Genetic therapeutic advancements for Dravet Syndrome

Dravet Syndrome is a genetic epileptic syndrome characterized by severe and intractable seizures associated with cognitive, motor, and behavioral impairments. The disease is also linked with increased mortality mainly due to sudden unexpected death in epilepsy. Over 80% of cases are due to a de novo mutation in one allele of the SCN1A gene, which encodes the α-subunit of the voltage-gated ion channel NaV1.1. Dravet Syndrome is usually refractory to antiepileptic drugs, which only alleviate seizures to a small extent. Viral, non-viral genetic therapy, and gene editing tools are rapidly enhancing and providing new platforms for more effective, alternative medicinal treatments for Dravet syndrome. These strategies include gene supplementation, CRISPR-mediated transcriptional activation, and the use of antisense oligonucleotides. In this review, we summarize our current knowledge of novel genetic therapies that are currently under development for Dravet syndrome

Development of a Grazing Land Management Education Program for Northern Australia’s Grasslands and Grassy Woodlands

Recognition of the potential to enhance grazing land management to meet the goal of sustainable beef production has been increasing over the past decade. Recognition of the relationship between poor land management and negative off-site environmental impacts, such as soil erosion and a decline in the condition of rivers and adjacent near shore coastal areas from sediment transport, has increased also. This concern has matured somewhat to include the critical link between land condition and production, and the threat to sustainable carrying capacity that comes from declining land condition. Concurrently, interest has increased in optimising the use of pasture, e.g. through the development of infrastructure (watering points, fencing), through more pro-active management e.g. alternative grazing systems, spelling of pastures, and through pasture development. In fact, it can be argued that achieving production goals while improving and maintaining the health of the land has become the major on-property issue for northern Australian graziers

A cost-effectiveness analysis of condom distribution programmes for the prevention of sexually transmitted infections in England

Background Prevention of sexually transmitted infection (STI) incidence in England is a high priority, particularly among young people, men who have sex with men (MSM) and black ethnic minorities. An economic evaluation of condom distribution programmes (CDPs) to reduce STI transmission is presented. Methods An economic model using a Bernoulli process estimated the number of people acquiring an STI as a function of its prevalence, transmission rate, condom use, condom failure rate and number of sexual contacts. Models were developed for young people (13–24 years), black ethnic minorities, MSM and the general English population. Effectiveness evidence came from a recent systematic review. For young people, a CDP was modelled (relative risk for condom use=1.23), along with an exploratory analysis of the impact on unintended pregnancies. For other populations, threshold analyses were used to identify the combination of costs and effect size required to make a programme cost-effective. Results The base case predicted that CDP for all young people in England could avert 5123 STI cases per annum, with an incremental cost–effectiveness ratio of £17 411. In addition, it could avert 118 pregnancies and 82 abortions and save £333 000 in associated costs. Schemes for black ethnic minorities and MSM could also be cost-effective even with relatively high costs and small effect sizes. Conclusion CDPs for young people are likely to be cost-effective or cost-saving. CDPs for other high-risk populations may also be cost-effective if they can increase condom use, since high HIV prevalence in these groups imposes a considerable health and cost burden

A cost-effectiveness analysis of newborn screening for severe combined immunodeficiency in the UK

Severe combined immunodeficiency (SCID) can be detected through newborn bloodspot screening. In the UK, the National Screening Committee (NSC) requires screening programmes to be cost-effective at standard UK thresholds. To assess the cost-effectiveness of SCID screening for the NSC, a decision-tree model with lifetable estimates of outcomes was built. Model structure and parameterisation were informed by systematic review and expert clinical judgment. A public service perspective was used and lifetime costs and quality-adjusted life years (QALYs) were discounted at 3.5%. Probabilistic, one-way sensitivity analyses and an exploratory disbenefit analysis for the identification of non-SCID patients were conducted. Screening for SCID was estimated to result in an incremental cost-effectiveness ratio (ICER) of £18,222 with a reduction in SCID mortality from 8.1 (5–12) to 1.7 (0.6–4.0) cases per year of screening. Results were sensitive to a number of parameters, including the cost of the screening test, the incidence of SCID and the disbenefit to the healthy at birth and false-positive cases. Screening for SCID is likely to be cost-effective at £20,000 per QALY, key uncertainties relate to the impact on false positives and the impact on the identification of children with non-SCID T Cell lymphopenia

Demonstration of Universal Parametric Entangling Gates on a Multi-Qubit Lattice

We show that parametric coupling techniques can be used to generate selective entangling interactions for multi-qubit processors. By inducing coherent population exchange between adjacent qubits under frequency modulation, we implement a universal gateset for a linear array of four superconducting qubits. An average process fidelity of $\mathcal{F}=93\%$ is estimated for three two-qubit gates via quantum process tomography. We establish the suitability of these techniques for computation by preparing a four-qubit maximally entangled state and comparing the estimated state fidelity against the expected performance of the individual entangling gates. In addition, we prepare an eight-qubit register in all possible bitstring permutations and monitor the fidelity of a two-qubit gate across one pair of these qubits. Across all such permutations, an average fidelity of $\mathcal{F}=91.6\pm2.6\%$ is observed. These results thus offer a path to a scalable architecture with high selectivity and low crosstalk

Effectiveness and cost-effectiveness of an educational intervention for practice teams to deliver problem focused therapy for insomnia: rationale and design of a pilot cluster randomised trial

Background: Sleep problems are common, affecting over a third of adults in the United Kingdom and leading to reduced productivity and impaired health-related quality of life. Many of those whose lives are affected seek medical help from primary care. Drug treatment is ineffective long term. Psychological methods for managing sleep problems, including cognitive behavioural therapy for insomnia (CBTi) have been shown to be effective and cost effective but have not been widely implemented or evaluated in a general practice setting where they are most likely to be needed and most appropriately delivered. This paper outlines the protocol for a pilot study designed to evaluate the effectiveness and cost-effectiveness of an educational intervention for general practitioners, primary care nurses and other members of the primary care team to deliver problem focused therapy to adult patients presenting with sleep problems due to lifestyle causes, pain or mild to moderate depression or anxiety. Methods and design: This will be a pilot cluster randomised controlled trial of a complex intervention. General practices will be randomised to an educational intervention for problem focused therapy which includes a consultation approach comprising careful assessment (using assessment of secondary causes, sleep diaries and severity) and use of modified CBTi for insomnia in the consultation compared with usual care (general advice on sleep hygiene and pharmacotherapy with hypnotic drugs). Clinicians randomised to the intervention will receive an educational intervention (2 × 2 hours) to implement a complex intervention of problem focused therapy. Clinicians randomised to the control group will receive reinforcement of usual care with sleep hygiene advice. Outcomes will be assessed via self-completion questionnaires and telephone interviews of patients and staff as well as clinical records for interventions and prescribing. Discussion: Previous studies in adults have shown that psychological treatments for insomnia administered by specialist nurses to groups of patients can be effective within a primary care setting. This will be a pilot study to determine whether an educational intervention aimed at primary care teams to deliver problem focused therapy for insomnia can improve sleep management and outcomes for individual adult patients presenting to general practice. The study will also test procedures and collect information in preparation for a larger definitive cluster-randomised trial. The study is funded by The Health Foundation

Embracing plurality through oral language

The transmission and dissemination of knowledge in Aboriginal societies for the most part occurs orally in an Aboriginal language or in Aboriginal English. However, whilst support is given to speaking skills in Indigenous communities, in our education system less emphasis is given to developing equivalent oral communicative competence in Standard Australian English (SAE). Instead the focus is given to the ongoing assessment of reading and writing skills and grammatical knowledge – this is in direct contrast to the existing language experience of Aboriginal students. Therefore, for Aboriginal students to participate in mainstream society, we suggest that there is a need to nurture oral language skills in SAE and provide learners with the experience to develop their code-switching ability to maintain continuity with their first language or dialect. Drawing on previous research that we and others have undertaken at several schools, this paper highlights the need for three fundamental changes to take place within language education: (1) school policies to change and explicitly accept and support Aboriginal English in code-switching situations; (2) familiarity among school staff about the major differences between Aboriginal English and SAE; and (3) tasks that focus on developing and practising the ‘when, why and how’ of code-switching

The effectiveness of interventions aimed at improving access to health and mental health services for looked after children and young people: a systematic review

Background: Compared with children and young people in the general population, looked after children and young people (LACYP) are more likely to experience behavioural, physical and psychological problems. Consequently, LACYP are likely to have greater need of health and mental health services to address any specific problems. This systematic review aimed to identify and synthesise evidence on the effectiveness of interventions to improve access to services accessed by LACYP. Methods: Searches of health, social science and social care databases were conducted and records were screened for relevance. Results: Five studies were included (four prospective cohort studies and one non-comparative study). There was considerable variation in terms of the services, interventions and outcomes reported. Conclusions: Little appropriate evidence was identified by this review, suggesting that the evidence base is at a very early stage

Factors associated with outcomes for looked-after children and young people: a correlates review of the literature.

In 2008, the Department of Health made a referral to the National Institute for Health and Clinical Excellence and the Social Care Institute for Excellence to develop joint public health guidance on improving the physical and emotional health and well-being of children and young people looked after by the local authority/state. To help inform the decision-making process by identifying potential research questions pertinent to the outcomes of looked-after children and young people (LACYP), a correlates review was undertaken. Iterative searches of health and social science databases were undertaken; searches of reference lists and citation searches were conducted and all included studies were critically appraised. The correlates review is a mapping review conducted using systematic and transparent methodology. Interventions and factors that are associated (or correlated) with outcomes for LACYP were identified and presented as conceptual maps. This review maps the breadth (rather than depth) of the evidence and represents an attempt to use the existing evidence base to map associations between potential risk factors, protective factors, interventions and outcomes for LACYP. Ninety-two studies were included: four systematic reviews, five non-systematic reviews, eight randomized controlled trials, 66 cohort studies and nine cross-sectional studies. The conceptual maps provide an overview of the key relationships addressed in the current literature, in particular, placement stability and emotional and behavioural factors in mediating outcomes. From the maps, there appear to be some key factors that are associated with a range of outcomes, in particular, number of placements, behavioural problems and age at first placement. Placement stability seems to be a key mediator of directional associations. The correlates review identified key areas where sufficient evidence to conduct a systematic review might exist. These were: transition support, training and support for carers and access to services

Sebomic identification of sex- and ethnicity-specific variations in residual skin surface components (RSSC) for bio-monitoring or forensic applications

Background: “Residual skin surface components” (RSSC) is the collective term used for the superficial layer of sebum, residue of sweat, small quantities of intercellular lipids and components of natural moisturising factor present on the skin surface. Potential applications of RSSC include use as a sampling matrix for identifying biomarkers of disease, environmental exposure monitoring, and forensics (retrospective identification of exposure to toxic chemicals). However, it is essential to first define the composition of “normal” RSSC. Therefore, the aim of the current study was to characterise RSSC to determine commonalities and differences in RSSC composition in relation to sex and ethnicity. Methods: Samples of RSSC were acquired from volunteers using a previously validated method and analysed by high-pressure liquid chromatography–atmospheric pressure chemical ionisation–mass spectrometry (HPLC-APCI-MS). The resulting data underwent sebomic analysis. Results: The composition and abundance of RSSC components varied according to sex and ethnicity. The normalised abundance of free fatty acids, wax esters, diglycerides and triglycerides was significantly higher in males than females. Ethnicity-specific differences were observed in free fatty acids and a diglyceride. Conclusions: The HPLC-APCI-MS method developed in this study was successfully used to analyse the normal composition of RSSC. Compositional differences in the RSSC can be attributed to sex and ethnicity and may reflect underlying factors such as diet, hormonal levels and enzyme expression.Peer reviewedFinal Published versio