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It is clear that people can learn a new sensory skill – a new way of mapping sensory inputs onto world states. It remains unclear how flexibly a new sensory skill can become embedded in multisensory perception and decision-making. To address this, we trained typically-sighted participants (N=12) to use a new echo-like auditory cue to distance in a virtual world, together with a noisy visual cue. Using model-based analyses, we tested for key markers of efficient multisensory perception and decision-making with the new skill. We found that twelve of fourteen participants learned to judge distance using the novel auditory cue. Their use of this new sensory skill showed three key features: (1) it enhanced the speed of timed decisions; (2) it largely resisted interference from a simultaneous digit span task; and (3) it integrated with vision in a Bayes-like manner to improve precision. We also show some limits following this relatively short training: precision benefits were lower than the Bayesoptimal prediction, and there was no forced fusion of signals. We conclude that people already embed new sensory skills in flexible multisensory perception and decision-making after a short training period. A key application of these insights is to the development of sensory augmentation systems that can enhance human perceptual abilities in novel ways. The limitations we reveal (sub-optimality, lack of fusion) provide a foundation for further investigations of the limits of these abilities and their brain basis.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.

Outer membrane vesicle (OMV)- based vaccines have been used to provide strain-specific protection against capsular group B Neisseria meningitidis infections, but the full breadth of the immune response against the components of the OMV has not been established. Sera from adults vaccinated with an OMV vaccine were used to screen 91 outer membrane proteins (OMPs) incorporated in an antigen microarray panel. Antigen-specific IgG levels were quantified pre-vaccination, and after 12 and 18 weeks. These results were compared with IgG levels from mice vaccinated with the same OMV vaccine. The repertoires of highly responding antigens in humans and mice overlapped, but were not identical. The highest responding antigens to human IgG comprised four integral OMPs (PorA, PorB, OpcA and PilQ), a protein which promotes the stability of PorA and PorB (RmpM) and two lipoproteins (BamC and GNA1162). These observations will assist in evaluating the role of minor antigen components within OMVs in providing protection against meningococcal infection. In addition, the relative dominance of responses to integral OMPs in humans emphasizes the importance of this subclass and points to the value of maintaining conformational epitopes from integral membrane proteins in vaccine formulations.

Background Primary dental practitioners prescribe approximately 10% of all prescriptions. In 2016 NHS England launched a national programme to combat antibiotic over-usage; the main contributing factor to antimicrobial resistance.\ud Aim To identify prescribing habits in the North East and Cumbria, UK, in October 2016 using NHS Community Pharmacy\ud Data. Method The Business Services Authority were commissioned to undertake an audit during this timeframe. Data collected included the antibiotic name, dose, frequency, duration, practice contract number and location. Results The rate of prescriptions issued per 1,000 population reported ranged from 7.02 in Middlesbrough to 0.77 in Eden (Cumbria), with\ud deprived areas showing higher prescribing rates. Prescriptions issued per 1,000 Units of Dental Activity (UDAs) commissioned per practice ranged from 0.02 to 16.6 per thousand. Prescription rates were highly correlated with higher dental access rates. Eleven different antibiotics were prescribed. Discussion The variability of rates of antibiotic prescribing in areas of similar deprivation indicated practitioner bias/preferences influenced rates significantly. Education on antibiotic prescribing guidelines would be of benefit. Conclusion We recommend all dentists regularly undertake self-audit to assess their own prescribing habits and a peer review assessment and/or mentored support groups be established to support colleagues that demonstrate outlying prescribing patterns.

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Archaeological monitoring's were undertaken by AOC Archaeology Group on the 14th-15th March 2018 and on the 2nd-3rd June 2018 during refurbishment works of an overhead power line which runs between Yeovil and Axminster (AD Line- ST 57672 16876 and SY 35306 99240; Figure 1). The archaeological watching brief consisted of monitoring two areas of undergrounding associated with the refurbishment of total of 114 towers. The archaeological watching brief included monitoring of the intrusive works associated with under cabling near the towers known as AD_12 and AD_14. No archaeological remains were identified during the works. Due to the lack of significant archaeological deposits encountered, it is recommended that no further archaeological fieldwork be undertaken. The results of the watching brief will be summarised and published via the Archaeological Data Service (ADS) website.

Demand charges, which are based on a customer’s maximum demand in kilowatts (kW), are a common element of electricity rate structures for commercial customers. Customer-sited solar photovoltaic (PV) systems can potentially reduce demand charges, but the level of savings is difficult to predict, given variations in demand charge designs, customer loads, and PV generation profiles. Lawrence Berkeley National Laboratory (Berkeley Lab) and the National Renewable Energy Laboratory (NREL) are collaborating on a series of studies to understand how solar PV can impact demand charges. Prior studies in the series examined demand charge reductions from solar on a stand-alone basis for residential and commercial customers. Those earlier analyses found that solar, alone, has limited ability to reduce demand charges depending on the specific design of the demand charge and on the shape of the customer’s load profile. This latest analysis estimates demand charge savings from solar in commercial buildings when co-deployed with behind-the-meter storage, highlighting the complementary roles of the two technologies. The analysis is based on simulated loads, solar generation, and storage dispatch across a wide variety of building types, locations, system configurations, and demand charge designs.

Commercial retail electricity rates commonly include a demand charge component, based on some measure of the customer’s peak demand. Customer-sited solar PV can potentially reduce demand charges, but the magnitude of these savings can be difficult to predict, given variations in demand charge designs, customer loads, and PV generation profiles. Moreover, depending on the circumstances, demand charges from solar may or may not align well with associated utility cost savings. Lawrence Berkeley National Laboratory (Berkeley Lab) and the National Renewable Energy Laboratory (NREL) are collaborating in a series of studies to understand how solar PV can reduce demand charge levels for a variety of customer types and demand charges designs. Previous work focused on residential customs with solar. This study, instead, focuses on commercial customers and seeks to understand the extent and conditions under which rooftop can solar reduce commercial demand charges. To answer these questions, we simulate demand charge savings for a broad range of commercial customer types, demand charge designs, locations, and PV system characteristics. This particular analysis does not include storage, but a subsequent analysis in this series will evaluate demand charge savings for commercial customers with solar and storage.

Mutations at either Tyr181 or Tyr188 within HIV-1 reverse transcriptase (RT) give high level resistance to many first generation non-nucleoside inhibitors (NNRTIs) such as the anti-AIDS drug nevirapine. By comparison second generation inhibitors, for instance the drug efavirenz, show much greater resilience to these mutations. In order to understand the structural basis for these differences we have determined a series of seven crystal structures of mutant RTs in complexes with first and second generation NNRTIs as well as one example of an unliganded mutant RT. These are Tyr181Cys RT (TNK-651) to 2.4 A, Tyr181Cys RT (efavirenz) to 2.6 A, Tyr181Cys RT (nevirapine) to 3.0 A, Tyr181Cys RT (PETT-2) to 3.0 A, Tyr188Cys RT (nevirapine) to 2.6 A, Tyr188Cys RT (UC-781) to 2.6 A and Tyr188Cys RT (unliganded) to 2.8 A resolution. In the two previously published structures of HIV-1 reverse transcriptase with mutations at 181 or 188 no side-chain electron density was observed within the p66 subunit (which contains the inhibitor binding pocket) for the mutated residues. In contrast the mutated side-chains can be seen in the NNRTI pocket for all seven structures reported here, eliminating the possibility that disordering contributes to the mechanism of resistance. In the case of the second generation compounds efavirenz with Tyr181Cys RT and UC-781 with Tyr188Cys RT there are only small rearrangements of either inhibitor within the binding site compared to wild-type RT and also for the first generation compounds TNK-651, PETT-2 and nevirapine with Tyr181Cys RT. For nevirapine with the Tyr188Cys RT there is however a more substantial movement of the drug molecule. We conclude that protein conformational changes and rearrangements of drug molecules within the mutated sites are not general features of these particular inhibitor/mutant combinations. The main contribution to drug resistance for Tyr181Cys and Tyr188Cys RT mutations is the loss of aromatic ring stacking interactions for first generation compounds, providing a simple explanation for the resilience of second generation NNRTIs, as such interactions make much less significant contribution to their binding.

INTRODUCTION The recent Care Quality Commission (2011) report into dignity and nutrition 2011 suggested that only 51% of hospital trusts were fully compliant with Outcome 5: Meeting nutritional needs. The Northamptonshire Healthcare Foundation NHS Trust (NHFT) Adult Speech and Language Therapy Department provides several levels of high quality dysphagia and feeding training to Northampton General Hospital (NGH) staff. They provide dysphagia training (Magnus, 2001) that is designed to increase the swallowing identification, management skills and knowledge base within hospitals. This approach is supported by interprofessional guidelines such as the framework proposed by Boaden, Davies, Storey & Watkins in 2006. It is suggested that this traditional approach to training reduces the likelihood of clients presenting with dehydration, malnutrition, choking and aspiration pneumonia. The Northampton ward based swallowing and feeding training initiative was introduced to provide a sustainable training package that would overcome the two problems that become apparent when training packages are provided within acute trusts. The Northampton package overcame the need for employees to be released from their primary and immediate role of providing patient care and it also accommodated the need to provide training comprehensively enough to reach the majority of NHS employees involved in direct patient care. RESEARCH METHOD This research was conducted in four phases on an acute/rehabilitation stroke unit in Northampton General Hospital: Baseline 1(B1), Teaching 1(T1), Baseline 2(B2) and Baseline 3(B3). NGH and De Montfort University gave ethical approval for the study. In the first baseline phase (B1) four members of nursing staff were asked to answer a feeding and swallowing knowledge questionnaire. In the second phase of this project ward based teaching was provided on eight consecutive working days. Training lasted up to one hour and was delivered by two therapists from the hospital SLT team. The feeding and swallowing awareness training was client centered and was offered to all ward staff. On the tenth day (B2) four members of staff were asked to answer the same questionnaire that had been answered in B1. Two weeks after the completion of the teaching phase, a further four members of staff were asked to complete the questionnaire for the B3 measure. The research design allowed the feeding and swallowing knowledge questionnaires to be completed by different participants. This overcame the problem of unpredictable ward staffing and was intended to capture the widespread increase in knowledge that should result from this type of generic intensive ward based training. SUMMARY OF RESULTS & CONCLUSIONS All twelve questionnaires were analysed independently without reference to the phase in which they had been produced. After the questionnaires had been scored they were sorted back into the phase in which they had been produced and the results from each phase were compared. Initial quantitative and qualitative analysis suggested that the training had significantly improved the feeding and swallowing knowledge of ward staff in this busy general hospital. It also suggested that this improvement was maintained two weeks after the training programme had been completed. As the training package proved successful the scheme is being extended to more hospital wards to see if the success of the pilot study can be replicated hospital wide. REFERENCES Bixley, M., Blagdon, B., Dean, M., Langley, J. & Stanton, D. (2011) In search of consensus on aphasia management. Royal College of Speech and Language Therapists Bulletin, October, 18-20. Boaden, E. & Davies, S., Storey, L., & Watkins, C. (2006) Interprofessional Dysphagia Framework. www.uclan.aca.uk/facs/health/nursing/research/groups/stroke Care Quality Commission (2011) Dignity and Nutrition Inspection Programme. Newcastle upon Tyne: Care Quality Commission. Magnus, V. (2001) Dysphagia training for nurses in an acute hospital setting – a pragmatic approach. International Journal of Language and Communication Disorders, 36, 375-378.

This briefing paper is about the findings and\ud recommendations from a research project\ud conducted at the University of Nottingham,\ud with funding awarded by Macmillan Cancer\ud Support. The project was set up to study the\ud experiences and main support needs of\ud older carers* looking after someone with\ud advanced cancer and to facilitate the active\ud involvement of carers in the research\ud process

BACKGROUND AND METHOD In the measurement of glomerular filtration rate from the plasma clearance of 51Cr ethylenediamine tetraacetic acid by using the slope-intercept method, the first sample is conventionally taken at 2 h, the time by which it is generally assumed that the clearance curve has reached a single exponential. We examined this assumption by comparing the slopes, alpha 12 and alpha 23, based, respectively, on samples at 2 and 3 h, and at 3 and 4 h. RESULTS In 421 patient studies in whom the first sample was taken between 110 and 130 min after injection, the mean ratio, alpha 12/alpha 23, was 1.101 (SEM 0.011) which is significantly higher than unity (P<

Background Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. Methods A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. Results Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. Conclusions Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.

One of the two X chromosomes in each somatic cell of normal human females becomes inactivated very early in embryonic development. Although the inactivation of an X chromosome in any particular somatic cell of the embryonic lineage is thought to be a stochastic and epigenetic event, a strong genetic influence on this process has been described in the mouse. We have attempted to uncover evidence for genetic control of X-chromosome inactivation in the human by examining X chromosome-inactivation patterns in 255 females from 36 three-generation pedigrees, to determine whether this quantitative character exhibits evidence of heritability. We have found one family in which all seven daughters of one male and the mother of this male have highly skewed patterns of X-chromosome inactivation, suggesting strongly that this quantitative character is controlled by one or more X-linked genes in some families.

Batteries that extend performance beyond the intrinsic limits of Li-ion batteries are among the most important developments required to continue the revolution promised by electrochemical devices. Of these next-generation batteries, lithium sulfur (Li���S) chemistry is among the most commercially mature, with cells offering a substantial increase in gravimetric energy density, reduced costs and improved safety prospects. However, there remain outstanding issues to advance the commercial prospects of the technology and benefit from the economies of scale felt by Li-ion cells, including improving both the rate performance and longevity of cells. To address these challenges, the Faraday Institution, the UK���s independent institute for electrochemical energy storage science and technology, launched the Lithium Sulfur Technology Accelerator (LiSTAR) programme in October 2019. This Roadmap, authored by researchers and partners of the LiSTAR programme, is intended to highlight the outstanding issues that must be addressed and provide an insight into the pathways towards solving them adopted by the LiSTAR consortium. In compiling this Roadmap we hope to aid the development of the wider Li���S research community, providing a guide for academia, industry, government and funding agencies in this important and rapidly developing research space.

Contains fulltext : 70803.pdf (Publisher’s version ) (Closed access) Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.

Batteries that extend performance beyond the intrinsic limits of Li-ion batteries are among the most important developments required to continue the revolution promised by electrochemical devices. Of these next-generation batteries, lithium sulfur (Li–S) chemistry is among the most commercially mature, with cells offering a substantial increase in gravimetric energy density, reduced costs and improved safety prospects. However, there remain outstanding issues to advance the commercial prospects of the technology and benefit from the economies of scale felt by Li-ion cells, including improving both the rate performance and longevity of cells. To address these challenges, the Faraday Institution, the UK’s independent institute for electrochemical energy storage science and technology, launched the Lithium Sulfur Technology Accelerator (LiSTAR) programme in October 2019. This Roadmap, authored by researchers and partners of the LiSTAR programme, is intended to highlight the outstanding issues that must be addressed and provide an insight into the pathways towards solving them adopted by the LiSTAR consortium. In compiling this Roadmap we hope to aid the development of the wider Li–S research community, providing a guide for academia, industry, government and funding agencies in this important and rapidly developing research space.