utility in the joint interpretation of indices from the two tests, providing motivations for future clinical investigations.

The Impact of the Extreme Amazonian Flood Season on the Incidence of Viral Gastroenteritis Cases.

During the Amazonian flood season in 2012, the Negro River reached its highest level in 110 years, submerging residential and commercial areas which appeared associated with an elevation in the observed gastroenteritis cases in the city of Manaus. The aim of this study was to evaluate the microbiological water quality of the Negro River basin during this extreme flood to investigate this apparent association between the illness cases and the population exposed to the contaminated waters. Forty water samples were collected and analysed for classic and emerging enteric viruses. Human adenoviruses, group A rotaviruses and genogroup II noroviruses were detected in 100, 77.5 and 27.5% of the samples, respectively, in concentrations of 103-106 GC/L. All samples were compliant with local bacteriological standards. HAdV2 and 41 and RVA G2, P[6], and P[8] were characterised. Astroviruses, sapoviruses, genogroup IV noroviruses, klasseviruses, bocaviruses and aichiviruses were not detected. Statistical analyses showed correlations between river stage level and reported gastroenteritis cases and, also, significant differences between virus concentrations during this extreme event when compared with normal dry seasons and previous flood seasons of the Negro River. These findings suggest an association between the extreme flood experienced and gastrointestinal cases in the affected areas providing circumstantial evidence of causality between the elevations in enteric viruses in surface waters and reported illness.

Dinosaur incubation periods directly determined from growth-line counts in embryonic teeth show reptilian-grade development.

Birds stand out from other egg-laying amniotes by producing relatively small numbers of large eggs with very short incubation periods (average 11-85 d). This aspect promotes high survivorship by limiting exposure to predation and environmental perturbation, allows for larger more fit young, and facilitates rapid attainment of adult size. Birds are living dinosaurs; their rapid development has been considered to reflect the primitive dinosaurian condition. Here, nonavian dinosaurian incubation periods in both small and large ornithischian taxa are empirically determined through growth-line counts in embryonic teeth. Our results show unexpectedly slow incubation (2.8 and 5.8 mo) like those of outgroup reptiles. Developmental and physiological constraints would have rendered tooth formation and incubation inherently slow in other dinosaur lineages and basal birds. The capacity to determine incubation periods in extinct egg-laying amniotes has implications for dinosaurian embryology, life history strategies, and survivorship across the Cretaceous-Paleogene mass extinction event.

A stabilized finite element method for finite-strain three-field poroelasticity.

We construct a stabilized finite-element method to compute flow and finite-strain deformations in an incompressible poroelastic medium. We employ a three-field mixed formulation to calculate displacement, fluid flux and pressure directly and introduce a Lagrange multiplier to enforce flux boundary conditions. We use a low order approximation, namely, continuous piecewise-linear approximation for the displacements and fluid flux, and piecewise-constant approximation for the pressure. This results in a simple matrix structure with low bandwidth. The method is stable in both the limiting cases of small and large permeability. Moreover, the discontinuous pressure space enables efficient approximation of steep gradients such as those occurring due to rapidly changing material coefficients or boundary conditions, both of which are commonly seen in physical and biological applications.