An analysis of media reporting on the closure of freestanding midwifery units in England

PROBLEM: Despite clinical guidelines and policy promoting choice of place of birth, 14 Freestanding Midwifery Units were closed between 2008 and 2015, closures justified by low use and financial constraints. BACKGROUND: The Birthplace in England Programme found that freestanding midwifery units provided the most cost-effective birthplace for women at low risk of complications. Women planning birth in a freestanding unit were less likely to experience interventions than those planning obstetric unit birth, with no difference in outcomes for babies. METHODS: This paper uses an interpretative technique developed for policy analysis to explore the representation of these closures in 191 news articles, to explore the public climate in which they occurred. FINDINGS AND DISCUSSION: The articles focussed on underuse by women and financial constraints on services. Despite the inclusion of service user voices, the power of framing was held by service managers and commissioners. The analysis exposed how neoliberalist and austerity policies has privileged representation of individual consumer choice and market-driven provision as drivers of changes in health services. This normative framing makes the reasons given for closure as hard to refute and cultural norms persist that birth is safest in an obstetric setting, despite evidence to the contrary. CONCLUSION: The rise of neoliberalism and austerity in contemporary Britain has influenced the reform of maternity services, in particular the closure of midwifery units. Justifications given for closure silence other narratives, predominantly from service users, that attempt to present women's choice in terms of rights and a social model of care

‘What are you going to do, confiscate their passports?’ Professional perspectives on cross-border reproductive travel

Objective: This article reports findings from a UK-based study which explored the phenomenon of overseas travel for fertility treatment. The first phase of this project aimed to explore how infertility clinicians and others professionally involved in fertility treatment understand the nature and consequences of cross-border reproductive travel. Background: There are indications that, for a variety of reasons, people from the UK are increasingly travelling across national borders to access assisted reproductive technologies. While research with patients is growing, little is known about how ‘fertility tourism’ is perceived by health professionals and others with a close association with infertility patients. Methods: Using an interpretivist approach, this exploratory research included focussed discussions with 20 people professionally knowledgeable about patients who had either been abroad or were considering having treatment outside the UK. Semi-structured interviews were recorded, transcribed verbatim and subjected to a thematic analysis. Results: Three conceptual categories are developed from the data: ‘the autonomous patient’; ‘cross-border travel as risk’, and ‘professional responsibilities in harm minimisation’. Professionals construct nuanced, complex and sometimes contradictory narratives of the ‘fertility traveller’, as vulnerable and knowledgeable; as engaged in risky behaviour and in its active minimisation. Conclusions: There is little support for the suggestion that states should seek to prevent cross-border treatment. Rather, an argument is made for less direct strategies to safeguard patient interests. Further research is required to assess the impact of professional views and actions on patient choices and patient experiences of treatment, before, during and after travelling abroad

Epigenetic Regulation of Matrix Metalloproteinase-1 and -3 Expression in Mycobacterium tuberculosis Infection.

In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between -2,001 and -2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance

Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo:Sulforaphane is protective in the articular Joint

Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis

A mechanism-aware and multiomic machine-learning pipeline characterizes yeast cell growth

Metabolic modeling and machine learning are key components in the emerging next generation of systems and synthetic biology tools, targeting the genotype–phenotype–environment relationship. Rather than being used in isolation, it is becoming clear that their value is maximized when they are combined. However, the potential of integrating these two frameworks for omic data augmentation and integration is largely unexplored. We propose, rigorously assess, and compare machine-learning–based data integration techniques, combining gene expression profiles with computationally generated metabolic flux data to predict yeast cell growth. To this end, we create strain-specific metabolic models for 1,143 Saccharomyces cerevisiae mutants and we test 27 machine-learning methods, incorporating state-of-the-art feature selection and multiview learning approaches. We propose a multiview neural network using fluxomic and transcriptomic data, showing that the former increases the predictive accuracy of the latter and reveals functional patterns that are not directly deducible from gene expression alone. We test the proposed neural network on a further 86 strains generated in a different experiment, therefore verifying its robustness to an additional independent dataset. Finally, we show that introducing mechanistic flux features improves the predictions also for knockout strains whose genes were not modeled in the metabolic reconstruction. Our results thus demonstrate that fusing experimental cues with in silico models, based on known biochemistry, can contribute with disjoint information toward biologically informed and interpretable machine learning. Overall, this study provides tools for understanding and manipulating complex phenotypes, increasing both the prediction accuracy and the extent of discernible mechanistic biological insights

Avoidance as a strategy of (not) coping: qualitative interviews with carers of Huntington's Disease patients

Peer reviewedPublisher PD

Metagenomic Analysis of RNA Viruses in a Fresh Water Lake

Freshwater lakes and ponds present an ecological interface between humans and a variety of host organisms. They are a habitat for the larval stage of many insects and may serve as a medium for intraspecies and interspecies transmission of viruses such as avian influenza A virus. Furthermore, freshwater bodies are already known repositories for disease-causing viruses such as Norwalk Virus, Coxsackievirus, Echovirus, and Adenovirus. While RNA virus populations have been studied in marine environments, to this date there has been very limited analysis of the viral community in freshwater. Here we present a survey of RNA viruses in Lake Needwood, a freshwater lake in Maryland, USA. Our results indicate that just as in studies of other aquatic environments, the majority of nucleic acid sequences recovered did not show any significant similarity to known sequences. The remaining sequences are mainly from viral types with significant similarity to approximately 30 viral families. We speculate that these novel viruses may infect a variety of hosts including plants, insects, fish, domestic animals and humans. Among these viruses we have discovered a previously unknown dsRNA virus closely related to Banna Virus which is responsible for a febrile illness and is endemic to Southeast Asia. Moreover we found multiple viral sequences distantly related to Israeli Acute Paralysis virus which has been implicated in honeybee colony collapse disorder. Our data suggests that due to their direct contact with humans, domestic and wild animals, freshwater ecosystems might serve as repositories of a wide range of viruses (both pathogenic and non-pathogenic) and possibly be involved in the spread of emerging and pandemic diseases

Computational modelling for decision-making: where, why, what, who and how

In order to deal with an increasingly complex world, we need ever more sophisticated computational models that can help us make decisions wisely and understand the potential consequences of choices. But creating a model requires far more than just raw data and technical skills: it requires a close collaboration between model commissioners, developers, users and reviewers. Good modelling requires its users and commissioners to understand more about the whole process, including the different kinds of purpose a model can have and the different technical bases. This paper offers a guide to the process of commissioning, developing and deploying models across a wide range of domains from public policy to science and engineering. It provides two checklists to help potential modellers, commissioners and users ensure they have considered the most significant factors that will determine success. We conclude there is a need to reinforce modelling as a discipline, so that misconstruction is less likely; to increase understanding of modelling in all domains, so that the misuse of models is reduced; and to bring commissioners closer to modelling, so that the results are more useful

Investigation of the structural requirements for N-methyl-D-aspartate receptor positive and negative allosteric modulators based on 2-naphthoic acid.

The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC50s of 1.4 μM and 2.9 μM, respectively, for inhibition of GluN2D but showed only 70-80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists.National Institute of Mental Health of the National Institutes of Health under Award Number R01MH060252, the Medical Research Council, United Kingdom (Grants G0601509, G0601812) and the BBSRC (grant BB/L001977/1)

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions