Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the United Kingdom to accelerate population coverage with a single dose. At this time, trial data were lacking, and we addressed this in a study of United Kingdom healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a substudy of 589 individuals, we show that this single dose induces severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody (NAb) responses and a sustained B and T cell response to the spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared with the conventional 3- to 4-week regimen, accompanied by enrichment of CD4+ T cells expressing interleukin-2 (IL-2). Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective immunogenic protocol.

High-threshold and low-overhead fault-tolerant quantum memory.

The accumulation of physical errors1-3 prevents the execution of large-scale algorithms in current quantum computers. Quantum error correction4 promises a solution by encoding k logical qubits onto a larger number n of physical qubits, such that the physical errors are suppressed enough to allow running a desired computation with tolerable fidelity. Quantum error correction becomes practically realizable once the physical error rate is below a threshold value that depends on the choice of quantum code, syndrome measurement circuit and decoding algorithm5. We present an end-to-end quantum error correction protocol that implements fault-tolerant memory on the basis of a family of low-density parity-check codes6. Our approach achieves an error threshold of 0.7% for the standard circuit-based noise model, on par with the surface code7-10 that for 20 years was the leading code in terms of error threshold. The syndrome measurement cycle for a length-n code in our family requires n ancillary qubits and a depth-8 circuit with CNOT gates, qubit initializations and measurements. The required qubit connectivity is a degree-6 graph composed of two edge-disjoint planar subgraphs. In particular, we show that 12 logical qubits can be preserved for nearly 1 million syndrome cycles using 288 physical qubits in total, assuming the physical error rate of 0.1%, whereas the surface code would require nearly 3,000 physical qubits to achieve said performance. Our findings bring demonstrations of a low-overhead fault-tolerant quantum memory within the reach of near-term quantum processors.

Encoding a magic state with beyond break-even fidelity.

To run large-scale algorithms on a quantum computer, error-correcting codes must be able to perform a fundamental set of operations, called logic gates, while isolating the encoded information from noise1-8. We can complete a universal set of logic gates by producing special resources called magic states9-11. It is therefore important to produce high-fidelity magic states to conduct algorithms while introducing a minimal amount of noise to the computation. Here we propose and implement a scheme to prepare a magic state on a superconducting qubit array using error correction. We find that our scheme produces better magic states than those that can be prepared using the individual qubits of the device. This demonstrates a fundamental principle of fault-tolerant quantum computing12, namely, that we can use error correction to improve the quality of logic gates with noisy qubits. Moreover, we show that the yield of magic states can be increased using adaptive circuits, in which the circuit elements are changed depending on the outcome of mid-circuit measurements. This demonstrates an essential capability needed for many error-correction subroutines. We believe that our prototype will be invaluable in the future as it can reduce the number of physical qubits needed to produce high-fidelity magic states in large-scale quantum-computing architectures.

Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Neutrophil function following treatment of psoriatic arthritis patients with secukinumab: altered cytokine signalling but no impairment of host defence.

OBJECTIVES: Identifying that dysfunction of the IL-23/17 axis underlies PsA has led to the development of effective targeted therapies such as the IL-17A inhibitor secukinumab. As IL-17A stimulates the secretion of neutrophil chemoattractants, such as CXCL8 (IL-8), we examined the effect of secukinumab on neutrophil function in PsA. METHODS: Nineteen patients with active PsA were treated with secukinumab. Clinical response [PsA Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI)] and peripheral blood neutrophil function (apoptosis, receptor expression, phagocytosis/killing, chemotaxis and RNA expression) were measured at 12 week intervals for 48 weeks and compared with age- and sex-matched healthy controls. RESULTS: At 12 weeks, 12/16 (75%) patients had a PsARC response (100% at 36 weeks) and 10/14 (71%) achieved a 90% PASI response. At baseline, there were no differences in PsA neutrophil reactive oxygen species generation, constitutive or cytokine-delayed apoptosis, chemotaxis or phagocytosis of opsonized Staphylococcus aureus compared with healthy controls. Similarly, there were no differences in these functions from baseline to 12 weeks of therapy. However, surface levels of CD11b/CD18 and CD63 increased and expression of CD16 decreased during therapy. In addition, in a subgroup of early (12 week) responders to secukinumab, RNA sequencing revealed transcriptome changes predicting down-regulation of cytokine signalling and chemotaxis pathways and up-regulation of de novo gene expression pathways, including translation initiation, mRNA catabolism and translation. CONCLUSION: Complex changes in the properties of circulating neutrophils occur with secukinumab treatment in PsA that may indicate altered responsiveness to changes in both local and systemic levels of pro-inflammatory cytokines. However, host defence processes of neutrophils were unaltered.

Calibrated Decoders for Experimental Quantum Error Correction.

Arbitrarily long quantum computations require quantum memories that can be repeatedly measured without being corrupted. Here, we preserve the state of a quantum memory, notably with the additional use of flagged error events. All error events were extracted using fast, midcircuit measurements and resets of the physical qubits. Among the error decoders we considered, we introduce a perfect matching decoder that was calibrated from measurements containing up to size-four correlated events. To compare the decoders, we used a partial postselection scheme shown to retain ten times more data than full postselection. We observed logical errors per round of 2.2±0.1×10^{-2} (decoded without postselection) and 5.1±0.7×10^{-4} (full postselection), which was less than the physical measurement error of 7×10^{-3} and therefore surpasses a pseudothreshold for repeated logical measurements.

Who is accessing community lateral flow device testing and why? Characteristics and motivations of individuals participating in COVID-19 community testing in two English local authority areas.

BACKGROUND: Antigen testing using lateral flow devices (LFDs) plays an important role in the management of the novel coronavirus pandemic of 2019 (COVID-19) by rapidly identifying individuals who are asymptomatically carrying high levels of the virus. By January 2021, LFD community testing sites were set up across English local authority areas to support the management and containment of regional COVID-19 cases, initially targeting essential workers unable to work from home during the national lockdown. This study aimed to examine the characteristics and motivations of individuals accessing community LFD testing across two local authority areas (LAAs) in the South West of England. METHODS: Data were collected as part of a service evaluation from December 22nd 2020 until March 15th 2021 for two LAAs. Demographic and postcode data were collected from an online test appointment booking platform and the National Health Service testing service online system, with data accessed from Public Health England. An online survey was sent to individuals who made a testing appointment at an LAA1 site using the online booking platform, consisting of 12 questions to collect data on individual's motivations for and experiences of testing. RESULTS: Data were available for individuals who completed 12,516 tests in LAA1 and 12,327 tests in LAA2. Most individuals who engaged with testing were female, working age, white, and worked as early years or education staff, health and social care staff, and supermarket or food production staff. 1249 individuals completed the survey with 60% of respondents reported getting tested for work-related reasons. Individuals first heard about LFD testing through various channels including work, media, and word of mouth, and decided to get tested based on the ease and convenience of testing, workplace communications, and to identify asymptomatic cases to help stop the spread. Most tests were completed by individuals living in less deprived areas based on national deciles of deprivation. CONCLUSIONS: While national and local COVID-19 testing strategies have evolved, community and personal LFD testing remains a crucial pillar of the testing strategy. Future studies should collect quantitative and qualitative data from residents to most effectively shape testing offers based on the needs and preferences of their population.

Internalization of Neutrophil-Derived Microvesicles Modulates TNFα-Stimulated Proinflammatory Cytokine Production in Human Fibroblast-Like Synoviocytes.

Neutrophil-derived microvesicles (NDMVs) have the potential to exert anti-inflammatory effects. Our study aimed to explore the effects of NDMVs on proinflammatory cytokines expressed by tumor necrosis factor α (TNFα)-stimulated fibroblast-like synoviocytes (FLS). FLS were isolated from the synovium of knee osteoarthritis (OA) patients undergoing surgery. NDMVs, isolated from TNFα-stimulated healthy neutrophils, were characterized by electron microscopy and nanoparticle tracking analysis. MTT and scratch wound healing assays were used to measure FLS viability and migration after treatment with NDMVs, while internalization of fluorescently labeled NDMVs was appraised by flow cytometry and confocal microscopy. Levels of proinflammatory cytokines in supernatants were quantified by the Bio-Plex system. Incubation of FLS with NDMVs at a vesicle/cell ratio of 100 resulted in a time-dependent uptake, with 35% of synoviocytes containing microvesicles over a 6-24 h time period, with no significant change in cell viability. TNFα stimulated the cytokine expression in FLS, and NDMVs down-regulated TNFα-induced expression of IL-5, IL-6, IL-8, MCP-1, IFNγ and MIP-1ß. However, this down-regulation was selective, as NDMVs had no significant effects on TNFα-stimulated expression of IL-2 or IL-4. NDMVs were internalized by FLS to inhibit TNFα-stimulated broad-spectrum proinflammatory cytokine secretion. NDMVs, therefore, may exhibit an anti-inflammatory role in the regulation of the FLS function.

Uniform Additivity in Classical and Quantum Information.

Information theory quantifies the optimal rates of resource interconversions, usually in terms of entropies. However, nonadditivity often makes evaluating entropic formulas intractable. In a few auspicious cases, additivity allows a full characterization of optimal rates. We study uniform additivity of formulas, which is easily evaluated and captures all known additive quantum formulas. Our complete characterization of uniform additivity exposes an intriguing new additive quantity and identifies a remarkable coincidence-the classical and quantum uniformly additive functions with one auxiliary variable are identical.

Experimental Demonstration of Fault-Tolerant State Preparation with Superconducting Qubits.

Robust quantum computation requires encoding delicate quantum information into degrees of freedom that are hard for the environment to change. Quantum encodings have been demonstrated in many physical systems by observing and correcting storage errors, but applications require not just storing information; we must accurately compute even with faulty operations. The theory of fault-tolerant quantum computing illuminates a way forward by providing a foundation and collection of techniques for limiting the spread of errors. Here we implement one of the smallest quantum codes in a five-qubit superconducting transmon device and demonstrate fault-tolerant state preparation. We characterize the resulting code words through quantum process tomography and study the free evolution of the logical observables. Our results are consistent with fault-tolerant state preparation in a protected qubit subspace.

Demonstration of Weight-Four Parity Measurements in the Surface Code Architecture.

We present parity measurements on a five-qubit lattice with connectivity amenable to the surface code quantum error correction architecture. Using all-microwave controls of superconducting qubits coupled via resonators, we encode the parities of four data qubit states in either the X or the Z basis. Given the connectivity of the lattice, we perform a full characterization of the static Z interactions within the set of five qubits, as well as dynamical Z interactions brought along by single- and two-qubit microwave drives. The parity measurements are significantly improved by modifying the microwave two-qubit gates to dynamically remove nonideal Z errors.

Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo.

OBJECTIVES: Reports on the regulation of neutrophil function by IL-6 are often conflicting. Therapeutic inhibition of IL-6 in RA is associated with occasional neutropenia, but the mechanisms underlying this observation are poorly understood. This study investigated interactions between IL-6, the anti-IL-6 receptor agent tocilizumab (TCZ) and neutrophils in vitro and in vivo. METHODS: Neutrophils were isolated from healthy controls and incubated in vitro with pharmacologically relevant concentrations of IL-6 or TCZ. Neutrophils were also isolated from RA patients, including a cohort following TCZ therapy. Apoptosis was measured by annexin V/propidium iodide (PI) flow cytometry; phagocytosis was measured by incubating apoptotic neutrophils with THP-1-derived macrophages; chemotaxis was measured using cell migration through hanging-cell inserts towards IL-8 and cell surface proteins, including adhesion molecules CD11b (αMß2 integrin) and CD62L (L-selectin) were measured by flow cytometry. RESULTS: IL-6 (10-100 ng/ml) did not affect the rate of neutrophil apoptosis, priming of the respiratory burst or adhesion molecule expression nor act as a neutrophil chemoattractant. However, IL-6 enhanced signal transducer and activator of transcription 3 (STAT3) activation and neutrophil migration towards IL-8. TCZ in vitro did not induce apoptosis or phagocytosis of neutrophils, nor did it have a significant effect upon apoptosis or cell surface molecule expression. Neutrophil functions in ex vivo neutrophils from RA patients receiving TCZ treatment were unaffected. CONCLUSION: Therapeutic blockade of IL-6, while inducing a transient neutropenia, does not directly affect neutrophil functions associated with host defence. TCZ-associated neutropenia cannot be explained by direct induction of apoptosis by TCZ, induction of apoptosis following depletion of IL-6, nor increased phagocytosis of neutrophils.

Changes in immune cell subtypes during ageing.

BACKGROUND: The immune system comprises many different types of cells, each with different functions and properties during immune defence. The numbers and types of immune cells in the circulation is highly dynamic and regulated by infections, ageing and certain types of cancers. It is recognised that immune function decreases during ageing, but the biological age at which these functional changes occur is variable, and how ageing affects the different sub-types of lymphocytes, monocytes and NK cells in the circulation is not fully defined. METHODS: In this study, we recruited 24 healthy volunteers over the age range of 23y to 89y and measured the numbers of different subclasses of circulating cells by immuno-phenotyping and flow cytometry. RESULTS: We show increased monocyte:lymphocyte ratios in a > 50y cohort and most T cell subsets were decreased, except for CD4+ cells, which were increased in this cohort. In addition, there was NK cell expansion and increased HLA-DR+ T cells, but decreased numbers of classical monocytes and increased numbers of CD4+ monocytes in this >50y cohort. CONCLUSIONS: These data indicate that healthy ageing is associated with changes in both the major cell groups but also individual subclasses of cells, and these are likely to result from continuous immune challenge and impaired development.

Effects of a Continuous Adductor Canal Block After Total Knee Arthroplasty.

This retrospective cohort study analyzed the short-term outcomes of patients undergoing total knee arthroplasty receiving periarticular anesthetic injections (PAIs) with and without continuous adductor canal blocks (CACBs) regarding early postoperative narcotic use, pain scores, and range of motion with otherwise similar postoperative regimens. Two hundred ninety-four patients were included: 120 received PAIs with CACBs, and 174 received PAIs only. Matched analysis was performed for type of anesthesia. There were substantial decreases in early inpatient narcotic use with the addition of CACBs to PAIs with general and spinal anesthesia without an adverse effect on pain, knee range of motion, or length of stay. [Orthopedics. 2023;46(3):185-191.].

Demonstrating multi-round subsystem quantum error correction using matching and maximum likelihood decoders.

Quantum error correction offers a promising path for performing high fidelity quantum computations. Although fully fault-tolerant executions of algorithms remain unrealized, recent improvements in control electronics and quantum hardware enable increasingly advanced demonstrations of the necessary operations for error correction. Here, we perform quantum error correction on superconducting qubits connected in a heavy-hexagon lattice. We encode a logical qubit with distance three and perform several rounds of fault-tolerant syndrome measurements that allow for the correction of any single fault in the circuitry. Using real-time feedback, we reset syndrome and flag qubits conditionally after each syndrome extraction cycle. We report decoder dependent logical error, with average logical error per syndrome measurement in Z(X)-basis of ~0.040 (~0.088) and ~0.037 (~0.087) for matching and maximum likelihood decoders, respectively, on leakage post-selected data.

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens.

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease. FUNDING: Department for Health and Social Care, Medical Research Council.

Angiopoietin like protein 4 expression is decreased in activated macrophages.

Angiopoietin like protein 4 (ANGPTL4) inhibits lipoprotein lipase (LPL) activity. Previous studies have shown that Toll-like Receptor (TLR) activation increases serum levels of ANGPTL4 and expression of ANGPTL4 in liver, heart, muscle, and adipose tissue in mice. ANGPTL4 is expressed in macrophages and is induced by inflammatory saturated fatty acids. The absence of ANGPTL4 leads to the increased uptake of pro-inflammatory saturated fatty acids by macrophages in the mesentery lymph nodes due to the failure of ANGPTL4 to inhibit LPL activity, resulting in peritonitis, intestinal fibrosis, weight loss, and death. Here we determined the effect of TLR activation on the expression of macrophage ANGPTL4. LPS treatment resulted in a 70% decrease in ANGPTL4 expression in mouse spleen, a tissue enriched in macrophages. In mouse peritoneal macrophages, LPS treatment also markedly decreased ANGPTL4 expression. In RAW cells, a macrophage cell line, LPS, zymosan, poly I:C, and imiquimod all inhibited ANGPTL4 expression. In contrast, neither TNF, IL-1, nor IL-6 altered ANGPTL4 expression. Finally, in cholesterol loaded macrophages, LPS treatment still decreased ANGPTL4 expression. Thus, while in most tissues ANGPTL4 expression is stimulated by inflammatory stimuli, in macrophages TLR activators inhibit ANGPTL4 expression, which could lead to a variety of down-stream effects important in host defense and wound repair.

Assessment of mold contamination in hurricane-damaged homes in Houston, Texas after sanitization by volunteers.

The purpose of this pilot study was to evaluate the effectiveness of mold sanitation in homes that suffered hurricane-related water damage. After a home is flooded, sanitation of the structure for mold is necessary before the interior of the home can be rebuilt. In this study, homes (n = 6) in Houston, Texas that had been flooded by Hurricane Harvey were sanitized by volunteers. At either 6, 8, 15, 25, 34, or 56 days after the sanitation was completed, a Button™ sampler was used to collect a 48-hour air sample, so that the mold cells in the air could be quantified. Each air sample was then analyzed by quantitative PCR (qPCR) assays for the 36 molds in the Environmental Relative Moldiness Index (ERMI) panel of indicator molds. Quantifying the 36-ERMI molds in air samples results in "ERMI-like" values. The ERMI-like values in the sanitized homes were inversely correlated (Pearson p - value 0.04) with the log of the number of days after the sanitation was completed, an indication that it takes time after sanitation for the mold levels to stabilize. This pilot study demonstrated that the ERMI-like metric was useful in assessing post-sanitation mold levels in previously flooded homes.

Metabolic Profiling of Rheumatoid Arthritis Neutrophils Reveals Altered Energy Metabolism That Is Not Affected by JAK Inhibition.

Neutrophils play a key role in the pathophysiology of rheumatoid arthritis (RA) where release of ROS and proteases directly causes damage to joints and tissues. Neutrophil function can be modulated by Janus Kinase (JAK) inhibitor drugs, including tofacitinib and baricitinib, which are clinically effective treatments for RA. However, clinical trials have reported increased infection rates and transient neutropenia during therapy. The subtle differences in the mode of action, efficacy and safety of JAK inhibitors have been the primary research topic of many clinical trials and systematic reviews, to provide a more precise and targeted treatment to patients. The aim of this study was to determine both the differences in the metabolome of neutrophils from healthy controls and people with RA, and the effect of different JAK inhibitors on the metabolome of healthy and RA neutrophils. Isolated neutrophils from healthy controls (HC) (n = 6) and people with RA (n = 7) were incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200 ng/mL) for 2 h. Metabolites were extracted, and 1H nuclear magnetic resonance (NMR) was applied to study the metabolic changes. Multivariate analyses and machine learning models showed a divergent metabolic pattern in RA neutrophils compared to HC at 0 h (F1 score = 86.7%) driven by energy metabolites (ATP, ADP, GTP and glucose). No difference was observed in the neutrophil metabolome when treated with JAK inhibitors. However, JAK inhibitors significantly inhibited ROS production and baricitinib decreased NET production (p < 0.05). Bacterial killing was not impaired by JAK inhibitors, indicating that the effect of JAK inhibitors on neutrophils can inhibit joint damage in RA without impairing host defence. This study highlights altered energy metabolism in RA neutrophils which may explain the cause of their dysregulation in inflammatory disease.