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Lessons from the PROTECT-CH COVID-19 platform trial in care homes
Get PDFBackground: Coronavirus disease-2019 (COVID-19) was associated with significant mortality and morbidity in care homes in 2020–21. Repurposed antiviral drugs might reduce morbidity and mortality through reducing viral transmission, infection, replication and inflammation. We aimed to compare the safety and efficacy of potential antiviral drugs in care home residents.Methods: We designed a cluster-randomised open-label blinded-endpoint platform-trial to test drugs in a post-exposure prophylaxis paradigm. Participants aged 65+ years from UK care homes with or without nursing, were eligible for participation. Care homes were to be allocated at random by computer to administer 42 days of antiviral agent (ciclesonide or niclosamide) plus standard care versus standard care to residents. The primary outcome at 60 days after randomisation comprised the most serious outcome defined as all-cause mortality, all-cause hospitalisation, SARS-CoV-2 infection or no infection. Analysis would be by intention-to-treat using ordinal logistic regression. Other outcomes included individual components of the primary outcome, transmission, plus health economic and process evaluation outcomes. The planned sample size was 300 care homes corresponding to 9,600 residents. With ~40% of care homes predicted to develop an outbreak during the trial, we needed to recruit 750 homes/24,000 residents.Results: We initiated the trial including protocol, approvals, insurance, website, database, data algorithms, intervention selection and training materials. We built a network of principal investigators and staff (91) and care homes (299) to support the trial. However, we never contracted care homes or general practitioners (GPs) since the trial was stopped in September 2021, as vaccination in care homes had significantly reduced infections. Multiple delays significantly delayed the start date: i) reduced prioritisation of pandemic trials in 2021; ii) cumbersome mechanisms for choosing the investigational medicinal products (IMPs); iii) contracting between NIHR and the IMP manufacturers; iv) publicising the IMPs; v) identification of sufficient numbers of care homes; vi) identification and contracting with several thousand GPs; vii) limited research nurse availability; and viii) identification of adequate insurance to cover care homes for research. Generic challenges including working across the four home nations with their different structures and regulations.Limitations: The feasibility of contracting between the sponsor and the PIs, GPs and care homes; screening, consent and treatment of care home residents; data acquisition and the potential benefit of post-exposure prophylaxis were never tested.Conclusions: The success of vaccination meant that the role of post-exposure prophylaxis of COVID-19 in care home residents was not tested. Significant progress was made in developing the infrastructure and expertise necessary for a large scale Clinical Trial of IMPs in UK care homes.Future work: The role of post-exposure prophylaxis of COVID-19 in care home residents remains undefined. Significant logistical barriers to conducting research in care homes need to be removed urgently before future studies are possible. Further work is required to develop the infrastructure for clinical trials of investigational medicinal products in care homes. Serious consideration should be given to building and then hibernating a pandemic-ready platform trial suitable for care home research.Registration: EudraCT 2021-000185-15.Funding: This project was funded by the National Institute for Health and Care Research (NIHR) XP programme (NIHR133443) and will be published in XXX Journal: Vol. XX, No. XX. See the NIHR Journals Library website for further project information.<br/
Competitive pricing using model-based bandits
Get PDFThe use of learning algorithms for automatic price adjustments in markets is on the rise. However, these algorithms often assume that reward distributions for actions are uncorrelated and stationary, a condition that does not hold in competitive pricing environments.In this paper, we introduce a pricing environment, find conditions under which a unique Nash equilibrium exists and verify the assumptions numerically. Then, we propose a bandit algorithm that approximates the structure of the environment and extend it to accommodate non-stationary settings. We perform numerical tests in both stationary and competitive pricing environments, analysing the potential benefits and drawbacks of incorporating the structure of the environment within learning algorithms. While modelling the stationary environment improves the algorithm's performance in a stationary setting, it does not offer an advantage in pricing competitions between non-stationary learning agents
Quasi-invariance of Gaussian measures of negative regularity for fractional nonlinear Schrödinger equations
Get PDFWe consider the Cauchy problem for the fractional nonlinear Schrödinger equation (FNLS) on the one-dimensional torus with cubic nonlinearity and high dispersion parameter α>1, subject to a Gaussian random initial data of negative Sobolev regularity σ<s−12, for s≤12. We show that for all s∗(α)<s≤12, the equation is almost surely globally well-posed. Moreover, the associated Gaussian measure supported on Hs(T) is quasi-invariant under the flow of the equation. For α<120(17+321−−√)≈1.537, the regularity of the initial data is lower than the one provided by the deterministic well-posedness theory.We obtain this result by following the approach of DiPerna-Lions (1989); first showing global-in-time bounds for the solution of the infinite-dimensional Liouville equation for the transport of the Gaussian measure, and then transferring these bounds to the solution of the equation by adapting Bourgain's invariant measure argument to the quasi-invariance setting. This allows us to bootstrap almost sure global bounds for the solution of (FNLS) from its probabilistic local well-posedness theory
On the necessity of multi-disciplinarity in the development of at-home health monitoring platforms for older adults:Systematic review
Get PDFBackground - The growth in ageing populations globally has increased the demand for new models of care. At-home, computerized healthcare monitoring is a growing paradigm which explores the possibility of reducing workloads, lowering the demand for resource-intensive secondary care and providing more precise and personalised care. Despite the potential societal benefit of autonomous monitoring systems when implemented properly, uptake in healthcare institutions is slow and a great volume of research across disciplines encounters similar common barriers to real-world implementation.Objectives - The goal of this review is to 1) construct an evaluation framework that can assess research in terms of how well it addresses already identified barriers to application and 2) to then use that framework to analyse the literature across disciplines and identify trends between multi-disciplinarity and the likelihood of research being developed robustly.Methods - This paper introduces a scoring framework for evaluating how well individual pieces of research address key development considerations using 10 identified common barriers to uptake found during meta-review from different disciplines across the domain of healthcare monitoring. A scoping review is then conducted using this framework to identify the impact that multi-disciplinarity involvement has on the effective development of new monitoring technologies. Specifically, we use this framework to measure the relationship between the use of multi-disciplinarity in research and the likelihood that a piece of research will be developed in away that gives it genuine practical application.Results - We show that viewpoints of multi-disciplinarity; namely across computer science and medicine alongside public and patient involvement (PPI) have a significant positive impact in addressing commonly encountered barriers to application research and development according to the evaluation criteria. Using our evaluation metric, multi-disciplinary teams score on average 5.43/10 compared to 3.5 for teams made up of medical experts and social scientists, and 2.68 for technical-based teams, encompassing computer science and engineering. Also identified is the significant effect that involving either caregivers or end-users in the research in a co-design or PPI-based capacity has on the evaluation score (2.93 without any input and 4.83/3.67 for end-user or caregiver input respectively, on average).Conclusion - This review recommends that, to limit the volume of novel research arbitrarily re-encountering the same issues in the limitations of their work and hence improve the efficiency and effectiveness of research, multi-disciplinarity should be promoted as a priority to accelerate the rate of advancement in this field and encourage the development of more technology in this domain that can be of tangible societal benefit
From “Evil Doers” to “Very Fine People”:The politics of shifting counterterrorism targets
Get PDFOver two decades ago, the United States launched the “Global War on Terror” to vanquish Al Qaeda and associated foes. This counterterrorism campaign was characterized by abusive interrogations, indefinite detentions, targeted killing, and mass surveillance. Today, US counterterrorist doctrine must contend with cascading forms of far-right political violence. The rapid ascendency of far-right extremism motivated by white supremacism and nationalism, neo-Nazism, and various conspiracy theories, raises questions about how the contemporary national security state will adapt. To what extent have US authorities utilized the legal framework of post-9/11 counterterrorism and related social and political discourses to counter far-right extremism? Evidence from government reactions to the 2017 Charlottesville hate rally to the 2021 January 6 attack on the Capitol to uneven approaches to preempting and prosecuting domestic terrorism point to significant inconsistencies. This article examines differences between state responses to domestic and international threats, analyzing how political violence is framed, whether far-right violence is classified as terrorism, and how legal and political dynamics limit the extension of global counterterrorism methods to the domestic sphere
Multicomponent Interventions for Adults With Cancer Cachexia:A Systematic Review
Get PDFBackground: Cancer cachexia has substantial impacts on patient quality of life. There is no current gold standard treatment, but the complex pathophysiology of cachexia suggests a multi-targeted and individualised treatment approach is needed. We aimed to evaluate the extent to which multi-component interventions have targeted the key features of cachexia and been tailored to individuals, and differential effects on quality of life.Methods: We conducted a systematic review of multi-component interventions for adults with cancer cachexia. We searched four databases, two clinical trial registers, and MedRxiv on 20 June 2024. Intervention components were classified by intervention category (nutritional, exercise/physical activity, pharmacological, psycho-social), cachexia feature(s) targeted (reduced energy intake, altered metabolism, involuntary weight loss, and decline in physical function), and level of tailoring. Within-arm standardised mean changes in quality of life over time, and standardised mean differences between study arms, were calculated.Results: 62 multi-component interventions were included, of which two combined components from all four intervention categories, and nine targeted all four key features of cachexia. 18 multi-component interventions were fully tailored and 30 were partly tailored to individuals. Within-arm standardised mean changes in quality of life were calculated for 13 studies; all had a high risk of bias or raised concerns. In 11 studies, quality of life scores improved following intervention, while in two studies they declined. Standardised mean differences between study arms were calculated for four studies; in three the intervention arm showed a greater improvement in quality of life scores than the usual care arm. Amongst these data, there was no indication that the number of cachexia features targeted, or the extent of tailoring, was associated with a greater improvement in quality of life scores amongst these data, however the heterogeneity prevented us from concluding on our hypothesis.Conclusions: This review mapped out in detail the combinations of intervention categories used, key features of cachexia targeted, and extent of tailoring across multi-component interventions for adults with cancer cachexia. Only a small proportion of the multi-component interventions targeted all four key features of cachexia, but most were either partly or fully tailored to individuals. Despite 62 multi-component interventions being investigated, only four studies compared these to usual care and reported quality of life outcomes. High risk of bias, low sample sizes, and variable outcome data remain challenges to the interpretability of results in this field.<br/
Programmable trans-splicing riboregulators for complex cellular logic computation
Get PDFSynthetic genetic circuits program the cellular input–output relationships to execute customized functions. However, efforts to scale up these circuits have been hampered by the limited number of reliable regulatory mechanisms with high programmability, performance, predictability and orthogonality. Here we report a class of split-intron-enabled trans-splicing riboregulators (SENTRs) based on de novo designed external guide sequences. SENTR libraries provide low leakage expression, wide dynamic range, high predictability with machine learning and low crosstalk at multiple component levels. SENTRs can sense RNA targets, process signals by logic computation and transduce them into various outputs, either mRNAs or noncoding RNAs. We subsequently demonstrate that digital logic operation with up to six inputs can be implemented using multiple orthogonal SENTRs to regulate a single gene simultaneously and coupling SENTRs with split intein-mediated protein trans-splicing. SENTR represents a powerful and versatile regulatory tool at the post-transcriptional level in Escherichia coli, suggesting broad biotechnological applications
Categories of sets with infinite addition
Get PDFWe consider sets with infinite addition, called Σ-monoids, and contribute to their literature in three ways. First, our definition subsumes those from previous works and allows us to relate them in terms of adjuctions between their categories. In particular, we discuss Σ-monoids with additive inverses. Second, we show that every Hausdorff commutative monoid is a Σ-monoid, and that there is a free Hausdorff commutative monoid for each Σ-monoid. Third, we prove that Σ-monoids have well-defined tensor products, unlike topological abelian groups
Queer workers, diversity data and the UK television industry:Is more data always better?
Get PDFThis paper introduces new, interdisciplinary perspectives for understanding and analysing what diversity data is and works to do. Combining critical data studies with research on diversity and inclusion in the UK television industry, we explore the case of sexual orientation data. We discuss the ambiguous relationship between diversity data and its use to remedy structural inequity and exclusion. We show that diversity data brings into view a narrow selection of queer workers’ lives and experiences while further marginalising others, and that it is generative and productive rather than merely representative of the world around us. In so doing we provide novel and transferable insights for scholars and practitioners to improve both our understanding of diversity data and its practical use in workplace interventions
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