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Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known:• The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways.• CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New:• This review summarises the physiological differences in haemostasis between neonates and adults described using CAT.• The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.

A post hoc appraisal of the PDA RCT to assess the relationship between early patent ductus arteriosus (PDA) shunt elimination and chronic lung disease or death (CLD/Death). Infants 0.05). A persistent PDA beyond Day 8 was associated with CLD/Death (aOR 6.5 [1.7–25.5]). Early shunt elimination in preterm infants with a PDA may reduce respiratory morbidity when compared to infants with prolonged shunt exposure.

Background Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. Methods We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn−/−; SMN2 and the less severe Smn2B/− SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. Results Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak−/−, and Fn14−/− mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. Conclusions Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Extracellular vesicles (EVs) are cell-derived membrane-bound particles, extensively investigated across many fields to improve the understanding of pathophysiological processes, as biomarkers of disease and as therapeutic targets for pharmacological intervention. We aim to describe the current knowledge of EVs detected in the body fluids of human neonates, both term and preterm, from birth to 4 weeks of age. To date, EVs have been described in several neonatal body fluids, including cerebrospinal fluid, umbilical cord blood, neonatal blood, tracheal aspirates and urine. These studies demonstrate some important roles of EVs in the neonatal population, particularly in haemostasis. Moreover, some studies have demonstrated the pathophysiological mechanisms and the identification of potential biomarkers of neonatal disease. We must continue to build on this knowledge, evaluating the role of EVs in neonatal pathology, particularly in prematurity and during the perinatal adaption period. Future studies should use larger numbers, robust EV characterisation techniques and always correlate the findings to clinical outcomes. IMPACT: This article summarises the current knowledge of the effect of EVs in neonates. It describes the potential compensatory role of EVs in neonatal haemostasis. It also describes the role of EVs as mediators of pathology and as potential biomarkers of perinatal and neonatal disease.

The clinical needs of young people with gender dysphoria (GD) have outpaced the capacity of health services to provide appropriate care. The study aimed to explore the interface of Paediatric Endocrinology and young people with GD, detailing the clinical characteristics and the clinical care provided, in order to inform future service development. Medical records of all young people with GD (n=91, 59 (65%) birth-assigned females and 32 (35%) birth-assigned males) referred to Paediatric Endocrinology during 2011-2019 for puberty suppression were reviewed. Median age at initial assessment was 14.6 years (range 8.8-17.6 years). There was a threefold increase from 2016 (n=22) to 2019 (n=73). Mental health disorders were present in 34 (37%) and autistic spectrum disorder in 21 (23%), while 54 (59%) had at least one comorbidity. Sixty-four (70%) young people fulfilled the criteria for consideration of fertility preservation, with 6 (9%) of them preserving their gametes. Seventy-nine (87%) young people commenced treatment with gonadotrophin-releasing hormone analogue, at a median age of 14.8 years (range 9.7-18.0 years). Six (8%) of those discontinued treatment, following a median duration of 6 months (range 6-18 months). Forty-one young people commenced gender-affirming hormones. One (2%) of those who started gender-affirming hormones discontinued treatment.Conclusions: We have witnessed increasing numbers of young people with GD attending Paediatric Endocrinology, with an over-representation of comorbidities, necessitating provision of an individualised approach to treatment. Addressing young people's acceptability of fertility services and ongoing close collaboration between endocrinology and mental health professionals require innovative models of multidisciplinary care. What is Known: • A worldwide increase in presentation of gender dysphoria has been mirrored in our service, with majority assigned female at birth and post-pubertal. • An over-representation of comorbidities exists, notably mental health disorders and autistic spectrum disorder. What is New: • Coordination of interprofessional care to meet complex needs, at an individual level, while improving efficiency of working, at a systemic level, can be met by the development of specialist centres. • The reasons for low uptake of fertility services demand further exploration.

Most variants implicated in common human disease by genome-wide association studies (GWAS) lie in noncoding sequence intervals. Despite the suggestion that regulatory element disruption represents a common theme, identifying causal risk variants within implicated genomic regions remains a major challenge. Here we present a new sequence-based computational method to predict the effect of regulatory variation, using a classifier (gkm-SVM) that encodes cell type-specific regulatory sequence vocabularies. The induced change in the gkm-SVM score, deltaSVM, quantifies the effect of variants. We show that deltaSVM accurately predicts the impact of SNPs on DNase I sensitivity in their native genomic contexts and accurately predicts the results of dense mutagenesis of several enhancers in reporter assays. Previously validated GWAS SNPs yield large deltaSVM scores, and we predict new risk-conferring SNPs for several autoimmune diseases. Thus, deltaSVM provides a powerful computational approach to systematically identify functional regulatory variants.

To assess the relationship between ventricular index (VI) measurements and postmenstrual age in preterm infants and to generate centile charts and normal ranges for frontal horn ratio (FHR) for a large contemporary cohort of preterm infants. A retrospective cohort study of 253 infants with birth gestation less than 32 weeks admitted between January 2009 and December 2011 to a tertiary NICU in Ireland. A total of 816 cranial ultrasounds were reviewed. Data collected were grouped according to postmenstrual age at the time of scan from 23 weeks to 45 weeks. Median values for VI show a general trend to increase with gestation. FHR did not significantly change with postmenstrual age at scan with a median value of 0.31. There is a slight increase in VI as gestation at the time of scans increases. These results provide the basis for updated centile charts which we propose for current practice.

LMX1A and LMX1B encode two closely related members of the LIM homeobox family of transcription factors. These genes play significant, and frequently overlapping, roles in the development of many structures in the nervous system, including the cerebellum, hindbrain, spinal cord roof plate, sensory systems and dopaminergic midbrain neurons. Little is known about the cis-acting regulatory elements (REs) that dictate their temporal and spatial expression or about the regulatory landscape surrounding them. The availability of comparative sequence data and the advent of genomic technologies such as ChIP-seq have revolutionized our capacity to identify regulatory sequences like enhancers. Despite this wealth of data, the vast majority of loci lack any significant in vivo functional exploration of their non-coding regions. We have completed a significant functional screen of conserved non-coding sequences (putative REs) scattered across these critical human loci, assaying the temporal and spatial control using zebrafish transgenesis. We first identify and describe the LMX1A paralogs lmx1a and lmx1a-like, comparing their expression during embryogenesis with that in mammals, along with lmx1ba and lmx1bb genes. Consistent with their prominent neuronal expression, 47/71 sequences selected within and flanking LMX1A and LMX1B exert spatial control of reporter expression in the central nervous system (CNS) of mosaic zebrafish embryos. Upon germline transmission, we identify CNS reporter expression in multiple independent founders for 22 constructs (LMX1A, n = 17; LMX1B, n = 5). The identified enhancers display significant overlap in their spatial control and represent only a fraction of the conserved non-coding sequences at these critical genes. Our data reveal the abundance of regulatory instruction located near these developmentally important genes.

This article addresses a new religious movement within one of the oldest ecclesiastical organizations in Christendom—the Catholic Church. The Catholic New Evangelization (NE) is an intra-ecclesial movement articulated and inspired by the late Pope John Paul II. Our analysis of this movement focuses on the emerging tensions between the contrasting individualist and communalist orientations of what we call “Vatican II Catholics” and “NE Catholics,” respectively. We examine responses to NE rhetoric and its implementation in the Catholic Archdiocese of Detroit’s central services, the archdiocesan seminary, and two local Detroit parishes. At these sites, the NE rhetoric, especially in its emphasis on having a “personal relationship with Jesus,” has intensified individual versus community tensions among Catholic professionals and lay leaders in the Detroit area.

This article explores the employment opportunities, working conditions and the salary one can expect to encounter when starting out as a newly qualified academic in Ireland or the UK. The article evaluates these issues through a personal perspective and concludes that that's life! If one wants to break into academic life in either Ireland or the UK one should not expect a smooth journey, however, it is well worth it.

In three experiments, we examined the relationship between orthographic and phonological distinctiveness and incidental recall. In each experiment, participants were given a surprise free recall test after they read words aloud as quickly and accurately as possible. The pattern of results replicated those reported in Cortese, Watson, Wang, and Fugett (2004) for intentional and explicit free recall and recognition memory tasks in which items were read silently. Specifically, we found that phonological-to-orthographic neighborhood size influenced recall performance, whereas orthographic-to-phonological consistency and phonological-to-orthographic consistency did not. Also, we failed to replicate the orthographic-tophonological consistency effect reported by Hirshman and Jackson (1997), and argue that their results were due to a confounding of consistency with phonological neighborhood size. Our results suggest that the processing of words sharing both orthography and phonology with a large number of words produces interference that reduces one’s ability to remember them.

Genetic studies of Hirschsprung disease, a common congenital malformation, have identified eight genes with mutations that can be associated with this condition. Mutations at individual loci are, however, neither necessary nor sufficient to cause clinical disease. We conducted a genome-wide association study in 43 Mennonite family trios using 2,083 microsatellites and single-nucleotide polymorphisms and a new multipoint linkage disequilibrium method that searches for association arising from common ancestry. We identified susceptibility loci at 10q11, 13q22 and 16q23; the gene at 13q22 is EDNRB, encoding a G protein-coupled receptor (GPCR) and the gene at 10q11 is RET, encoding a receptor tyrosine kinase (RTK). Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and non-complementation of aganglionosis in mouse intercrosses between Ret null and the Ednrb hypomorphic piebald allele are suggestive of epistasis between EDNRB and RET. Thus, genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.

Objective: To assess self-reported compliance with prescribed medications in a population of elderly patients prior to their hospital admission in an attempt to understand further the factors which influence drug-taking patterns. Methods: Information which, based on personal clinical experience and published research, may impact on compliance was collected for patients by way of a chart review within 3 days of hospital admission, a search of patient computerised hospital records and an interview. All crude data were coded and entered into a computerised relational database. Each patient's data were assessed using the Naranjo algorithm and the score was recorded. Chi-square analysis highlighted those factors which significantly influenced compliance, sub-divided into under-compliance (taking less medicine than prescribed) and over-compliance (taking more medicine than prescribed). Inter-relationships between variables were investigated using multiple-regression analysis. Results: Overall, 13.7% of the population (n=512) reported non-compliance, with 10.7% reporting under-compliance and 4.3% reporting over-compliance. A number of patients reported both under- and over-compliance. Being prescribed bronchodilators, for example, was found to be associated with under-compliance, while being prescribed analgesics (excluding non-steroidal anti-inflammatories) was associated with over-compliance using Chi-square analysis. A five-variable non-compliance risk model was obtained from logistic regression analysis. This model had a specificity of 88.9% and a sensitivity of 33.3%. The factors shown to influence compliance were the type of drug being taken (diuretics, bronchodilators and benzodiazepines), independence when taking medicines and the number of non-prescription drugs being taken. All other laboratory/test data, diseases/diagnoses, reasons for hospital admission and socio-demographic factors were not significant risk factors for self-reported non-compliance in the present model. Conclusions: Although it is accepted that self-reporting of poor compliance is generally lower than actual poor compliance, the present risk model provides further insight into the drug-taking habits of elderly patients.

The aim of this study was to develop a predictive model for adverse drug events (ADEs) in elderly patients. Socio-demographic and medical data were collected from chart reviews, computerised information and a patient interview, for a population of 929 elderly patients (aged > 65 years) whose admission to the Waveney/Braid Valley Hospital in Northern Ireland was not scheduled. A further 204 patients formed a validation group. An ADE score was assigned to each patient using a modified Naranjo algorithm scoring system. The ADE scores ranged from 0 to 8. For the purposes of developing a risk model, scores of 4 or more were considered to constitute a high risk of an ADE. Logistic regression analysis was used to produce a risk model for ADEs in the elderly. Seven variables significantly influenced the risk of an elderly person developing an ADE. Prescribed digoxin [odds ratio (OR) = 1.99], antidepressants (OR = 5.79), and a number of disease states, i.e. gastrointestinal disorders (nausea, vomiting, diarrhoea) [OR = 2.16], chronic obstructive airways disease (OR = 2.41) and angina (OR = 0.17), significantly influenced ADE score. An abnormal potassium level (OR = 2.57) and patient belief that their medication was in some way responsible for their hospital admission (OR = 4.21) also significantly influenced ADE score. Validation of the model revealed that it had a specificity of 69%, a sensitivity of 41%, with an overall accuracy of 63%. This model was therefore better at predicting elderly patients with ADE scores of 3 or less. Nonetheless, the variables highlighted are significant risk factors for ADEs in the elderly.

Purpose. Empirical formulae relate the mean size of primary droplets from jet and ultrasonic nebulizers to a fluid's physicochemical properties. Although the size selective “filtering” effects of baffling and evaporation may modify the secondary aerosol produced, this research sought to evaluate whether viscosity and surface tension of nebulized fluids influenced the aerosol's size and output characteristics.

The purpose of this paper is to explain the philosophical and methodological basis of the Singer/Churchman/Ackoff School of Thought (experimentalism). The key features of experimentalism relate to its philosophy, methodology, and imagery. The paper traces and explains the development of experimentalist philosophy from a philosophy of science to a philosophy of life. The basis of this philosophy is the pursuit of ideals. Next the experimentalist methodology is discussed. This is teleological, deriving its justification from the pursuit of the scientific ideal of truth. The paper shows how the methodology changed from optimizing, problem solving to interactive planning. Then experimentalist imagery is discussed in depth. This consists of a formal, rigorous, conceptual framework that provides a conceptual link among the mechanical, probabilistic, and functional images of nature. The authors conclude by discussing how experimentalism could be further developed.

Background The ERBB3 gene is essential for the proper development of the neural crest (NC) and its derivative populations such as Schwann cells. As with all cell fate decisions, transcriptional regulatory control plays a significant role in the progressive restriction and specification of NC derived lineages during development. However, little is known about the sequences mediating transcriptional regulation of ERBB3 or the factors that bind them. Results In this study we identified three transcriptional enhancers at the ERBB3 locus and evaluated their regulatory potential in vitro in NC-derived cell types and in vivo in transgenic zebrafish. One enhancer, termed ERBB3_MCS6, which lies within the first intron of ERBB3, directs the highest reporter expression in vitro and also demonstrates epigenetic marks consistent with enhancer activity. We identify a consensus SOX10 binding site within ERBB3_MCS6 and demonstrate, in vitro, its necessity and sufficiency for the activity of this enhancer. Additionally, we demonstrate that transcription from the endogenous Erbb3 locus is dependent on Sox10. Further we demonstrate in vitro that Sox10 physically interacts with that ERBB3_MCS6. Consistent with its in vitro activity, we also show that ERBB3_MCS6 drives reporter expression in NC cells and a subset of its derivative lineages in vivo in zebrafish in a manner consistent with erbb3b expression. We also demonstrate, using morpholino analysis, that Sox10 is necessary for ERBB3_MCS6 expression in vivo in zebrafish. Conclusions Taken collectively, our data suggest that ERBB3 may be directly regulated by SOX10, and that this control may in part be facilitated by ERBB3_MCS6.

Background Transcriptional regulatory elements are central to development and interspecific phenotypic variation. Current regulatory element prediction tools rely heavily upon conservation for prediction of putative elements. Recent in vitro observations from the ENCODE project combined with in vivo analyses at the zebrafish phox2b locus suggests that a significant fraction of regulatory elements may fall below commonly applied metrics of conservation. We propose to explore these observations in vivo at the human PHOX2B locus, and also evaluate the potential evidence for genome-wide applicability of these observations through a novel analysis of extant data. Results Transposon-based transgenic analysis utilizing a tiling path proximal to human PHOX2B in zebrafish recapitulates the observations at the zebrafish phox2b locus of both conserved and non-conserved regulatory elements. Analysis of human sequences conserved with previously identified zebrafish phox2b regulatory elements demonstrates that the orthologous sequences exhibit overlapping regulatory control. Additionally, analysis of non-conserved sequences scattered over 135 kb 5' to PHOX2B, provides evidence of non-conserved regulatory elements positively biased with close proximity to the gene. Furthermore, we provide a novel analysis of data from the ENCODE project, finding a non-uniform distribution of regulatory elements consistent with our in vivo observations at PHOX2B. These observations remain largely unchanged when one accounts for the sequence repeat content of the assayed intervals, when the intervals are sub-classified by biological role (developmental versus non-developmental), or by gene density (gene desert versus non-gene desert). Conclusion While regulatory elements frequently display evidence of evolutionary conservation, a fraction appears to be undetected by current metrics of conservation. In vivo observations at the PHOX2B locus, supported by our analyses of in vitro data from the ENCODE project, suggest that the risk of excluding non-conserved sequences in a search for regulatory elements may decrease as distance from the gene increases. Our data combined with the ENCODE data suggests that this may represent a genome wide trend.

This paper describes the development of a Programme of Care for elderly people in Northern Ireland. The problems of the elderly were previously identified, and a classification system was designed in key areas which allocated groups of individuals with similar needs to particular services. It was thus possible to quantify the resources required to meet the future needs of elderly people in Northern Ireland. The major implications for the Health and Social Services were then stressed on the basis of certain assumptions. Generally, resources are currently being channelled in the right direction but considerable expansion of resources is necessary in the future especially in community care. In showing one method of planning services for the elderly people and the possible results, this study also offers a methodology to assist the planning process in general. (Aging 3: 337-342, 1991)