Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service

In 2013, as part of our genetic investigation of patients with inherited retinal disease, we utilized multigene panel testing of 105 genes known to cause retinal disease in our patient cohorts. This test was performed in a UK National Health Service (NHS) accredited laboratory. The results of all multigene panel tests requested between 1.4.13 and 31.8.14 were retrospectively reviewed. All patients had been previously seen at Moorfields Eye Hospital, London, UK and diagnosed with an inherited retinal dystrophy after clinical examination and detailed retinal imaging. The results were categorized into three groups: (i) Testing helped establish a certain molecular diagnosis in 45 out of 115 (39%). Variants in USH2A (n = 6) and RP1 (n = 4) were most common. (ii) Definitive conclusions could not be drawn from molecular testing alone in 13 out of 115 (11%) as either insufficient pathogenic variants were discovered or those identified were not consistent with the phenotype. (iii) Testing did not identify any pathogenic variants responsible for the phenotype in 57 out of 115 (50%). Multigene panel testing performed in an NHS setting has enabled a molecular diagnosis to be confidently made in 40% of cases. Novel variants accounted for 38% of all identified variants. Detailed retinal phenotyping helped the interpretation of specific variants. Additional care needs to be taken when assessing polymorphisms in genes that have been infrequently associated with disease, as historical techniques were not as rigorous as contemporary ones. Future iterations of sequencing are likely to offer higher sensitivity, testing a broader range of genes, more rapidly and at a reduced cost

A systematic review of the effectiveness and cost-effectiveness of peer education and peer support in prisons.

BACKGROUND: Prisoners experience significantly worse health than the general population. This review examines the effectiveness and cost-effectiveness of peer interventions in prison settings. METHODS: A mixed methods systematic review of effectiveness and cost-effectiveness studies, including qualitative and quantitative synthesis was conducted. In addition to grey literature identified and searches of websites, nineteen electronic databases were searched from 1985 to 2012. Study selection criteria were: Population: Prisoners resident in adult prisons and children resident in Young Offender Institutions (YOIs). INTERVENTION: Peer-based interventions Comparators: Review questions 3 and 4 compared peer and professionally led approaches. OUTCOMES: Prisoner health or determinants of health; organisational/ process outcomes; views of prison populations. STUDY DESIGNS: Quantitative, qualitative and mixed method evaluations. RESULTS: Fifty-seven studies were included in the effectiveness review and one study in the cost-effectiveness review; most were of poor methodological quality. Evidence suggested that peer education interventions are effective at reducing risky behaviours, and that peer support services are acceptable within the prison environment and have a positive effect on recipients, practically or emotionally. Consistent evidence from many, predominantly qualitative, studies, suggested that being a peer deliverer was associated with positive effects. There was little evidence on cost-effectiveness of peer-based interventions. CONCLUSIONS: There is consistent evidence from a large number of studies that being a peer worker is associated with positive health; peer support services are also an acceptable source of help within the prison environment and can have a positive effect on recipients. Research into cost-effectiveness is sparse. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ref: CRD42012002349

The Temporal Dynamics of Voluntary Emotion Regulation

Background: Neuroimaging has demonstrated that voluntary emotion regulation is effective in reducing amygdala activation to aversive stimuli during regulation. However, to date little is known about the sustainability of these neural effects once active emotion regulation has been terminated. Methodology/Principal Findings: We addressed this issue by means of functional magnetic resonance imaging (fMRI) in healthy female subjects. We performed an active emotion regulation task using aversive visual scenes (task 1) and a subsequent passive viewing task using the same stimuli (task 2). Here we demonstrate not only a significantly reduced amygdala activation during active regulation but also a sustained regulation effect on the amygdala in the subsequent passive viewing task. This effect was related to an immediate increase of amygdala signal in task 1 once active emotion regulation has been terminated: The larger this peak postregulation signal in the amygdala in task 1, the smaller the sustained regulation effect in task 2. Conclusions/Significance: In summary, we found clear evidence that effects of voluntary emotion regulation extend beyond the period of active regulation. These findings are of importance for the understanding of emotion regulation i

Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study

To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors

Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin

Autonomic Function following Acute Organophosphorus Poisoning: A Cohort Study

Autonomic dysfunction after chronic low level exposure to organophosphorus (OP) pesticides has been consistently reported in the literature, but not following a single acute overdose. In order to study autonomic function after an acute OP overdose, sixty-six overdose patients were compared to 70 matched controls. Assessment of autonomic function was done by heart rate response to standing, deep breathing (HR-DB) and Valsalva manoeuvre; blood pressure (BP) response to standing and sustained hand grip; amplitude and latency of sympathetic skin response (SSR); pupil size and post-void urine volume. The patients were assessed one and six weeks after the exposure. The number of patients who showed abnormal autonomic function compared to standard cut-off values did not show statistically significantly difference from that of controls by Chi-Square test. When compared to the controls at one week the only significant differences consistent with autonomic dysfunction were change of diastolic BP 3 min after standing, HR-DB, SSR-Amplitude, SSR-Latency, post-void urine volume and size of the pupil. At 6 weeks significant recovery of autonomic function was observed and only HR-DB was decreased to a minor degree, −5 beats/min [95%CI 2–8]. This study provides good evidence for the lack of long term autonomic dysfunction following acute exposure to OP pesticides

A qualitative synthesis of the positive and negative impacts related to delivery of peer-based health interventions in prison settings

Background Peer interventions involving prisoners in delivering peer education and peer support in a prison setting can address health need and add capacity for health services operating in this setting. This paper reports on a qualitative synthesis conducted as part of a systematic review of prison-based peer interventions. One of the review questions aimed to investigate the positive and negative impacts of delivering peer interventions within prison settings. This covered organisational and process issues relating to peer interventions, including prisoner and staff views. Methods A qualitative synthesis of qualitative and mixed method studies was undertaken. The overall study design comprised a systematic review involving searching, study selection, data extraction and validity assessment. Studies reporting interventions with prisoners or ex-prisoners delivering education or support to prisoners resident in any type of prison or young offender institution, all ages, male and female, were included. A thematic synthesis was undertaken with a subset of studies reporting qualitative data (n=33). This involved free coding of text reporting qualitative findings to develop a set of codes, which were then grouped into thematic categories and mapped back to the review question. Results Themes on process issues and wider impacts were grouped into four thematic categories: peer recruitment training and support; organisational support; prisoner relationships; prison life. There was consistent qualitative evidence on the need for organisational support within the prison to ensure smooth implementation and on managing security risks when prisoners were involved in service delivery. A suite of factors affecting the delivery of peer interventions and the wider organisation of prison life were identified. Alongside reported benefits of peer delivery, some reasons for non-utilisation of services by other prisoners were found. There was weak qualitative evidence on wider impacts on the prison system, including better communication between staff and prisoners. Gaps in evidence were identified. Conclusions The quality of included studies limited the strength of the conclusions. The main conclusion is that peer interventions cannot be seen as independent of prison life and health services need to work in partnership with prison services to deliver peer interventions. More research is needed on long-term impacts

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions