Ecological functional near-infrared spectroscopy in mobile children: using short separation channels to correct for systemic contamination during naturalistic neuroimaging.

Significance: The advances and miniaturization in functional near-infrared spectroscopy (fNIRS) instrumentation offer the potential to move the classical laboratory-based cognitive neuroscience investigations into more naturalistic settings. Wearable and mobile fNIRS devices also provide a novel child-friendly means to image functional brain activity in freely moving toddlers and preschoolers. Measuring brain activity in more ecologically valid settings with fNIRS presents additional challenges, such as the increased impact of physiological interferences. One of the most popular methods for minimizing such interferences is to regress out short separation channels from the long separation channels [i.e., superficial signal regression (SSR)]. Although this has been extensively investigated in adults, little is known about the impact of systemic changes on the fNIRS signals recorded in children in either classical or novel naturalistic experiments. Aim: We aim to investigate if extracerebral physiological changes occur in toddlers and preschoolers and whether SSR can help minimize these interferences. Approach: We collected fNIRS data from 3- to 7-year-olds during a conventional computerized static task and in a dynamic naturalistic task in an immersive virtual reality (VR) cave automatic virtual environment. Results: Our results show that superficial signal contamination data are present in young children as in adults. Importantly, we find that SSR helps in improving the localization of functional brain activity, both in the computerized task and, to a larger extent, in the dynamic VR task. Conclusions: Following these results, we formulate suggestions to advance the field of developmental neuroimaging with fNIRS, particularly in ecological settings.

Naturalistic assessments across the lifespan: Systematic review of inhibition measures in ecological settings.

Inhibitory control is essential for our everyday lives. Despite this, it is commonly assessed using non-naturalistic assessments. In this systematic review, we argue for the importance of taking an ecological approach to assess cognition. The aims are to present the state-of-knowledge in naturalistic assessments of inhibitory control, focusing on their methodological characteristics, including psychometric properties and user experience. PubMed, PsycINFO and Web of Science were searched until September 2024. Studies were included if they used at least one naturalistic method of assessing inhibition. The included studies (N=64) were grouped into three methodological categories: gamification, virtual reality, and brief, repeated assessments in participants' usual environment in the form of ecological momentary assessments. Sample sizes spanned three orders of magnitude (N=12-22,098). We report considerable heterogeneity in the types of tasks used, and the psychometric details reported. Nonetheless, naturalistic tasks were generally comparable with standardised equivalents, although some tasks assessed mixed-domain constructs. Tasks were feasible and acceptable for participants, with generally high completion rates and engagement. Recommendations for future research are discussed.

Predictive modelling of the UK physician associate supply: 2014-2038.

Introduction: The NHS Long Term Workforce Plan aims for 10,000 physician associates (PAs, formerly physician assistants) by 2036/7. This article uses three modelling approaches to project the UK PA supply from a baseline of 2014-2021 through to 2038 to forecast the profession's growth. Methods: The number of cClinically available PAs' (cPAs; qualified PAs either working clinically or seeking clinical employment) was estimated using raw data from the 2014-2021 Faculty of Physician Associates censuses. This provided baseline data for all models (linear regression (LRM), exponential regression (ERM) and time-series forecast (TSFM)). Attrition, using data from other healthcare professions, was also modelled. Results: R 2 values together with authors' judgement ruled the LRM more realistic than the ERM. The LRM projected up to 8,232 cPAs by 2038, although attrition reduced this significantly. The TSFM optimistically projected an upper limit (95% confidence interval) of 13,922 cPAs by 2038. Discussion: This article permits a wider view of potential PA numbers, with broad agreement between the LRM and the TSFM. It appears that future PA demand will be met, but factors such as attrition could impede this. Attrition itself may be mitigated through adequate resourcing, appropriate support mechanisms, and the development of a career structure. Professional regulation and legislation will further support PAs to work to their potential, subject to appropriate patient safety measures.

Immune effects of α and ß radionuclides in metastatic prostate cancer.

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmed cell death 1 ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.

CRISPR-Cas9 potential for identifying novel therapeutic targets in muscle-invasive bladder cancer.

Gene editing technologies help identify the genetic perturbations driving tumour initiation, growth, metastasis and resistance to therapeutics. This wealth of information highlights tumour complexity and is driving cancer research towards precision medicine approaches based on an individual's tumour genetics. Bladder cancer is the 11th most common cancer in the UK, with high rates of relapse and low survival rates in patients with muscle-invasive bladder cancer (MIBC). MIBC is highly heterogeneous and encompasses multiple molecular subtypes, each with different responses to therapeutics. This evidence highlights the need to identify innovative therapeutic targets to address the challenges posed by this heterogeneity. CRISPR-Cas9 technologies have been used to advance our understanding of MIBC and determine novel drug targets through the identification of drug resistance mechanisms, targetable cell-cycle regulators, and novel tumour suppressor and oncogenes. However, the use of these technologies in the clinic remains a substantial challenge and will require careful consideration of dosage, safety and ethics. CRISPR-Cas9 offers considerable potential for revolutionizing bladder cancer therapies, but substantial research is required for validation before these technologies can be used in the clinical setting.

Implementation of Oxygen Enhanced Magnetic Resonance Imaging (OE-MRI) and a Pilot Genomic Study of Hypoxia in Bladder Cancer Xenografts.

BACKGROUND/AIM: Patients with hypoxic bladder cancer benefit from hypoxia modification added to radiotherapy, but no biomarkers exist to identify patients with hypoxic tumours. We, herein, aimed to implement oxygen-enhanced MRI (OE-MRI) in xenografts derived from muscle-invasive bladder cancer (MIBC) for future hypoxia biomarker discovery work; and generate gene expression data for future biomarker discovery. MATERIALS AND METHODS: The flanks of female CD-1 nude mice inoculated with HT1376 MIBC cells. Mice with small (300 mm3) or large (700 mm3) tumours were imaged, breathing air then 100% O2, 1 h post injection with pimonidazole in an Agilant 7T 16cm bore magnet interfaced to a Bruker Avance III console with a T2-TurboRARE sequence using a dynamic MPRAGE acquisition. Dynamic Spoiled Gradient Recalled Echo images were acquired for 5 min, with 0.1mmol/kg Gd-DOTA (Dotarem, Guerbet, UK) injected after 60 s (1 ml/min). Voxel size and field of view of dynamic contrast enhanced (DCE)-MRI and OE-MRI scans were matched. The voxels considered as perfused with significant post-contrast enhancement (p<0.05) in DCE-MRI scans and tissue were further split into pOxyE (normoxic) and pOxyR (hypoxic) regions. Tumours harvested in liquid N2, sectioned, RNA was extracted and transcriptomes analysed using Clariom S microarrays. RESULTS: Imaged hypoxic regions were greater in the larger versus smaller tumour. Expression of known hypoxia-inducible genes and a 24 gene bladder cancer hypoxia score were higher in pimonidazole-high versus -low regions: CA9 (p=0.012) and SLC2A1 (p=0.012) demonstrating expected transcriptomic behaviour. CONCLUSION: OE-MRI was successfully implemented in MIBC-derived xenografts. Transcriptomic data derived from hypoxic and non-hypoxic xenograft regions will be useful for future studies.

Gene Abnormalities and Modulated Gene Expression Associated with Radionuclide Treatment: Towards Predictive Biomarkers of Response.

Molecular radiotherapy (MRT), also known as radioimmunotherapy or targeted radiotherapy, is the delivery of radionuclides to tumours by targeting receptors overexpressed on the cancer cell. Currently it is used in the treatment of a few cancer types including lymphoma, neuroendocrine, and prostate cancer. Recently reported outcomes demonstrating improvements in patient survival have led to an upsurge in interest in MRT particularly for the treatment of prostate cancer. Unfortunately, between 30% and 40% of patients do not respond. Further normal tissue exposure, especially kidney and salivary gland due to receptor expression, result in toxicity, including dry mouth. Predictive biomarkers to select patients who will benefit from MRT are crucial. Whilst pre-treatment imaging with imaging versions of the therapeutic agents is useful in demonstrating tumour binding and potentially organ toxicity, they do not necessarily predict patient benefit, which is dependent on tumour radiosensitivity. Transcript-based biomarkers have proven useful in tailoring external beam radiotherapy and adjuvant treatment. However, few studies have attempted to derive signatures for MRT response prediction. Here, transcriptomic studies that have identified genes associated with clinical radionuclide exposure have been reviewed. These studies will provide potential features for seeding multi-component biomarkers of MRT response.

Surgical treatment of a giant right coronary aneurysm.

This case report is a step-by-step description of the surgical treatment of a giant right coronary aneurysm with a maximum diameter of 80 mm in a 57-year-old male.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Social threat processing in adults and children: Faster orienting to, but shorter dwell time on, angry faces during visual search.

Attention to emotional signals conveyed by others is critical for gleaning information about potential social partners and the larger social context. Children appear to detect social threats (e.g., angry faces) faster than non-threatening social signals (e.g., neutral faces). However, methods that rely on behavioral responses alone are limited in identifying different attentional processes involved in threat detection or responding. To address this question, we used a visual search paradigm to assess behavioral (i.e., reaction time to select a target image) and attentional (i.e., eye-tracking fixations, saccadic shifts, and dwell time) responses in children (ages 7-10 years old, N = 42) and adults (ages 18-23 years old, N = 46). In doing so, we compared behavioral responding and attentional detection and engagement with threatening (i.e., angry and fearful faces) and non-threatening (i.e., happy faces) social signals. Overall, children and adults were faster to detect social threats (i.e., angry faces), but spent a smaller proportion of time dwelling on them and had slower behavioral responses. Findings underscore the importance of combining different measures to parse differences between processing versus responding to social signals across development. RESEARCH HIGHLIGHTS: Children and adults are slower to select angry faces when measured by time to mouse-click but faster to detect angry faces when measured by time to first eye fixation. The use of eye-tracking addresses some limitations of prior visual search tasks with children that rely on behavioral responses alone. Results suggest shorter time to first fixation, but subsequently, shorter duration of dwell on social threat in children and adults.

Macro- and micro-scale culture environment differentially regulate the effects of crowding on macrophage function.

Macrophages hold vital roles in immune defense, wound healing, and tissue homeostasis, and have the exquisite ability to sense and respond to dynamically changing cues in their microenvironment. Much of our understanding of their behavior has been derived from studies performed using in vitro culture systems, in which the cell environment can be precisely controlled. Recent advances in miniaturized culture platforms also offer the ability to recapitulate some features of the in vivo environment and analyze cellular responses at the single-cell level. Since macrophages are sensitive to their surrounding environments, the specific conditions in both macro- and micro-scale cultures likely contribute to observed responses. In this study, we investigate how the presence of neighboring cells influence macrophage activation following proinflammatory stimulation in both bulk and micro-scale culture. We found that in bulk cultures, higher seeding density negatively regulated the average TNF-α secretion from individual macrophages in response to inflammatory agonists, and this effect was partially caused by the reduced cell-to-media volume ratio. In contrast, studies conducted using microwells to isolate single cells and groups of cells revealed that increasing numbers of cells positively influences their inflammatory activation, suggesting that the absolute cell numbers in the system may be important. In addition, a single inflammatory cell enhanced the inflammatory state of a small group of cells. Overall, this work helps to better understand how variations of macroscopic and microscopic culture environments influence studies in macrophage biology and provides insight into how the presence of neighboring cells and the soluble environment influences macrophage activation.

Testing the social motivation theory of autism: the role of co-occurring anxiety.

BACKGROUND: The Social Motivation Theory proposes that social reward processing differences underlie autism. However, low social motivation has also been linked to higher anxiety. Given the co-occurrence between autism and anxiety, it is possible that anxiety drives the association between social motivation and autistic characteristics. This study tests the mechanisms underlying the association between social motivation and autistic traits. METHODS: Participants were 165 adolescents (71 male), aged 10-16 years, from the Mapping profiles of cognition, motivation and attention in childhood (C-MAPS) study, enriched for autistic traits (70 participants with an autism diagnosis, 37 male). Participants completed a battery of online experimental tasks, including a Choose-a-Movie social motivation task and social cognition measures (theory of mind; emotion recognition), alongside parent-reported child anxiety and autistic traits. RESULTS: Higher social motivation was significantly associated with lower autistic traits (ß = -.26, p < .001). Controlling for social cognition did not change the association between social motivation and autistic traits. Controlling for anxiety did significantly reduce the strength of the association (unstandardized coefficient change: p = .003), although social motivation remained associated with autistic traits (ß = -.16, p = .004). Post hoc analyses demonstrated differential sex-effects: The association between social motivation and autistic traits was significant only in the females (ß = -.38, p < .001), as was the attenuation by anxiety (unstandardized coefficient change: p < .001). CONCLUSIONS: The association between social motivation and autistic traits could be partially attributed to co-occurring anxiety. Sex-specific effects found in females may be due to environmental factors such as increased social demands in adolescent female relationships. Results are consistent with self-report by autistic individuals who do not identify as having reduced social motivation.

Surgical bypass to the left subclavian artery: an extra-anatomical transpleural approach.

A distal anastomosis in zone 3 is technically demanding during the frozen elephant trunk procedure. Proximalization of the distal anastomosis to zone 2 with subsequent revascularization of the left subclavian artery is an attractive alternative. This video tutorial describes the technique of an extra-anatomical bypass from the aortic prosthesis to the infraclavicular left subclavian (axillary) artery in arch replacement with the distal aortic graft anastomosis in zone 2.

Automated production of gene-modified chimeric antigen receptor T cells using the Cocoon Platform.

Autologous cell-based therapeutics have gained increasing attention in recent years because of their efficacy at treating diseases with limited therapeutic options. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical success in hematologic oncology indications, providing critically ill patients with a potentially curative therapy. Although engineered cell therapies such as CAR T cells provide new options for patients with unmet needs, the high cost and complexity of manufacturing may hinder clinical and commercial translation. The Cocoon Platform (Lonza, Basel, Switzerland) addresses many challenges, such as high labor demand, process consistency, contamination risks and scalability, by enabling efficient, functionally closed and automated production, whether at clinical or commercial scale. This platform is customizable and easy to use and requires minimal operator interaction, thereby decreasing process variability. We present two processes that demonstrate the Cocoon Platform's capabilities. We employed different T-cell activation methods-OKT3 and CD3/CD28 Dynabeads (Thermo Fisher Scientific, Waltham, MA, USA)-to generate final cellular products that meet the critical quality attributes of a clinical autologous CAR T-cell product. This study demonstrates a manufacturing solution for addressing challenges with manual methods of production and facilitating the scale-up of autologous cell therapy.

The role of individual differences in resistance to persuasion on memory for political advertisements.

When people see political advertisements on a polarized issue they take a stance on, what factors influence how they respond to and remember the adverts contents? Across three studies, we tested competing hypotheses about how individual differences in social vigilantism (i.e., attitude superiority) and need for cognition relate to intentions to resist attitude change and memory for political advertisements concerning abortion. In Experiments 1 and 2, we examined participants' intentions to use resistance strategies to preserve their pre-existing attitudes about abortion, by either engaging against opposing opinions or disengaging from them. In Experiment 3, we examined participants' memory for information about both sides of the controversy presented in political advertisements. Our results suggest higher levels of social vigilantism are related to greater intentions to counterargue and better memory for attitude-incongruent information. These findings extend our understanding of individual differences in how people process and respond to controversial social and political discourse.

The audience who knew too much: investigating the role of spontaneous theory of mind on the processing of dramatic irony scenes in film.

As in real life, cinema viewers rely on spontaneous theory of mind (SToM) to interpret characters' mental states. Thus, analyzing cinematic structures offers a unique opportunity to examine ecologically valid sociocognitive processes. We conducted a proof-of-concept study (N = 42) to explore how SToM inferences impact film event comprehension in dramatic irony scenes, where knowledge divergence exists between the audience and characters. We hypothesized that spectators would focus more on characters' mental states in such false-belief inducing scenarios compared to scenarios without such disparity. We used six Harold Lloyd silent comedy clips in a narrative comprehension and spontaneous mental state attribution study with a between-subject (Knowledge Manipulation: Installation vs. Control) and within-subject (Phase: Context vs. Exploitation) comparisons. We provided critical information unknown to the characters only to the Installation group and withheld it from the Control group. By comparing differences in participants' descriptions of the clips during the Context phase (varying across groups) and Exploitation phase (same across groups), we evaluated viewers' processing of the same scenes based on their false- or true-belief representations. Our findings indicate that the Installation group used more cognitive mental state words during the Exploitation phase relative to the Context phase, suggesting that exposure to undisclosed critical information enhances the frequency of spontaneous epistemic state inferences and integration into event models of the exploitation. This research advances neurocinematics by highlighting spontaneous sociocognitive processes in event perception and comprehension and provides a novel dramatic irony film corpus and measures for future moment-to-moment SToM processing studies across cognitive-behavioral, physiological, and neural levels.

Improved Maximal Workload and Systolic Blood Pressure After Cardiac Rehabilitation Following Thoracic Aortic Repair: A SYSTEMATIC REVIEW AND META-ANALYSIS.

PURPOSE: It is of clinical importance to gain more knowledge about the risks and benefits of exercise in patients recovering from thoracic aortic repair. Therefore, the aim of this review was to perform a meta-analysis on changes in cardiorespiratory fitness, blood pressure, and the incidence of adverse events during cardiac rehabilitation (CR) in patients recovering from thoracic aortic repair. REVIEW METHODS: We performed a systematic review and random-effects meta-analysis of outcomes before versus after outpatient CR in patients recovering from thoracic aortic repair. The study protocol was registered (PROSPERO CRD42022301204) and published. MEDLINE, EMBASE, and CINAHL were systematically searched for eligible studies. Overall certainty of evidence was scored with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). SUMMARY: We included five studies with data from in total 241 patients. Data from one study could not be used in our meta-analysis because they were provided in a different unit of measure. Four studies with data of 146 patients were included in the meta-analysis. The mean maximal workload increased with 28.7 W (95% CI: 21.8-35.6 W, n = 146, low certainty of evidence). The mean systolic blood pressure during exercise testing increased with 25.4 mm Hg (95% CI: 16.6-34.3, n = 133, low certainty of evidence). No exercise-induced adverse events were reported. These outcomes indicate that CR seems beneficial and safe to improve exercise tolerance in patients recovering from thoracic aortic repair, although outcomes were based on data from a small, heterogeneous group of patients.

Studying the concentration of polymers in blended microplastics using 2D and 3D Raman mapping.

The combination of different polymers in the form of blended plastics has been used in the plastic industry for a long time. Nevertheless, analyses of microplastics (MPs) have been mainly limited to the study of particles made of single-type polymers. Accordingly, two members of the Polyolefins (POs) family, i.e., Polypropylene (PP) and Low-density Polyethylene (LDPE) are blended and extensively studied in this work due to their applications in industry as well as abundance in the environment. It is shown that 2-D Raman mapping only provides information about the surface of blended MPs (B-MPs). While complimentary 3-D volume analysis is needed to fully understand the presence of various polymers in such complex samples. Therefore, 3-D Raman mapping is applied to visualize the morphology of the distribution of polymers within the B-MPs together with the quantitative estimation of their concentrations. A parameter defined as the concentration estimate error (CEE) evaluates the precision of the quantitative analysis. Furthermore, the impact of four excitation wavelengths 405, 532, 633, and 785 nm is investigated on the obtained results. Finally, the application of a line-shaped laser beam profile (line-focus) is introduced for reducing the measurement time from 56 to 2 h.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine.

BACKGROUND: The SARS-CoV-2 global pandemic has fuelled the generation of vaccines at an unprecedented pace and scale. However, many challenges remain, including: the emergence of vaccine-resistant mutant viruses, vaccine stability during storage and transport, waning vaccine-induced immunity, and concerns about infrequent adverse events associated with existing vaccines. METHODS: We report on a protein subunit vaccine comprising the receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein, dimerised with an immunoglobulin IgG1 Fc domain. These were tested in conjunction with three different adjuvants: a TLR2 agonist R4-Pam2Cys, an NKT cell agonist glycolipid α-Galactosylceramide, or MF59® squalene oil-in-water adjuvant, using mice, rats and hamsters. We also developed an RBD-human IgG1 Fc vaccine with an RBD sequence of the immuno-evasive beta variant (N501Y, E484K, K417N). These vaccines were also tested as a heterologous third dose booster in mice, following priming with whole spike vaccine. FINDINGS: Each formulation of the RBD-Fc vaccines drove strong neutralising antibody (nAb) responses and provided durable and highly protective immunity against lower and upper airway infection in mouse models of COVID-19. The 'beta variant' RBD vaccine, combined with MF59® adjuvant, induced strong protection in mice against the beta strain as well as the ancestral strain. Furthermore, when used as a heterologous third dose booster, the RBD-Fc vaccines combined with MF59® increased titres of nAb against other variants including alpha, delta, delta+, gamma, lambda, mu, and omicron BA.1, BA.2 and BA.5. INTERPRETATION: These results demonstrated that an RBD-Fc protein subunit/MF59® adjuvanted vaccine can induce high levels of broadly reactive nAbs, including when used as a booster following prior immunisation of mice with whole ancestral-strain spike vaccines. This vaccine platform offers a potential approach to augment some of the currently approved vaccines in the face of emerging variants of concern, and it has now entered a phase I clinical trial. FUNDING: This work was supported by grants from the Medical Research Future Fund (MRFF) (2005846), The Jack Ma Foundation, National Health and Medical Research Council of Australia (NHMRC; 1113293) and Singapore National Medical Research Council (MOH-COVID19RF-003). Individual researchers were supported by an NHMRC Senior Principal Research Fellowship (1117766), NHMRC Investigator Awards (2008913 and 1173871), Australian Research Council Discovery Early Career Research Award (ARC DECRA; DE210100705) and philanthropic awards from IFM investors and the A2 Milk Company.