Pneumococcal vaccine uptake in patients with inflammatory arthritis: a single centre cohort study.

INTRODUCTION: Current guidelines recommend pneumococcal vaccination in individuals who are over the age of 65 or are immunosuppressed due to a disease or treatment. The objective of this study was to assess vaccine uptake rates in people with inflammatory arthritis for the pneumococcal, influenza and Covid-19 vaccines and factors determining uptake. METHODS: We conducted a retrospective single centre cohort study in the UK of individuals with rheumatoid arthritis, psoriatic arthritis and axial spondylarthritis between October and December 2023. Data were collected for age, gender, co-morbidities, immunosuppressive therapies, and dates of vaccines. Logistic regression was used to evaluate predictors of vaccine uptake, with adjustments for demographic and clinical factors. RESULTS: 906 individuals were identified. 46% were receiving treatment with csDMARD, 26% on biologic monotherapy, and 23% were on both biologic and csDMARDs. 316 individuals (35%) received a pneumococcal vaccine, lower than uptake for influenza (63%) and Covid-19 (87%) vaccines. Predictors of pneumococcal vaccine uptake included age, with older patients more likely to be vaccinated (odds ratio [OR] for age ≥ 65 years: 1.67, 95% CI 1.21-2.29). Those on biological therapy demonstrated higher likelihood of vaccination (OR for biologic therapy: 1.81, 95% CI 1.33-2.47). Additional Joint committee for immunisation and vaccination (JCVI) Green Book indicators also positively influenced vaccine uptake (OR: 1.67, 95% CI 1.19-2.33). CONCLUSION: Pneumococcal vaccine uptake in inflammatory rheumatic diseases is low, especially in younger patients and those not on biological therapy. The study highlights the need for a focused approach, distinct from strategies for other vaccines, to address this public health challenge.

Quantum approximate optimization of the long-range Ising model with a trapped-ion quantum simulator.

Quantum computers and simulators may offer significant advantages over their classical counterparts, providing insights into quantum many-body systems and possibly improving performance for solving exponentially hard problems, such as optimization and satisfiability. Here, we report the implementation of a low-depth Quantum Approximate Optimization Algorithm (QAOA) using an analog quantum simulator. We estimate the ground-state energy of the Transverse Field Ising Model with long-range interactions with tunable range, and we optimize the corresponding combinatorial classical problem by sampling the QAOA output with high-fidelity, single-shot, individual qubit measurements. We execute the algorithm with both an exhaustive search and closed-loop optimization of the variational parameters, approximating the ground-state energy with up to 40 trapped-ion qubits. We benchmark the experiment with bootstrapping heuristic methods scaling polynomially with the system size. We observe, in agreement with numerics, that the QAOA performance does not degrade significantly as we scale up the system size and that the runtime is approximately independent from the number of qubits. We finally give a comprehensive analysis of the errors occurring in our system, a crucial step in the path forward toward the application of the QAOA to more general problem instances.

Gross, computed tomographic, and endoscopic anatomy of the equine carpal extensor tendon sheaths.

OBJECTIVE: (1) To describe the computed tomography (CT) and gross anatomy of the equine extensor carpi radialis sheath (ECRS) and common digital extensor sheath (CDETS); (2) to describe a single-portal endoscopic examination of the ECRS and CDETS. STUDY DESIGN: Ex vivo experimental. SAMPLE POPULATION: Thirty clinically normal cadaver thoracic equine limbs severed at the humeral diaphysis. METHODS: Ten limbs underwent plain and intrathecal contrast CT examinations and gross dissection of the ECRS and CDETS. Single-portal endoscopic examination of ECRS and CDETS was attempted in 4 limbs and endoscopic examination was performed on 16 limbs. Endoscopic video recordings were reviewed by 3 observers for quality of visualization before dissection and examination for iatrogenic damage. Interobserver agreement for ECRS and CDETS visualization was determined with Fleiss' κ agreement. RESULTS: Extensor carpi radialis sheath and CDETS anatomy was consistent between gross dissection and CT examinations. The ECRS endoscopic portal was medial at the level of the intersection between the extensor carpi obliquus and extensor carpi radialis tendon. The CDETS endoscopic portal was lateral, 5 cm proximal to the lateral styloid process of the ulna. The ECRS and CDETS were well visualized and interobserver agreement was substantial (κ = .73; P < .0001) and moderate (κ = .53; P < .0001), respectively. CONCLUSION: Computed tomography examinations provided useful anatomical information, consistent with gross dissection of the ECRS and CDETS. The described single-portal endoscopic techniques allowed consistent tenoscopic examination of the majority of the ECRS and CDETS. CLINICAL SIGNIFICANCE: Awareness of the intrathecal anatomy of the ECRS and CDETS should facilitate the treatment of these tendon sheaths. The proposed portals provide good to excellent single-site endoscopic visualization of the majority of the ECRS and CDETS.

One-Step Biocatalytic Synthesis of Sustainable Surfactants by Selective Amide Bond Formation.

N-alkanoyl-N-methylglucamides (MEGAs) are non-toxic surfactants widely used as commercial ingredients, but more sustainable syntheses towards these compounds are highly desirable. Here, we present a biocatalytic route towards MEGAs and analogues using a truncated carboxylic acid reductase construct tailored for amide bond formation (CARmm-A). CARmm-A is capable of selective amide bond formation without the competing esterification reaction observed in lipase catalysed reactions. A kinase was implemented to regenerate ATP from polyphosphate and by thorough reaction optimisation using design of experiments, the amine concentration needed for amidation was significantly reduced. The wide substrate scope of CARmm-A was exemplified by the synthesis of 24 commercially relevant amides, including selected examples on a preparative scale. This work establishes acyl-phosphate mediated chemistry as a highly selective strategy for biocatalytic amide bond formation in the presence of multiple competing alcohol functionalities.

Lieb-Robinson Light Cone for Power-Law Interactions.

The Lieb-Robinson theorem states that information propagates with a finite velocity in quantum systems on a lattice with nearest-neighbor interactions. What are the speed limits on information propagation in quantum systems with power-law interactions, which decay as 1/r^{α} at distance r? Here, we present a definitive answer to this question for all exponents α>2d and all spatial dimensions d. Schematically, information takes time at least r^{min{1,α-2d}} to propagate a distance r. As recent state transfer protocols saturate this bound, our work closes a decades-long hunt for optimal Lieb-Robinson bounds on quantum information dynamics with power-law interactions.

Optimal Protocols in Quantum Annealing and Quantum Approximate Optimization Algorithm Problems.

Quantum annealing (QA) and the quantum approximate optimization algorithm (QAOA) are two special cases of the following control problem: apply a combination of two Hamiltonians to minimize the energy of a quantum state. Which is more effective has remained unclear. Here we analytically apply the framework of optimal control theory to show that generically, given a fixed amount of time, the optimal procedure has the pulsed (or "bang-bang") structure of QAOA at the beginning and end but can have a smooth annealing structure in between. This is in contrast to previous works which have suggested that bang-bang (i.e., QAOA) protocols are ideal. To support this theoretical work, we carry out simulations of various transverse field Ising models, demonstrating that bang-anneal-bang protocols are more common. The general features identified here provide guideposts for the nascent experimental implementations of quantum optimization algorithms.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades*.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross-reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine.

Microscopic origins of anisotropic active stress in motor-driven nematic liquid crystals.

The cytoskeleton, despite comprising relatively few building blocks, drives an impressive variety of cellular phenomena ranging from cell division to motility. These building blocks include filaments, motor proteins, and static crosslinkers. Outside of cells, these same components can form novel materials exhibiting active flows and nonequilibrium contraction or extension. While dipolar extensile or contractile active stresses are common in nematic motor-filament systems, their microscopic origin remains unclear. Here we study a minimal physical model of filaments, crosslinking motors, and static crosslinkers to dissect the microscopic mechanisms of stress generation in a two-dimensional system of orientationally aligned rods. We demonstrate the essential role of filament steric interactions which have not previously been considered to significantly contribute to active stresses. With this insight, we are able to tune contractile or extensile behavior through the control of motor-driven filament sliding and crosslinking. This work provides a roadmap for engineering stresses in active liquid crystals. The mechanisms we study may help explain why flowing nematic motor-filament mixtures are extensile while gelled systems are contractile.

Unilateral laser ventriculocordectomy results in increased arytenoid stability in horses with severe left sided recurrent laryngeal neuropathy.

BACKGROUND: There is no objective information reporting the effect of unilateral laser ventriculocordectomy (VeC) on arytenoid abduction or stability. OBJECTIVES: To evaluate arytenoid stability and abduction in horses with severe recurrent laryngeal neuropathy (RLN) before and after unilateral laser VeC. STUDY DESIGN: Prospective cohort. METHODS: Eight horses with grade C or D exercising laryngeal function that underwent unilateral laser VeC were included. Exercising endoscopy was performed before and ≥6 weeks after left-sided laser VeC. Arytenoid stability at maximal exercise was calculated by measuring the left-to-right quotient angle ratio (LRQ) of the corniculate processes at the points of maximal arytenoid abduction (expiration) and maximal arytenoid collapse (inspiration). For each horse, means of measurements obtained for four breaths pre- and post-operatively were used for statistical analysis. RESULTS: The difference in LRQ between inspiration and expiration was lower post-operatively (median 0.039; interquartile range [IQR] 0.032-0.047) compared with pre-operatively (median 0.158; IQR 0.083-0.249; p = 0.01) confirming the left arytenoid was more stable following unilateral laser VeC. The degree of improvement was significantly greater for grade D horses compared with grade C horses (p = 0.04). The LRQ measured on maximal abduction was also lower post-operatively (median 0.467; IQR 0.444-0.506) compared with pre-operatively (median 0.578; IQR 0.554-0.655; p = 0.02) indicating the left arytenoid was less abducted following surgery. MAIN LIMITATIONS: The sample size was small, no racehorses were included and post-operative assessment was conducted at a variable time after surgery. CONCLUSION: Unilateral laser VeC in grade C and D RLN-affected horses results in slightly reduced left arytenoid abduction but increased arytenoid stability.

Glass transition of quantum hard spheres in high dimensions.

We study the equilibrium thermodynamics of quantum hard spheres in the infinite-dimensional limit, determining the boundary between liquid and glass phases in the temperature-density plane by means of the Franz-Parisi potential. We find that as the temperature decreases from high values, the effective radius of the spheres is enhanced by a multiple of the thermal de Broglie wavelength, thus increasing the effective filling fraction and decreasing the critical density for the glass phase. Numerical calculations show that the critical density continues to decrease monotonically as the temperature decreases further, suggesting that the system will form a glass at sufficiently low temperatures for any density. The methods used in this paper can be extended to more general potentials, and also to other transitions such as the Kauzman/Replica Symmetry Breaking (RSB) transition, the Gardner transition, and potentially even jamming.

No Waning of Pneumococcal Vaccine Responses over Time in People with Inflammatory Arthritis: Findings from a Single Centre Cohort.

BACKGROUND: Vaccination against pneumococcus reduces the risk of infective events, hospitalisation, and death in individual with inflammatory arthritis, particularly in those on immunomodulating therapy who are at risk of worse outcomes from pneumococcal disease. The objective of this study was to investigate the serological protection following vaccination against pneumococcal serovars over time. Methods: This was a single centre, retrospective cohort study of individuals with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis who had previously received the PPSV23 polysaccharide pneumococcal vaccine (Pneumovax). Data were retrieved between January 2021 to August 2023. Dates of previous pneumococcal vaccination were identified using linked primary care records. Serum serotype levels were collected. The primary outcome was serological response defined as a titre ≥0.35 mcg/mL in at least five from a total of 12 evaluated pneumococcal serovars, examined using a Luminex platform. Multivariate logistic regression models adjusting for age, gender, ethnicity, co-morbidities, and the use of prednisolone, conventional synthetic and biological DMARDs were used to determine the odds of a sustained serological response according to time categorised into ≤5 years, 5-10 years, and ≥10 years since vaccination. Results: Serological response was measured in 296 individuals with inflammatory arthritis, with rheumatoid arthritis the most common diagnosis (74% of patients). The median time between pneumococcal vaccine administration and serological assessment was 6 years (interquartile range 2.4 to 9.9). A positive serological response to at least 5 serovars was present in 195/296 (66%) of patients. Time since vaccination did not significantly associate with serological protection compared with those vaccinated <5 years, the adjusted ORs of vaccine response was 1.15 (95% CI 0.64 to 2.07) in those 5-10 years and 1.26 (95% CI: 0.64 to 2.48) in those vaccinated over 10 years ago. No individual variable from the multivariate model reached statistical significance as an independent predictor of vaccine response, although steroid use at the time of vaccine had a consistent detrimental impact on serological immunity. Conclusions: We demonstrated that antibody titres following vaccination against pneumococcal serovars do not appear to wane over time. It appears more critical to focus on maximising the initial vaccine response, which is known to be diminished in this patient population.

Clinical features and outcome of 40 horses with mesodiverticular bands identified during exploratory laparotomy for management of acute colic.

BACKGROUND: Mesodiverticular bands (MDBs) are an embryonic remnant of the vitelline artery. Information about the clinical significance of equine MDBs is currently limited. OBJECTIVES: To report the clinical features, surgical findings and outcomes of horses undergoing exploratory laparotomy where a MDB was identified. STUDY DESIGN: Retrospective case series. METHODS: Case records of horses undergoing exploratory laparotomy for colic over a 14-year period (2009-2022) were reviewed. MDBs identified at laparotomy were classified as the primary or contributory cause of abdominal pain, or as incidental. RESULTS: MDBs were identified in 40/1943 horses (2.1%) and 15 were primary (32.5%), 10 contributory (25%) and 15 incidental (32.5%). Horses with primary MDBs (median 2 years, IQR 1-12) were significantly younger than horses with incidental MDBs (median 8 years, IQR 6-16; P = 0.01). MDBs were more likely to be incidental if located in the mid-jejunum (5/5) (P < 0.001) or where a mesenteric pocket was absent (11/15) (P = 0.01). Primary MDBs caused extra-mural obstruction due to mesenteric shortening (n = 4), small intestinal entrapment within the MDB pocket (n = 5) or in an adjacent mesenteric rent (n = 4), and volvulus around the MDB (n = 2), with intestinal resection required in 8/15 cases. For horses with primary MDBs, survival to hospital discharge was 60% overall (9/15) and 75% for horses that stood following anaesthesia (9/12) with 88.9% of cases discharged from hospital (8/9) surviving >1 year. Excision of MDB tissue was not associated with complications but 3/4 non-incidental MDBs left in situ required relaparotomy to treat MDB-associated colic. MAIN LIMITATIONS: Retrospective single centre data. CONCLUSIONS: Most MDBs in horses undergoing surgical treatment of colic in this population were not incidental. MDB-associated colic was most commonly classified as strangulating obstruction, but non-strangulating extra-mural compression was also identified. Excision of MDB tissue should be undertaken where possible, particularly in non-incidental cases.

Wonder, delusions and meaning.

SUMMARY: Strands of thought in the philosophy of mind offer another way of looking at the nature of mental illness and how it arises from intense emotional states. Analysing the phenomenon of wonder is suggested as a novel approach to explaining delusions and variations in insight.

Development of Continuous Flow Systems to Access Secondary Amines Through Previously Incompatible Biocatalytic Cascades.

A key aim of biocatalysis is to mimic the ability of eukaryotic cells to carry out multistep cascades in a controlled and selective way. As biocatalytic cascades get more complex, reactions become unattainable under typical batch conditions. Here a number of continuous flow systems were used to overcome batch incompatibility, thus allowing for successful biocatalytic cascades. As proof-of-principle, reactive carbonyl intermediates were generated in situ using alcohol oxidases, then passed directly to a series of packed-bed modules containing different aminating biocatalysts which accordingly produced a range of structurally distinct amines. The method was expanded to employ a batch incompatible sequential amination cascade via an oxidase/transaminase/imine reductase sequence, introducing different amine reagents at each step without cross-reactivity. The combined approaches allowed for the biocatalytic synthesis of the natural product 4O-methylnorbelladine.

Natural heterogeneous catalysis with immobilised oxidase biocatalysts.

The generation of immobilised oxidase biocatalysts allowing multifunctional oxidation of valuable chemicals using molecular oxygen is described. Engineered galactose oxidase (GOase) variants M1 and M3-5, an engineered choline oxidase (AcCO6) and monoamine oxidase (MAO-N D9) displayed long-term stability and reusability over several weeks when covalently attached on a solid support, outperforming their free counterparts in terms of stability (more than 20 fold), resistance to heat at 60 °C, and tolerance to neat organic solvents such as hexane and toluene. These robust heterogenous oxidation catalysts can be recovered after each reaction and be reused multiple times for the oxidation of different substrates.

Synthesis of protected 3-aminopiperidine and 3-aminoazepane derivatives using enzyme cascades.

Multi-enzyme cascades utilising variants of galactose oxidase and imine reductase led to the successful conversion of N-Cbz-protected l-ornithinol and l-lysinol to l-3-N-Cbz-aminopiperidine and l-3-N-Cbz-aminoazepane respectively, in up to 54% isolated yield. Streamlining the reactions into one-pot prevented potential racemisation of key labile intermediates and led to products with high enantiopurity.

Selection of T1249-resistant human immunodeficiency virus type 1 variants.

Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.

Topical negative pressure stimulates endothelial migration and proliferation: a suggested mechanism for improved integration of Integra.

Topical negative pressure is an effective technique to promote wound healing and the integration of skin graft and synthetic dermal equivalents. We describe an in vitro model to investigate the effect of negative pressure on angiogenesis, a pivotal step. Dermal fibroblasts or human microvascular endothelial cells were cultured on Integra and subjected to intermittent or continuous negative pressure. At fixed intervals of over 120 hours, the Integra was fixed and assessed for cell migration (microscopy), cell viability (MTS assay), and cell proliferation (Ki67 immunostaining). Under control conditions, endothelial cells formed a monolayer and failed to ingress, whereas fibroblasts migrated throughout the Integra within 24 hours. Negative pressure switches endothelial cell to a migratory and proliferative phenotype. Ingress is greatest with intermittent rather than continuous negative pressure. It has no effect on dermal fibroblast function. This study identifies an important, potential pro-angiogenic mechanism by which topical negative pressure promotes wound healing.

In vitro optimisation of topical negative pressure regimens for angiogenesis into synthetic dermal replacements.

BACKGROUND: The use of synthetic dermal replacements (SDRs) in the treatment of large wounds, which have associated morbidity and mortality, has attracted great interest. However, because of poor outcome, SDRs have limited use. The addition of topical negative pressure (TNP) has increased their success, but little research has focused on the underlying mechanisms. This paper studies the in vitro effects of TNP on commonly used SDRs to identify the most effective TNP regimen and optimum SDR for encouraging endothelial cell ingress. METHODS: Endothelial cells were co-cultured in vitro on four SDRs with or without TNP. Negative pressure (125mmHg) was applied intermittently, continuously, for 4h per day, or not at all. Endothelial ingress was measured for each condition. RESULTS: In the collagen controls, cell migration was minimal. Integratrade mark gave the greatest endothelial cell migration (p<0.05, n=3). TNP increased endothelial cell migration, intermittent application being the optimum regimen. CONCLUSIONS: Integratrade mark has an open sponge structure which may account for greater angiogenicity than Allodermtrade mark, Permacoltrade mark and Xenodermtrade mark. In vitro intermittent TNP stimulates the greatest angiogenic response. The majority of clinical studies investigating SDR success with TNP have used continuous regimens; this study suggests a change in clinical practice to intermittent application.

Thermal Signatures of Plasmonic Fano Interferences: Toward the Achievement of Nanolocalized Temperature Manipulation.

A consequence of thermal diffusion is that heat, even when applied to a localized region of space, has the tendency to produce a temperature change that is spatially uniform throughout a material with a thermal conductivity that is much larger than that of its environment. This implies that the degree of spatial correlation between the heat power supplied and the temperature change that it induces is likely to be small. Here, we show, via theory and simulation, that through a Fano interference, temperature changes can be both localized and controllably directed within certain plasmon-supporting metal nanoparticle assemblies. This occurs even when all particles are composed of the same material and contained within the same diffraction-limited spot. These anomalous thermal properties are compared and contrasted across three different nanosystems, the coupled nanorod-antenna, the heterorod dimer, and the nanocube on a substrate, known to support both spatial and spectral Fano interferences. We conclude that the presence of a Fano resonance is not sufficient by itself to induce a controllably nanolocalized temperature change. However, when present in a nanosystem of the right composition and morphology, temperature changes can be manipulated with nanoscale precision, despite thermal diffusion.