764 research outputs found
A Report From The NIHR UK Working Group On Remote Trial Delivery For The COVID-19 Pandemic and Beyond
Exome sequencing in dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.This study was funded by the NHS National Institute of Health Research Biomedical Research Unit for Lewy body dementia at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Tissue for this study was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council and by Brains for Dementia Research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK. MJK is a Wellcome Trust Clinical Research Training Fellow. PFC is a Wellcome Trust Senior Fellow in Clinical Science and National Institute for Health Research Senior Investigator. He receives funding from the Medical Research Council and the National Institute for Health Research Biomedical Research Centre for Ageing and Age-Related Disease award to the Newcastle upon Tyne Foundation Hospitals National Health Service Trust. The funding sources had no role in study design, data collection/analysis, the writing of the paper or the decision of when or where to publish it. The views expressed here are the views of the authors and not necessarily those of the NHS, NIHR or the Department of Health.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v6/n2/full/tp2015220a.html
A report from the NIHR UK working group on remote trial delivery for the COVID-19 pandemic and beyond
Abstract Background Prior to the COVID-19 pandemic, the majority of clinical trial activity took place face to face within clinical or research units. The COVID-19 pandemic resulted in a significant shift towards trial delivery without in-person face-to-face contact or “Remote Trial Delivery”. The National Institute of Health Research (NIHR) assembled a Remote Trial Delivery Working Group to consider challenges and enablers to this major change in clinical trial delivery and to provide a toolkit for researchers to support the transition to remote delivery. Methods The NIHR Remote Trial Delivery Working Group evaluated five key domains of the trial delivery pathway: participant factors, recruitment, intervention delivery, outcome measurement and quality assurance. Independent surveys were disseminated to research professionals, and patients and carers, to ascertain benefits, challenges, pitfalls, enablers and examples of good practice in Remote Trial Delivery. A toolkit was constructed to support researchers, funders and governance structures in moving towards Remote Trial Delivery. The toolkit comprises a website encompassing the key principles of Remote Trial Delivery, and a repository of best practice examples and questions to guide research teams. Results The patient and carer survey received 47 respondents, 34 of whom were patients and 13 of whom were carers. The professional survey had 115 examples of remote trial delivery practice entered from across England. Key potential benefits included broader reach and inclusivity, the ability for standardisation and centralisation, and increased efficiency and patient/carer convenience. Challenges included the potential exclusion of participants lacking connectivity or digital skills, the lack of digitally skilled workforce and appropriate infrastructure, and validation requirements. Five key principles of Remote Trial Delivery were proposed: national research standards, inclusivity, validity, cost-effectiveness and evaluation of new methodologies. Conclusions The rapid changes towards Remote Trial Delivery catalysed by the COVID-19 pandemic could lead to sustained change in clinical trial delivery. The NIHR Remote Trial Delivery Working Group provide a toolkit for researchers recommending five key principles of Remote Trial Delivery and providing examples of enablers. </jats:sec
L,L-Diaminopimelate Aminotransferase from Chlamydomonas reinhardtii: A Target for Algaecide Development
In some bacterial species and photosynthetic cohorts, including algae, the enzyme
l,l-diaminopimelate aminotransferase
(DapL) (E.C. 2.6.1.83) is involved in the anabolism of the essential amino acid
L-lysine. DapL catalyzes the conversion of
tetrahydrodipicolinate (THDPA) to
l,l-diaminopimelate
(l,l-DAP), in one step bypassing the
DapD, DapC and DapE enzymatic reactions present in the acyl DAP pathways. Here
we present an in vivo and in vitro
characterization of the DapL ortholog from the alga Chlamydomonas
reinhardtii (Cr-DapL). The in
vivo analysis illustrated that the enzyme is able to functionally
complement the E. coli dap auxotrophs and was essential for
plant development in Arabidopsis. In vitro, the enzyme was able
to inter-convert THDPA and l,l-DAP, showing
strong substrate specificity. Cr-DapL was dimeric in both
solution and when crystallized. The structure of Cr-DapL was
solved in its apo form, showing an overall architecture of a
α/β protein with each monomer in the dimer adopting a pyridoxal
phosphate-dependent transferase-like fold in a V-shaped conformation. The active
site comprises residues from both monomers in the dimer and shows some
rearrangement when compared to the apo-DapL structure from
Arabidopsis. Since animals do not possess the enzymatic machinery necessary for
the de novo synthesis of the amino acid
l-lysine, enzymes involved in this pathway are
attractive targets for the development of antibiotics, herbicides and
algaecides
Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders
Anxiety disorders that are the most commonly occurring psychiatric disorders in childhood, are associated with a range of social and educational impairments and often continue into adulthood. Cognitive behaviour therapy (CBT) is an effective treatment option for the majority of cases, although up to 35-45% of children do not achieve remission. Recent research suggests that some genetic variants may be associated with a more beneficial response to psychological therapy. Epigenetic mechanisms such as DNA methylation work at the interface between genetic and environmental influences. Furthermore, epigenetic alterations at the serotonin transporter (SERT) promoter region have been associated with environmental influences such as stressful life experiences. In this study, we measured DNA methylation upstream of SERT in 116 children with an anxiety disorder, before and after receiving CBT. Change during treatment in percentage DNA methylation was significantly different in treatment responders vs nonresponders. This effect was driven by one CpG site in particular, at which responders increased in methylation, whereas nonresponders showed a decrease in DNA methylation. This is the first study to demonstrate differences in SERT methylation change in association with response to a purely psychological therapy. These findings confirm that biological changes occur alongside changes in symptomatology following a psychological therapy such as CBT
Engaging rural preceptors in new longitudinal community clerkships during workforce shortage: a qualitative study
Background: In keeping with its mission to produce doctors for rural and regional Australia, the University of Wollongong, Graduate School of Medicine has established an innovative model of clinical education. This includes a 12-month integrated community-based clerkship in a regional or rural setting, offering senior students longitudinal participation in a \u27community of practice\u27 with access to continuity of patient care experiences, continuity of supervision and curriculum, and individualised personal and professional development. This required developing new teaching sites, based on attracting preceptors and providing them with educational and physical infrastructure. A major challenge was severe health workforce shortages. Methods: Before the new clerkship started, we interviewed 28 general practitioners to determine why they engaged as clerkship preceptors. Independent researchers conducted semi-structured interviews. Responses were transcribed for inductive qualitative content analysis. Results: The new model motivated preceptors to engage because it enhanced their opportunities to contribute to authentic learning when compared with the perceived limitations of short-term attachments. Preceptors appreciated the significant recognition of the value of general practice teaching and the honour of major involvement in the university. They predicted that the initiative would have positive effects on general practitioner morale and improve the quality of their practice. Other themes included the doctors\u27 commitment to their profession, \u27handing on\u27 to the next generation and helping their community to attract doctors in the future. Conclusions: Supervisors perceive that new models of clinical education offer alternative solutions to health care education, delivery and workforce. The longitudinal relationship between preceptor, student and community was seen as offering reciprocal benefits. General practitioners are committed to refining practice and ensuring generation of new members in their profession. They are motivated to engage in novel regional and rural longitudinal clinical clerkships as they perceive that they offer students an authentic learning experience and are a potential strategy to help address workforce shortages and maldistribution
A Systematic Review of Mosquito Coils and Passive Emanators: Defining Recommendations for Spatial Repellency Testing Methodologies.
Mosquito coils, vaporizer mats and emanators confer protection against mosquito bites through the spatial action of emanated vapor or airborne pyrethroid particles. These products dominate the pest control market; therefore, it is vital to characterize mosquito responses elicited by the chemical actives and their potential for disease prevention. The aim of this review was to determine effects of mosquito coils and emanators on mosquito responses that reduce human-vector contact and to propose scientific consensus on terminologies and methodologies used for evaluation of product formats that could contain spatial chemical actives, including indoor residual spraying (IRS), long lasting insecticide treated nets (LLINs) and insecticide treated materials (ITMs). PubMed, (National Centre for Biotechnology Information (NCBI), U.S. National Library of Medicine, NIH), MEDLINE, LILAC, Cochrane library, IBECS and Armed Forces Pest Management Board Literature Retrieval System search engines were used to identify studies of pyrethroid based coils and emanators with key-words "Mosquito coils" "Mosquito emanators" and "Spatial repellents". It was concluded that there is need to improve statistical reporting of studies, and reach consensus in the methodologies and terminologies used through standardized testing guidelines. Despite differing evaluation methodologies, data showed that coils and emanators induce mortality, deterrence, repellency as well as reduce the ability of mosquitoes to feed on humans. Available data on efficacy outdoors, dose-response relationships and effective distance of coils and emanators is inadequate for developing a target product profile (TPP), which will be required for such chemicals before optimized implementation can occur for maximum benefits in disease control
A Nonparametric Mean-Variance Smoothing Method to Assess Arabidopsis Cold Stress Transcriptional Regulator CBF2 Overexpression Microarray Data
Microarray is a powerful tool for genome-wide gene expression analysis. In microarray expression data, often mean and variance have certain relationships. We present a non-parametric mean-variance smoothing method (NPMVS) to analyze differentially expressed genes. In this method, a nonlinear smoothing curve is fitted to estimate the relationship between mean and variance. Inference is then made upon shrinkage estimation of posterior means assuming variances are known. Different methods have been applied to simulated datasets, in which a variety of mean and variance relationships were imposed. The simulation study showed that NPMVS outperformed the other two popular shrinkage estimation methods in some mean-variance relationships; and NPMVS was competitive with the two methods in other relationships. A real biological dataset, in which a cold stress transcription factor gene, CBF2, was overexpressed, has also been analyzed with the three methods. Gene ontology and cis-element analysis showed that NPMVS identified more cold and stress responsive genes than the other two methods did. The good performance of NPMVS is mainly due to its shrinkage estimation for both means and variances. In addition, NPMVS exploits a non-parametric regression between mean and variance, instead of assuming a specific parametric relationship between mean and variance. The source code written in R is available from the authors on request
A single-atom quantum memory in silicon
Long coherence times and fast gate operations are desirable but often conflicting requirements for physical qubits. This conflict can be resolved by resorting to fast qubits for operations, and by storing their state in a 'quantum memory' while idle. The 31 P donor in silicon comes naturally equipped with a fast qubit (the electron spin) and a long-lived qubit (the 31 P nuclear spin), coexisting in a bound state at cryogenic temperatures. Here, we demonstrate storage and retrieval of quantum information from a single donor electron spin to its host phosphorus nucleus in isotopically enriched 28 Si. The fidelity of the memory process is characterised via both state and process tomography. We report an overall process fidelity %, and memory storage times up to 80 ms. These values are limited by a transient shift of the electron spin resonance frequency following high-power radiofrequency pulses
Creating European guidelines for Chiropractic Incident Reporting and Learning Systems (CIRLS): relevance and structure
<p>Abstract</p> <p>Background</p> <p>In 2009, the heads of the Executive Council of the European Chiropractors' Union (ECU) and the European Academy of Chiropractic (EAC) involved in the European Committee for Standardization (CEN) process for the chiropractic profession, set out to establish European guidelines for the reporting of adverse reactions to chiropractic treatment. There were a number of reasons for this: first, to improve the overall quality of patient care by aiming to reduce the application of potentially harmful interventions and to facilitate the treatment of patients within the context of achieving maximum benefit with a minimum risk of harm; second, to inform the training objectives for the Graduate Education and Continuing Professional Development programmes of all 19 ECU member nations, regarding knowledge and skills to be acquired for maximising patient safety; and third, to develop a guideline on patient safety incident reporting as it is likely to be part of future CEN standards for ECU member nations.</p> <p>Objective</p> <p>To introduce patient safety incident reporting within the context of chiropractic practice in Europe and to help individual countries and their national professional associations to develop or improve reporting and learning systems.</p> <p>Discussion</p> <p>Providing health care of any kind, including the provision of chiropractic treatment, can be a complex and, at times, a risky activity. Safety in healthcare cannot be guaranteed, it can only be improved. One of the most important aspects of any learning and reporting system lies in the appropriate use of the data and information it gathers. Reporting should not just be seen as a vehicle for obtaining information on patient safety issues, but also be utilised as a tool to facilitate learning, advance quality improvement and to ultimately minimise the rate of the occurrence of errors linked to patient care.</p> <p>Conclusions</p> <p>Before a reporting and learning system can be established it has to be clear what the objectives of the system are, what resources will be required and whether the implementing organisation has the capacity to operate the system to its full advantage. Responding to adverse event reports requires the availability of experts to analyse the incidents and to provide feedback in a timely fashion. A comprehensive strategy for national implementation must be in place including, but not limited to, presentations at national meetings, the provision of written information to all practitioners and the running of workshops, so that all stakeholders fully understand the purposes of adverse event reporting. Unless this is achieved, any system runs the risk of failure, or at the very least, limited usefulness.</p
- …