Aiming higher : the Plymouth and Peninsula Tri-Level Model (PPM) for school/HE links : putting the university into school and community

"This report outlines an innovative, effective model of school/higher education (HE) liaison, the Plymouth & Peninsula Model (PPM). The PPM is of major national and international importance. The defining quality of PPM is that it is a genuine partnership, with parity of esteem between HEIs, schools and local authorities (LAs), supported by other major stakeholders. The PPM is based upon firm research evidence, is highly cost effective and could be rolled out nationally to cover geographically all primary and secondary schools and college grouped in consortia" - page iii

Clinical outcomes and cost-effectiveness of brief guided parent-delivered cognitive behavioural therapy and solution-focused brief therapy for treatment of childhood anxiety disorders: a randomised controlled trial

Background—Half of lifetime anxiety disorders emerge before 12 years of age, however access to evidence-based psychological therapies for affected children is poor. This Randomised Controlled Trial (RCT) compared the clinical outcome and cost-effectiveness of two brief psychological treatments for anxious children referred to routine child mental health settings. Methods—Children (5-12 years) referred to Primary Child and Mental Health Services across Oxfordshire, UK, for anxiety difficulties were randomly allocated (1:1) to brief Guided Parent-Delivered Cognitive Behavior Therapy (GPD-CBT) or Solution Focused Brief Therapy (SFBT). The primary outcome was Clinical Global Impressions of Improvement (CGI-I). Secondary outcomes were absence of primary anxiety diagnosis and all anxiety disorder diagnoses, self- and parent-reported anxiety symptoms and interference. Parents recorded patient level resource use. Quality Adjusted Life Years (QALYs) were derived from the CHU9D. Assessments were conducted pre-, post- (primary endpoint), and 6- months after treatment. Findings—136 patients were assigned to GPD-CBT (n=68) or SFBT (n=68). Analyses were conducted with the intent to treat population. No significant differences were observed on any clinical (CGI-I; Relative Risk (RR) = 1·01 (0·86, 1·19), p = 0·95) or economic (QALY mean difference = 0·006 (-0·009- 0·02), p = 0·42) outcome measure. However, the GPD-CBT treatment was associated with lower costs (mean difference: -£448; 95% CI: -£934, £37; p=0.070). Interpretation— There was no evidence of clinical superiority, however brief GPD-CBT is likely to be a cost-effective alternative to brief psychological treatment (SFBT) and could be considered as a first-line treatment for children with anxiety problems

Developing a population data science approach to assess increased risk of COVID-19 associated with attending large sporting events.

Objectives To design and test a method to assess whether test events were associated with an increase in risk of confirmed COVID-19, in order to inform policy on the safe re-introduction of spectator events following decreasing incidence of COVID-19 and relaxing of restrictions. Approach We designed a cohort study to measure relative risk of confirmed COVID-19 in those attending two large sporting events in South Wales during May-June 2021. First, we linked ticketing information to records on the Welsh Demographic Service (WDS) and identified NHS numbers for attendees. We then linked attendees to routine SARS-CoV-2 test data to calculate incidence rates in people attending each event for a fourteen days period following the event.  We selected a comparison cohort from WDS for each event, individually matched by age band, gender and locality of residence. Risk ratios were then computed for the two events. Results We successfully assigned NHS numbers to 91% and 84% of people attending the two events, respectively. Other identifiers were available for the remainder. Only a small number of attendees (1) than event 2 (<1), which did include pre-event testing. Conclusions We demonstrate the potential for data linkage to inform COVID-19 policy regarding sporting events. At that point in the epidemic, there was no evidence that attending large sporting events increased risk of COVID-19. However, these events took place between epidemic waves when background incidence and testing rate was low

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Acidic residues in the membrane-proximal stalk region of vaccinia virus protein B5 are required for glycosaminoglycan-mediated disruption of the extracellular enveloped virus outer membrane

The extracellular enveloped virus (EEV) form of vaccinia virus (VACV) is surrounded by two lipid envelopes. This presents a topological problem for virus entry into cells, because a classical fusion event would only release a virion surrounded by a single envelope into the cell. Recently, we described a mechanism in which the EEV outer membrane is disrupted following interaction with glycosaminoglycans (GAGs) on the cell surface and thus allowing fusion of the inner membrane with the plasma membrane and penetration of a naked core into the cytosol. Here we show that both the B5 and A34 viral glycoproteins are required for this process. A34 is required to recruit B5 into the EEV membrane and B5 acts as a molecular switch to control EEV membrane rupture upon exposure to GAGs. Analysis of VACV strains expressing mutated B5 proteins demonstrated that the acidic stalk region between the transmembrane anchor sequence and the fourth short consensus repeat of B5 are critical for GAG-induced membrane rupture. Furthermore, the interaction between B5 and A34 can be disrupted by the addition of polyanions (GAGs) and polycations, but only the former induce membrane rupture. Based on these data we propose a revised model for EEV entry

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases.

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe

Solving unsolved rare neurological diseases-a Solve-RD viewpoint.

Funder: Durch Princess Beatrix Muscle Fund Durch Speeren voor Spieren Muscle FundFunder: University of Tübingen Medical Faculty PATE programFunder: European Reference Network for Rare Neurological Diseases | 739510Funder: European Joint Program on Rare Diseases (EJP-RD COFUND-EJP) | 44140962