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Play, which is both a context and process for children's learning, has become a pivotal pedagogical component in global early childhood education. The uptake of intentional teaching has contributed to the shift in understandings of play, from viewing play as a means of recreation and entertainment to a more socio-cultural perspective that advocates for educators' proactive and engaged roles in play. The recent update of the Early Years Learning Framework (2023) in Australia has included an emphasis on intentionality in play-based learning. However, there is little academic work on intentionality, and recent studies demonstrate educators' struggles in conceptualising their roles as intentional teachers. Drawing on the findings of a literature review, this discussion paper aims to conceptualise intentional teaching from two aspects: intentionality and decision-making. This paper argues that while educator and child intentionality are the starting point of intentional actions, the decision-making process enables educators to have ongoing intentionality behind their teaching practices. It concludes by advocating for a broader understanding of intentional teaching that focusses on the underlying thought processes behind educators' decisions and actions.

The epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary Aspergillus prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations. While the figure depicted within this article is static, an internet-based version could provide pop-up highlights of any given flows origin and destination nodes. A future version could highlight links to publications that support the color-coded incidence rates or other actionable items, such as bundles of applicable pharmacologic or non-pharmacologic interventions. The figure, as part of the upcoming Infectious Diseases Society of Americas aspergillosis clinical practice guidelines, can guide decision-making in clinical settings.

Peroxisomes are membrane-bound organelles harboring metabolic enzymes. In humans, peroxisomes are required for normal development, yet the genes regulating peroxisome function remain unclear. We performed a genome-wide CRISPRi screen to identify novel factors involved in peroxisomal homeostasis. We found that inhibition of RNF146, an E3 ligase activated by poly(ADP-ribose), reduced the import of proteins into peroxisomes. RNF146-mediated loss of peroxisome import depended on the stabilization and activity of the poly(ADP-ribose) polymerase tankyrase, which binds the peroxisomal membrane protein PEX14. We propose that RNF146 and tankyrase regulate peroxisome import efficiency by PARsylation of proteins at the peroxisome membrane. Interestingly, we found that the loss of peroxisomes increased tankyrase and RNF146-dependent degradation of non-peroxisomal substrates, including the beta-catenin destruction complex component AXIN1, which was sufficient to alter the amplitude of beta-catenin transcription. Together, these observations not only suggest previously undescribed roles for RNF146 in peroxisomal regulation, but also a novel role in bridging peroxisome function with Wnt/beta-catenin signaling during development.

In this article the affiliation details for Baylin J. Bennett, Thomas D. Brewer and Lora E. Flemming were incorrectly given as 'European Centre for the Environment and Human Health, University of Exeter Medical School, Truro Cornwall TR1 3HD, UK, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233 and Australian National Centre for Ocean Resources and Security, Building 233, Innovation Campus, University of Wollongong, Wollongong, NSW 2522, Australia' but should have been 'Baylin J. Bennett (Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233), Thomas D. Brewer (Australian National Centre for Ocean Resources and Security, Building 233, Innovation Campus, University of Wollongong, Wollongong, NSW 2522, Australia) and Lora E. Flemming (European Centre for the Environment and Human Health, University of Exeter Medical School, Truro Cornwall TR1 3HD, UK). The original article has been corrected.

A healthy ocean is essential for human health, and yet the links between the ocean and human health are often overlooked. By providing new medicines, technologies, energy, foods, recreation, and inspiration, the ocean has the potential to enhance human health and wellbeing. However, climate change, pollution, biodiversity loss, and inequity threaten both ocean and human health. Sustainable realisation of the oceans health benefits will require overcoming these challenges through equitable partnerships, enforcement of laws and treaties, robust monitoring, and use of metrics that assess both the oceans natural capital and human wellbeing. Achieving this will require an explicit focus on human rights, equity, sustainability, and social justice. In addition to highlighting the potential unique role of the healthcare sector, we offer science-based recommendations to protect both ocean health and human health, and we highlight the unique potential of the healthcare sector tolead this effort.

Aquaporin-1 (Aqp1), a water channel, has garnered significant interest for cell-based medicine and in vivo synthetic biology due to its ability to be genetically encoded to produce magnetic resonance signals by increasing the rate of water diffusion in cells. However, concerns regarding the effects of Aqp1 overexpression and increased membrane diffusivity on cell physiology have limited its widespread use as a deep-tissue reporter. In this study, we present evidence that Aqp1 generates strong diffusion-based magnetic resonance signals without adversely affecting cell viability or morphology in diverse cell lines derived from mice and humans. Our findings indicate that Aqp1 overexpression does not induce ER stress, which is frequently associated with heterologous expression of membrane proteins. Furthermore, we observed that Aqp1 expression had no detrimental effects on native biological activities, such as phagocytosis, immune response, insulin secretion, and tumor cell migration in the analyzed cell lines. These findings should serve to alleviate any lingering safety concerns regarding the utilization of Aqp1 as a genetic reporter and should foster its broader application as a noninvasive reporter for in vivo studies.

The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2E62K also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2E62K stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2+/E62K bone-marrow-derived macrophages also cannibalize primary Rac2+/E62K T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2+/E62K macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2E62K also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2+/E62K human immunodeficiency and enhance CAR-M cancer immunotherapy.

Abstract Background Hypertension, or high blood pressure, is a key modifiable risk factor for heart disease and stroke. International guidelines have highlighted ‘poor adherence to treatment’ and ‘physician inertia’ as major barriers to effective blood pressure management. The Maximising Adherence, Minimising Inertia (MIAMI) intervention, a theory-based complex intervention, supports General Practitioners (GPs) and people with hypertension in maximising medication use to manage blood pressure. This pilot cluster randomised control trial (RCT) aimed to collect and analyse feasibility data to refine the MIAMI intervention and assess the feasibility of a definitive RCT. Method A pilot cluster RCT with a MIAMI intervention arm and usual care control arm was conducted. Quantitative data collection consisting of clinical measures and a self-report questionnaire took place at baseline and twelve week follow up. Semi-structured interviews with GP and patient participants were conducted. Fidelity (as measured by a protocol checklist and through qualitative interviews) and health economics costings were assessed. Results Six GP practices (intervention arm n = 3, control arm n = 3) and 52 patients (intervention arm n = 25, control arm n = 27) took part. All six GP practices and 92% of patients were retained. Fidelity, as measured by a checklist and through qualitative interviews, was good but three deviations from protocol were identified. Outcomes and measures used were acceptable. The implementation cost of the MIAMI intervention was estimated at €490 per participant. The qualitative data demonstrated that the intervention was considered acceptable and feasible by both GP and patient participants, except for the urine test component, which GPs found difficult to incorporate into practice due to logistical challenges. Conclusions The MIAMI intervention was considered largely acceptable and feasible. Some changes to both intervention components and trial processes are required but with these in place a definitive RCT could be considered worthwhile. Trial registration ISRCTN registry, ISRCTN85009436, registered 17/1/23.

Abstract Background The National Institute for Health and Care Excellence (NICE) recommend that men with prostate cancer on androgen deprivation therapy (ADT) are offered twice weekly supervised aerobic and resistance exercise to address side effects of treatment. However, supervised exercise is not routinely offered in standard clinical practice. The STAMINA programme grant for applied research (PGfAR) has been designed to evaluate whether this recommendation can be delivered within standard NHS care. This paper describes how future implementation of NICE recommendations within the NHS was explored during complex intervention development to enable evaluation of a lifestyle intervention. Methods Two stakeholder workshops were conducted to explore factors pertinent to future implementation of the STAMINA Lifestyle intervention (SLI). Normalisation Process Theory (NPT) provided the theoretical framework for discussion and analysis. Stakeholder workshop 1 focussed on intervention coherence and buy-in. Stakeholder workshop 2 explored barriers and facilitators for embedding SLI into the context of the NHS, with delivery partner Nuffield Health, in the future. Results Workshops were attended by healthcare professionals (n = 16), exercise professionals (n = 17), members of public involved in PPI including patients (n = 12), health psychologists (n = 2), clinical commissioners (n = 4), cancer charities (n = 3), a cancer alliance (n = 1) and health economist (n = 1). Stakeholders agreed that professional training packages should emphasise the uniqueness of the SLI and underpinning theory and evidence (Coherence). To further engagement, the use of STAMINA champions and information about the delivery partner were recommended to enhance confidence and knowledge (Cognitive participation). Furthermore, a simple communication (Collective Action) and progress reporting system (Reflexive Monitoring) was suggested to fit into existing infrastructure within the NHS and community partner. Conclusions Application of NPT within two stakeholder workshops enhanced complex intervention development. Context-specific strategies to support implementation of SLI within the context of a trial were proposed, sensed-checked, and considered acceptable. The organisational implications of embedding and sustaining the intervention in preparation for wider NHS roll-out were considered (if proven to be effective) and will be explored in the qualitative component of a process evaluation underpinned by NPT. Trial registration (ISRCTN: 46385239 ). Registered on July 30, 2020.

ABSTRACT: Objectives: This study was performed to investigate the activity of the novel ß-lactam/ß-lactamase inhibitor combination cefepime/enmetazobactam, against recently circulating Enterobacterales isolates from Europe from 2019 to 2021. Methods: A total of 2627 isolates were collected, and antimicrobial susceptibility was determined according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Isolates with phenotypic resistance to ceftriaxone and ceftazidime (but susceptible to meropenem) and isolates nonsusceptible to meropenem were screened for the presence of ß-lactamases. Results: Overall, susceptibility to third-generation cephalosporins was 77%, and 97.3% were susceptible to meropenem. Cefepime/enmetazobactam susceptibility was 97.9% (72% of these isolates were Klebsiella pneumoniae from Italy), compared with 80.0% susceptibility to piperacillin/tazobactam and 99.4% to ceftazidime/avibactam. A total of 320 isolates (12.2%) were resistant to third-generation cephalosporins but susceptible to meropenem, and virtually all (96.3%) carried an extended-spectrum ß-lactamase with or without an AmpC and these were all susceptible to cefepime/enmetazobactam. Most meropenem-nonsusceptible isolates carried a KPC (68%), which were not inhibited by cefepime/enmetazobactam but were inhibited by ceftazidime/avibactam. Additionally, most meropenem-nonsusceptible isolates carrying OXA-48 (9/12 isolates) were susceptible to cefepime/enmetazobactam. Conclusions: Cefepime/enmetazobactam was highly active against Enterobacterales isolates, especially those resistant to third-generation cephalosporins. These data suggest that cefepime/enmetazobactam could be used as a carbapenem-sparing agent to replace piperacillin/tazobactam.

"Research Findings:" Despite the importance of early care and education (ECE) for children's early learning and parents' labor force participation, workers average low pay with few benefits. The precarity of work and low compensation contribute to staff turnover and other problems, with potential implications for staff well-being, children's development, and parents' employment. The COVID-19 pandemic exacerbated problems relating to the supply of and staff recruitment and retention in ECE. This paper provides a brief background and then reviews the empirical research linking early ECE worker compensation with program quality, children's outcomes, and staff turnover. We identified a range of studies that examined pay or workplace benefits in ECE, the majority of which used nonexperimental methods. In general, most studies found small associations among low compensation, poor worker mental health or well-being, or turnover or intentions to leave their jobs or the early childhood field. Fewer studies examined associations between compensation and measures of quality or children's outcomes, finding small or nonsignificant associations. One study using experimental methods found evidence that financial bonuses reduced staff turnover. "Practice or Policy:" Together, evidence suggests that low worker compensation is linked with poorer worker outcomes and staff turnover in ECE.

Many countries have adopted targets to increase marine protected areas (MPAs) to limit the degradation of water bodies. Although there is evidence that MPAs can conserve marine life and promote biodiversity, there are limited data on the human health implications of MPAs. Using panel data from 1990, 2000, and 2014, we estimated the country-level associations between MPAs (i.e., percentage of territorial waters designated as marine reserves) and age-standardized mortality (i.e., age-standardized probability of dying between 15 and 60 years from all-causes among ages 15-60/100,000 population) by sex, among 110 countries. We fit mixed-effects linear regression models of mortality as a function of current MPA coverage, gross domestic product growth, year, the prior extent of MPA, electricity coverage, governance, and country-level random effects. We observed a significant inverse association between current MPA coverage and adult mortality. For each 5-percentage-point increase in current MPA coverage, a country had 0.982 times the geometric means of female and male mortality [geometric mean ratio: 0.982 (95% CI 0·976, 0·988)] conditional on past %MPA coverage and other modeled variables. The model showed no significant residual association of mortality with past %MPA conditional on current %MPA and other modeled variables. This is one of the first studies to show a positive association between increasing marine conservation and human health. This macro-level study suggests there may be important co-benefits for human health from expanding MPAs that merit further investigation.

Abstract Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real‐world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia‐Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow‐up time of 29.5 months (interquartile range 13.3–54.3 months) were included in the analysis – 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in‐situ hybridisation status, receive first‐line myeloma treatment with immunomodulatory drugs or anti‐CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow‐up (adjusted hazard ratio 0.72, 95% CI 0.46–1.14, p = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources.

Abstract Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.