Intrathecal Administration of AYX2 DNA Decoy Produces a Long-Term Pain Treatment in Rat Models of Chronic Pain by Inhibiting the KLF6, KLF9, and KLF15 Transcription Factors

Background: Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia—spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo–in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. Results: Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks–month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models. Conclusions: These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain

Pharmacology, Pharmacokinetics, and Metabolism of the DNA-Decoy AYX1 for the Prevention of Acute and Chronic Post-Surgical Pain

Background: AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord. Results: The effects of ascending dose-levels of AYX1 on mechanical hypersensitivity were measured in the spared nerve injury model of chronic pain and in a plantar incision model of acute post-surgical pain. AYX1 dose-response profile shows that efficacy rapidly increases from a minimum effective dose of ∼ 0.5 mg to a peak maximum effective dose of ∼ 1 mg. With further dose escalation, the efficacy paradoxically appears to decrease by ∼ 30% and then returns to full efficacy at the maximum feasible dose of ∼ 4 mg. The reduction of efficacy is associated to doses triggering a near-saturation of AYX1 metabolism by nucleases in the cerebrospinal fluid and a paradoxical reduction of AYX1 exposure during the period of early growth response protein 1 induction. This effect is overcome at higher doses that compensate for the effect of metabolism. Discussion: AYX1 is a competitive antagonist of early growth response protein 1, which is consistent with the overall increased efficacy observed as dose-levels initially escalate. Chemically, AYX1 is unprotected against degradation by nucleases. The sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose-response curve. Conclusions: These findings point to the importance of the nuclease environment of the cerebrospinal fluid to the research and development of AYX1 and other intrathecal nucleotide-based therapeutics

ChatGPT versus human essayists: an exploration of the impact of artificial intelligence for authorship and academic integrity in the humanities

Generative AI has prompted educators to reevaluate traditional teaching and assessment methods. This study examines AI’s ability to write essays analysing Old English poetry; human markers assessed and attempted to distinguish them from authentic analyses of poetry by first-year undergraduate students in English at the University of Oxford. Using the standard UK University grading system, AI-written essays averaged a score of 60.46, whilst human essays achieved 63.57, a margin of difference not statistically significant (p = 0.10). Notably, student submissions applied a nuanced understanding of cultural context and secondary criticism to their close reading, while AI essays often described rather than analysed, lacking depth in the evaluation of poetic features, and sometimes failing to properly recognise key aspects of passages. Distinguishing features of human essays included detailed and sustained analysis of poetic style, as well as spelling errors and lack of structural cohesion. AI essays, on the other hand, exhibited a more formal structure and tone but sometimes fell short in incisive critique of poetic form and effect. Human markers correctly identified the origin of essays 79.41% of the time. Additionally, we compare three purported AI detectors, finding that the best, ‘Quillbot’, correctly identified the origin of essays 95.59% of the time. However, given the high threshold for academic misconduct, conclusively determining origin remains challenging. The research also highlights the potential benefits of generative AI’s ability to advise on structuring essays and suggesting avenues for research. We advocate for transparency regarding AI’s capabilities and limitations, and this study underscores the importance of human critical engagement in teaching and learning in Higher Education. As AI’s proficiency grows, educators must reevaluate what authentic assessment is, and consider implementing dynamic, holistic methods to ensure academic integrity

Demonstration of Universal Parametric Entangling Gates on a Multi-Qubit Lattice

We show that parametric coupling techniques can be used to generate selective entangling interactions for multi-qubit processors. By inducing coherent population exchange between adjacent qubits under frequency modulation, we implement a universal gateset for a linear array of four superconducting qubits. An average process fidelity of $\mathcal{F}=93\%$ is estimated for three two-qubit gates via quantum process tomography. We establish the suitability of these techniques for computation by preparing a four-qubit maximally entangled state and comparing the estimated state fidelity against the expected performance of the individual entangling gates. In addition, we prepare an eight-qubit register in all possible bitstring permutations and monitor the fidelity of a two-qubit gate across one pair of these qubits. Across all such permutations, an average fidelity of $\mathcal{F}=91.6\pm2.6\%$ is observed. These results thus offer a path to a scalable architecture with high selectivity and low crosstalk

Pressure injury and risk in the inpatient paediatric and neonatal populations: a single centre point-prevalence study

Introduction: Prevention and management of pressure injury is a key nurse-sensitive quality indicator. From clinical insights, pressure injury effects hospitalised neonates and children, however it is unclear how prevalent this is. The aim of this study was to quantify prevalence of pressure injury, assess skin integrity risk level, and quantify preventive interventions in both neonatal and child inpatient populations at a large children’s hospital in the UK. Methods: A cross-sectional study was undertaken, assessing the skin integrity of all children allocated to a paediatric or neonatal bed in June/July 2020. A data collection tool was adapted from two established pressure ulcer point prevalence surveys (EUPAP and Medstrom pre-prevalence survey). Risk assessment was performed using the Braden QD scale.Results: Eighty-eight participants were included, with median age of 0.85 years [range 0-17.5 years), with 32 (36%) of participants being preterm. Median length of hospital stay was 11 days [range 0 – 174 days]. Pressure ulcer prevalence was 3.4%. The majority of participants had at least two medical devices, with 16 (18.2%) having more than four. Having a medical device was associated with increased risk score of developing pressure injury (odds ratio [OR] 0.03, 95% Confidence Interval [CI] 0.01 – 0.05, p = 0.02). Most children (39 (44%)) were reported not having proposed preventive measures in place aligned to their risk assessment. However, for those that did , 2 to 4 hourly repositioning was associated with a risk reduction on pressure damage (OR 0.13, 95% CI 0.03 – 0.23, p = 0.01).Conclusion: Overall, we found a low prevalence of pressure injury across preterm infants, children and young people at a tertiary children’s hospital. Accurate risk assessment as well as availability and implementation of preventive interventions are a priority for healthcare institutes to avoid pressure injury

Society for Cardiovascular Magnetic Resonance (SCMR) guidance for re-activation of cardiovascular magnetic resonance practice after peak phase of the COVID-19 pandemic

During the peak phase of the COVID-19 pandemic, alterations of standard operating procedures were necessary for health systems to protect patients and healthcare workers and ensure access to vital hospital resources. As the peak phase passes, re-activation plans are required to safely manage increasing clinical volumes. In the context of cardiovascular magnetic resonance (CMR), re-activation objectives include continued performance of urgent CMR studies and resumption of CMR in patients with semi-urgent and elective indications in an environment that is safe for both patients and health care workers

Toxoplasma and Plasmodium protein kinases: roles in invasion and host cell remodelling

Some apicomplexan parasites have evolved distinct protein kinase families to modulate host cell structure and function. Toxoplasma gondii rhoptry protein kinases and pseudokinases are involved in virulence and modulation of host cell signalling. The proteome of Plasmodium falciparum contains a family of putative kinases called FIKKs, some of which are exported to the host red blood cell and might play a role in erythrocyte remodelling. In this review we will discuss kinases known to be critical for host cell invasion, intracellular growth and egress, focusing on (i) calcium-dependent protein kinases and (ii) the secreted kinases that are unique to Toxoplasma (rhoptry protein kinases and pseudokinases) and Plasmodium (FIKKs)

Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed