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Effective influenza surveillance requires new methods capable of rapid and inexpensive genomic analysis of evolving viral species for pandemic preparedness, to understand the evolution of circulating viral species, and for vaccine strain selection. We have developed one such approach based on previously described broad-range reverse transcription PCR/electrospray ionization mass spectrometry (RT-PCR/ESI-MS) technology.Analysis of base compositions of RT-PCR amplicons from influenza core gene segments (PB1, PB2, PA, M, NS, NP) are used to provide sub-species identification and infer influenza virus H and N subtypes. Using this approach, we detected and correctly identified 92 mammalian and avian influenza isolates, representing 30 different H and N types, including 29 avian H5N1 isolates. Further, direct analysis of 656 human clinical respiratory specimens collected over a seven-year period (1999-2006) showed correct identification of the viral species and subtypes with >97% sensitivity and specificity. Base composition derived clusters inferred from this analysis showed 100% concordance to previously established clades. Ongoing surveillance of samples from the recent influenza virus seasons (2005-2006) showed evidence for emergence and establishment of new genotypes of circulating H3N2 strains worldwide. Mixed viral quasispecies were found in approximately 1% of these recent samples providing a view into viral evolution.Thus, rapid RT-PCR/ESI-MS analysis can be used to simultaneously identify all species of influenza viruses with clade-level resolution, identify mixed viral populations and monitor global spread and emergence of novel viral genotypes. This high-throughput method promises to become an integral component of influenza surveillance.

The low-lying energy spectrum of the static-colour-source-anti-source system in a vacuum containing light and strange quarks is computed using lattice QCD for a range of different light quark masses. The resulting levels are described using a simple model Hamiltonian and the parameters in this model are extrapolated to the physical light-quark masses. In this framework, the QCD string tension is found to be σ=445(3)stat(6)sys MeV.

Abstract Background In many grant review settings, proposals are selected for funding on the basis of summary statistics of review ratings. Challenges of this approach (including the presence of ties and unclear ordering of funding preference for proposals) could be mitigated if rankings such as top-k preferences or paired comparisons, which are local evaluations that enforce ordering across proposals, were also collected and incorporated in the analysis of review ratings. However, analyzing ratings and rankings simultaneously has not been done until recently. This paper describes a practical method for integrating rankings and scores and demonstrates its usefulness for making funding decisions in real-world applications. Methods We first present the application of our existing joint model for rankings and ratings, the Mallows-Binomial, in obtaining an integrated score for each proposal and generating the induced preference ordering. We then apply this methodology to several theoretical “toy” examples of rating and ranking data, designed to demonstrate specific properties of the model. We then describe an innovative protocol for collecting rankings of the top-six proposals as an add-on to the typical peer review scoring procedures and provide a case study using actual peer review data to exemplify the output and how the model can appropriately resolve judges’ evaluations. Results For the theoretical examples, we show how the model can provide a preference order to equally rated proposals by incorporating rankings, to proposals using ratings and only partial rankings (and how they differ from a ratings-only approach) and to proposals where judges provide internally inconsistent ratings/rankings and outlier scoring. Finally, we discuss how, using real world panel data, this method can provide information about funding priority with a level of accuracy in a well-suited format for research funding decisions. Conclusions A methodology is provided to collect and employ both rating and ranking data in peer review assessments of proposal submission quality, highlighting several advantages over methods relying on ratings alone. This method leverages information to most accurately distill reviewer opinion into a useful output to make an informed funding decision and is general enough to be applied to settings such as in the NIH panel review process.

We describe an unusual case of multi-vessel giant coronary artery aneurysms complicated by acute coronary syndrome despite escalation of therapy. A 65-year-old man with hypertension and hypercholesterolemia presented to clinic with atypical chest pain over 4 months. Outpatient computed tomography coronary angiography (CTCA) demonstrated giant coronary aneurysms involving all 3 major coronary arteries. Outpatient coronary angiogram findings were in concordance with the CTCA with no definite obstructive coronary disease. Myocardial perfusion imaging was normal. He was commenced on dual antiplatelet therapy (DAPT). At 6 months, he presented with chest pain and non-ST-elevation myocardial infarction. Repeat coronary angiogram demonstrated occluded first septal LAD branch which previously had aneurysmal dilatation. DAPT was changed to long-term oral anticoagulation. He remains well at 18 months. This case highlights the importance of multi-modality imaging in the diagnosis and workup of coronary artery aneurysms and challenges in management; an individualized approach is required.

Background:. Ongoing innovation leads to a continuous influx of new technologies related to shoulder arthroplasty. These are made available to surgeons and marketed to both health-care providers and patients with the hope of improving outcomes. We sought to evaluate how preoperative planning technologies for shoulder arthroplasty affect outcomes. Methods:. This was a retrospective cohort study conducted using data from an integrated health-care system’s shoulder arthroplasty registry. Adult patients who underwent primary elective anatomic or reverse total shoulder arthroplasty (2015 to 2020) were identified. Preoperative planning technologies were identified as (1) a computed tomography (CT) scan and (2) patient-specific instrumentation (PSI). Multivariable Cox regression and logistic regression were used to compare the risk of aseptic revision and 90-day adverse events, respectively, between procedures for which technologies were and were not used. Results:. The study sample included 8,117 procedures (in 7,372 patients) with an average follow-up of 2.9 years (maximum, 6 years). No reduction in the risk of aseptic revision was observed for patients having either preoperative CT scans (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.87 to 1.72) or PSI (HR = 1.44; 95% CI = 0.71 to 2.92). Patients having CT scans had a lower likelihood of 90-day emergency department visits (odds ratio [OR] = 0.84; 95% CI = 0.73 to 0.97) but a higher likelihood of 90-day venous thromboembolic events (OR = 1.79; 95% CI = 1.18 to 2.74). Patients with PSI use had a higher likelihood of 90-day deep infection (OR = 7.74; 95% CI = 1.11 to 53.94). Conclusions:. We found no reduction in the risk of aseptic revision with the use of these technologies. Patients having CT scans and PSI use had a higher likelihood of venous thromboembolism and deep infection, respectively. Ongoing research with extended follow-up is being conducted to further examine the effects of these technologies on patient outcomes. Level of Evidence:. Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The incidence of open tibia/fibula fractures in the elderly is increasing, but current national guidelines focus on the aggressive treatment of high-energy injuries in younger patients. There is conflicting evidence regarding whether older age affects treatment provision and outcomes in open fractures. The aim of this study was to determine if elderly patients are sustaining a different injury to younger patients and how their treatment and outcomes differ. This may have implications for future guidelines and verify their application in the elderly.In this retrospective single centre cohort study (December 2015–July 2018), we compared the injury characteristics, operative management and outcomes of elderly (≥65 years) and younger (18–65 years) patients with open tibia/fibula fractures. An extended cohort examined free flap reconstruction.In total, 157 patients were included. High-energy injuries were commoner in younger patients (88% vs 37%; p

Aims: As the world continues to fight successive waves of COVID-19 variants, we have seen worldwide infections surpass 100 million. London, UK, has been severely affected throughout the pandemic, and the resulting impact on the NHS has been profound. The aim of this study is to evaluate the impact of COVID-19 on theatre productivity across London’s four major trauma centres (MTCs), and to assess how the changes to normal protocols and working patterns impacted trauma theatre efficiency. Methods: This was a collaborative study across London’s MTCs. A two-month period was selected from 5 March to 5 May 2020. The same two-month period in 2019 was used to provide baseline data for comparison. Demographic information was collected, as well as surgical speciality, procedure, time to surgery, type of anaesthesia, and various time points throughout the patient journey to theatre. Results: In total, 1,243 theatre visits were analyzed as part of the study. Of these, 834 patients presented in 2019 and 409 in 2020. Fewer open reduction and internal fixations were performed in 2020 (33.5% vs 38.2%), and there was an increase in the number of orthoplastic cases in 2020 (8.3% vs 2.2%), both statistically significant results (p < 0.000). There was a statistically significant increase in median time from 2019 to 2020, between sending for a patient and their arrival to the anaesthetic room (29 vs 35 minutes; p = 0.000). Median time between arrival in the anaesthetic room and commencement of anaesthetic increased (7 to 9 minutes; p = 0.104). Conclusion: Changes in working practices necessitated by COVID-19 led to modest delays to all aspects of theatre use, and consequently theatre efficiency. However, the reality is that the major concerns of impact of service did not occur to the levels that were expected.

Abstract Background Segmental tibial fractures are fractures in two or more areas of the tibial diaphysis resulting in a separate intercalary segment of the bone. Surgical fixation is recommended for patients with segmental tibial fractures as non-operative treatment outcomes are poor. The most common surgical interventions are intramedullary nailing (IMN) and circular frame external fixation (CFEF), but evidence about which is better is of poor quality. An adequately powered randomised controlled trial (RCT) to determine optimum treatment is required. STIFF-F aimed to assess the feasibility of a multicentre RCT comparing IMN with CFEF for segmental tibial fracture. Methods STIFF-F was a mixed-methods feasibility study comprising a pilot RCT conducted at six UK Major Trauma Centres, qualitative interviews drawing on Phenomenology and an online survey of rehabilitation. The primary outcome was recruitment rate. Patients, 16 years and over, with a segmental tibial fracture (open or closed) deemed suitable for IMN or CFEF were eligible to participate. Randomisation was stratified by site using random permuted blocks of varying sizes. Participant or assessor blinding was not possible. Interviews were undertaken with patients about their experience of injury, treatment, recovery and participation. Staff were interviewed to identify contextual factors affecting trial processes, their experience of recruitment and the treatment pathway. An online survey was developed to understand the rehabilitation context of the treatments. Results Eleven patients were screened and three recruited to the pilot RCT. Nineteen staff and four patients participated in interviews, and 11 physiotherapists responded to the survey. This study found the following: (i) segmental tibial fractures were rarer than anticipated, (ii) the complexity of the injury, study setup times and surgeon treatment preferences impeded recruitment, (iii) recovery from a segmental tibial fracture is challenging, and rehabilitation protocols are inconsistent and (iv) despite the difficulty recruiting, staff valued this research question and strived to find a way forward. Conclusion The proposed multicentre RCT comparing IMN with CFEF is not feasible. This study highlighted the difficulty of recruiting patients to an RCT of a complex rare injury over a short time period. Trial registration The study was registered with the International Standard Randomised Controlled Trials Number Registry: ISRCTN11229660

Abstract Elastic scattering amplitudes for I = 0 DK and I = 0, 1 D K ¯ $$ D\overline{K} $$ are computed in S, P and D partial waves using lattice QCD with light-quark masses corresponding to m π = 239 MeV and m π = 391 MeV. The S-waves contain interesting features including a near-threshold J P = 0+ bound state in I = 0 DK, corresponding to the D s 0 ∗ $$ {D}_{s0}^{\ast } $$ (2317), with an effect that is clearly visible above threshold, and suggestions of a 0+ virtual bound state in I = 0 D K ¯ $$ D\overline{K} $$ . The S-wave I = 1 D K ¯ $$ D\overline{K} $$ amplitude is found to be weakly repulsive. The computed finite-volume spectra also contain a deeply-bound D * vector resonance, but negligibly small P -wave DK interactions are observed in the energy region considered; the P and D-wave D K ¯ $$ D\overline{K} $$ amplitudes are also small. There is some evidence of 1+ and 2+ resonances in I = 0 DK at higher energies.

Abstract Where there are a limited number of patients, such as in a rare disease, clinical trials in these small populations present several challenges, including statistical issues. This led to an EU FP7 call for proposals in 2013. One of the three projects funded was the Innovative Methodology for Small Populations Research (InSPiRe) project. This paper summarizes the main results of the project, which was completed in 2017. The InSPiRe project has led to development of novel statistical methodology for clinical trials in small populations in four areas. We have explored new decision-making methods for small population clinical trials using a Bayesian decision-theoretic framework to compare costs with potential benefits, developed approaches for targeted treatment trials, enabling simultaneous identification of subgroups and confirmation of treatment effect for these patients, worked on early phase clinical trial design and on extrapolation from adult to pediatric studies, developing methods to enable use of pharmacokinetics and pharmacodynamics data, and also developed improved robust meta-analysis methods for a small number of trials to support the planning, analysis and interpretation of a trial as well as enabling extrapolation between patient groups. In addition to scientific publications, we have contributed to regulatory guidance and produced free software in order to facilitate implementation of the novel methods.

Artificial intelligence: Algorithm predicts clinical outcomes for hospital inpatients Artificial intelligence outperforms traditional statistical models at predicting a range of clinical outcomes from a patient’s entire raw electronic health record (EHR). A team led by Alvin Rajkomar and Eyal Oren from Google in Mountain View, California, USA, developed a data processing pipeline for transforming EHR files into a standardized format. They then applied deep learning models to data from 216,221 adult patients hospitalized for at least 24 h each at two academic medical centers, and showed that their algorithm could accurately predict risk of mortality, hospital readmission, prolonged hospital stay and discharge diagnosis. In all cases, the method proved more accurate than previously published models. The authors provide a case study to serve as a proof-of-concept of how such an algorithm could be used in routine clinical practice in the future.

Abstract Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Abstract Background Most confirmatory randomised controlled clinical trials (RCTs) are designed with specified power, usually 80% or 90%, for a hypothesis test conducted at a given significance level, usually 2.5% for a one-sided test. Approval of the experimental treatment by regulatory agencies is then based on the result of such a significance test with other information to balance the risk of adverse events against the benefit of the treatment to future patients. In the setting of a rare disease, recruiting sufficient patients to achieve conventional error rates for clinically reasonable effect sizes may be infeasible, suggesting that the decision-making process should reflect the size of the target population. Methods We considered the use of a decision-theoretic value of information (VOI) method to obtain the optimal sample size and significance level for confirmatory RCTs in a range of settings. We assume the decision maker represents society. For simplicity we assume the primary endpoint to be normally distributed with unknown mean following some normal prior distribution representing information on the anticipated effectiveness of the therapy available before the trial. The method is illustrated by an application in an RCT in haemophilia A. We explicitly specify the utility in terms of improvement in primary outcome and compare this with the costs of treating patients, both financial and in terms of potential harm, during the trial and in the future. Results The optimal sample size for the clinical trial decreases as the size of the population decreases. For non-zero cost of treating future patients, either monetary or in terms of potential harmful effects, stronger evidence is required for approval as the population size increases, though this is not the case if the costs of treating future patients are ignored. Conclusions Decision-theoretic VOI methods offer a flexible approach with both type I error rate and power (or equivalently trial sample size) depending on the size of the future population for whom the treatment under investigation is intended. This might be particularly suitable for small populations when there is considerable information about the patient population.

Background: We consider the problem of quantifying the human lifespan using a statistical approach that probabilistically forecasts the maximum reported age at death (MRAD) through 2100. Objective: We seek to quantify the probability that any person attains various extreme ages, such as those above 120, by the year 2100. Methods: We use the exponential survival model for supercentenarians (people over age 110) of Rootzén and Zholud (2017) but extend the forecasting window, quantify population uncertainty using Bayesian population projections, and incorporate the most recent data from the International Database on Longevity (IDL) to obtain unconditional estimates of the distribution of MRAD this century in a fully Bayesian analysis. Results: We find that the exponential survival model for supercentenarians is consistent with the most recent IDL data and that projections of the population aged 110-114 through 2080 are sensible. We integrate over the posterior distributions of the exponential model parameter and uncertainty in the supercentenarian population projections to estimate an unconditional distribution of MRAD by 2100. Conclusions: Based on the Bayesian analysis, there is a greater than 99Š probability that the current MRAD of 122 will be broken by 2100. We estimate the probabilities that a person lives to at least age 126, 128, or 130 this century, as 89Š, 44Š, and 13Š, respectively. Contribution: We have updated the supercentenarian survival model of Rootzén and Zholud using the most recent IDL data, incorporated Bayesian population projections, and extended the forecasting window to create the first fully Bayesian and unconditional probabilistic projection of MRAD by 2100.

In this article I analyse how Jackie Sibblies Drury’s play Fairview makes white audience members feel white. As a play that exposes whiteness and calls white people to account for their racism, Fairview speaks to contemporary global antiracist activism efforts. Therefore, I begin by situating Fairview in the transatlantic cultural and political context of Black Lives Matter. I then discuss the theatrical devices Drury employs in Fairview in order to make whiteness felt before going on to analyse a range of white audience responses to the production at London’s Young Vic Theatre in 2019/2020. I reflect on these responses in relation to how white people react to accusations of white privilege and power in the public sphere and identify shared strategies for sustaining whiteness. In conclusion, I consider Fairview as a model of affective antiracist activism.

We all enact change over time, but are not nearly as concerned with where we are writing about. One recent trend in general historiography may help our maritime studies. This is the matter of place. To illustrate this, let me say a little about three particular spaces, that is, ships, then coasts, and finally port cities.

Non-attendance at mental health clinics is an international problem. A survey was conducted in the UK investigating communication methods used by staff to inform and remind patients about appointments. Increased number of communication methods used was associated with a reduced non-attendance rate. A care modelling analysis is provided that explores the healthcare use of three hypothetical patients following clinic non-attendance. The financial and environmental costs of each are then calculated and results discussed. Reducing non-attendance is achievable through the use of multiple communication methods. This small change can improve the sustainability of mental healthcare in different countries by improving quality of care and reducing financial and environmental costs.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Amniotic fluid embolism (AFE, also known as anaphylactoid syndrome of pregnancy) at the time of surgery for placenta percreta has been previously reported. We report here a case in which AFE and associated cardiac arrest occurred following a hysterectomy for placenta percreta. In this case, subhepatic manual aortic compression during the cardiac arrest and chest compressions followed by infrarenal aortic cross-clamping during volume infusion and reversal of the coagulopathy were associated with a successful resuscitation and good maternal outcome.

Abstract What are the origins and history of the ethnonym Geordie in North East England? How does this history — which according to some authorities has never adequately been explained — help us to understand its current usage and meanings? I attempt to answer these questions by drawing on evidence from a range of sources (including newly available material in the British Newspaper Archive).

Transgene delivery systems, particularly those involving retroviruses, often result in the integration of multiple copies of the transgene throughout the host genome. Since site-specific silencing of trangenes can occur, it becomes important to identify the number and chromosomal location of the multiple copies of the transgenes in order to correlate inheritance of the transgene at a particular chromosomal site with a specific and robust phenotype. Using a technique that combines restriction endonuclease digest and several rounds of PCR amplification followed by nucleotide sequencing, it is possible to identify multiple chromosomal integration sites in transgenic founder animals. By designing genotyping assays to detect each individual integration site in the offspring of these founders, the inheritance of transgenes integrated at specific chromosomal locations can be followed efficiently as the transgenes randomly segregate in subsequent generations. Phenotypic characteristics can then be correlated with inheritance of a transgene integrated at a particular chromosomal location to allow rational selection of breeding animals in order to establish the transgenic line.

This article explores a corpus of all the UK election manifestos produced by the three main political parties in the period 1900–2010. It offers an alternative perspective on function words in corpus-assisted critical discourse analysis, placing them at the centre rather than the periphery. Using a combination of WordSmith Tools and Sketch Engine, I identify four key function words and show how a consideration of their phraseological behaviour can – perhaps surprisingly – reveal aspects of party ideology, as well as pointing to generic change over time.

The segmentation gene network of Drosophila consists of maternal and zygotic factors that generate, by transcriptional (cross-) regulation, expression patterns of increasing complexity along the anterior-posterior axis of the embryo. Using known binding site information for maternal and zygotic gap transcription factors, the computer algorithm Ahab recovers known segmentation control elements (modules) with excellent success and predicts many novel modules within the network and genome-wide. We show that novel module predictions are highly enriched in the network and typically clustered proximal to the promoter, not only upstream, but also in intronic space and downstream. When placed upstream of a reporter gene, they consistently drive patterned blastoderm expression, in most cases faithfully producing one or more pattern elements of the endogenous gene. Moreover, we demonstrate for the entire set of known and newly validated modules that Ahab's prediction of binding sites correlates well with the expression patterns produced by the modules, revealing basic rules governing their composition. Specifically, we show that maternal factors consistently act as activators and that gap factors act as repressors, except for the bimodal factor Hunchback. Our data suggest a simple context-dependent rule for its switch from repressive to activating function. Overall, the composition of modules appears well fitted to the spatiotemporal distribution of their positive and negative input factors. Finally, by comparing Ahab predictions with different categories of transcription factor input, we confirm the global regulatory structure of the segmentation gene network, but find odd skipped behaving like a primary pair-rule gene. The study expands our knowledge of the segmentation gene network by increasing the number of experimentally tested modules by 50%. For the first time, the entire set of validated modules is analyzed for binding site composition under a uniform set of criteria, permitting the definition of basic composition rules. The study demonstrates that computational methods are a powerful complement to experimental approaches in the analysis of transcription networks.