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Introduction Cigarette package inserts that describe quitting benefits and tips may promote cessation; however, research is needed to understand better their effects, including potentially enhancing the effects of pictorial health warning labels (PHWLs). Methods A randomized trial with a 2×2 factorial design was conducted with adult smokers (n=356) assigned to either small text-only health warning labels (HWLs; control); inserts with cessation messages, and the small text-only HWLs (insertsonly); large PHWLs (PHWLs-only); both inserts and PHWLs (inserts + PHWLs). Participants received a 14-day supply of their preferred cigarettes with packs labeled to reflect their group. Upon finishing the trial, participants reported their past 14-day frequency of noticing, reading, thinking about smoking harms and cessation benefits, talking about labels, and forgoing cigarettes because of the labels. Ordered logistic models regressed these outcomes on labeling groups, and mediation analyses assessed whether attention (i.e. noticing, reading) to labels mediated effects of labeling exposure on other outcomes (i.e. thinking about harms/benefits, talking, forgoing). Results The inserts + PHWLs group reported higher frequencies than the control group for all outcomes. Compared to the control group, both the inserts-only and PHWLs-only groups reported higher frequency of noticing (AOR=3.53 and 2.46, respectively) and reading labels (AOR=2.89 and 1.71), thinking about smoking risks because of the labels (AOR=1.93 and 1.82), and talking about labels (AOR=2.30 and 2.70). Participants in the inserts-only group also reported more frequent thinking about quitting benefits (AOR=1.98). Attention mediated all labeling effects except for the contrast between PHWLs only and control. Conclusions Compared to text-only HWLS, cigarette labeling that involves inserts, PHWLs, or both appears more effective at drawing attention to warnings, which mediated the effects on cessation-related psychosocial and behavioral outcomes.

Objective Cluster randomised trials (CRTs) are used for evaluating health-related interventions in low-income and middle-income countries (LMICs) but raise complex ethical issues. To inform the development of future ethics guidance, we aim to characterise CRTs conducted exclusively in LMICs by examining the types of clusters, settings, author affiliations and primary clinical focus and to evaluate adherence to trial registration and ethics reporting requirements over time.Design A systematic scoping review using the Preferred Reporting Items for Systematic Review and Meta-Analyses Extension for Scoping Reviews.Data sources We searched MEDLINE between 1 January 2017 and 17 August 2022.Eligibility criteria for selecting studies We included primary reports of CRTs evaluating health-related interventions, conducted exclusively in LMICs and published in English between 2017 and 2022.Data extraction and synthesis Data were extracted by one reviewer; a second reviewer verified accuracy by extracting data from 10% of the reports. Results were summarised overall and categorised by country’s economic level or publication year.Results Among 800 identified CRTs, 400 (50.0%) randomised geographical areas and 373 (46.6%) were conducted in Africa. 30 (3.7%) had no authors with an LMIC affiliation, and 246 (30.8%) had neither first nor last author with an LMIC affiliation. The relative frequency of first or last authors holding an LMIC affiliation increases as a country’s economic level increases. Most CRTs focused on reducing maternal and neonatal disorders (106, 13.3%). 670 (83.8%) CRTs reported trial registration, 786 (98.2%) reported research ethics committee review and 757 (94.6%) reported consent statements. Among the 757 CRTs, 46 (6.1%) reported a waiver or no consent and, among these, 10 (21.7%) did not provide a rationale. Gatekeepers were identified in 403 (50.4%) CRTs. No meaningful trends were observed in adherence to trial registration or ethics reporting requirements over time.Conclusion Our findings suggest existing inequity in authorship practices. There is high adherence to trial registration and ethics reporting requirements, although greater attention to reporting a justification for using a waiver of consent is needed.

Dilated cardiomyopathy (DCM) is an inherited disorder often leading to severe heart failure. Linkage studies in affected families have revealed hundreds of different mutations that can cause DCM, with most occurring in genes associated with the cardiac sarcomere. We have developed an investigational pipeline for discovering mechanistic genotype-phenotype relationships in DCM and here apply it to the DCM-linked tropomyosin mutation TPM1 M8R. Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin. Applying these molecular effects to a Markov model of the cardiac thin filament reproduced the shifts in Ca2+sensitivity, maximum force, and a qualitative drop in cooperativity that were observed in an in vitro system containing TPM1 M8R. The model was then used to simulate the impact of M8R expression on twitch contractions of intact cardiac muscle, predicting that M8R would reduce peak force and duration of contraction in a dose-dependent manner. To evaluate this prediction, TPM1 M8R was expressed via adenovirus in human engineered heart tissues and isometric twitch force was observed. The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions. Additional exploratory simulations suggest that M8R-mediated alterations in tropomyosin-actin interactions contribute more potently than tropomyosin chain stiffness to cardiac twitch dysfunction, and presumably to the ultimate manifestation of DCM. This study is an example of the growing potential for successful in silico prediction of mutation pathogenicity for inherited cardiac muscle disorders.

Molecular visualization is a powerful way to represent the complex structure of molecules and their higher order assemblies, as well as the dynamics of their interactions. Although conventions for depicting static molecular structures and complexes are now well established and guide the viewer’s attention to specific aspects of structure and function, little attention and design classification has been devoted to how molecular motion is depicted. As we continue to probe and discover how molecules move - including their internal flexibility, conformational changes and dynamic associations with binding partners and environments - we are faced with difficult design challenges that are relevant to molecular visualizations both for the scientific community and students of cell and molecular biology. To facilitate these design decisions, we have identified twelve molecular animation design principles that are important to consider when creating molecular animations. Many of these principles pertain to misconceptions that students have primarily regarding the agency of molecules, while others are derived from visual treatments frequently observed in molecular animations that may promote misconceptions. For each principle, we have created a pair of molecular animations that exemplify the principle by depicting the same content in the presence and absence of that design approach. Although not intended to be prescriptive, we hope this set of design principles can be used by the scientific, education, and scientific visualization communities to facilitate and improve the pedagogical effectiveness of molecular animation.

Abstract This study investigates the humoral and cellular immune responses and health-related quality of life measures in individuals with mild to moderate long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24 months. LC participants show elevated nucleocapsid IgG levels at 3 months, and higher neutralizing capacity up to 8 months post-infection. Increased spike-specific and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells were observed at 3 and 8 months, but these differences do not persist at 24 months. Some LC participants had detectable IFN-γ and IFN-β, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at the 24 month timepoint shows similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC and MC. No significant differences in exhaustion scores or antigen-specific T cell clones are observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24 months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count are associated with improvements in health-related quality of life.

Abstract We investigate experimentally and theoretically a system ruled by an intricate interplay between topology, nonlinearity, and spontaneous symmetry breaking. The experiment is based on a two-mode coherently-driven optical resonator where photons interact through the Kerr nonlinearity. In presence of a phase defect, the modal structure acquires a synthetic Möbius topology enabling the realization of spontaneous symmetry breaking in inherently bias-free conditions without fine tuning of parameters. Rigorous statistical tests confirm the robustness of the underlying symmetry protection, which manifests itself by a periodic alternation of the modes reminiscent of period-doubling. This dynamic also confers long term stability to various localized structures including domain walls, solitons, and breathers. Our findings are supported by an effective Hamiltonian model and have relevance to other systems of interacting bosons and to the Floquet engineering of quantum matter. They could also be beneficial to the implementation of coherent Ising machines.

Abstract Background Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. Methods Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for ‘patient engagement in preclinical laboratory research.’ First, our team will create a ‘deliberative knowledge space’ to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. Discussion Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

A rare subseasonal-to-seasonal phenomenon – two consecutive flash drought events interrupted by a period of recovery – occurred across eastern Oklahoma, Arkansas, and southern Missouri, spanning the summer and early fall of 2022. These flash drought events (the first in June–July, the second in August–September) led to severe (D2) and extreme (D3) drought conditions via the United States Drought Monitor across much of the region following the first period of rapid drought intensification, and extreme (D3) and exceptional (D4) drought conditions by the end of the second event. A notable driver of both flash drought events included a persistent upper-level ridge either centered over or shifted west and upstream of the flash drought region, leading to broad-scale subsidence and reduced mid-level moisture which acted to limit precipitation development and increase evaporative demand. In addition, several heatwave events developed during the warm season in 2022 and either (1) acted to drive flash drought development via increased evaporative demand or (2) were enhanced by land surface desiccation and land-atmosphere feedbacks following rapid drought intensification. Furthermore, S2S composite forecasts predicted drought development for both events. However, only 20% of the ensembles predicted rapid drought development associated with flash drought for the first event and 16% of the ensembles predicted rapid drought development during the second event. This result highlights a key challenge in S2S prediction of rapidly developing drought conditions versus that of more conventional and slower drought development. The ensembles that did predict rapid drought intensification were associated with the forecasting of positive 500 hPa geopotential height anomalies over the south-central United States (first event) or an amplified wave pattern centered over the west-central United States (second event). Lastly, the compounding effects of two flash droughts in a single warm season led to substantial impacts on agricultural, environmental, and hydrologic sectors across the region.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Abstract Background In the UK, tens of millions of working days are lost due to work‐related ill health every year, costing billions of pounds. The role of Occupational Health (OH) services is vital in helping workers to maintain employment when they encounter injury or illness. OH providers traditionally rely on a clinical workforce to deliver these services, particularly doctors and nurses with OH qualifications. However, the increasing demand for OH services is unlikely to be met in the future using this traditional model, due to the declining number of OH‐trained doctors and nurses in the UK. Multi‐disciplinary models of OH delivery, including a more varied range of healthcare and non‐healthcare professionals, could provide a way to meet this new demand for OH services. There is a need to identify collaborative models of OH service delivery and review their effectiveness on return‐to work outcomes. There is an existing pool of systematic review evidence evaluating workplace based, multi‐disciplinary OH interventions, but it is difficult to identify which aspects of the content and/or delivery of these interventions may be associated with improved work‐related outcomes. Objectives The aim of this evidence and gap map (EGM) was to provide an overview of the systematic review evidence that evaluates the effectiveness and cost‐effectiveness of multi‐disciplinary OH interventions intending to improve work‐related outcomes. Search Methods In June 2021 we searched a selection of bibliographic databases and other academic literature resources covering a range of relevant disciplines, including health care and business studies, to identify systematic review evidence from a variety of sectors of employment. We also searched Google Search and a selection of topically relevant websites and consulted with stakeholders to identify reports already known to them. Searches were updated in February 2023. Selection Criteria Systematic reviews needed to be about adults (16 years or over) in employment, who have had absence from work for any medical reason. Interventions needed to be multi‐disciplinary (including professionals from different backgrounds in clinical and non‐clinical professions) and designed to support employees and employers to manage health conditions in the workplace and/or to help employees with health conditions retain and/or return to work following medical absence. Effectiveness needed to be measured in terms of return to work, work retention or measures of absence, or economic evaluation outcomes. These criteria were applied to the title and abstract and full text of each systematic review independently by two reviewers, with disagreements resolved through discussion. We awarded each systematic review a rating of ‘High’, ‘Medium’ or ‘Low’ relevance to indicate the extent to which the populations, interventions and their contexts synthesised within the review were consistent with our research question. We also recorded the number of primary studies included within each of the ‘High’ and ‘Medium’ reviews that were relevant to research question using the same screening process applied at review level. Data Collection and Analysis Summary data for each eligible review was extracted. The quality of the systematic reviews, rated as ‘High’ or ‘Medium’ relevance following full text screening, was appraised using the AMSTAR‐2 quality appraisal tool. All data were extracted by one reviewer and checked by a second, with disagreements being settled through discussion. Summary data for all eligible systematic reviews were tabulated and described narratively. The data extracted from reviews of ‘High’ and ‘Medium’ relevance was imported into EPPI‐Mapper software to create an EGM. Stakeholder Involvement We worked alongside commissioners and policy makers from the Department of Health and Social Care (DHSC) and Department of Work and Pensions (DWP), OH personnel, and people with lived experience of accessing OH services themselves and/or supporting employees to access OH services. Individuals contributed to decision making at all stages of the project. This ensured our EGM reflects the needs of individuals who will use it. Main Results We identified 98 systematic reviews that contained relevant interventions, which involved a variety of professionals and workplaces, and which measured effectiveness in terms of return to work (RTW). Of these, we focused on the 30 reviews where the population and intervention characteristics within the systematic reviews were considered to be of high or medium relevance to our research questions. The 30 reviews were of varying quality, split evenly between High/Moderate quality and Low/Critically‐Low quality ratings. We did not identify any relevant systematic review evidence on any other work‐related outcome of interest. Interventions were heterogenous, both within and across included systematic reviews. The EGM is structured according to the health condition experienced by participants, and the effectiveness of the interventions being evaluated, as reported within the included systematic reviews. It is possible to view (i) the quality and quantity of systematic review evidence for a given health condition, (ii) how review authors assessed the effectiveness or cost‐effectiveness of the interventions evaluated. The EGM also details the primary studies relevant to our research aim included within each review. Authors’ Conclusions This EGM map highlights the array of systematic review evidence that exists in relation to the effectiveness or cost‐effectiveness of multi‐disciplinary, workplace‐based OH interventions in supporting RTW. This evidence will allow policy makers and commissioners of services to determine which OH interventions may be most useful for supporting different population groups in different contexts. OH professionals may find the content of the EGM useful in identifying systematic review evidence to support their practice. The EGM also identifies where systematic review evidence in this area is lacking, or where existing evidence is of poor quality. These may represent areas where it may be particularly useful to conduct further systematic reviews.

Summary: In July/August 2023, the highly mutated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BA.2.86 lineage emerged and its descendant JN.1 is on track to become the dominant SARS-CoV-2 lineage globally. Compared to the spike (S) protein of the parental BA.2.86 lineage, the JN.1 S protein contains one mutation, L455S, which may affect receptor binding and antibody evasion. Here, we performed a virological assessment of the JN.1 lineage employing pseudovirus particles bearing diverse SARS-CoV-2 S proteins. Using this strategy, it was found that S protein mutation L455S confers increased neutralization resistance but reduces ACE2 binding capacity and S protein-driven cell entry efficiency. Altogether, these data suggest that the benefit of increased antibody evasion outweighs the reduced ACE2 binding capacity and further enabled the JN.1 lineage to effectively spread in the human population.

Background NHS England’s ‘Enhanced Health in Care Homes’ specification aims to make the healthcare of care home residents more proactive. Primary care networks (PCNs) are contracted to provide this, but approaches vary widely: challenges include frailty identification, multidisciplinary team (MDT) capability/capacity and how the process is structured and delivered.Aim To determine whether a proactive healthcare model could improve healthcare outcomes for care home residents.Design and setting Quality improvement project involving 429 residents in 40 care homes in a non-randomised crossover cohort design. The headline outcome was 2-year survival.Method All care home residents had healthcare coordinated by the PCN’s Older Peoples’ Hub. A daily MDT managed the urgent healthcare needs of residents. Proactive healthcare, comprising information technology-assisted comprehensive geriatric assessment (i-CGA) and advanced care planning (ACP), were completed by residents, with prioritisation based on clinical needs.Time-dependent Cox regression analysis was used with patients divided into two groups:Control group: received routine and urgent (reactive) care only.Intervention group: additional proactive i-CGA and ACP.Results By 2 years, control group survival was 8.6% (n=108), compared with 48.1% in the intervention group (n=321), p

Abstract Background An integral aspect of patient engagement in research, also known as patient and public involvement, is appropriately recognising patient partners for their contributions through compensation (e.g., coauthorship, honoraria). Despite known benefits to compensating patient partners, our previous work suggested compensation is rarely reported and researchers perceive a lack of guidance on this issue. To address this gap, we identified and summarised available guidance and policy documents for patient partner compensation. Methods We conducted this scoping review in accordance with methods suggested by the JBI. We searched the grey literature (Google, Google Scholar) in March 2022 and Overton (an international database of policy documents) in April 2022. We included articles, guidance or policy documents regarding the compensation of patient partners for their research contributions. Two reviewers independently extracted and synthesised document characteristics and recommendations. Results We identified 65 guidance or policy documents. Most documents were published in Canada (57%, n = 37) or the United Kingdom (26%, n = 17). The most common recommended methods of nonfinancial compensation were offering training opportunities to patient partners (40%, n = 26) and facilitating patient partner attendance at conferences (38%, n = 25). The majority of guidance documents (95%) suggested financially compensating (i.e., offering something of monetary value) patient partners for their research contributions. Across guidance documents, the recommended monetary value of financial compensation was relatively consistent and associated with the role played by patient partners and/or specific engagement activities. For instance, the median monetary value for obtaining patient partner feedback (i.e., consultation) was $19/h (USD) (range of $12–$50/h). We identified several documents that guide the compensation of specific populations, including youth and Indigenous peoples. Conclusion Multiple publicly available resources exist to guide researchers, patient partners and institutions in developing tailored patient partner compensation strategies. Our findings challenge the perception that a lack of guidance hinders patient partner financial compensation. Future efforts should prioritise the effective implementation of these compensation strategies to ensure that patient partners are appropriately recognised. Patient or Public Contributions The patient partner coauthor informed protocol development, identified data items, and interpreted findings.

Abstract Introduction Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family‐centred care need information about the characteristics of existing interventions, their development and the domains of family‐centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family‐centred interventions designed to improve experiences with care for children with chronic conditions. Methods We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7–20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family‐centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full‐text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family‐centred care. Results Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed‐methods studies (n = 9 each). The most frequently addressed domains of family‐centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). Conclusion This review, which identified 61 unique interventions aimed at improving family‐centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high‐needs population. Patient or Public Contribution This study was co‐developed with three patient partner co‐investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co‐investigators contributed to this study at all stages, from conceptualization to dissemination.

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir’s potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.

Engager is a complex, collaborative, but flexible intervention providing psychological and practical support to male prison leavers with sentences of two years or less. Engager was not shown to be effective from an evaluation of standard outcome measures, although full delivery of the intervention was also not achieved. The success of interventions relies partly on how able individuals are to attend, so we used an exploratory analysis of the Engager evaluation data to investigate what factors impacted on the extent to which participants attended Engager sessions. The results showed that problems with alcohol at baseline have a positive relationship with subsequent attendance (i.e., predict greater engagement). This finding was somewhat unexpected. Several other factors were found not to be predictive of either increased or decreased attendance, including depression, anxiety and psychological distress. This is a potentially positive finding, in that Engager appears to overcome some barriers to engagement in those with more severe common mental health issues, rather than them engaging less. This is despite previous evidence of these factors reducing attendance for mental health and psychological support. Potential reasons for these findings and implications for future research are discussed.

Abstract Previous work has shown that motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursor cells (OLPs) in the brains of adult mice. In the present study we ask whether OL production is also required for non-motor learning and cognition, using T-maze and radial-arm-maze tasks that tax spatial working memory. We find that maze training stimulates OLP proliferation and OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation of adult male mice; myelin sheath formation is also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impairs training-induced improvements in maze performance. We find a strong positive correlation between the performance of individual wild type mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in their mPFC, underscoring the important role played by OL lineage cells in cognitive processing.

Abstract Background Patient engagement in research refers to collaboration between researchers and patients (i.e., individuals with lived experience including informal caregivers) in developing or conducting research. Offering non-financial (e.g., co-authorship, gift) or financial (e.g., honoraria, salary) compensation to patient partners can demonstrate appreciation for patient partner time and effort. However, little is known about how patient partners are currently compensated for their engagement in research. We sought to assess the prevalence of reporting patient partner compensation, specific compensation practices (non-financial and financial) reported, and identify benefits, challenges, barriers and enablers to offering financial compensation. Methods We conducted a systematic review of studies citing the Guidance for Reporting the Involvement of Patients and the Public (GRIPP I and II) reporting checklists (October 2021) within Web of Science and Scopus. Studies that engaged patients as research partners were eligible. Two independent reviewers screened full texts and extracted data from included studies using a standardized data abstraction form. Data pertaining to compensation methods (financial and non-financial) and reported barriers and enablers to financially compensating patient partners were extracted. No formal quality assessment was conducted since the aim of the review is to describe the scope of patient partner compensation. Quantitative data were presented descriptively, and qualitative data were thematically analysed. Results The search identified 843 studies of which 316 studies were eligible. Of the 316 studies, 91% (n = 288) reported offering a type of compensation to patient partners. The most common method of non-financial compensation reported was informal acknowledgement on research outputs (65%, n = 206) and co-authorship (49%, n = 156). Seventy-nine studies (25%) reported offering financial compensation (i.e., honoraria, salary), 32 (10%) reported offering no financial compensation, and 205 (65%) studies did not report on financial compensation. Two key barriers were lack of funding to support compensation and absence of institutional policy or guidance. Two frequently reported enablers were considering financial compensation when developing the project budget and adequate project funding. Conclusions In a cohort of published studies reporting patient engagement in research, most offered non-financial methods of compensation to patient partners. Researchers may need guidance and support to overcome barriers to offering financial compensation.

Abstract Engineered whole lungs may one day expand therapeutic options for patients with end-stage lung disease. However, the feasibility of ex vivo lung regeneration remains limited by the inability to recapitulate mature, functional alveolar epithelium. Here, we modulate multimodal components of the alveolar epithelial type 2 cell (AEC2) niche in decellularized lung scaffolds in order to guide AEC2 behavior for epithelial regeneration. First, endothelial cells coordinate with fibroblasts, in the presence of soluble growth and maturation factors, to promote alveolar scaffold population with surfactant-secreting AEC2s. Subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-magnitude mechanical strain to induce the differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an epithelium of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial alveolar-like units, and highlight the critical interplay amongst cellular, biochemical, and mechanical niche cues within the reconstituting alveolus.

Abstract Background Addressing persistent and pervasive health inequities is a global moral imperative, which has been highlighted and magnified by the societal and health impacts of the COVID-19 pandemic. Observational studies can aid our understanding of the impact of health and structural oppression based on the intersection of gender, race, ethnicity, age and other factors, as they frequently collect this data. However, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline, does not provide guidance related to reporting of health equity. The goal of this project is to develop a STROBE-Equity reporting guideline extension. Methods We assembled a diverse team across multiple domains, including gender, age, ethnicity, Indigenous background, disciplines, geographies, lived experience of health inequity and decision-making organizations. Using an inclusive, integrated knowledge translation approach, we will implement a five-phase plan which will include: (1) assessing the reporting of health equity in published observational studies, (2) seeking wide international feedback on items to improve reporting of health equity, (3) establishing consensus amongst knowledge users and researchers, (4) evaluating in partnership with Indigenous contributors the relevance to Indigenous peoples who have globally experienced the oppressive legacy of colonization, and (5) widely disseminating and seeking endorsement from relevant knowledge users. We will seek input from external collaborators using social media, mailing lists and other communication channels. Discussion Achieving global imperatives such as the Sustainable Development Goals (e.g., SDG 10 Reduced inequalities, SDG 3 Good health and wellbeing) requires advancing health equity in research. The implementation of the STROBE-Equity guidelines will enable a better awareness and understanding of health inequities through better reporting. We will broadly disseminate the reporting guideline with tools to enable adoption and use by journal editors, authors, and funding agencies, using diverse strategies tailored to specific audiences.

Here, Rouet et al. present a strategy for the identification of broadly neutralising antibodies against SARS-CoV-2 receptor binding domain from peripheral blood mononuclear cells of convalescent patients, which enabled the identification of a new class 6 epitope.

Microtubule-associated protein Tau (MAPT) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the MAPT gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that MAPT mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of MAPT were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in MAPT mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in MAPT mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson’s disease pathology.

Abstract Purpose To inform recommendations by the Canadian Task Force on Preventive Health Care on potentially inappropriate prescribing and over-the-counter (OTC) medication use among adults aged 65 years and older in primary care settings. This protocol outlines the planned scope and methods for a systematic review of the benefits and harms and acceptability of interventions to reduce potentially inappropriate prescriptions and OTC medication use. Methods De novo systematic reviews will be conducted to synthesize the available evidence on (a) the benefits and harms of interventions to reduce potentially inappropriate prescriptions and OTC medications compared to no intervention, usual care, or non- or minimally active intervention among adults aged 65 years and older and (b) the acceptability of these interventions or attributes among patients. Outcomes of interest for the benefits and harms review are all-cause mortality, hospitalization, non-serious adverse drug reactions, quality of life, emergency department visits, injurious falls, medical visits, and the number of medications (and number of pills). Outcomes for the acceptability review are the preference for and relative importance of different interventions or their attributes. For the benefits and harms review, we will search MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled trials. For the acceptability review, we will search MEDLINE, Embase, PsycInfo, Cochrane Central Register of Controlled Trials, and the NHS Economic Evaluation Database for experimental and observational studies with a comparator. Websites of relevant organizations, other grey literature sources, and reference lists of included studies and reviews will be searched. Title and abstract screening will be completed by two independent reviewers using the liberal accelerated approach. Full-text review, data extraction, risk of bias assessments, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers, with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE approach will be used to assess the certainty of the evidence for outcomes. Discussion The results of this systematic review will be used by the Canadian Task Force on Preventive Health Care to inform their recommendation on potentially inappropriate prescribing and OTC medication use among adults aged 65 years and older. Systematic review registration PROSPERO (KQ1: CRD42022302313; KQ2: CRD42022302324); Open Science Framework ( https://osf.io/urj4b/ ).

Plain English summary We interviewed 10 individuals associated with studies that were funded through the Ontario Strategy for Patient Oriented Research (SPOR) Unit. We asked them about how they had engaged patients, families or caregivers in their study, how this engagement had influenced their study, the challenges they faced, and advice for other researchers considering engaging with patients, families and caregivers. We found that patients had been engaged in a variety of ways and at different times. The changes brought about by the patient engagement varied between studies but tended to reflect an improvement in how relevant the study was to patients. Researchers also shared how engagement with patients, families, and caregivers had changed their approaches to future research. Key challenges facing researchers included finding partners that were appropriate for the study, as well making sure that the approach to engagement overcame issues such as financial or logistical barriers that could prevent patients, families or caregivers from partnering with the study.

Abstract Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation (p A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

The spike (S) glycoprotein of SARS CoV-2 is the target of neutralizing antibodies (NAbs) that are crucial for vaccine effectiveness. The S1 subunit binds ACE2 while the S2 subunit mediates virus-cell membrane fusion. S2 is a class I fusion glycoprotein subunit and contains a central coiled coil that acts as a scaffold for the conformational changes associated with fusion function. The coiled coil of S2 is unusual in that the 3-4 repeat of inward-facing positions are mostly occupied by polar residues that mediate few inter-helical contacts in the prefusion trimer. We examined how insertion of bulkier hydrophobic residues (Val, Leu, Ile, Phe) to fill a cavity next to Ala1016 and Ala1020 in the 3-4 repeat affects the stability and antigenicity of S trimers. Substitution of Ala1016 with bulkier hydrophobic residues in the context of a prefusion-stabilized S trimer, S2P-FHA, was associated with increased thermal stability. S glycoprotein membrane fusion function was retained with Ala1016/Ala1020 cavity-filling mutations associated with improved recombinant S2P-FHA thermostability, however 2 mutants, A1016L and A1016V/A1020I, lacked ability to mediate entry of S-HIV-1 pseudoparticles into 293-ACE2 cells. When assessed as immunogens, two thermostable S2P-FHA mutants derived from the ancestral isolate, A1016L (16L) and A1016V/A1020I (VI) elicited neutralizing antibody with 50%-inhibitory dilutions (ID50s) in the range 2,700-5,110 for ancestral and Delta-derived viruses, and 210-1,744 for Omicron BA.1. The antigens elicited antibody specificities directed to the receptor-binding domain (RBD), N-terminal domain (NTD), fusion peptide and stem region of S2. The VI mutation enabled the production of intrinsically stable Omicron BA.1 and Omicron BA.4/5 S2P-FHA-like ectodomain oligomers in the absence of an external trimerization motif (T4 foldon), thus representing an alternative approach for stabilizing oligomeric S glycoprotein vaccines.

Respirometric microbial assays are gaining popularity, but their uptake is limited by the availability of optimal O2 sensing materials and the challenge of validating assays with complex real samples. We conducted a comparative evaluation of four different O2-sensing probes based on Pt-porphyrin phosphors in respirometric bacterial assays performed on standard time-resolved fluorescence reader. The macromolecular MitoXpress, nanoparticle NanO2 and small molecule PtGlc4 and PtPEG4 probes were assessed with E. coli cells in five growth media: nutrient broth (NB), McConkey (MC), Rapid Coliform ChromoSelect (RCC), M-Lauryl lauryl sulfate (MLS), and Minerals-Modified Glutamate (MMG) media. Respiration profiles of the cells were recorded and analyzed, along with densitometry profiles and quenching studies of individual media components. This revealed several limiting factors and interferences impacting assay performance, which include probe quenched lifetime, instrument temporal resolution, inner filter effects (mainly by indicator dyes), probe binding to lipophilic components, and dynamic and static quenching by media components. The study allowed for the ranking of the probes based on their ruggedness, resilience to interferences and overall performance in respirometric bacterial assays. The ‘shielded’ probe NanO2 outperformed the established MitoXpress probe and the small molecule probes PtGlc4 and PtPEG4.

Plain English summary Background Partnering with patients, caregivers and members of the public to co-develop and co-conduct research is becoming more accepted and prevalent. However, it is unclear how researchers recognize patient partners for their contributions to research projects. In this publication we outline a series of three studies that will help us better understand when and how patient partners are being financially compensated for their involvement. Methods First, we will conduct a review of the literature to identify an international group of researchers that engage patients as research partners. Evaluating these studies will give us an idea about how often patient partners are compensated, and the methods of compensation being used (e.g. offered gifts, cash, etc.). Second, we will survey researchers and institutions who have experience with patient engagement to ask them for more details about their experiences with patient partner compensation (i.e. challenges that they have encountered and their attitudes). Third, we will conduct another review to identify any guidance documents or policies that can help guide researchers through the processes of financially compensating patient partners. We will provide a summary of all of these guidance documents so that researchers, patient partners, and institutions have a one-stop-shop of resources. Discussion We hope that our three studies will inform and help researchers and patient partners navigate the processes for compensating patient engagement in research.

Abstract Background Flow-controlled ventilation (FCV), a novel mode of mechanical ventilation characterised by constant flow during active expiration, may result in more efficient alveolar gas exchange, better lung recruitment and might be useful in limiting ventilator-induced lung injury. However, data regarding FCV in mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome (ARDS) are scarce. Objectives We hypothesised that the use of FCV is feasible and would improve oxygenation in moderate COVID-19 ARDS compared to conventional ventilation. Design Open-label repeated-measures controlled trial. Setting From February to April 2021, patients with moderate COVID-19 ARDS were recruited in a tertiary referral intensive care unit. Patients Patients with moderate ARDS (PaO2/FIO2 ratio 100–200 mmHg, SpO2 88–94% and PaO2 60–80 mmHg) were considered eligible. Exclusion criteria were: extremes of age ( 80 years), obesity (body mass index > 40 kg/m2), prone positioning at the time of intervention, mechanical ventilation for more than 10 days and extracorporeal membrane oxygenation. Eleven patients were recruited. Intervention Participants were ventilated in FCV mode for 30 min, and subsequently in volume-control mode (VCV) for 30 min. Main outcome measures Feasibility of FCV to maintain oxygenation was assessed by the PaO2/FiO2 ratio (mmHg) as a primary outcome parameter. Secondary outcomes included ventilator parameters, PaCO2 and haemodynamic data. All adverse events were recorded. Results FCV was feasible in all patients and no adverse events were observed. There was no difference in the PaO2/FIO2 ratio after 30 min of ventilation in FCV mode (169 mmHg) compared to 30 min of ventilation in VCV mode subsequently (168 mmHg, 95% CI of pseudo-medians (− 10.5, 3.6), p = 0.56). The tidal volumes (p

Tuneable microresonator frequency combs offer low-power, coherent light with a small device footprint. Here, the concept of controlling the comb frequency by detuning the probe phase is translated from photonic crystal fibres to a Kerr microresonator.

Calcium-permeable AMPA-type glutamate receptors (CP-AMPARs) contribute to many forms of synaptic plasticity and pathology. They can be distinguished from GluA2-containing calcium-impermeable AMPARs by the inward rectification of their currents, which reflects voltage-dependent channel block by intracellular spermine. However, the efficacy of this weakly permeant blocker is differentially altered by the presence of AMPAR auxiliary subunits – including transmembrane AMPAR regulatory proteins, cornichons, and GSG1L – which are widely expressed in neurons and glia. This complicates the interpretation of rectification as a measure of CP-AMPAR expression. Here, we show that the inclusion of the spider toxin analog 1-naphthylacetyl spermine (NASPM) in the intracellular solution results in a complete block of GluA1-mediated outward currents irrespective of the type of associated auxiliary subunit. In neurons from GluA2-knockout mice expressing only CP-AMPARs, intracellular NASPM, unlike spermine, completely blocks outward synaptic currents. Thus, our results identify a functional measure of CP-AMPARs, that is unaffected by their auxiliary subunit content.

Summary: Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies. Methods: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab. Findings: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022. Interpretation: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants. Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M.

This paper reviews theoretical developments specific to applied research around the “psychology of practice” in skill acquisition settings, which we argue is under-considered in applied sport psychology. Centered upon the Self-Regulation of Sport Practice Survey (SRSP), we explain how self-regulated learning conceptually underpins this survey and review recent data supporting its empirical validation for gauging athletes’ psychological processes in relation to sport practice. This paper alternates between a review of applied research on self-regulated sport practice and new data analyses to: (a) show how scores on the SRSP combine to determine an expert practice advantage and (b) illustrate the large scope of self-organized or athlete-led time to which SRSP processes may apply. At this stage, the SRSP has been established as a reliable and valid tool in the empirical, theoretical domain. In order to move the narrative from theory and assessment toward applied practice, we present evidence to propose that it has relevance as a dialogue tool for fostering meaningful discussions between athletes and sport psychology consultants. We review initial case study insights on how the SRSP could be located in consultation in professional practice, propose initial considerations for its practical use and invite practitioners to examine its utility in applied settings.

Introduction For close to a century opioid administration has been a standard of care to complement anaesthesia during surgery. Considering the worldwide opioid epidemic, this practice is now being challenged and there is a growing use of systemic pharmacological opioid minimising strategies. Our aim is to conduct a scoping review that will examine clinical trials that have evaluated the impact of intraoperative opioid minimisation strategies on patient-centred outcomes and identify promising strategies.Methods and analysis Our scoping review will follow the framework developed by Arksey and O’Malley. We will search MEDLINE, Embase, CENTRAL, Web of Science and CINAHL from their inception approximately in March 2023. We will include randomised controlled trials, assessing the impact of systemic intraoperative pharmacologic opioid minimisation strategies on patient-centred outcomes. We define an opioid minimisation strategy as any non-opioid drug with antinociceptive properties administered during the intraoperative period. Patient-centred outcomes will be defined and classified based on the consensus definitions established by the Standardised Endpoints in Perioperative Medicine initiative (StEP-COMPAC group) and informed by knowledge users and patient partners. We will use a coproduction approach involving interested parties. Our multidisciplinary team includes knowledge users, patient partners, methodologists and knowledge user organisations. Knowledge users will provide input on methods, outcomes, clinical significance of findings, implementation and feasibility. Patient partners will participate in assessing the relevance of our design, methods and outcomes and help to facilitate evidence translation. We will provide a thorough description of available clinical trials, compare their reported patient-centred outcome measures with established recommendations and identify promising strategies.Ethics and dissemination Ethics approval is not required for the review. Our scoping review will inform future research including clinical trials and systematic reviews through identification of important intraoperative interventions. Results will be disseminated through a peer-reviewed publication, presentation at conferences and through our network of knowledge user collaborators.Registration Open Science Foundation (currently embargoed)

IntroductionSelf-regulated learning entails psychological processes that elite athletes employ to optimize their practice. Although self-regulated learning provides insights into athlete-led practice, research has been limited to few cultures, and the particularities of how SRL surveys perform in new cultural contexts require attention. Moreover, there exists no measure to assess SRL and its relationship to quality sport practice in Polish. Thus, we examined the Short Form of the Self-Regulated Learning—Sport Practice survey in Polish. Analyses addressed the factorial validity and reliability, the criterion validity (by assessing differences in scores between competition levels), and the concurrent validity (by correlating scores with conceptually related constructs) of a Polish Short Form survey.MethodsAthletes (N = 324, Mage = 21.4, nfemales = 144, nmales = 180) from amateur, regional, national, and international-elite levels completed the survey, along with concurrent subscales (General Self-Efficacy Scale; GSES; Metacognitive-Self Scale; MS-24; Action Control Scale; ACS-90).ResultsConfirmatory factor analysis indicated a two-factor (metacognitive; motivational) model (RMSEA = 0.082, SRMR = 0.057, CFI = 0.89). Between-group tests showed international-elite scoring higher than all other groups on metacognitive and motivational subscales. On both subscales, significant trends indicated that more skilled levels consistently reported higher scores than lesser-skilled levels. The short form scores were associated with certain concurrent variables, including GSES (rmeta = 0.41, rmotiv = 0.48), MS-24 (rmeta = 0.39, rmotiv = 0.24), and ACS-90 (AOF subscale: rmotiv = 0.26).DiscussionOn the basis of strong criterion validity, and moderate evidence for concurrent validity, we conclude that the Polish Short Form of the Self-Regulated Learning—Sport Practice survey is a promising tool for use in Polish sport and we discuss future avenues of work to enhance its validation. Limitations that inform future research include our reliance on a mixed-sport sample, the lack of priming of obstacles/challenge ahead of self-report, and a lack of consideration of sport-specific practice variables in analyses.

Two new endosomolytic small compounds increase delivery of splice-switching oligonucleotides by interfering with their trafficking to the LAMP1-positive endosomal compartments, inducing endosomal membrane rupture and concurrent oligonucleotide escape into the cytosol.

Abstract Introduction To improve dementia care delivery for persons across all backgrounds, it is imperative that health equity is integrated into pragmatic trials. Methods We reviewed 62 pragmatic trials of people with dementia published 2014 to 2019. We assessed health equity in the objectives; design, conduct, analysis; and reporting using PROGRESS‐Plus which stands for Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and other factors such as age and disability. Results Two (3.2%) trials incorporated equity considerations into their objectives; nine (14.5%) engaged with communities; 4 (6.5%) described steps to increase enrollment from equity‐relevant groups. Almost all trials (59, 95.2%) assessed baseline balance for at least one PROGRESS‐Plus characteristic, but only 10 (16.1%) presented subgroup analyses across such characteristics. Differential recruitment, attrition, implementation, adherence, and applicability across PROGRESS‐Plus were seldom discussed. Discussion Ongoing and future pragmatic trials should more rigorously integrate equity considerations in their design, conduct, and reporting. Highlights Few pragmatic trials are explicitly designed to inform equity‐relevant objectives. Few pragmatic trials take steps to increase enrollment from equity‐relevant groups. Disaggregated results across equity‐relevant groups are seldom reported. Adherence to existing tools (e.g., IMPACT Best Practices, CONSORT‐Equity) is key.

Abstract Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties of bacille Calmette-Guérin (BCG), the existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination of BCG with a stabilised, trimeric form of SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the blood of vaccinated mice, that was further augmented by the addition of alum. This vaccine formulation, BCG:CoVac, induced high-titre SARS-CoV-2 neutralising antibodies (NAbs) and Th1-biased cytokine release by vaccine-specific T cells, which correlated with the early emergence of T follicular helper cells in local lymph nodes and heightened levels of antigen-specific plasma B cells after vaccination. Vaccination of K18-hACE2 mice with a single dose of BCG:CoVac almost completely abrogated disease after SARS-CoV-2 challenge, with minimal inflammation and no detectable virus in the lungs of infected animals. Boosting BCG:CoVac-primed mice with a heterologous vaccine further increased SARS-CoV-2-specific antibody responses, which effectively neutralised B.1.1.7 and B.1.351 SARS-CoV-2 variants of concern. These findings demonstrate the potential for BCG-based vaccination to protect against major SARS-CoV-2 variants circulating globally.

Objectives To describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated with under-recruitment and over-recruitment.Study design and setting Secondary analysis of an existing database of primary trial reports published during 2014–2019, registered in ClinicalTrials.gov, self-labelled as pragmatic and with target and achieved sample sizes available.Results Of 372 eligible trials, the prevalence of under-recruitment (achieving 110% of target) was 87 (23.4%). Under-recruiting trials commonly acknowledged that they did not achieve their targets (51, 71.8%), with the majority providing an explanation, but only 11 (12.6%) over-recruiting trials acknowledged recruitment excess. The prevalence of under-recruitment in individually randomised versus cluster randomised trials was 41 (17.0%) and 30 (22.9%), respectively; prevalence of over-recruitment was 39 (16.2%) vs 48 (36.7%), respectively. Overall, 101 025 participants were recruited to trials that did not achieve at least 90% of their target sample size. When considering trials with over-recruitment, the total number of participants recruited in excess of the target was a median (Q1–Q3) 319 (75–1478) per trial for an overall total of 555 309 more participants than targeted. In multinomial logistic regression, cluster randomisation and lower journal impact factor were significantly associated with both under-recruitment and over-recruitment, while using exclusively routinely collected data and educational/behavioural interventions were significantly associated with over-recruitment; we were unable to detect significant associations with obtaining consent, publication year, country of recruitment or public engagement.Conclusions A clear explanation for under-recruitment or over-recruitment in pragmatic trials should be provided to encourage transparency in research, and to inform recruitment to future trials with comparable designs. The issues and ethical implications of over-recruitment should be more widely recognised by trialists, particularly when designing cluster randomised trials.

Summary: This protocol outlines a translational lipidomic approach to discover lipid biomarkers that could predict morphometric body and histological organ measurements (e.g., weight and adiposity gains) during specific stages of life (e.g., early life). We describe procedures ranging from animal experimentation and histological analyses to downstream analytical steps through lipid profiling, both in mice and humans. This protocol represents a reliable and versatile approach to translate and validate candidate lipid biomarkers from animal models to a human cohort.For complete details on the use and execution of this protocol, please refer to Olga et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background Human microbiomes assemble in an ordered, reproducible manner yet there is limited information about early colonisation and development of bacterial communities that constitute the oral microbiome.Aim The aim of this study was to determine the effect of exposure to breastmilk on assembly of the infant oral microbiome during the first 20 months of life.Methods The oral microbiomes of 39 infants, 13 who were never breastfed and 26 who were breastfed for more than 10 months, from the longitudinal VicGeneration birth cohort study, were determined at four ages. In total, 519 bacterial taxa were identified and quantified in saliva by sequencing the V4 region of the bacterial 16S rRNA genes.Results There were significant differences in the development of the oral microbiomes of never breastfed and breastfed infants. Bacterial diversity was significantly higher in never breastfed infants at 2 months, due largely to an increased abundance of Veillonella and species from the Bacteroidetes phylum compared with breastfed infants.Conclusion These differences likely reflect breastmilk playing a prebiotic role in selection of early-colonising, health-associated oral bacteria, such as the Streptococcus mitis group. The microbiomes of both groups became more heterogenous following the introduction of solid foods.

Abstract Objective To describe transient and permanent hypocalcaemia following partial and total pharyngolaryngectomy with parathyroid gland preservation or autotransplantation. Methods Thirty patients underwent partial or total pharyngolaryngectomy by a single surgeon during the period 2009‐2020. Intraoperative parathyroid gland preservation or autotransplantation (where the gland appeared devascularized) was routinely performed. Calcium levels performed on day 1, 3 months, and at 12 months postoperatively were collected. Rates of transient and permanent hypocalcaemia were calculated. Results A total of 13% of patients had transient hypocalcaemia, and 10% permanent hypocalcaemia. Rates of transient and permanent hypocalcaemia in total pharyngolaryngectomy were 14% and 14%, respectively. Partial pharyngectomy hypocalcaemia rates were 13% for transient and 0% for permanent. The majority of patients underwent salvage surgery for oncological resection, often following radiotherapy (63%). Ipsilateral hemithyroidectomy was preferred to total (57% vs 7%), with high rates of concurrent neck dissection (67%) and reconstruction (87%). Conclusion This data supports preservation or autotransplantation of parathyroid glands as a means of reducing permanent postoperative hypocalcaemia. Level of Evidence Level IV, case series, retrospective.

Plain English summary Core outcome sets (COS) are lists of outcomes agreed upon by a group of people to be measured and reported in studies about certain diseases and populations. Core outcomes are meant to represent what is useful to study from the perspectives of health care providers, researchers and patients. For researchers who seek to include patients in the development of a COS, there is little guidance about how to do this well. We recently developed COS for two rare diseases in children, medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria. We did this by reviewing available information from published research, surveying health care providers, researchers, and patients, and eventually coming to agreement during a workshop. We included two adult patient partner co-researchers who helped design the COS study and co-developed the patient engagement strategy. These partners formed relationships with seven adult family advisors, who helped ensure that materials were accessible, participated in outcome selection, and helped select tools to measure core outcomes. Strategies we used to engage patient partners included a) training about both the scientific research process and how to help other researchers in the future, and b) frequent communication about study progress and how family advisor feedback was used. Also, we made sure that the impacts of power imbalances between health care providers, researchers and patients were low. Our approach to patient engagement in COS development for two rare conditions in children proved to be both feasible and considered valuable by all study team members, including patient partners and family advisors. To include patient perspectives and values, future COS developers may take a similar approach.

Summary: Background: Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction of global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences and clinical effects from other variants of concern. Shortly after dominating global spread in early 2022, BA.1 was supplanted by the genetically distinct Omicron lineage BA.2. A sub-lineage of BA.2, designated BA.5, presently has an outgrowth advantage over BA.2 and other BA.2 sub-lineages. Here we study the neutralisation of Omicron BA.1, BA.2 and BA.5 and pre-Omicron variants using a range of vaccine and convalescent sera and therapeutic monoclonal antibodies using a live virus neutralisation assay. Using primary nasopharyngeal swabs, we also tested the relative fitness of BA.5 compared to pre-Omicron and Omicron viral lineages in their ability to use the ACE2-TMPRSS2 pathway. Methods: Using low passage clinical isolates of Clade A.2.2, Beta, Delta, BA.1, BA.2 and BA.5, we determined humoral neutralisation in vitro in vaccinated and convalescent cohorts, using concentrated human IgG pooled from thousands of plasma donors, and licensed monoclonal antibody therapies. We then determined infectivity to particle ratios in primary nasopharyngeal samples and expanded low passage isolates in a genetically engineered ACE2/TMPRSS2 cell line in the presence and absence of the TMPRSS2 inhibitor Nafamostat. Findings: Peak responses to 3 doses of BNT162b2 vaccine were associated with a 9-fold reduction in neutralisation for Omicron lineages BA.1, BA.2 and BA.5. Concentrated pooled human IgG from convalescent and vaccinated donors and BNT162b2 vaccination with BA.1 breakthrough infections were associated with greater breadth of neutralisation, although the potency was still reduced 7-fold across all Omicron lineages. Testing of clinical grade antibodies revealed a 14.3-fold reduction using Evusheld and 16.8-fold reduction using Sotrovimab for the BA.5. Whilst the infectivity of BA.1 and BA.2 was attenuated in ACE2/TMPRSS2 entry, BA.5 was observed to be equivalent to that of an early 2020 circulating clade and had greater sensitivity to the TMPRSS2 inhibitor Nafamostat. Interpretation: Observations support all Omicron variants to significantly escape neutralising antibodies across a range of vaccination and/or convalescent responses. Potency of therapeutic monoclonal antibodies is also reduced and differs across Omicron lineages. The key difference of BA.5 from other Omicron sub-variants is the reversion in tropism back to using the well-known ACE2-TMPRSS2 pathway, utilised efficiently by pre-Omicron lineages. Monitoring if these changes influence transmission and/or disease severity will be key for ongoing tracking and management of Omicron waves globally. Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).

The identification of metabolomic biomarkers relies on the analysis of large cohorts of patients compared to healthy controls followed by the validation of markers in an independent sample set. Indeed, circulating biomarkers should be causally linked to pathology to ensure that changes in the marker precede changes in the disease. However, this approach becomes unfeasible in rare diseases due to the paucity of samples, necessitating the development of new methods for biomarker identification. The present study describes a novel approach that combines samples from both mouse models and human patients to identify biomarkers of OPMD. We initially identified a pathology-specific metabolic fingerprint in murine dystrophic muscle. This metabolic fingerprint was then translated into (paired) murine serum samples and then to human plasma samples. This study identified a panel of nine candidate biomarkers that could predict muscle pathology with a sensitivity of 74.3% and specificity of 100% in a random forest model. These findings demonstrate that the proposed approach can identify biomarkers with good predictive performance and a higher degree of confidence in their relevance to pathology than markers identified in a small cohort of human samples alone. Therefore, this approach has a high potential utility for identifying circulating biomarkers in rare diseases.

Dissipative solitons and their symmetry breaking is important for photonic applications. Here the authors show that dissipative solitons can undergo spontaneous symmetry breaking in a two-component nonlinear optical ring resonator, resulting in the coexistence of distinct vectorial solitons with asymmetric, mirror-like states of polarization.

The immunology of Indigenous populations is generally understudied outside the context of diseases that are prevalent in these communities. Here the authors identify prevalence of influenza CD8+ T cell epitopes in an Indigenous Australian population expressing the susceptibility allomorph HLA A*24:02 and validate immunodominance of some of these epitopes in mice.

Background and aims: Although adjustment of the environment is recommended as a support strategy in evidence-based interventions for children with autism, the impact of doing so (and the how and why) is not well understood. One essential environmental factor to consider when providing supports for preschool-aged autistic children is the play setting, specifically, the materials available in the child's play context. The aim of this study was to compare engagement states and number of utterances produced by preschool-aged autistic children within symbolic vs. gross motor play settings. Examining the relationship between gross motor play settings and children's social engagement and spoken language use is particularly important to explore for autistic children given differences in their sensory processing, motor skill development, and choice of and interaction with toys relative to neurotypical peers. Methods: Seventy autistic children aged 25-57 months were videotaped during natural play interactions with a parent. Children's social engagement and number of spoken utterances were examined in five minutes each of play with symbolic toys and play with gross motor toys. Continuous time-tagged video coding of the child-caregiver engagement states was conducted, and the child's frequency of spoken language was identified using language sample analysis. The specific variables examined were; (a) engagement with caregiver, (b) engagement with objects only, (c) unengaged (no evident engagement with objects or people), and (d) total number of spoken utterances. The relationship between play setting (symbolic vs gross motor) and child language and engagement state variables was examined with linear mixed effects modelling. Results: Significant main effects were revealed for the interaction between play setting and autistic children's engagement. Young autistic children were more likely to engage with caregivers in play environments with gross motor toys (moderate effect) and also were more likely to have periods of unengaged time (not overtly directing their attention to objects or people; small effect) in this setting. Further, when in a setting with symbolic toys, autistic children were more likely to spend their time focusing attention solely on objects (large effect). No interaction was found between play setting and total number of utterances spoken by autistic children. Conclusions and implications: This study confirmed the importance of continued research focused on understanding the relationship between children's play settings and their social engagement and language use. Although preliminary, findings support the idea that there is an interaction between preschool-aged autistic children's social engagement and their play settings. Further, our results suggest that there can be value in clinicians differentiating children's play settings (i.e., gross motor vs symbolic) when assessing and supporting social engagement capacities of young autistic children.

Objective: Polyunsaturated fatty acid (PUFA) supplements have been trialled as a treatment for a number of conditions and produced a variety of results. This variety is ascribed to the supplements, that often comprise a mixture of fatty acids, and to different effects in different organs. In this study, we tested the hypothesis that the supplementation of individual PUFAs has system-level effects that are dependent on the molecular structure of the PUFA. Methods: We undertook a network analysis using Lipid Traffic Analysis to identify both local and system-level changes in lipid metabolism using publicly available lipidomics data from a mouse model of supplementation with FA(20:4n-6), FA(20:5n-3), and FA(22:6n-3); arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, respectively. Lipid Traffic Analysis is a new computational/bioinformatics tool that uses the spatial distribution of lipids to pinpoint changes or differences in control of metabolism, thereby suggesting mechanistic reasons for differences in observed lipid metabolism. Results: There was strong evidence for changes to lipid metabolism driven by and dependent on the structure of the supplemented PUFA. Phosphatidylcholine and triglycerides showed a change in the variety more than the total number of variables, whereas phosphatidylethanolamine and phosphatidylinositol showed considerable change in both which variables and the number of them, in a highly PUFA-dependent manner. There was also evidence for changes to the endogenous biosynthesis of fatty acids and to both the elongation and desaturation of fatty acids. Conclusions: These results show that the full biological impact of PUFA supplementation is far wider than any single-organ effect and implies that supplementation and dosing with PUFAs require a system-level assessment.