Translational regulation shapes the molecular landscape of complex disease phenotypes.

The extent of translational control of gene expression in mammalian tissues remains largely unknown. Here we perform genome-wide RNA sequencing and ribosome profiling in heart and liver tissues to investigate strain-specific translational regulation in the spontaneously hypertensive rat (SHR/Ola). For the most part, transcriptional variation is equally apparent at the translational level and there is limited evidence of translational buffering. Remarkably, we observe hundreds of strain-specific differences in translation, almost doubling the number of differentially expressed genes. The integration of genetic, transcriptional and translational data sets reveals distinct signatures in 3'UTR variation, RNA-binding protein motifs and miRNA expression associated with translational regulation of gene expression. We show that a large number of genes associated with heart and liver traits in human genome-wide association studies are primarily translationally regulated. Capturing interindividual differences in the translated genome will lead to new insights into the genes and regulatory pathways underlying disease phenotypes

Appropriately smoothing prevalence data to inform estimates of growth rate and reproduction number

The time-varying reproduction number () can change rapidly over the course of a pandemic due to changing restrictions, behaviours, and levels of population immunity. Many methods exist that allow the estimation of from case data. However, these are not easily adapted to point prevalence data nor can they infer across periods of missing data. We developed a Bayesian P-spline model suitable for fitting to a wide range of epidemic time-series, including point-prevalence data. We demonstrate the utility of the model by fitting to periodic daily SARS-CoV-2 swab-positivity data in England from the first 7 rounds (May 2020–December 2020) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Estimates of over the period of two subsequent rounds (6–8 weeks) and single rounds (2–3 weeks) inferred using the Bayesian P-spline model were broadly consistent with estimates from a simple exponential model, with overlapping credible intervals. However, there were sometimes substantial differences in point estimates. The Bayesian P-spline model was further able to infer changes in over shorter periods tracking a temporary increase above one during late-May 2020, a gradual increase in over the summer of 2020 as restrictions were eased, and a reduction in during England’s second national lockdown followed by an increase as the Alpha variant surged. The model is robust against both under-fitting and over-fitting and is able to interpolate between periods of available data; it is a particularly versatile model when growth rate can change over small timescales, as in the current SARS-CoV-2 pandemic. This work highlights the importance of pairing robust methods with representative samples to track pandemics

Evaluation of the safety of C-spine clearance by paramedics: design and methodology

<p>Abstract</p> <p>Background</p> <p>Canadian Emergency Medical Services annually transport 1.3 million patients with potential neck injuries to local emergency departments. Less than 1% of those patients have a c-spine fracture and even less (0.5%) have a spinal cord injury. Most injuries occur before the arrival of paramedics, not during transport to the hospital, yet most patients are transported in ambulances immobilized. They stay fully immobilized until a bed is available, or until physician assessment and/or X-rays are complete. The prolonged immobilization is often unnecessary and adds to the burden of already overtaxed emergency medical services systems and crowded emergency departments.</p> <p>Methods/Design</p> <p>The goal of this study is to evaluate the safety and potential impact of an active strategy that allows paramedics to assess very low-risk trauma patients using a validated clinical decision rule, the Canadian C-Spine Rule, in order to determine the need for immobilization during transport to the emergency department.</p> <p>This cohort study will be conducted in Ottawa, Canada with one emergency medical service. Paramedics with this service participated in an earlier validation study of the Canadian C-Spine Rule. Three thousand consecutive, alert, stable adult trauma patients with a potential c-spine injury will be enrolled in the study and evaluated using the Canadian C-Spine Rule to determine the need for immobilization. The outcomes that will be assessed include measures of safety (numbers of missed fractures and serious adverse outcomes), measures of clinical impact (proportion of patients transported without immobilization, key time intervals) and performance of the Rule.</p> <p>Discussion</p> <p>Approximately 40% of all very low-risk trauma patients could be transported safely, without c-spine immobilization, if paramedics were empowered to make clinical decisions using the Canadian C-Spine Rule. This safety study is an essential step before allowing all paramedics across Canada to selectively immobilize trauma victims before transport. Once safety and potential impact are established, we intend to implement a multi-centre study to study actual impact.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01188447">NCT01188447</a></p

Regulatory Fitness: Fintech, Funny Money, and Smart Contracts

© 2019, The Author(s). This article argues that there are many questions that lawyers might ask, and conversations that they might have, about smart contracts; that some questions that are asked are more important than others; and that there are some questions that are not asked but which should be asked. First, it is argued that the question that preoccupies ‘coherentists’ (concerning the application of the law of contract to smart contracts, and the fit between smart contracts and the paradigmatic ‘fiat contracts’ that are recognised by the law of contract) is neither as puzzling nor as important as might be supposed. Secondly, it is argued that, if there are concerns about the acceptability of smart contracts, then the conversation that needs to be had is of a ‘regulatory-instrumentalist’ nature; in particular, if the question is one of public policy restrictions on the use of smart contracts, then the appropriate balance of interests needs to be made by an institution that has both the necessary mandate and the appropriate mind-set. Thirdly, it is argued that there are conversations that we currently do not have but which urgently need to be had. Blockchain is a potentially transformative technology and it is important to have more fundamental conversations about the kind of community that we want to be

Opening practice: Supporting Reproducibility and Critical Spatial Data Science

This paper reflects on a number of trends towards a more open and reproducible approach to geographic and spatial data science over recent years. In particular, it considers trends towards Big Data, and the impacts this is having on spatial data analysis and modelling. It identifies a turn in academia towards coding as a core analytic tool, and away from proprietary software tools offering ‘black boxes’ where the internal workings of the analysis are not revealed. It is argued that this closed form software is problematic and considers a number of ways in which issues identified in spatial data analysis (such as the MAUP) could be overlooked when working with closed tools, leading to problems of interpretation and possibly inappropriate actions and policies based on these. In addition, this paper considers the role that reproducible and open spatial science may play in such an approach, taking into account the issues raised. It highlights the dangers of failing to account for the geographical properties of data, now that all data are spatial (they are collected somewhere), the problems of a desire for n = all observations in data science and it identifies the need for a critical approach. This is one in which openness, transparency, sharing and reproducibility provide a mantra for defensible and robust spatial data science

Report of the Workshop for maturity staging chairs (WKMATCH), 11–15 June 2012, Split, Croatia

59 páginas, 8 anexosThe recorded maturity stage at the time of observation is an important biological parameter to be used in the calculation of maturity ogives (and therefore of Spawning Stock Biomass), for the definition of the spawning season of a species, for the moni-toring of long-term changes in the spawning cycle, and for many other research needs regarding the biology of species. Thus, maturity data are fundamental part of the stock assessment process and hence a vast effort is put on validating the macro-scopic inspection of gonads. In the last decade a series of workshops addressed the maturity staging of different species with the objective of developing common ma-turity scales, decreasing discrepancies between laboratories and validating maturity staging through microscopic evaluation. A total of 11 of those workshops on species-specific maturity staging were revised here. These workshops have analysed 20 teleosts, elasmobranchs as a whole subclass, three orders of cephalopods and four crustacean species. The WKMAT 2007, and later WKMSCWHS 2007, proposed a six point maturity scale for both males and fe-males that have been used as a reference in the different maturity workshops to de-velop and adopt a common scale between laboratories for each species. A notable effort has been made by all workshop participants to standardize the existing maturi-ty scales and accommodate the standard scale proposed. All workshops acknowl-edged the biological differences between the reference scale stages. All workshops proposed new scales that although were generally consistent with WKMAT scale, showed several differences. As a result, the four stage scale proposed in WKMAT has generally not adopted, partially because such scale does not allow reflecting specific particularities, useful for a number of species.To overcome this, we propose the use a single scale of 4+2 stages or divisions which is believed to be universal, that is, it can be used for the majority of species, although viviparous and hermaphrodites may need some adaptation. This 6 stage codes and names should be used for all species and both sexes without exception; species-specific particularities should be reflected creating subdivisions and never modifying the 6 main stages. Using this proposed coding system, particularities of species and stocks can be addressed by each workshop (subdivisions), without losing consistency and traceability (divisions). In this way the code number of the divisions or main stages has the same biological meaning across species and laboratories. Some poten-tial subdivisions are proposed as well, for its facultative use in some batch spawners an in viviparous species. The merging of different stages should be avoided and in-stead a combined code should be used. In this manner the consistency of stages defi-nition and codes is maintained across species. The definition of each stage needs to be linked to biological phases and incorporate into its description species-specific aspects relevant for an easy identification of each stage. The use of the terminology for maturity stages considers a general scheme of the reproduction that can be applied to all male and female elasmobranchs and tele-ost fishes, including hermaphrodites and livebearers. A full glossary of terminology was compiled. Training (of the observers) is the major issue for maturity staging, and it should be strengthen within the umbrella of ICES.When staging maturity macroscopically timing of the sampling is critical to obtain reliable results. To define this period it is important to know the timing of the repro-ductive cycle, as this is species specific. If maturity staging outside the optimal peri-ods is required, this should be based on histological information. However, we suggest that whole mounts preparations are useful to validate macroscopic staging of ovaries being particularly useful to separate between early developing and develop-ing specimens, immature and regressing/regenerating specimens, or even specimens that have just completed a spawning season from those have not yet entered sexual maturity. Nevertheless, it is recommended that the whole-mounts method is careful-ly calibrated before taken into practical use. The maturity Workshops should discuss the new and general scale in their respective WKs by e-mail to assess the correspondence with the agreed scale, and evaluate the uncertainties and the problems this new general scale may cause. At the same time, ICES should ensure an appropriate attendance and a required level of basic knowledge, both on maturity studies and on the species targeted by the Workshop. Beyond of experts in the matter, the participants should be trained people, this can be achieved by training courses in ICES. We have revised and updated the Guidelines for Workshops on Maturity Staging, and provided general recommendations for future workshops.We reviewed a total of 148 stocks of 53 species from 8 ecoregions from which ICES provides some type of advice. In 88 stocks (59%) maturity data are not used or are used improperly. This includes the use of time invariant maturity ogives when annu-al ogives can be available. In 39 stocks (26%) the assessment uses a proper maturity ogive, but over a limited time period. Finally in only 21 stocks 14% of the total ad-vised stocks the maturity ogive has been estimated on regular basis and in these cases they are used properly in the assessment. Therefore, lack of data and/or poor quality is the main causes of maturity not being used. However, there is a general lack of information in the reports on how the maturity data was collected, ogive estimated, quality control and other relevant information. There is a need to determine what maturity data are required for assessment purposes, including how phenomena such as skipping spawning should be included in assessments. In spite of the effort on collecting maturity data, almost in 100% of the cases sex-specific ogives are combined without analysing the impact of this. Expert groups should provide comprehensive reports on how the maturity data is used, and more specifically, at least: the method used to estimate maturity, in which sex and how a sex-specific maturity ogive is used in the assessment, source of data (survey, commercial sampling), the time of the year when the sampling was conduct-ed, and years of proper estimation. The impact on the assessment of combining sex-specific maturity ogives should be analysed.Peer reviewe

High prevalence of SARS-CoV-2 swab positivity and increasing R number in England during October 2020: REACT-1 round 6 interim report

Background REACT-1 measures prevalence of SARS-CoV-2 infection in representative samples of the population in England using PCR testing from self-administered nose and throat swabs. Here we report interim results for round 6 of observations for swabs collected from the 16th to 25th October 2020 inclusive. Methods REACT-1 round 6 aims to collect data and swab results from 160,000 people aged 5 and above. Here we report results from the first 86,000 individuals. We estimate prevalence of PCR-confirmed SARS-CoV-2 infection, reproduction numbers (R) and temporal trends using exponential growth or decay models. Prevalence estimates are presented both unweighted and weighted to be representative of the population of England, accounting for response rate, region, deprivation and ethnicity. We compare these interim results with data from round 5, based on swabs collected from 18th September to 5th October 2020 inclusive. Results Overall prevalence of infection in the community in England was 1.28% or 128 people per 10,000, up from 60 per 10,000 in the previous round. Infections were doubling every 9.0 (6.1, 18) days with a national reproduction number (R) estimated at 1.56 (1.27, 1.88) compared to 1.16 (1.05, 1.27) in the previous round. Prevalence of infection was highest in Yorkshire and The Humber at 2.72% (2.12%, 3.50%), up from 0.84% (0.60%, 1.17%), and the North West at 2.27% (1.90%, 2.72%), up from 1.21% (1.01%, 1.46%), and lowest in South East at 0.55% (0.45%, 0.68%), up from 0.29% (0.23%, 0.37%). Clustering of cases was more prevalent in Lancashire, Manchester, Liverpool and West Yorkshire, West Midlands and East Midlands. Interim estimates of R were above 2 in the South East, East of England, London and South West, but with wide confidence intervals. Nationally, prevalence increased across all age groups with the greatest increase in those aged 55-64 at 1.20% (0.99%, 1.46%), up 3-fold from 0.37% (0.30%, 0.46%). In those aged over 65, prevalence was 0.81% (0.58%, 0.96%) up 2-fold from 0.35% (0.28%, 0.43%). Prevalence remained highest in 18 to 24-year olds at 2.25% (1.47%, 3.42%). Conclusion The co-occurrence of high prevalence and rapid growth means that the second wave of the epidemic in England has now reached a critical stage. Whether via regional or national measures, it is now time-critical to control the virus and turn R below one if further hospital admissions and deaths from COVID-19 are to be avoided

SARS-CoV-2 antibody prevalence in England following the first peak of the pandemic.

England has experienced a large outbreak of SARS-CoV-2, disproportionately affecting people from disadvantaged and ethnic minority communities. It is unclear how much of this excess is due to differences in exposure associated with structural inequalities. Here we report from the REal-time Assessment of Community Transmission-2 (REACT-2) national study of over 100,000 people. After adjusting for test characteristics and re-weighting to the population, overall antibody prevalence is 6.0% (95% CI: 5.8-6.1). An estimated 3.4 million people had developed antibodies to SARS-CoV-2 by mid-July 2020. Prevalence is two- to three-fold higher among health and care workers compared with non-essential workers, and in people of Black or South Asian than white ethnicity, while age- and sex-specific infection fatality ratios are similar across ethnicities. Our results indicate that higher hospitalisation and mortality from COVID-19 in minority ethnic groups may reflect higher rates of infection rather than differential experience of disease or care