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Antifibrinolytics (lysine analogues) for the prevention of bleeding in people with haematological disorders
Get PDFRationale
People with haematological disorders are frequently at risk of severe or life‐threatening bleeding as a result of thrombocytopenia (reduced platelet count). This is despite the routine use of prophylactic platelet transfusions to prevent bleeding once the platelet count falls below a certain threshold. Platelet transfusions are not without risk and adverse events may be life‐threatening. A possible adjunct to prophylactic platelet transfusions is the use of antifibrinolytics, specifically the lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA). This is an update of a Cochrane review last published in 2016 (with database searches conducted on 7 March 2016).
Objectives
To determine the benefits and harms of antifibrinolytics (lysine analogues) in preventing bleeding in people with haematological disorders.
Search methods
We searched CENTRAL, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Transfusion Evidence Library, and ongoing trial databases on 21 January 2025. We handsearched the reference lists of all identified randomised controlled trials (RCTs). We contacted the authors of relevant studies, study groups, and experts worldwide known to be active in the field to request information about unpublished material or further information on ongoing studies.
Eligibility criteria
We included RCTs in people with haematological disorders who required prophylactic platelet transfusions to prevent bleeding. We only included RCTs in which the interventions were the lysine analogues TXA or EACA.
Outcomes
We assessed bleeding severity using the World Health Organization (WHO) bleeding scale (ordinal grades 0 to 4, with higher grades indicating more severe bleeding), which has been widely applied in thrombocytopenia studies. The outcomes prioritised for the summary of findings tables were: number of participants with grade 2 bleeding or higher; number of participants with grade 3 bleeding or higher; number of participants with any thromboembolism; all‐cause mortality; and adverse events attributable to antifibrinolytic drugs. We provide results only for these outcomes below.
Risk of bias
We used Cochrane's risk of bias 2 (RoB 2) tool. We used this tool to re‐assess the previously included trials.
Synthesis methods
For this update, two review authors independently selected trials for inclusion, assessed methodological quality and risk of bias, and extracted data. We used fixed‐effect models for the meta‐analysis. We analysed dichotomous outcomes using risk ratios (RRs) with 95% confidence intervals (CIs), and the Peto odds ratio (Peto OR) for outcomes with very low event rates (< 3% in both arms). We assessed the certainty of the evidence using the GRADE approach.
Included studies
We included eight RCTs (four newly included studies plus four from the previous versions) with a total of 1041 participants in this review update. Six trials compared TXA to placebo, one trial compared EACA to no EACA, and one trial compared EACA to standard platelet transfusion. We found no trials comparing TXA to EACA. Seven trials recruited adults, while one enroled children.
Synthesis of results
Tranexamic acid (TXA) versus placebo
There may be no difference between TXA and placebo in the risk of experiencing grade 2 bleeding or higher, grade 3 bleeding or higher, thromboembolism, death, and drug‐related adverse events, although the certainty of the evidence varied from very low to moderate for these outcomes: grade 2 bleeding or higher: RR 0.89, 95% CI 0.75 to 1.05; I² = 7%; 3 studies, 894 participants; moderate‐certainty evidence; grade 3 bleeding or higher: RR 1.07, 95% CI 0.51 to 2.22; I² = 6%; 3 studies, 894 participants; low‐certainty evidence; any thromboembolism: Peto OR 0.85, 95% CI 0.39 to 1.86; I² = 0%; 5 studies, 984 participants; low‐certainty evidence; all‐cause mortality: Peto OR 1.50, 95% CI 0.62 to 3.63; I² = 37%; 3 studies, 930 participants; very low‐certainty evidence; and number of adverse events attributable to antifibrinolytic drugs: Peto OR 2.24, 95% CI 0.64 to 7.78; I² = 0%; 3 studies, 949 participants; very low‐certainty evidence.
Epsilon aminocaproic acid (EACA) versus no EACA
The single study addressing this comparison did not report bleeding severity in a form suitable for analysis, and did not report on the number of participants with any thromboembolism or all‐cause mortality. The study reported that no patient died of thrombosis. There was insufficient evidence to analyse adverse events attributable to antifibrinolytic drugs.
Authors' conclusions
For people with thrombocytopenia and haematological malignancies, TXA probably makes little to no difference to clinically significant bleeding (i.e. grade 2 or higher), and may make little to no difference to severe or life‐threatening bleeding (i.e. grade 3 or higher) or any thromboembolism. The evidence is of very low certainty for all‐cause mortality and serious adverse events attributable to antifibrinolytic drugs.
For EACA compared to no EACA, there are insufficient data to assess clinically significant bleeding, life‐threatening bleeding, any thromboembolism, all‐cause mortality, and serious adverse events.
Those making decisions about administration of prophylactic TXA to people with thrombocytopenia and haematological malignancies should consider that current evidence does not show a benefit or harm for TXA for preventing clinically significant or life‐threatening bleeding.
Funding
This Cochrane review had no dedicated funding.
Registration
Protocol (2012): DOI: 10.1002/14651858.CD009733.
Original review (2013): DOI: 10.1002/14651858.CD009733.pub2.
Review update (2016): DOI: 10.1002/14651858.CD009733.pub3.kljk
Is the bar higher for female scholars? Evidence from career steps in economics
Get PDFDo gender disparities in academia reflect that female scholars are held to higher standards than males? We address this question by comparing the academic achievement of male and female scholars in economics who make the same career step. Across four domains – faculty appointments, network invitations, grant awards and editor appointments – we find no evidence that standards are higher for females. By contrast, the average female has fewer citations and publications than the average male who makes the same career step. In most domains, this reflects a gender gap for “marginal” scholars, consistent with a lower bar for females
A nanoparticle dynamics model: computational analysis of nanomedicine in the circulatory system
Get PDFInfo: Jeffrey Colin Howman, St. Cross College, DPhil Engineering Science, Michaelmas Term 2024
Background: The brain is one of the most complex organs in the human body and greatly varies from person to person. The delivery of drugs vital for fighting disease occurs largely within the microvasculature. This creates unique challenges when developing patient-specific medical therapies. Modern research has focused on nanoparticle drug delivery methods to treat diseases such as cancer. Generating a model that considers subject variability and nanoparticle characteristics to determine treatment efficacy thus has potential use in a clinical context.
Methods: A model was developed that utilises a Green’s function method to simulate the transport of gold nanoparticles in human microvasculature. This open-source C++ code was adapted here to simulate gold nanoparticle delivery in the cerebral capillary bed using experimental and synthetic statistical networks. This code was used to simulate gold nanoparticles in both steady-state and time-dependent conditions.
Results: Simulations of flow within a series of experimental and synthetic networks provided a set of visual and statistical data describing the delivery of gold nanoparticles to cerebral tissue. Results show a high degree of variability within individual test networks but statistical similarity across all test networks. These results were compared to oxygen, which showed similar transport phenomena despite different solute characteristics.
Conclusions: This thesis emphasizes the importance of simulating the transport of gold nanoparticles within the microvasculature of the human brain. This will become especially significant when analysing nanoparticle treatment efficacy
The legal dimensions of international knowledge transfer in religious education across Europe: the role of national and supranational courts
No full textSome key parameters of religious education are often set by international laws and obligations, notably human rights conventions, and enforced through courts - both national and supranational, such as the European Court of Human Rights (ECtHR, or the Court). This Court thereby determines international benchmarks for the subject, which not only apply to the country involved in a hearing but also across Europe as an imposed form of judicial international knowledge transfer. First, the ECtHR must consider previous cases and their circumstances when deciding on a particular case, thereby comparing and contrasting the different contexts; the subsequent use of a classic case involving Denmark is reviewed. However, national courts must balance these obligations with national laws and precedents, thereby acting either as agents of international knowledge transfer, such as a 2023 case in England in the inclusion of non-religious perspectives. Further, the ECtHR’s decision about one country will also be mobilized in debates by activists in other countries, both in the courts and in the media, and activism in Romania is considered. In conclusion, the implications of a legally bounded European site of international knowledge transfer are set out
Lipid‐Facilitated Opening of the ADAM10 Sheddase Revealed by Enhanced Sampling Simulations
Get PDFADAM10 is a crucial membrane‐bound metalloprotease that regulates cellular physiology by cleaving and releasing membrane‐anchored proteins, including adhesion molecules and growth factor precursors, thereby modulating cell signaling, adhesion, and migration. Despite its central role, its activation mechanisms are not fully understood. Here, we model how phosphatidylserine (PS) exposure during apoptosis triggers ADAM10 activation. We confirm that PS externalization is associated with ADAM10‐mediated CD43 shedding from the surface of T cells. Intriguingly, ADAM10 activation correlated with loss of ADAM10 monoclonal antibody binding, suggesting a PS‐induced conformational change that alters epitope accessibility. To explore this lipid‐mediated conformational change of ADAM10, we employed molecular dynamics simulations to map its conformational landscape. Our simulations revealed that in the absence of PS, ADAM10 samples predominantly closed and intermediate states. By contrast, the presence of PS destabilizes the closed conformation, thereby favoring open states. We provide a mechanistic explanation for this PS‐induced conformational change, which drives ADAM10 activation and loss of mAb binding through conformational change. These findings offer new insights into the lipid‐mediated regulation of ADAM10 and its conformational dynamics
Mythologising the ultra-nation, theorising the international: fascist international thought and the study of international relations in Britain, 1922-1945
Get PDFWhile revisionist scholarship has redressed many of the fallacies once plaguing disciplinary histories of interwar International Relations (IR), there remains scant research concerned with the place of fascists and other fellow travellers of the extreme right within the nascent academic discipline or the wider intellectual field of ‘expertise’ in which it was situated. It thus remains unclear the degree to which or how fascists and sympathisers engaged with the fledgling field in order to propound alternative projects of worldmaking or offer diverging (and perhaps similar) responses to salient international questions. By discerning the international thought of key extremists operating within Britain, and how they were situated with respect to, and engaged with, prevailing ideas percolating interwar discourse on world politics and sites of scholarly or ‘expert’ knowledge on the international, I aim to offer a corrective to this historiographical gap. Focusing on select thinkers orbiting around the British Union of Fascists and the Chatham House-linked London Group for the Study of the Corporate State, this dissertation contends that several of the more intellectually astute adherents of fascism were not simply contemplating the international in an obscure abyss of extremism. Rather, they variously engaged with prevailing debates, thinkers, and institutions associated with IR’s formative evolution. Indeed, some thinkers of the extreme right even had a direct impact on this intellectual landscape, whether by virtue of their contribution to the practical debates occupying mainstream thinkers and journals, or via their professional roles and ‘intellectual labour’. In turn, this dissertation complicates prevailing conceptions of what was then an emergent field of study centred on international politics and fascism’s relationship thereto, presents an immeasurably more complex image of fascist international thought relative to those commonly typifying historical IR, and carries interpretive implications for understanding IR’s contemporary extra-disciplinary reception amongst far-right figures
Neural dynamics in sleep and memory
Get PDFOur ability to store and retrieve information in memory is supported by the complex activity of billions of neurons across trillions of synaptic connections. These neurons do not send and receive signals randomly; rather, they covary in structured ways over time and space. This gives rise to emergent electrophysiological properties, including neural oscillations and latent population trajectories. By exploring these emergent patterns, we can better understand how the brain uses neural dynamics at different scales to support memory function in wake and sleep. In this thesis, I focus on three related dynamic neural signals at distinct spatio-temporal scales: cortical spindles, hippocampal ripples, and unit-level latent population trajectories.Spindles are characteristic sleep oscillations linked to memory function. The local expression of spindles is influenced by task-related endogenous cortical excitation before sleep. However, it is unclear whether spindle topographies respond to exogenous stimulation. In Chapter 2, I present a nap study in which I used non-invasive brain stimulation to experimentally excite local cortical sites before recording scalp electroencephalography (EEG) during subsequent sleep. The results show spindle rates track the excited cortical sites, indicating spindle topography is directed by cortical excitability before sleep. This contributes to our understanding of local spindle expression and establishes a new method for experimentally manipulating spindle topographies.Next, I zoom in and examine hippocampal ripples. The hippocampus plays a functional role in indexing and reactivating associations; however, it is unknown whether ripple activity in wakefulness responds to associative memory load. Chapter 3 describes an intracranial EEG (iEEG) study where participants performed associative and non-associative memory tasks in 11 an intermixed paradigm. The results showed higher ripple rates in associative retrieval and delay periods. Moreover, the amplitude and duration of ripple events were greater during the delay period after encoding memory items in the associative task. Together, this suggests hippocampal ripples track associative task demands during active memory retrieval and rest periods.Subsequently, I zoom in further to explore the dynamic properties of unit-level population activity. During cued recall, population activity shifts to represent the associated target memory. Recalling a more stable or well-connected memory may result in faster “shifts” to express the target representation. Moreover, successful memory search may require the population activity to rapidly activate multiple representations before triggering the correct memory trace. Therefore, faster changes of the population activity may relate to memory success. In Chapter 4, I test how the rapid activity changes, reflected in the velocities of population trajectories, relate to memory behaviour, reinstatement, and ripple activity. My results reveal that peak velocities in trials are related to memory behaviour, representational reinstatement, and local ripples. This reveals correlations between properties of dynamic latent population activity and memory processing.Finally, Chapter 5 summarises and discusses the significance of the main findings, whilst highlighting limitations and future directions.Together, this thesis makes methodological and theoretical progress that advances our understanding of the emergent dynamics of neural activity related to memory function in wake and sleep
Electrochemical direct air capture with intermittent renewable energy: techno-economic insights from solar-driven electrodialysis systems
Get PDFElectrochemical direct air capture (DAC) driven by renewable electricity offers a fully electrified pathway for scalable carbon removal, yet its integration with intermittent renewable power and the resulting system-level constraints remain poorly understood. Here we present a comprehensive techno-economic assessment of bipolar membrane electrodialysis (BPMED)-based DAC systems powered by solar electricity, explicitly accounting for diurnal and seasonal variability, energy storage requirements, and operational flexibility. Using a physics-based, time-resolved modelling framework with real solar irradiance data, we evaluate three representative configurations: battery storage, integrated hydrogen production, and decoupled hydrogen generation. While battery storage achieves the lowest specific energy consumption (430 kJ per mol-CO2), hydrogen-based configurations are more cost-effective for long-duration storage under strict off-grid operation. Flexible BPMED load reduces seasonal storage demand, yielding a minimum DAC cost of 2163 MWh−1 and DAC costs below 1000 MWh−1 electricity and 100 per t-CO2. Beyond BPMED-specific results, this work identifies generalizable constraints and design principles applicable to electrochemical DAC technologies under renewable electricity supply
Utilizing Constrained Bicyclic Peptides for In Vitro Diagnostics
Get PDFConstrained bicyclic peptides (Bicycle molecules) with high affinity for biological targets have emerged as potentially powerful therapeutic agents, particularly for the in vivo targeting of cancer receptors. However, their antibody-mimetic properties have yet to be explored for use in diagnostic immunoassays. These synthetically derived compounds serve as biorecognition scaffolds that allow for facile site-selective modification and large-scale production. A phage display screen against various constructs of the SARS-CoV-2 nucleocapsid (N) protein identified several Bicycle molecules with binding affinities ranging from the micromolar to the low nanomolar range. These Bicycle molecules were validated in the development of enzyme- and nanozyme-linked immunosorbent assays, as well as enzymatic and colorimetric nanoparticle-based lateral flow immunoassays (LFIA) for the detection of ultralow concentrations of the SARS-CoV-2 N protein. We envision that these moieties enable robust, cost-effective, and large-scale development of ultrasensitive biosensors for a diverse range of biomarkers by leveraging their high binding affinity, minimalistic scaffold, and synthetic accessibility
Measurement of Born cross sections and effective form factors of e + e − → Ω − Ω ¯ + from s = 3.7 to 4. 7 GeV
Get PDFUsing e+e− collision data corresponding to an integrated luminosity of 22.7 fb−1, collected at center-of-mass energies between 3.7 and 4.7 GeV with the BESIII detector at the BEPCII storage ring, we measure the energy-dependent Born cross sections of e+e−→Ω−Ω¯+ and the effective form factors of the Ω− baryon. The analysis employs a single baryon tagging method, and the results are consistent with theoretical predictions, providing critical constraints on the electromagnetic structure of the Ω− hyperon. No significant signal of charmonium or charmonium-like states decaying to Ω−Ω¯+ is observed in the investigated energy range