Application of compositional models for glycan HILIC data

Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. The enzymatic process in which glycans (sugar chains) are linked to proteins or lipids is called glycosylation. Glycosylation is involved in many biological processes, both physiological and pathological, inlcuding host-pathogen interactions, tumour invasion, cell trafficking and signalling. Changes in glycan structure are thought be be at least partly responsible for the development of inflammation, infection, arteriosclerosis, immune defects and autoimmunity. Such changes have been observed in human diseases such as diabetes mellitus, rheumatoid arthritis and Alzheimer’s Disease. Aberrant patterns of glycosylation are also a universal feature of cancer cells. The field of glycobiology thus shows great potential for the discovery of glycan biomarkers for disease diagnosis and prognosis. Here we focus specifically on N-glycans, that is, glycans attached to protein molecules via a nitrogen atom. This class of glycans is the best characterized. High-throughput HILIC analysis is a well-established technique for the separation and quantification of N-linked glycans released from glycoproteins. HILIC analysis quantifies theN-glycan structures in serum via a chromatogram, which is subsequently standardized and integrated. The generated data for each sample is a set of relative HILIC peak areas and as a result, the data is compositional. To-date, most statistical analyses of these glycan data fail to account for their compositional nature. We compare and contrast three compositional data models for the glycan HILIC data: the Dirichlet, Nested Dirichlet and Logistic Normal models, with the intention of providing tools for the statistical analysis of compositional data analysis in the glycobiology field. We use these three models for classification of disease/control cases in ovarian and lung cancer diagnosis applications. We discuss and compare these models in terms of their classification performance and goodness-of-fit

Simulated Dynamics of Mixed Versus Uniform Grain Size Sediment Pulses in a Gravel-Bedded River

Mountain rivers often receive sediment in the form of episodic, discrete pulses from a variety of natural and anthropogenic processes. Once emplaced in the river, the movement of this sediment depends on flow, grain size distribution, and channel and network geometry. Here, we simulate downstream bed elevation changes that result from discrete inputs of sediment (10,000 m3), differing in volume and grain size distribution, under medium and high flow conditions. We specifically focus on comparing bed responses between mixed and uniform grain size sediment pulses. This work builds on a Lagrangian, bed-material sediment transport model and applies it to a 27 km reach of the mainstem Nisqually River, Washington, USA. We compare observed bed elevation change and accumulation rates in a downstream lake to simulation results. Then we investigate the magnitude, timing, and persistence of downstream changes due to the introduction of synthetic sediment pulses by comparing the results against a baseline condition (without pulse). Our findings suggest that bed response is primarily influenced by the sediment-pulse grain size and distribution. Intermediate mixed-size pulses (~50% of the median bed gravel size) are likely to have the largest downstream impact because finer sizes translate quickly and coarser sizes (median bed gravel size and larger) disperse slowly. Furthermore, a mixed-size pulse, with a smaller median grain size than the bed, increases bed mobility more than a uniform-size pulse. This work has important implications for river management, as it allows us to better understand fluvial geomorphic responses to variations in sediment supply

High-flow nasal cannulae, bronchopulmonary dysplasia and retinopathy of prematurity

Aims: To determine if HFNC use was associated with changes in incidence of BPD and ROP. Methods: This retrospective study examined premature infants (<30 weeks GA or <1500g) in a tertiary neonatal unit from 2010-2016. Patients were compared before and after introduction of HFNC. Further analysis of high-risk infants (<28 weeks GA or <750g or ventilated) compared those who received HFNC to those who did not across the whole period. Primary outcomes were incidence of BPD and ROP requiring surgery. Results: Incidence of BPD rose following the introduction of HFNC (82/232 (35.3%) after vs 33/251 (13.1%) before, p<0.001). On multivariate analysis, the chance of developing BPD after HFNC introduction remained higher (OR 4.353, 95% CI2.546-7.443). More infants received surgery for ROP following HFNC introduction (0/214 vs 11/205 (5.4%), p=<0.001). In the second analysis, the rate of BPD was higher in those who received HFNC (90/132 (68.1%) vs 33/153 (21.6%), p<0.001). Receiving HFNC demonstrated higher chance of BPD in multivariate analysis (OR 7.802, 95% CI 4.223-14.423). Rate of ROP surgery was higher in those who received HFNC (0/153 vs 13/134 (9.7%), p<0.001). Conclusions: In this study, use of HFNC was associated with significantly increased risk of adverse outcomes

Sex differences in misperceptions of sexual interest can be explained by sociosexual orientation and men projecting their own interest onto women

Sex differences in misperceptions of sexual interest have been well documented; however, it is unclear whether this cognitive bias could be explained by other factors. In the current study, 1226 participants (578 men, 630 women) participated in a speed-dating study, where participants rated their sexual interest in each other as well as the sexual interest they perceived from their partners. Consistent with previous findings, we found that men tended to overperceive sexual interest from their partners, while women tended to underperceive sexual interest. However, this sex difference becomes negligible when considering potential mediators, such as the raters’ sociosexual orientation, and raters projecting their own levels of sexual interest onto their partners. These findings challenge the popular notion that sex differences in misperceptions in sexual interest have evolved as a specialised adaptation due to different selection pressures in men and women

Optimising preterm nutrition: present and future

The goal of preterm nutrition in achieving growth and body composition approximating that of the fetus of the same postmenstrual age is difficult to achieve. Current nutrition recommendations depend largely on expert opinion, due to lack of evidence, and are primarily birth weight based, with no consideration given to gestational age and/or need for catch-up growth. Assessment of growth is based predominately on anthropometry, which gives insufficient attention to the quality of growth. The present paper provides a review of the current literature on the nutritional management and assessment of growth in preterm infants. It explores several approaches that may be required to optimise nutrient intakes in preterm infants, such as personalising nutritional support, collection of nutrient intake data in real-time, and measurement of body composition. In clinical practice, the response to inappropriate nutrient intakes is delayed as the effects of under- or overnutrition are not immediate, and there is limited nutritional feedback at the cot-side. The accurate and non-invasive measurement of infant body composition, assessed by means of air displacement plethysmography, has been shown to be useful in assessing quality of growth. The development and implementation of personalised, responsive nutritional management of preterm infants, utilising real-time nutrient intake data collection, with ongoing nutritional assessments that include measurement of body composition is required to help meet the individual needs of preterm infants

Exploring Metapopulation-Scale Suppression Alternatives for a Global Invader in a River Network Experiencing Climate Change

Invasive species can dramatically alter ecosystems, but eradication is difficult, and suppression is expensive once they are established. Uncertainties in the potential for expansion and impacts by an invader can lead to delayed and inadequate suppression, allowing for establishment. Metapopulation viability models can aid in planning strategies to improve responses to invaders and lessen invasive species’ impacts, which may be particularly important under climate change. We used a spatially-explicit metapopulation viability model to explore suppression strategies for ecologically-damaging invasive brown trout (Salmo trutta), established in the Colorado River and a tributary within Grand Canyon National Park. Our goals were to: 1) estimate the effectiveness of strategies targeting different life stages and subpopulations within a metapopulation, 2) quantify the effectiveness of a rapid response to a new invasion relative to delaying action until establishment; and 3) estimate whether future hydrology and temperature regimes related to climate change and reservoir management affect metapopulation viability and alter the optimal management response. We included scenarios targeting different life-stages with spatially-varying intensities of electrofishing, redd destruction, incentivized angler harvest, piscicides, and a weir. Quasi-extinction (QE) was obtainable only with metapopulation-wide suppression targeting multiple life-stages; subpopulations were most sensitive to age-0 and large adult mortality. The duration of suppression needed to reach QE for a large established subpopulation was triple compared to a rapid response to a new invasion. Isolated subpopulations were vulnerable to suppression; however, connected tributary subpopulations enhanced metapopulation persistence by serving as climate refuges. Water shortages driving changes in reservoir storage and subsequent warming would cause brown trout declines, but metapopulation QE was only achieved by re-focusing and increasing suppression. Our modeling approach improved our understanding of invasive brown trout metapopulation dynamics, which could lead to more focused and effective invasive species suppression strategies, and ultimately, maintenance of populations of endemic fishes

Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy.

Aim: To examine the relationship between electrographic seizures and long-term outcome in neonates with hypoxic-ischemic encephalopathy (HIE). Method: Full-term neonates with HIE born in Cork University Maternity Hospital from 2003 to 2006 (pre-hypothermia era) and 2009 to 2012 (hypothermia era) were included in this observational study. All had early continuous electroencephalography monitoring. All electrographic seizures were annotated. The total seizure burden and hourly seizure burden were calculated. Outcome (normal/abnormal) was assessed at 24 to 48 months in surviving neonates using either the Bayley Scales of Infant and Toddler Development, Third Edition or the Griffiths Mental Development Scales; a diagnosis of cerebral palsy or epilepsy was also considered an abnormal outcome. Results: Continuous electroencephalography was recorded for a median of 57.1 hours (interquartile range 33.5-80.5h) in 47 neonates (31 males, 16 females); 29 out of 47 (62%) had electrographic seizures and 25 out of 47 (53%) had an abnormal outcome. The presence of seizures per se was not associated with abnormal outcome (p=0.126); however, the odds of an abnormal outcome increased over ninefold (odds ratio [OR] 9.56; 95% confidence interval [95% CI] 2.43-37.67) if a neonate had a total seizure burden of more than 40 minutes (p=0.001), and eightfold (OR: 8.00; 95% CI: 2.06-31.07) if a neonate had a maximum hourly seizure burden of more than 13 minutes per hour (p=0.003). Controlling for electrographic HIE grade or treatment with hypothermia did not change the direction of the relationship between seizure burden and outcome. Interpretation: In HIE, a high electrographic seizure burden is significantly associated with abnormal outcome, independent of HIE severity or treatment with hypothermia

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations

The inherent jurisdiction of the Irish High Court: Interface with psychiatry

The term “inherent jurisdiction” refers to a set of default powers, usually not set out in statute, which enables a court to fulfil its roles. We discuss recently reported cases where such power has been exercised by the Irish High Court and what this means for psychiatrists in practice. These cases demonstrate that (a) the Irish High Court can be involved in decision-making where there is a lacuna in mental health legislation and a lack of mental capacity; (b) when a minor has been placed by the Court in a specialist facility in the UK and then attains the age of 18 years, decisions can be based on mental capacity but not on preventative detention on the basis of risk; (c) complexities arise when definitions of mental disorder vary between jurisdictions, especially when the Court orders involuntary detention in a case where statute would not ordinarily allow this; and (d) the appropriate route to seek decision-making for adults with mental incapacity is through Ireland's “Ward of Court” process, although, on the face of it, this seems to be contrary to the approach taken in other cases in which inherent jurisdiction was used. Overall, while it is reassuring for state health services that they can seek to approach higher courts in respect of decision-making in complex cases, some of these decisions raise important ethical questions for psychiatrists who may be asked to treat patients detained under their care who may not have a treatable mental illness as their condition falls outside of mental disorder within Irish legislation. We recommend that clear guidance is made available to psychiatrists in light of these judgments, particularly as there is likely to be a reconsideration of cases where Irish patients are placed in the UK given the UK's planned departure from the EU