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Long-term effects of early, recurrent human exposure to general anaesthesia remain unknown. The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial provided an opportunity to examine this issue in children randomly assigned in infancy to either repeated bronchoalveolar-lavage (BAL)-directed therapy with general anaesthesia or standard care with no planned lavages up to 5 years of age when all children received BAL-directed therapy under general anaesthesia.

A commercial process for vepdegestrant (1), the most advanced PROTAC protein degrader in human clinical trials, has been developed to support clinical and commercial needs. The process features an efficient convergent synthetic strategy through the final reductive amination of two advanced chiral intermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. The final commercial process of vepdegestrant (1) consists of seven proposed regulatory GMP steps with five isolations in an overall yield of 29%.

Ferroptosis is a distinct form of necrotic cell death caused by overwhelming lipid peroxidation, and emerging evidence indicates a major contribution to organ damage in multiple pathologies. However, ferroptosis has not yet been visualized in vivo due to a lack of specific probes, which has severely limited the study of how the immune system interacts with ferroptotic cells and how this process contributes to inflammation. Consequently, whether ferroptosis has a physiological role has remained a key outstanding question. Here we identify a distinct, ferroptotic-like, necrotic cell death occurring in vivo during wounding of the Drosophilaembryo using live imaging. We further demonstrate that macrophages rapidly engage these necrotic cells within the embryo but struggle to engulf them, leading to prolonged, frustrated phagocytosis and frequent corpse disintegration. Conversely, suppression of the ferroptotic programme during wounding delays macrophage recruitment to the injury site, pointing to conflicting roles for ferroptosis during inflammation in vivo.

Changes to neuronal connectivity are believed to be a key factor in cognitive impairments associated with normal aging. Because of its effect on activities of daily living, deficient motor control is a critical type of cognitive decline to understand. Diminished inhibitory networks in the cortex are implicated in such motor control deficits, pointing to the connectivity of inhibitory cortical interneurons as an important area for study. Here, we used chronic two-photon microscopy to track the structural plasticity of en passantboutons (EPBs) of parvalbumin-positive interneurons in the mouse motor cortex in the first longitudinal, in vivo study of inhibitory interneuron synapses in the context of aging. Young (3–5 months) and aged (23–28 months) mice underwent training on the accelerating rotarod to evoke motor learning-induced structural plasticity. Our analysis reveals that, in comparison with axons from young mice, those from aged mice have fewer EPBs at baseline that also tend to be larger in size. Aged axons also express learning-related structural plasticity—like new bouton stabilization and bouton enlargement—that is less persistent than that of young axons. This study reveals striking baseline differences in young and aged axon morphology as well as differences in the deployment of learning-related structural plasticity across axons.

ObjectiveTo describe the prevalence and severity of pain experienced by children with Bell’s palsy over the first 6 months of illness and its association with the severity of facial paralysis.MethodsThis was a secondary analysis of data obtained in a phase III, triple-blinded, randomised, placebo-controlled trial of prednisolone for the treatment of Bell’s palsy in children aged 6 months to <18 years conducted between 13 October 2015 and 23 August 2020 in Australia and New Zealand. Children were recruited within 72 hours of symptom onset and pain was assessed using a child-rated visual analogue scale (VAS), a child-rated Faces Pain Score-Revised (FPS-R) and/or a parent-rated VAS at baseline, and at 1, 3 and 6 months until recovered, and are reported combined across treatment groups.ResultsData were available for 169 of the 187 children randomised from at least one study time point. Overall, 37% (62/169) of children reported any pain at least at one time point. The frequency of any pain reported using the child-rated VAS, child-rated FPS-R and parent-rated VAS was higher at the baseline assessment (30%, 23% and 27%, respectively) compared with 1-month (4%, 0% and 4%, respectively) and subsequent follow-up assessments. At all time points, the median pain score on all three scales was 0 (no pain).ConclusionsPain in children with Bell’s palsy was infrequent and primarily occurred early in the disease course and in more severe disease. The intensity of pain, if it occurs, is very low throughout the clinical course of disease.Trial registration numberACTRN12615000563561.

Patients with COVID-19 are at increased risk of thrombosis, which is associated with altered platelet function and coagulopathy, contributing to excess mortality.

Pre-clinical experimental evidence, along with a plausible biological rational suggests that exposure of neonates and young children to anesthesia may harm brain development. However, the translational relevance of these observations remains unsolved. While a variety of lasting morpho-functional effects can be attributed to early life exposure to anesthetics in laboratory animals, we do not have a convincing human phenotype that reflects any causal effects of general anesthetic exposure on brain development and functional outcome. This review is aimed to provide a comprehensive description of the current state of clinical research alongside exploring future challenges in this field by focusing on the critical appraisal of methodological approaches applied in clinical research into developmental anesthesia neurotoxicity.

IMPORTANCE: Obstructive sleep-disordered breathing (SDB) in children is characterized by snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy children and is associated with significant morbidity. Evidence from small clinical trials suggests that intranasal corticosteroids improve SDB as measured by polysomnography; however, the effect on symptoms and quality of life is unclear. OBJECTIVE: To determine whether intranasal mometasone furoate is more effective than intranasal saline for improving symptoms and quality of life in children with SDB. DESIGN, SETTING, AND PARTICIPANTS: The MIST trial was a multicenter, randomized, double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for significant SDB symptoms were included; exclusions were previous adenotonsillectomy, body mass index greater than the 97th percentile, and severe SDB. Randomization was stratified by site, and data were analyzed on an intention-to-treat basis from October 28, 2020, to September 25, 2022. INTERVENTIONS: Participants were randomly assigned to receive mometasone furoate, 50 μg, or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles. MAIN OUTCOMES AND MEASURES: The primary outcome was resolution of significant SDB symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of symptoms using the SDB Score. RESULTS: A total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals [53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants (41%) in the saline group (risk difference, 4%; 95% CI, −8% to 16%; P = .51) with 26 participants lost to follow-up and missing values managed by multiple imputation. The main adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting 12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%) in the saline group. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial suggest that there was no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. The results suggest that almost one-half of children with SDB could be initially managed in the primary care setting and may not require referral to specialist services, as is currently recommended. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ANZCTRN12618000448246

Background: Candidaemia is the commonest fungal bloodstream infection in hospitalised patients. Diabetes is one of the risk factors for mortality from candidaemia.Methods: We compared the epidemiology, clinical characteristics and management of candidaemia in patients with and without diabetes.Results: Over a 10-year period, 200 episodes of Candida bloodstream infection were documented. Patients with diabetes were younger (58.7 vs 65.5 years), less likely to be suffering from cancer (21.8% vs 36%), and had significantly lower 30-day and 90-day crude mortality (17.2% vs 35.6% and 28.4% vs 48.6%, respectively). Candida glabratawas more common in patients with diabetes (39.3% vs 29.7%). Based on European Confederation of Medical Mycology (ECMM) quality indicators, the management of patients with and without diabetes was similar.Discussion: Our study highlights the importance of epidemiological data in relation to candidaemia in patients with diabetes and the growing threat of invasive C. glabratainfection in this subset of patients.

A significant ongoing initiative is to identify the conditions under which financial education is most effective, as it has been shown to work much better in some circumstances than others. One factor to consider is mathematical capability, as it has been linked to improved financial knowledge and financial outcomes. In this paper, we investigated one aspect of math capability: math confidence(that is, self-reported math ability). We examined how this factor interacts with financial education (measured by the number of financial education courses taken) with data from the 2018 National Financial Capability Survey (NFCS). We found that both mathematical confidence and financial education were positively associated with financial behaviors and, moreover, that the effects were largely independent rather than acting as substitutes – suggesting that future intervention work should consider both factors.

The Bronze Age in Britain is now a term often used to include both the first use of copper c. 2400 bcand also tin-bronze from c. 2100 bc, all of which required the extensive use of copper. Prehistoric mining for this metal has been identified in surface and underground workings in Parys Mine, Mynydd Parys, Anglesey, although almost all of the surface workings are now obscured by the extensive deep spoil from more recent mining in the industrial period. These copper-bearing ores are in bedded lodes, together with some intruded vein deposits. The Bronze Age workings have been exposed underground where they have been intersected by the early 19th century industrial workings on and above the 16 fathom and 20 fathom levels in the Parys Mine. Spoil exposures contain stone hammers (‘mauls’), wood fragments, and charcoal; samples of the latter have been radiocarbon dated with chronological modelling suggesting activity took place in the first half of the 2nd millennium cal bc. Although relatively limited in extent, these important prehistoric mining sites are among the earliest found in the UK. They have survived due to their protection from surface erosion and limited accessibility.

ABSTRACTThis paper explores the fields of actor training and music education in order to illuminate the historical and pedagogical connections between the work of Konstantin Stanislavski and Emile Jaques-Dalcroze. It identifies historical parallels between their artistic practices, including their dedication to rhythm and polyrhythm. It illustrates the ways in which their pedagogical paths crossed. It analyses the artistic lineage that can be drawn from the work of Jaques-Dalcroze at the Hellerau Institute to the work of Stanislavski at the Moscow Art Theatre. This includes the influence of Dalcroze Eurhythmics on the development of Tempo-Rhythm. The paper considers how aspects of Stanislavskian actor training are reflected in aspects of Dalcrozian music education, including ensemble work, intention and emotion, and the evolution of psychophysical performance. It proposes that there is a correlation between the creative process undertaken by an actor on a play text, known as Active Analysis, and the creative process undertaken by a musician on a compositional score, known as Plastique Animée. Comparing the pedagogical principles of Stanislavski and Jaques-Dalcroze from the author’s own perspective as an actor trainer and music educator reveals areas for further research. This paper presents themes that are transferable to artists and educators engaged in continuing professional development.

In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes.

Propylphosphonic anhydride, or T3P, is a commonly used reagent for amidation reactions with numerous examples of application on scale. One process-friendly aspect of the reagent is the ease of workup, in which quench and extraction or crystallization from aqueous systems should remove any residual T3P or related byproducts. This communication discusses the isolation and characterization of a T3P degradation byproduct and removal of the water-soluble byproduct by washing or further degradation at low pH. A second example demonstrates the degradation of a T3P-related phosphonic ester at low pH.

Intranasal fentanyl and inhaled nitrous oxide are increasingly combined to provide procedural sedation and analgesia in the pediatric emergency setting. This regimen is attractive because of its nonparenteral administration, but is associated with a higher incidence of vomiting than nitrous oxide alone. We seek to assess whether prophylactic oral ondansetron use could reduce the incidence of vomiting associated with intranasal fentanyl and nitrous oxide for procedural sedation compared with placebo.

Selectively labeling cells with damaged membranes is needed not only for identifying dead cells in culture, but also for imaging membrane barrier dysfunction in pathologies in vivo. Most membrane permeability stains are permanently colored or fluorescent dyes that need washing to remove their non-uptaken extracellular background and reach good image contrast. Others are DNA-binding environment-dependent fluorophores, which lack design modularity, have potential toxicity, and can only detect permeabilization of cell volumes containing a nucleus (i.e., cannot delineate damaged volumes in vivonor image non-nucleated cell types or compartments). Here, we develop modular fluorogenic probes that reveal the whole cytosolic volume of damaged cells, with near-zero background fluorescence so that no washing is needed. We identify a specific disulfonated fluorogenic probe type that only enters cells with damaged membranes, then is enzymatically activated and marks them. The esterase probe MDG1is a reliable tool to reveal live cells that have been permeabilized by biological, biochemical, or physical membrane damage, and it can be used in multicolor microscopy. We confirm the modularity of this approach by also adapting it for improved hydrolytic stability, as the redox probe MDG2. We conclude by showing the unique performance of MDGprobes in revealing axonal membrane damage (which DNA fluorogens cannot achieve) and in discriminating damage on a cell-by-cell basis in embryos in vivo. The MDGdesign thus provides powerful modular tools for wash-free in vivoimaging of membrane damage, and indicates how designs may be adapted for selective delivery of drug cargoes to these damaged cells: offering an outlook from selective diagnosis toward therapy of membrane-compromised cells in disease.

Across animal species, dopamine-operated memory systems comprise anatomically segregated, functionally diverse subsystems. Although individual subsystems could operate independently to support distinct types of memory, the logical interplay between subsystems is expected to enable more complex memory processing by allowing existing memory to influence future learning. Recent comprehensive ultrastructural analysis of the Drosophilamushroom body revealed intricate networks interconnecting the dopamine subsystems—the mushroom body compartments. Here, we review the functions of some of these connections that are beginning to be understood. Memory consolidation is mediated by two different forms of network: A recurrent feedback loop within a compartment maintains sustained dopamine activity required for consolidation, whereas feed-forward connections across compartments allow short-term memory formation in one compartment to open the gate for long-term memory formation in another compartment. Extinction and reversal of aversive memory rely on a similar feed-forward circuit motif that signals omission of punishment as a reward, which triggers plasticity that counteracts the original aversive memory trace. Finally, indirect feed-forward connections from a long-term memory compartment to short-term memory compartments mediate higher-order conditioning. Collectively, these emerging studies indicate that feedback control and hierarchical connectivity allow the dopamine subsystems to work cooperatively to support diverse and complex forms of learning.

Tubeless upper airway surgery in children is a complex procedure in which surgeons and anaesthetists share the same operating field. These procedures are often interrupted for rescue oxygen therapy. The efficacy of nasal high-flow oxygen to decrease the frequency of rescue interruptions in children undergoing upper airway surgery is unknown.

Background: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.

Cell migration is hypothesized to involve a cycle of behaviours beginning with leading edge extension. However, recent evidence suggests that the leading edge may be dispensable for migration, raising the question of what actually controls cell directionality. Here, we exploit the embryonic migration of Drosophilamacrophages to bridge the different temporal scales of the behaviours controlling motility. This approach reveals that edge fluctuations during random motility are not persistent and are weakly correlated with motion. In contrast, flow of the actin network behind the leading edge is highly persistent. Quantification of actin flow structure during migration reveals a stable organization and asymmetry in the cell-wide flowfield that strongly correlates with cell directionality. This organization is regulated by a gradient of actin network compression and destruction, which is controlled by myosin contraction and cofilin-mediated disassembly. It is this stable actin-flow polarity, which integrates rapid fluctuations of the leading edge, that controls inherent cellular persistence.

Diatoms, large bloom-forming marine microorganisms, build frustules out of silicate, which ballasts the cells and aids their export to the deep ocean. This unique physiology forges an important link between the marine silicon and carbon cycles. However, the effect of ocean acidification on the silicification of diatoms is unclear. Here we show that diatom silicification strongly diminishes with increased acidity in a natural Antarctic community. Analyses of single cells from within the community reveal that the effect of reduced pH on silicification differs among taxa, with several species having significantly reduced silica incorporation at CO2levels equivalent to those projected for 2100. These findings suggest that, before the end of this century, ocean acidification may influence the carbon and silicon cycle by both altering the composition of the diatom assemblages and reducing cell ballasting, which will probably alter vertical flux of these elements to the deep ocean.

Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus.

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BackgroundChronic conditions are the leading cause of mortality, morbidity and disability in children. However, children and caregivers are rarely involved in identifying research priorities, which may limit the value of research in supporting patient-centred practice and policy.ObjectiveTo identify priorities of patients, caregivers and health professionals for research in childhood chronic conditions and describe the reason for their choices.SettingAn Australian paediatric hospital and health consumer organisations.MethodsRecruited participants (n=73) included patients aged 8 to 14 years with a chronic condition (n=3), parents/caregivers of children aged 0 to 18 years with a chronic condition (n=19), representatives from consumer organisations (n=13) and health professionals including clinicians, researches (n=38) identified and discussed research priorities. Transcripts were thematically analysed.ResultsSeventy-eight research questions were identified. Five themes underpinned participants’ priorities: maintaining a sense of normality (enabling participation in school, supporting social functioning, promoting understanding and acceptance), empowering self-management and partnership in care (overcoming communication barriers, gaining knowledge and skills, motivation for treatment adherence, making informed decisions, access and understanding of complementary and alternative therapies),strengthening ability to cope (learning to have a positive outlook, preparing for home care management, transitioning to adult services), broadening focus to family (supporting sibling well-being, parental resilience and financial loss, alleviating caregiver burden), and improving quality and scope of health and social care (readdressing variability and inequities, preventing disease complications and treatment side effects, identifying risk factors, improving long-term outcomes, harnessing technology, integrating multidisciplinary services).ConclusionResearch priorities identified by children, caregivers and health professionals emphasise a focus on life participation, psychosocial well-being, impact on family and quality of care. These priorities may be used by funding and policy organisations in establishing a paediatric research agenda.