Turbulent channel flow near maximum drag reduction: simulations, experiments and mechanisms

It is well known that the drag in a turbulent flow of a polymer solution is significantly reduced compared to Newtonian flow. Here we consider this phenomenon by means of a direct numerical simulation of a turbulent channel flow. The polymers are modelled as elastic dumbbells using the FENE-P model. In the computations the polymer model is solved simultaneously with the flow equations, i.e. the polymers are deformed by the flow and in their turn influence the flow structures by exerting a polymer stress. We have studied the results of varying the polymer parameters, such as the maximum extension, the elasticity and the concentration. For the case of highly extensible polymers the results of our simulations are very close to the maximum drag reduction or Virk (1975) asymptote. Our simulation results show that at approximately maximum drag reduction the slope of the mean velocity profile is increased compared to the standard logarithmic profile in turbulent wall flows. For the r.m.s. of the streamwise velocity fluctuations we find initially an increase in magnitude which near maximum drag reduction changes to a decrease. For the velocity fluctuations in the spanwise and wall-normal directions we find a continuous decrease as a function of drag reduction. The Reynolds shear stress is strongly reduced, especially near the wall, and this is compensated by a polymer stress, which at maximum drag reduction amounts to about 40% of the total stress. These results have been compared with LDV experiments of Ptasinski et al. (2001) and the agreement, both qualitatively and quantitatively, is in most cases very good. In addition we have performed an analysis of the turbulent kinetic energy budgets. The main result is a reduction of energy transfer from the streamwise direction, where the production of turbulent kinetic energy takes place, to the other directions. A substantial part of the energy production by the mean flow is transferred directly into elastic energy of the polymers. The turbulent velocity fluctuations also contribute energy to the polymers. The elastic energy of the polymers is subsequently dissipated by polymer relaxation. We have also computed the various contributions to the pressure fluctuations and identified how these change as a function of drag reduction. Finally, we discuss some cross-correlations and various length scales. These simulation results are explained here by two mechanisms. First, as suggested by Lumley (1969) the polymers damp the cross-stream or wall-normal velocity fluctuations and suppress the bursting in the buffer layer. Secondly, the ‘shear sheltering’ mechanism acts to amplify the streamwise fluctuations in the thickened buffer layer, while reducing and decoupling the motions within and above this layer. The expression for the substantial reduction in the wall drag derived by considering the long time scales of the nonlinear fluctuations of this damped shear layer, is shown to be consistent with the experimental data of Virk et al. (1967) and Virk (1975)

Functional Analysis of Missense Mutations in Kv8.2 Causing Cone Dystrophy with Supernormal Rod Electroretinogram

Mutations in KCNV2 have been proposed as the molecular basis for cone dystrophy with supernormal rod electroretinogram. KCNV2 codes for the modulatory voltage-gated potassium channel α-subunit, Kv8.2, which is incapable of forming functional channels on its own. Functional heteromeric channels are however formed with Kv2.1 in heterologous expression systems, with both α-subunit genes expressed in rod and cone photoreceptors. Of the 30 mutations identified in the KCNV2 gene, we have selected three missense mutations localized in the potassium channel pore and two missense mutations localized in the tetramerization domain for analysis. We characterized the differences between homomeric Kv2.1 and heteromeric Kv2.1/Kv8.2 channels and investigated the influence of the selected mutations on the function of heteromeric channels. We found that two pore mutations (W467G and G478R) led to the formation of nonconducting heteromeric Kv2.1/Kv8.2 channels, whereas the mutations localized in the tetramerization domain prevented heteromer generation and resulted in the formation of homomeric Kv2.1 channels only. Consequently, our study suggests the existence of two distinct molecular mechanisms involved in the disease pathology

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE

Introduction: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. Aims: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. Methods: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. Discussion: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5

A role for DNA methylation in bumblebee morphogenesis hints at female-specific developmental erasure

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: All sequencing data related to this project can be found under NCBI BioProject PRJNA573598. Custom scripts for the genome-wide analysis can be found at https://github.com/MooHoll/bumblebee_developmental_methEpigenetic mechanisms, such as DNA methylation, are crucial factors in animal development. In some mammals, almost all DNA methylation is erased during embryo development and re-established in a sex- and cell-specific manner. This erasure and re-establishment is thought to primarily be a vertebrate-specific trait. Insects are particularly interesting in terms of development as many species often undergo remarkable morphological changes en route to maturity, that is, morphogenesis. However, little is known about the role of epigenetic mechanisms in this process across species. We have used whole-genome bisulfite sequencing to track genome-wide DNA methylation changes through the development of an economically and environmentally important pollinator species, the bumblebee Bombus terrestris (Hymenoptera:Apidae Linnaeus). We find overall levels of DNA methylation vary throughout development, and we find developmentally relevant differentially methylated genes throughout. Intriguingly, we have identified a depletion of DNA methylation in ovaries/eggs and an enrichment of highly methylated genes in sperm. We suggest this could represent a sex-specific DNA methylation erasure event. To our knowledge, this is the first suggestion of possible developmental DNA methylation erasure in an insect species. This study lays the required groundwork for functional experimental work to determine if there is a causal nature to the DNA methylation differences identified. Additionally, the application of single-cell methylation sequencing to this system will enable more accurate identification of if or when DNA methylation is erased during development.Natural Environment Research Council (NERC)Leverhulme Trus

Effectiveness and cost effectiveness of pharmacological thromboprophylaxis for medical inpatients: decision analysis modelling study.

OBJECTIVE: To determine the balance of costs, risks, and benefits for different thromboprophylaxis strategies for medical patients during hospital admission. DESIGN: Decision analysis modelling study. SETTING: NHS hospitals in England. POPULATION: Eligible adult medical inpatients, excluding patients in critical care and pregnant women. INTERVENTIONS: Pharmacological thromboprophylaxis (low molecular weight heparin) for all medical inpatients, thromboprophylaxis for none, and thromboprophylaxis given to higher risk inpatients according to risk assessment models (Padua, Caprini, IMPROVE, Intermountain, Kucher, Geneva, and Rothberg) previously validated in medical cohorts. MAIN OUTCOME MEASURES: Lifetime costs and quality adjusted life years (QALYs). Costs were assessed from the perspective of the NHS and Personal Social Services in England. Other outcomes assessed were incidence and treatment of venous thromboembolism, major bleeds including intracranial haemorrhage, chronic thromboembolic complications, and overall survival. RESULTS: Offering thromboprophylaxis to all medical inpatients had a high probability (>99%) of being the most cost effective strategy (at a threshold of £20 000 (€23 440; $25 270) per QALY) in the probabilistic sensitivity analysis, when applying performance data from the Padua risk assessment model, which was typical of that observed across several risk assessment models in a medical inpatient cohort. Thromboprophylaxis for all medical inpatients was estimated to result in 0.0552 additional QALYs (95% credible interval 0.0209 to 0.1111) while generating cost savings of £28.44 (-£47 to £105) compared with thromboprophylaxis for none. No other risk assessment model was more cost effective than thromboprophylaxis for all medical inpatients when assessed in deterministic analysis. Risk based thromboprophylaxis was found to have a high (76.6%) probability of being the most cost effective strategy only when assuming a risk assessment model with very high sensitivity is available (sensitivity 99.9% and specificity 23.7% v base case sensitivity 49.3% and specificity 73.0%). CONCLUSIONS: Offering pharmacological thromboprophylaxis to all eligible medical inpatients appears to be the most cost effective strategy. To be cost effective, any risk assessment model would need to have a very high sensitivity resulting in widespread thromboprophylaxis in all patients except those at the very lowest risk, who could potentially avoid prophylactic anticoagulation during their hospital stay

Individual risk factors predictive of venous thromboembolism in patients with temporary lower limb immobilisation due to injury: a systematic review

BACKGROUND: Patients immobilised after lower limb injury are at risk of venous thromboembolism (VTE). There is international variation in the use of thromboprophylaxis for such patients. Risk based strategies have been adopted to aid decision making in many settings. The accuracy of these strategies is unclear. OBJECTIVES: A systematic review was undertaken to identify all individual patient identifiable risk factors linked to any VTE outcome following lower limb immobilisation. METHODS: Several electronic databases were searched from inception to May 2017. Any studies which included a measurement of VTE patient outcome in adults requiring temporary immobilisation (e.g. leg cast or brace in an ambulatory setting) for an isolated lower limb injury and reported risk factor variables were included. Descriptive statistics and thematic analysis were used to synthesise the evidence. RESULTS: Our database search returned 4771 citations, of which 15 studies reporting outcome data on 80,678 patients were eligible for analysis. Risk factor associations were reported through regression analyses, non-parametric tests and descriptive statistics. All studies were assessed as at moderate or serious risk of bias using the ROBINS-I risk of bias tool. Advancing age and injury type were the only individual risk factors demonstrating a reproducible association with increased symptomatic and/or asymptomatic VTE rates. Several risk factors currently used in scoring tools did not appear to be robustly evaluated for subsequent association with VTE, within these studies. CONCLUSIONS: Clinicians should be aware of the limited evidence to support individual risk factors in guiding thromboprophylaxis use for this patient cohort

Aberrant splicing of a nicotinic acetylcholine receptor alpha 6 subunit is associated with spinosad tolerance in the thrips predator Orius laevigatus.

This is the final version. Available from Elsevier via the DOI in this record. Susceptibility to insecticides is one of the limiting factors preventing wider adoption of natural enemies to control insect pest populations. Identification and selective breeding of insecticide tolerant strains of commercially used biological control agents (BCAs) is one of the approaches to overcome this constraint. Although a number of beneficial insects have been selected for increased tolerance to insecticides the molecular mechanisms underpinning these shifts in tolerance are not well characterised. Here we investigated the molecular mechanisms of enhanced tolerance of a lab selected strain of Orius laevigatus (Fieber) to the commonly used biopesticide spinosad. Transcriptomic analysis showed that spinosad tolerance is not a result of overexpressed detoxification genes. Molecular analysis of the target site for spinosyns, the nicotinic acetylcholine receptor (nAChR), revealed increased expression of truncated transcripts of the nAChR α6 subunit in the spinosad selected strain, a mechanism of resistance which was described previously in insect pest species. Collectively, our results demonstrate the mechanisms by which some beneficial biological control agents can evolve insecticide tolerance and will inform the development and deployment of insecticide-tolerant natural enemies in integrated pest management strategies.Biotechnology and Biological Sciences Research Counci

A role for DNA methylation in bumblebee morphogenesis hints at female-specific developmental erasure

Epigenetic mechanisms, such as DNA methylation, are crucial factors in animal development. In some mammals, almost all DNA methylation is erased during embryo development and re-established in a sex- and cell-specific manner. This erasure and re-establishment is thought to primarily be a vertebrate-specific trait. Insects are particularly interesting in terms of development as many species often undergo remarkable morphological changes en route to maturity, that is, morphogenesis. However, little is known about the role of epigenetic mechanisms in this process across species. We have used whole-genome bisulfite sequencing to track genome-wide DNA methylation changes through the development of an economically and environmentally important pollinator species, the bumblebee Bombus terrestris (Hymenoptera:Apidae Linnaeus). We find overall levels of DNA methylation vary throughout development, and we find developmentally relevant differentially methylated genes throughout. Intriguingly, we have identified a depletion of DNA methylation in ovaries/eggs and an enrichment of highly methylated genes in sperm. We suggest this could represent a sex-specific DNA methylation erasure event. To our knowledge, this is the first suggestion of possible developmental DNA methylation erasure in an insect species. This study lays the required groundwork for functional experimental work to determine if there is a causal nature to the DNA methylation differences identified. Additionally, the application of single-cell methylation sequencing to this system will enable more accurate identification of if or when DNA methylation is erased during development

Interest and barriers to research in obstetric haematology – findings from a national survey in the United Kingdom

Introduction: In 2021, the steering committee members of British Society of Haematology Obstetric Haematology Special Interest Group noted difficulties in opening research studies. This led to the development of a survey to further evaluate this issue. Method: An electronic survey was distributed to all members of the British Society of Haematology Obstetric Haematology Special Interest Group and to relevant specialty leads of the National Institute for Health and Care Research Clinical Research Network for further dissemination within these networks. Results: Responses were received from 65 participants (73% consultant grade); mainly haematologists (52%) or obstetricians (39%). Less than a third of participants reported dedicated time for research in their job plan, with only five participants reporting no challenges in opening research studies in obstetric haematology. Discussion: The survey confirmed significant interest in obstetric haematology research, with barriers to participation. We propose further actions to facilitate increased research