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Styrylchromones (SC) are a group of oxygen-containing heterocyclic compounds, which are characterized by the attachment of a styryl group to the chromone core. SC can be found in nature or can be chemically synthesized in the laboratory. As their presence in nature is scarce, the synthetic origin is the most common. Two types of SC are known: 2-styrylchromones and 3-styrylchromones. However, 2-styrylchromones are the most common, being more broadly found in nature and whose chemical synthesis is more commonly described. A wide variety of SC has been described in the literature, with different substituents in different positions, the majority of which are distributed on the A- and/or B-rings. Over the years, several biological activities have been attributed to SC. This work presents a comprehensive review of the biological activities attributed to SC and their structure-activity relationship, based on a published literature search, since 1989. The following biological activities are thoroughly reviewed and discussed in this review: antioxidant, antiallergic, antiviral, antibacterial, antifungal, anti-inflammatory and antitumoral, affinity and selectivity for A 3 adenosine receptors, neuroprotective, and α-glucosidase inhibition. In general, SC are composed by a promising scaffold with great potential for the development of new drugs., (© 2024 Wiley-VCH GmbH.)

Objectives: SARS-CoV-2 nucleocapsid (N) protein antibodies can be used to detect the serological response to natural infection in those previously receiving a COVID-19 spike-based vaccine. Anti-N antibody responses can also be detected in those receiving inactivated whole SARS-CoV-2 virus vaccines, such as CoronaVac. We aimed to characterise antibody responses to the N protein following COVID-19 and following vaccination with CoronaVac., Methods: Using participants from an international randomised controlled trial, we investigated the evolution of anti-N antibody responses over time in two separate groups: following COVID-19, or following vaccination with CoronaVac., Results: In 212 participants who had COVID-19, the anti-N seroconversion rate was 96.9% in those infected following an incomplete course of COVID-19 (spike-based) vaccinations and 88.2% in those fully vaccinated. Anti-N antibody indices were highly variable between participants, and higher in participants who had more severe COVID-19 symptoms, were aged ≥60 years, were unvaccinated, had comorbidities and those resident in Brazil. Most participants remained seropositive after 12 months. In 317 separate participants, the anti-N seroconversion rate was 63.5% following CoronaVac vaccination, with variable antibody indices., Conclusions: Anti-N responses to COVID-19 and CoronaVac are highly variable but persistent. A prior complete COVID-19 spike-based vaccination course reduced both anti-N seroconversion and antibody indices following COVID-19., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC). Outside of the submitted work, JC has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir- Paxlovid (Pfizer). Outside of the submitted work, PCR has received payment, honoraria or support for lectures, presentations or meeting attendance from GlaxosmithKline, Pfizer, Resvinet Foundation related to meningococcal and pneumococcal diseases and RSV; received research grants or contracts (to institution) from Merck Sharpe & Dohme; participates on Scientific Advisory Boards related to COVID-19, meningococcal, RSV, pneumococcal disease/vaccines; and has a bacteriotherapy patent pending. All other authors declare no conflict of interest. Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC). Outside of the submitted work, JC has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir- Paxlovid (Pfizer). Outside of the submitted work, PCR has received payment, honoraria or support for lectures, presentations or meeting attendance from GlaxosmithKline, Pfizer, Resvinet Foundation related to meningococcal and pneumococcal diseases and RSV; received research grants or contracts (to institution) from Merck Sharpe & Dohme; participates on Scientific Advisory Boards related to COVID-19, meningococcal, RSV, pneumococcal disease/vaccines; and has a bacteriotherapy patent pending. All other authors declare no conflict of interest., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The fusion of non-Abelian anyons is a fundamental operation in measurement-only topological quantum computation 1 . In one-dimensional topological superconductors (1DTSs) 2-4 , fusion amounts to a determination of the shared fermion parity of Majorana zero modes (MZMs). Here we introduce a device architecture 5 that is compatible with future tests of fusion rules. We implement a single-shot interferometric measurement of fermion parity 6-11 in indium arsenide-aluminium heterostructures with a gate-defined superconducting nanowire 12-14 . The interferometer is formed by tunnel-coupling the proximitized nanowire to quantum dots. The nanowire causes a state-dependent shift of the quantum capacitance of these quantum dots of up to 1 fF. Our quantum-capacitance measurements show flux h/2e-periodic bimodality with a signal-to-noise ratio (SNR) of 1 in 3.6 μs at optimal flux values. From the time traces of the quantum-capacitance measurements, we extract a dwell time in the two associated states that is longer than 1 ms at in-plane magnetic fields of approximately 2 T. We discuss the interpretation of our measurements in terms of both topologically trivial and non-trivial origins. The large capacitance shift and long poisoning time enable a parity measurement with an assignment error probability of 1%., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The consequences of drug allergy remain a global health concern. Drug allergy is often a neglected topic and many non-specialists lack sufficient knowledge or confidence in evaluating or managing this common condition. Evidence-based interventions to better equip non-specialists to tackle drug allergy are needed. The aim of the study is to evaluate the effectiveness of an intensive educational course on drug allergy knowledge and practice of non-specialists., Methods: A randomized crossover trial (NCT06399601) was conducted among practicing physicians and nurses participating in an intensive drug allergy course-Advances in Drug Allergy & Penicillin Testing (ADAPT). Participants' baseline knowledge and self-reported practices were assessed with standardized questionnaires (scored from 0 to 100, with "satisfactory" defined as ≥60/100). Participants were randomized into two cohorts and attended ADAPT at different time points. Serial responses before and after the course were compared within and between cohorts., Results: Seventy participants (25 physicians, 45 nurses) randomized into two groups completed the course. Baseline drug allergy knowledge (58.0 ± 19.9) and self-reported practice (36.9 ± 24.3) were unsatisfactory among non-specialists, with significantly lower scores from nurses than physicians in both domains (knowledge: 49.0 ± 17.4 vs. 74.0 ± 12.7; practice: 32.1 ± 21.3 vs. 53.3 ± 23.1; all p < 0.001). Following completion of ADAPT, participants demonstrated significant improvements in knowledge (58.0 ± 19.9 vs. 77.7 ± 15.9, p < 0.001) and self-reported practice (36.9 ± 24.3 vs. 71.0 ± 20.2, p < 0.001). All participants (100%) and 99% of participants agreed that the course improved their clinical knowledge and practice, respectively., Conclusions: ADAPT, an intensive drug allergy educational course was effective in improving drug allergy knowledge and practice for non-specialists. Further longitudinal studies are required to evaluate long-term impact., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a by-product of TDP43 autoregulation and cleared by nonsense-mediated RNA decay (NMD). sTDP43-encoding transcripts that escape NMD are rapidly degraded post-translationally via the proteasome and macroautophagy. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA-binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and underscore the consequences of aberrant sTDP43 accumulation in disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A new focussed ultrasound surgery (FUS) transducer for soft tissue ablation is proposed, with a miniaturised configuration that can be readily integrated with a surgical robot. The transducer fills a gap in FUS technology at this size, with capability for acoustic focus steering within a very simple transducer configuration. Miniaturisation is enabled by the incorporation of an acoustic Fresnel lens as the focussing element driven by a single piezoceramic disc. The transducer housing and Fresnel lens are made from photopolymer resins in a mask stereolithography (mSLA) printer and a microballoon filled epoxy backing layer is added to approximate an air backing. In this study, four versions of the miniature FUS transducer were fabricated and tested, each incorporating a different piezoceramic material: a soft PZT, a specialised composition for high intensity focused ultrasound, a low acoustic impedance porous PZT, and a lead free piezoceramic. It is shown that the FUS transducer containing the porous piezoceramic disc, which has lower piezoelectric and coupling coefficients than the other materials, achieves the highest focal zone intensity. Through finite element analysis (FEA) and experimental characterisations of the acoustic field, the FUS transducer is demonstrated to be capable of both creating and steering a focal intensity suitable for tissue ablation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Objectives: Using a multimethod approach, this study sought to identify the contribution of different facets of resilience to Pacific peoples in Aotearoa New Zealand's mental health and well-being and to explore the construct of resilience in the light of COVID-19 lockdowns., Method: Study 1 ( N = 88) included a Pacific community sample (67% female, 33% male; M = 39 years, range = 19-80 years). Participants completed a survey measuring personal, spiritual, family and community resilience, well-being, Pacific identity, and mental distress. Study 2 comprised a focus group of one male and three female Pacific university students and used photovoice and talanoa methods. Study 3 comprised two community focus groups of four Pacific men and three Pacific women and was conducted via Zoom using talanoa methods., Results: In Study 1 greater well-being was associated with greater family resilience, whereas higher access to spiritual support and engagement were associated with lower mental distress. Eight themes were identified across Studies 2 and 3: resilience as overcoming adversity, nature as resilience, resilience as both personal and collective attributes, strength through adversity, vulnerability and coping, gratitude, responsibility that promotes individual resilience, and spirituality., Conclusions: Taken together, our study demonstrated that Pacific peoples living in Aotearoa exhibit a range of personal, spiritual, and collective attributes that support their resilience, and we discuss the implications of these findings for our theories of resilience, especially for Indigenous groups. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating proximity between a neosubstrate and hijacked E3 ligase. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2 KLHDC3 , which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and, thus, would also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1., Competing Interests: G.E.W. is a scientific founder and shareholder of Proxygen and Solgate. G.E.W. is on the Scientific Advisory Board of Nexo Therapeutics. The G.E.W. laboratory has received research funding from Pfizer. D.C.S. and B.A.S. are co-inventors of intellectual property related to DCUND1 inhibitors licensed to Cinsano. B.A.S. is a member of the scientific advisory boards of Proxygen and BioTheryX.

Migrant youth from Latin America who arrive in the United States are faced with a social and political context that dehumanizes migrants of color. These anti-immigrant sentiments become reflected in federal and state policies that deny migrants rights to freedom and safety. The present paper examined how the U.S. immigration context informed migrant young adults' structural analysis of immigration policies and rhetoric (critical reflection) and actions to challenge exclusionary immigration-related policies and rhetoric (critical action). We further examined facilitators and barriers to action. Semi-structured interviews were conducted with migrant young adults from Latin America living in Virginia (N = 30; M = 20.93; SD = 2.03; 53% female). We employed constructivist grounded theory strategies to analyze the data. Findings showed that migrant young adults offered a range of structural and individual-level attributions for unjust immigration policies. For some migrant young adults, their critical reflection informed decisions to engage in critical actions. Yet, many migrant young adults also noted constraints that impeded their engagement. By more thoroughly understanding migrant young adults' critical reflection and factors that may facilitate or impede action, researchers and practitioners may be better positioned to support migrant young adults who seek to dismantle systems of oppression., (© 2025 Society for Community Research and Action.)

Background: Antimicrobial stewardship (AMS) is crucial for optimizing antimicrobial use and restraining emergence of antimicrobial resistance. The overall increase in reported antibiotic allergies in children can pose a significant barrier to AMS, but its impact on clinical AMS care in children has not been addressed., Objective: To compare the clinical outcomes for children with a reported antibiotic allergy label (AAL) with those with no AAL reviewed by AMS., Methods: A retrospective cohort study was conducted in a pediatric tertiary hospital, capturing 1590 inpatient admissions reviewed under the AMS between 2017 and 2019. Logistic, log-binomial, and Cox regression analyses were undertaken. Data collected included a documented AAL, antibiotic prescriptions, principal diagnosis, admitting specialty, hospital length of stay, intensive care admissions, and hospital readmissions., Results: All 1590 pediatric patients were prescribed at least 1 antibiotic. AALs were recorded in 6.6% of patients; majority were β-lactam (82%), mostly penicillins (71%). AALs increased with age (P < .001); no gender effect was seen. Patients with AALs received more quinolones (P < .001), lincosamides (P = .001), aminoglycosides (P < .001), and metronidazole (P = .015) than patients with no AALs. In contrast, children with no AAL received more penicillin (P < .001). Children with any AAL had marginally longer hospital length of stay, median (interquartile range [IQR]) 7.0 (4.0, 15.0) days, than those without, median (IQR) 5.0 (3.75, 11.0) days, P = .027., Conclusion: This study is the first to show how AALs impact clinical outcomes in children under an AMS program. With recent advances in delabeling, early intervention in cases of AAL should target children under AMS services who are in immediate need of optimal antibiotic management., (Crown Copyright © 2025. Published by Elsevier Inc. All rights reserved.)

Background/Objectives: The use of silver diamine fluoride (SDF) has increased in recent years for the management of caries lesions in children and adults. The aim of this study is to determine the level of knowledge and the attitude of Spanish dentists (GDPs) and final-year dental students (DSs) regarding the use of SDF. Methods: A cross-sectional survey (questionnaire) was carried out aimed at final-year dental students (DSs) (n = 43) and registered dentists (GDPs) (n = 1050) in the autonomous community of the region of Murcia (Spain). Results: the response rates were GDPs 7.7% (n = 81) and DSs 84.5% (n = 38). Only 20.98% of GDP respondents reported having been trained on SDF versus 100% of DSs. Significant differences were observed between the groups ( p < 0.05). While 94.7% of the students were aware of the indications for the use of SDF, only 56.8% of the general dentists reported it. Similarly, for hypersensitivity treatment, 71.1% of the students were informed versus 40.7% of the general dentists, and indications for paediatric patients, 100% for the DS group and 59.3% in GDPs. In adult patients, indications vary from GDPs' (50%) to DSs' (25.9%) responses. About 94.7% of DSs know the advantages of use and only 50.6% of GDPs. Both groups showed reluctance to use SDF in esthetic zones, with greater acceptance in non-esthetic areas ( p < 0.05). In practice, fewer GDPs (27.16%) and DSs (23.68%) had applied SDF, reflecting a gap between knowledge and implementation. Conclusions: Dental students had a significantly higher level of knowledge, a situation that evidences the high level of education and training in the curricular guides of the universities.

The Retriever complex recycles a wide range of transmembrane proteins from endosomes to the plasma membrane. The cargo adapter protein SNX17 has been implicated in recruiting the Retriever complex to endosomal membranes, yet the details of this interaction have remained elusive. Through biophysical and structural model-guided mutagenesis studies with recombinant proteins and liposomes, we have gained a deeper understanding of this process. Here, we demonstrate a direct interaction between SNX17 and Retriever, specifically between the C-terminal region of SNX17 and the interface of the Retriever subunits VPS35L and VPS26C. This interaction is enhanced upon the binding of SNX17 to its cargo in solution, due to the disruption of an intramolecular autoinhibitory interaction between the C-terminal region of SNX17 and the cargo binding pocket. In addition, SNX17 binding to membranes containing phosphatidylinositol-3-phosphate also promotes Retriever recruitment in a cargo-independent manner. Therefore, this work provides evidence of the dual activation mechanisms by which SNX17 modulates Retriever recruitment to the proximity of cargo and membranes, offering significant insights into the regulatory mechanisms of protein recycling at endosomes., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

We present data on life history parameters from a long-term study of vervet monkeys in the Eastern Cape, South Africa. Estimates are presented of age at first conception for females and age at natal dispersal for males, along with the probability of survival to adulthood for infants born during the study, female reproductive life-span, reproductive output (including lifetime reproductive success for a subset of females), and inter-birth interval (IBI) duration. We also assess the effect of maternal age and infant survival on length of IBI. We then go on to compare life history parameters for our population with those from two East African populations in Kenya (Amboseli and Laikipia). We find there is broad consensus across the three populations, although mean infant survival was considerably lower for the two East African sites. Such comparisons must be made cautiously, however, as local ecology across the duration of the studies obviously has an impact on the estimates obtained. With this caveat in place, we consider that the concordance between values is sufficient to enable the values reported here to be used in comparative studies of primate life history, although data from habitats with higher rainfall and lower levels of seasonality are needed, and the results presented here should not be seen as canonical., (© 2023 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

How gender identity is assessed directly shapes how students are supported in elementary schools in the United States. Despite the existence of gender diversity, calls for more inclusive science, and recommendations from national research associations and societies to incorporate and emphasize the voices of individuals with diverse gender identities, most studies exploring gender disparities in education have relied heavily on the assumption of a gender binary. As a result, the omission of diverse gender identities from educational research in the elementary years is troubling. To address this area of need, the current article summarizes the opportunities for and constraints surrounding inclusive evaluation of gender identity in the elementary school years. We begin with a brief review of common methods used to assess gender identities for children in elementary school, including the strengths and limitations of each. We next contextualize these measures by outlining the current state-level barriers to including diverse gender identities in assessments of gender. In highlighting the best available practices and the structural systems of oppression realized through state-level policies that perpetuate an inability to represent student voices across the gender spectrum, we conclude with a call to action to inspire the evolution of best practices in the service of all students. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Invasive alien plant species (IAPS) are well known to disrupt biodiversity, natural ecosystems, and infrastructures, resulting in a significant worldwide economic cost. However, the impact of IAPS on human health has been generally disregarded, despite a significant potential risk. Currently, due to new evidence and the concept of One Health , this concern is gaining strength. The spread of invasive plants at a global scale can profoundly affect human health through pollen and toxin production. Allergic respiratory diseases caused by pollen are likely the primary risks posed by IAPS. Because of the frequent invasion of populated areas and their different pollination period throughout the year, IAPS might further contribute to the current striking increase in allergies. Respiratory allergies significantly affect the quality of life of patients, along with associated economic impacts. In this study, we focus on a paradigmatic IAPS that is invading considerable areas of the globe, Cortaderia selloana (Pampas grass), to illustrate the increasing and widely disregarded human health risk posed by IAPS. Our aim is to raise awareness of the IAPS concern among the medical community and health policymakers, suggesting rapid action to address associated concerns.

Traditional models of human brain activity often represent it as a network of pairwise interactions between brain regions. Going beyond this limitation, recent approaches have been proposed to infer higher-order interactions from temporal brain signals involving three or more regions. However, to this day it remains unclear whether methods based on inferred higher-order interactions outperform traditional pairwise ones for the analysis of fMRI data. To address this question, we conducted a comprehensive analysis using fMRI time series of 100 unrelated subjects from the Human Connectome Project. We show that higher-order approaches greatly enhance our ability to decode dynamically between various tasks, to improve the individual identification of unimodal and transmodal functional subsystems, and to strengthen significantly the associations between brain activity and behavior. Overall, our approach sheds new light on the higher-order organization of fMRI time series, improving the characterization of dynamic group dependencies in rest and tasks, and revealing a vast space of unexplored structures within human functional brain data, which may remain hidden when using traditional pairwise approaches., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Denitrification, a key process in soil nitrogen cycling, occurs predominantly within microbial hotspots, such as those around particulate organic matter (POM), where denitrifiers use nitrate as an alternative electron acceptor. For accurate prediction of dinitrogen (N 2 ) and nitrous oxide (N 2 O) emissions from denitrification, a precise quantification of these microscale hotspots is required. The distribution of POM is of crucial importance in this context, as the local oxygen (O 2 ) balance is governed not only by its high O 2 demand but also by the local O 2 availability. Employing a unique combination of X-ray CT imaging, microscale O 2 measurements, and 15 N labeling, we were able to quantify hotspots of aerobic respiration and denitrification. We analyzed greenhouse gas (GHG) fluxes, soil oxygen supply, and the distribution of POM in intact soil samples from grassland and cropland under different moisture conditions. Our findings reveal that both proximal and distal POM, identified through X-ray CT imaging, contribute to GHG emissions. The distal POM, i.e. POM at distant locations to air-filled pores, emerged as a primary driver of denitrification within structured soils of both land uses. Thus, the higher denitrification rates in the grassland could be attributed to the higher content of distal POM. Conversely, despite possessing compacted areas that could favor denitrification, the cropland had only small amounts of distal POM to stimulate denitrification in it. This underlines the complex interaction between soil structural heterogeneity, organic carbon supply, and microbial hotspot formation and thus contributes to a better understanding of soil-related GHG emissions. In summary, our study provides a holistic understanding of soil-borne greenhouse gas emissions and emphasizes the need to refine predictive models for soil denitrification and N 2 O emissions by incorporating the microscale distribution of POM., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Acute pulmonary embolism (PE) is a significant cause of mortality in the hospital setting. The objective of this study was to outline the long-term outcomes after surgical and non-surgical management for patients with massive and submassive PE., Methods: Population cohort observational study evaluating all patients who presented to three tertiary hospitals in the state of Western Australia with access to cardiothoracic services over 5 years (2013-2018). Reviewed notes of all patients as well as radiology, linked mortality data and all available echocardiography studies at the primary hospital., Results: In total, 245 patients were identified, of which 41 received surgical management and 204 non-surgical management; demographic data was similar. Clinically, the surgical group had higher rates of shock requiring vasopressors, severe bradycardia, or cardiopulmonary resuscitation prior to intervention. The 28-day mortality was not statistically significantly different between the surgical embolectomy group (2/41 [4.2%]) and the non-surgical group (17/201 [8.3%]) (p=0.382). There was no difference in 12-month mortality, including when this was adjusted for vasopressors, right ventricular (RV) strain, troponin, and brain natriuretic peptide. In the massive PE sub-group, 28-day mortality was not significantly different: 2/29 (6.9%) surgical group vs 7/34 (20.2%) non-surgical group (p=0.064). Higher rates of severe RV impairment and dilatation were present in the surgical group. All patients with available echocardiography studies at outpatient follow-up returned to normal or mild RV impairment., Conclusion: Patients who presented with massive or submassive PE had similar outcomes whether treated with surgical or non-surgical management. Surgical embolectomy is a safe option in a cardiothoracic centre setting., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses., Methods: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms., Findings: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath)., Interpretation: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There is a scarcity of prospective studies investigating the relative roles of skin prick and intradermal testing, serum specific IgE, and extended oral challenges in diagnosing children with reported β-lactam allergies., Objective: To determine the sensitivity and specificity of skin testing and serum specific IgE in children with β-lactam allergies, with immediate and nonimmediate historic reactions., Methods: Four hundred children with parent-reported β-lactam allergies were recruited into an open-label prospective study. Detailed allergy histories were collected. Those with medically observed and documented histories of anaphylaxis, requiring epinephrine, or severe cutaneous adverse reactions were excluded. In total, 380 children underwent all testing modalities and a direct provocation test. Each child was followed up for a minimum of 3 years., Results: True allergy in children was uncommon; 8.3% reacted to the direct provocation challenge or the 5-day extended oral provocation challenge. Children reporting cephalosporin allergy or a reaction within 1 year were more likely to react to direct provocation testing. The sensitivity, specificity, and positive predictive value of skin testing were 12.5%, 98.8%, and 20.0% for direct challenge outcomes, 4.76%, 99.0%, and 25.0% for extended challenge outcomes, and 6.9%, 99.0%, and 40.0% for both challenges combined, respectively. Follow-up investigations revealed that 5.7% of children had a mild repeat reaction and 2.7% continued to avoid the culprit despite successful delabeling. The relabeling rate for children readmitted to hospital was 15%, with the relabeing being unfounded., Conclusions: Genuine β-lactam allergies were rare, with over 90% of children effectively delabeled. Skin and serum specific IgE testing did not aid the diagnosis of β-lactam antibiotic allergy in children, regardless of medical history. Extended oral challenges proved valuable in confirming allergies and boosted parental confidence., (Copyright © 2024. Published by Elsevier Inc.)

The ultraviolet (UV) photodissociation dynamics of the 2-buten-2-yl (C 4 H 7 ) radical were studied using the high- n Rydberg atom time-of-flight (HRTOF) technique in the photolysis region of 226-246 nm. 2-Buten-2-yl radicals were generated by 193 nm photodissociation of the precursor 2-chloro-2-butene. The H-atom photofragment yield (PFY) spectrum of 2-buten-2-yl is broad, peaking at 234 nm. Quantum chemistry calculations show that the UV absorption is due to the 3p y and 3p x Rydberg states (parallel to the plane of CC double bond). The translational energy distributions of the H-atom loss product channel, P ( E T )'s, of 2-buten-2-yl show a bimodal distribution indicating two dissociation pathways. The major pathway peaks at E T ∼ 7 kcal mol -1 with a nearly constant fraction of average E T in the total excess energy, 〈 f T 〉, at ∼0.11-0.12. This main pathway has an isotropic product angular distribution with β ∼ 0, consistent with the unimolecular dissociation of a hot 2-buten-2-yl radical following internal conversion from the electronically excited state, resulting in the formation of 2-butyne + H (∼84%) and 1,2-butadiene + H (∼16%). Additionally, there is a minor non-statistical pathway with an isotropic angular distribution. The minor pathway peaks at E T ∼ 35 kcal mol -1 in the P ( E T ) distributions and exhibits a large 〈 f T 〉 of ∼0.40-0.46. This fast pathway suggests a direct dissociation of the methyl H-atom on a repulsive excited state surface or on the repulsive part of the ground state surface, forming 1,2-butadiene + H. The fast/slow pathway branching ratio is in the range of 0.03-0.08.

Rejection is a primary cause of allograft dysfunction after kidney transplantation. The diversity of immune subpopulations involved in the different endotypes of rejection remains to be delineated at single-cell resolution. In a cohort of 76 kidney transplant recipients, we conducted high-dimensional immune phenotyping of blood CD4 T and B cells, single-cell RNA and T/B cell receptor sequencing, and plasma cytokine profiling. Phenotypic, transcriptional, and clonal states of CD4T and B cells could significantly distinguish stable allograft states from rejection. Patients undergoing T cell-mediated rejection displayed accumulation of clonally expanded cytotoxic T helper (Th)1 cells and Th17-like cells, associated with predominant naive B cell responses. In contrast, antibody-mediated rejection was characterized by clonal expansion of Th1-polarized T follicular helper cells and effector T-bet+ memory B cells, both of which strongly expressed interleukin 12 and tumor necrosis factor-signaling pathways. Plasma cytokine analysis confirmed mixed Th1/Th17 and Th1/T follicular helper cell-driven inflammatory profiles distinguishing T cell-mediated rejection and antibody-mediated rejection, respectively. CD4T and B cell subpopulations and signatures were validated using bulk RNA-seq analysis of matched kidney allografts and using an independent single-cell RNA-seq data set. These data improve mechanistic understanding of the immune pathogenesis of rejection and support the development of more specific immunosuppressive therapies to treat allograft rejection., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Moving in straight lines is a behaviour that enables organisms to search for food, move away from threats, and ultimately seek suitable environments in which to survive and reproduce. This study explores a vision-based technique for detecting a change in heading direction using the Milky Way (MW), one of the navigational cues that are known to be used by night-active insects. An algorithm is proposed that combines the YOLOv8m-seg model and normalised second central moments to calculate the MW orientation angle. This method addresses many likely scenarios where segmentation of the MW from the background by image thresholding or edge detection is not applicable, such as when the moon is substantial or when anthropogenic light is present. The proposed YOLOv8m-seg model achieves a segment mAP@0.5 of 84.7% on the validation dataset using our own training dataset of MW images. To explore its potential role in autonomous system applications, we compare night sky imagery and GPS heading data from a field trial in rural South Australia. The comparison results show that for short-term navigation, the segmented MW image can be used as a reliable orientation cue. There is a difference of roughly 5-10° between the proposed method and GT as the path involves left or right 90° turns at certain locations.

Underrepresentation of people from racial and ethnic minoritized groups in clinical trials threatens external validity of clinical and translational science, diminishes uptake of innovations into practice, and restricts access to the potential benefits of participation. Despite efforts to increase diversity in clinical trials, children and adults from Latino backgrounds remain underrepresented. Quality improvement concepts, strategies, and tools demonstrate promise in enhancing recruitment and enrollment in clinical trials. To demonstrate this promise, we draw upon our team's experience conducting a randomized clinical trial that tests three behavioral interventions designed to promote equity in language and social-emotional skill acquisition among Latino parent-infant dyads from under-resourced communities. The recruitment activities took place during the COVID-19 pandemic, which intensified the need for responsive strategies and procedures. We used the Model for Improvement to achieve our recruitment goals. Across study stages, we engaged strategies such as (1) intentional team formation, (2) participatory approaches to setting goals, monitoring achievement, selecting change strategies, and (3) small iterative tests that informed additional efforts. These strategies helped our team overcome several barriers. These strategies may help other researchers apply quality improvement tools to increase participation in clinical and translational research among people from minoritized groups., Competing Interests: None., (© The Author(s) 2024.)

A key challenge of nonlinear dynamics and network science is to understand how higher-order interactions influence collective dynamics. Although many studies have approached this question through linear stability analysis, less is known about how higher-order interactions shape the global organization of different states. Here, we shed light on this issue by analyzing the rich patterns supported by identical Kuramoto oscillators on hypergraphs. We show that higher-order interactions can have opposite effects on linear stability and basin stability: They stabilize twisted states (including full synchrony) by improving their linear stability, but also make them hard to find by markedly reducing their basin size. Our results highlight the importance of understanding higher-order interactions from both local and global perspectives.

Objectives: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19., Design: Phase III double-blind randomised controlled trial., Setting: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic., Participants: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG., Intervention: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989)., Main Outcome Measures: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion)., Results: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group., Conclusions: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19., Trial Registration: ClinicalTrials.gov NCT04327206., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC), Melbourne Children’s Clinician-Scientist Fellowship Grant (KPP). Outside of the submitted work, JCr has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir-Paxlovid (Pfizer). KG is a member of the Royal Children’s Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The evolving field of chimeric antigen receptor (CAR) T-cell therapy, though promising, necessitates more comprehensive imaging methods to enhance therapeutic effectiveness and track cell trafficking in patients and ex vivo. This review examines the application of PET imaging in CAR T-cell trafficking and optimizing their therapeutic impact. The application of PET imaging using various radiotracers is promising in providing evaluation of CAR T-cell interaction within the host, thereby facilitating strategies for improved patient outcomes. As this technology progresses, further innovative strategies to streamline assessments of immunotherapeutic effectiveness are anticipated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Since the 1950s, Roger Barker's theory of behaviour settings has been useful for a wide number of disciplines. Few realize, however, that behaviour settings theory is also a methodology. Barker fully describes how to identify, describe and measure behaviour settings in his seminal book Ecological psychology: concepts and methods for studying the environment of human behavior (1968), and this method is further delineated in Phil Schoggen's Behavior settings: a revision and extension of Roger G. Barker's ecological psychology (1989). Nevertheless, beyond these two (rather expensive) books there are few other resources available to twenty-first century researchers who wish to systematically describe and measure behaviour in its ecological context using the principles of behaviour settings theory. In this article, I offer a practitioner's field guide to implementing the behaviour settings method, which includes a contemporary illustration of defining a behaviour setting using a recent observational study of an art gallery in Lethbridge, Canada. I discuss how researchers can use Barker's original methodology to determine what is a behaviour setting and how to define its boundaries, and I suggest best practices, offering practitioners the tools to replicate Barker's procedures. This article is part of the theme issue 'People, places, things, and communities: expanding behaviour settings theory in the twenty-first century'.

Trends and developments in recent behavioural and cognitive sciences demonstrate the need for a well-developed theoretical and empirical framework for examining the ecology of human behaviour. The increasing recognition of the role of the environment and interaction with the environment in the organization of behaviour within the cognitive sciences has not been met with an equally disciplined and systematic account of that environment (Heft 2018 Ecol. Psychol . 30 , 99-123 (doi:10.1080/10407413.2018.1410045); McGann 2014 Synth. Philos. 29 , 217-233). Several bodies of work in behavioural ecology, anthropology and ecological psychology provide some frameworks for such an account. At present, however, the most systematic and theoretically disciplined account of the human behavioural ecosystem is that of behaviour settings, as developed by the researchers of the Midwest Psychological Field Station (see Barker 1968 Ecological psychology: concepts and methods for studying the environment of human behavior ). The articles in this theme issue provide a critical examination of these theoretical and methodological resources. The collection addresses their theoretical value in connecting with contemporary issues in cognitive science and research practice in psychology, as well as the importance of the methodological specifics of behaviour settings research. Additionally, articles diagnose limitations and identify points of potential extension of both theory and methods, particularly with regard to changes owing to the advance of technology, and the complex relationship between the individual and the collective in behaviour settings work. This article is part of the theme issue 'People, places, things, and communities: expanding behaviour settings theory in the twenty-first century'.

Background: Diagnosing drug reaction with eosinophilia and systemic symptoms (DRESS) can be challenging., Objectives: We sought to identify clinical and laboratory features outside of the Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria that distinguish patients with probable DRESS (RegiSCAR ≥ 4) from those with drug rash and eosinophilia (DRE)., Methods: Using international coding classifications of drug-induced fever, generalized skin eruption due to medications, and eosinophilia, a retrospective audit from 2008 to 2023 of hospitalized patients was performed., Results: Forty-four cases of DRESS were compared to 80 cases of DRE. In addition to the RegiSCAR distinguishing factors for DRESS were longer drug latency before symptom onset (median 21 vs 5 days, P  < .001) and higher alanine transaminase levels (increase by a factor of 2.49 [95% confidence interval, 1.56, 4.00; P  = .009]). Follow-up (mean 5.67 years) revealed a low rate of statewide drug alert reporting (29.6%) and drug allergy testing in DRESS (20.5%). Inadvertent reexposure to a culprit or structurally related drug resulted in recurrent DRESS in 3 patients (7.5%), and tolerance of structurally related drugs occurred in 8 patients (17.5%)., Conclusion: In this large study evaluating DRE patients whose disease does not meet the RegiSCAR criteria for DRESS, we found that additional factors outside the RegiSCAR criteria may help clinicians differentiate DRESS, which is critical for optimal and timely patient management. Our study also highlights the need for development of local protocols to ensure appropriate allergy labeling and testing are performed to prevent recurrent DRESS., Competing Interests: Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.)

Background: Humans are commonly exposed to plastic through their dietary intake and food consumption patterns. Plastic-associated chemicals (PAC), such as bisphenols and phthalates, are recognized as endocrine-disrupting and are associated with increased risk of cardiovascular disease and metabolic syndrome. However, accurate methods to assess dietary exposure to plastic products and PAC are inadequate, limiting interrogation of health impacts., Aim: To develop a tool that captures complete dietary exposure to plastics and establish a diet quality score to measure adherence to a low plastic dietary pattern., Methods: We developed the 24-h Dietary Recall - Plastic Exposure (24DR-PE) and administered it to healthy adults ( n  = 422). This computer-assisted, interviewer-administered tool systematically collects data on food volumes and types, packaging materials, storage, processing, cooking, and consumption methods to assess a food's exposure to plastic. Specifically, the 24DR-PE incorporates predefined criteria for identifying high-risk practices and food characteristics, such as individually packaged items or those microwaved in plastic, enabling the assignment of scores based on a theoretically derived Dietary Plastics Scoring Matrix., Conclusion: The 24DR-PE is the first tool specifically designed to capture detailed data on dietary exposures to plastic products. The next step is to validate the score using laboratory results of urine samples we collected contemporaneous to the dietary information. Once validated, the tool has potential for widespread distribution making it valuable for population monitoring, intervention guidance, and future research investigating the interplay between plastics, diet, and human health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Harray, Herrmann, Papendorf, Miller, Vermeersch, Smith and Lucas.)

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8 + T cells and exhausted CD8 + T cell (T EX ) clones. Focused analyses of T EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T EX , which synergizes with anti-PD-1 to reinvigorate T EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies., Competing Interests: Declaration of interests A.C.H. performed consulting work for Immunai and received research funding from Bristol Myers Squibb and Merck. R.S.H. has performed consulting work for Bristol Myers Squibb (exclusive of the current work). T.C.M. received honorarium for Scientific Advisory Board participation from: BMS, GigaGen, Merck, Pliant, Pfizer. G.C.K. is on the Merck Advisory Board. J.W. consulted for and have received less than $10,000 per annum from Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar, Celldex, Incyte, Biond, Moderna, ImCheck, Sellas, Evaxion, Pfizer, Regeneron, and EMD Serono and received $10–$25,000 from BMS for membership on advisory boards. J.W. also holds equity in Biond, Evaxion, OncoC4, and Instil Bio, and on scientific advisory boards for CytomX, Incyte, ImCheck, Biond, Sellas, Instil Bio, OncoC4, and NexImmune and remunerated between $10,000–$50,000. In addition, J.W. is named on a patent filed by Moffitt Cancer Center on an ipilimumab biomarker and on TIL preparation and also on a PD-1 patent filed by Biodesix; J.W. receives less than $6000 in royalties. D.B., E.K., and C.S. were employed by Immunai when engaged in this project. S.G. and D.T. are employees of BMS. C.A. is a consultant for Biotherapy Partners., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Weather is an important short-term, local driver of population size and dispersal, which in turn contribute to patterns of genetic diversity and differentiation within species. Climate change is leading to greater weather variability and more frequent extreme weather events. While the effects of long-term and broad-scale mean climate conditions on genetic variation are well studied, our understanding of the effects of weather variability and extreme conditions on genetic variation is less developed. We assessed the influence of temperature and snow depth on genetic diversity and differentiation of populations of the alpine butterfly, Parnassius smintheus. We examined the relationships between a suite of variables, including those representing extreme conditions, and population-level genetic diversity and differentiation across 1453 single nucleotide polymorphisms, using both linear and gravity models. We additionally examined effects of land cover variables known to influence dispersal and gene flow in this species. We found that extreme low temperature events and the lowest recorded mean snow depth were significant predictors of genetic diversity. Extreme low temperature events, mean snow depth and land cover resistance were significant predictors of genetic differentiation. These results are congruent with known effects of early winter weather on population size and habitat connectivity on dispersal in P. smintheus. Our results demonstrate the potential for changes in the frequency or magnitude of extreme weather events to alter patterns of genetic diversity and differentiation., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/μL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/μL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Allergic rhinitis (AR) has a high burden of disease in the Asia-Pacific region (APAC). Although guidelines provide recommendations regarding the diagnosis and treatment of AR, it is increasingly being recognised that there are gaps in their implementation. Patient-centred care involves accounting for the specific needs and desires of patients as well as including the patient in the decision-making process, and this may provide a means to reduce these gaps and consequently the burden of AR., Methods: A group of 11 experts in immunology and otorhinolaryngology from APAC provided information regarding their practices and experiences in the management of AR through an online survey. The group then discussed the barriers and solutions for the implementation of patient-centred care across the patient journey in a face-to-face meeting., Results: Key barriers to the implementation of patient-centred care for AR in APAC included a lack of patient awareness of the condition and treatment options, low adherence to treatments, financial constraints for patients, and time constraints for physicians. The solutions proposed include improving the knowledge of the patients about their conditions, the use of shared decision-making, the consideration of patient characteristics when choosing treatments, and the use of outcome measures to aid the optimisation of patient care. We provide specific recommendations for clinical practice., Conclusion: A greater focus on patient-centred approaches has the potential to improve the management of AR in APAC. More emphasis should be placed on each patient's specific health needs and desired outcomes., (© 2024 The Authors.)

Background: The clinical consequences of an antibiotic allergy label are detrimental, impacting health care delivery and patient outcomes. We assessed hospital inpatients with intent to offer free antibiotic allergy labeling (AAL) assessment within a randomized controlled trial., Objective: We sought to determine the feasibility of establishing an adult antibiotic allergy delabeling service in a Western Australian tertiary public hospital., Methods: Inpatients (N = 1503) with AAL were identified through medical records and screened for eligibility to participate in a randomized controlled trial. Those recruited were randomized to undergo assessment by skin testing ± oral challenge, or direct oral challenge. A control group received usual care., Results: Of the 1503 inpatients with an AAL, 429 (28.5%) were eligible for AAL assessment. The primary excluding factor (1074 [71.5%]) was contraindicated medication use (387 [36.0%]), followed by cognitive impairment (298 [27.9%]). Thirty-nine patients were randomized, of which 20 received allergy testing and 19 usual care; all patients were followed up for 5 years. Older patients were less likely to be eligible (10-year increase: odds ratio, 0.82; 95% CI, 0.77-0.88; P  < .0001), whereas surgical patients were more likely to be eligible than medical patients (odds ratio, 2.49; 95% CI, 1.97-3.16; P  < .0001)., Conclusions: Antibiotic allergy delabeling in the acute care context is not straightforward. Competing clinical concerns and patient acceptance are some barriers to an inpatient service. Nor is it apparent that inpatient versus outpatient testing is cost saving although select patient groups may benefit. Testing younger people and those with predicted high antibiotic usage will derive maximal individual and health system benefits., Competing Interests: The Government of Western Australia, Department of Health, Research Translation Project. BSvUS is partly funded by the 10.13039/501100020265Stan Perron Charitable Foundation and through a 10.13039/501100000925National Health and Medical Research Council Investigator Grant (grant no. 2009322). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Riboflavin (vitamin B 2 ) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including Mycobacterium tuberculosis (Mtb), can biosynthesize riboflavin de novo . Riboflavin precursors have also been implicated in the activation of mucosal-associated invariant T (MAIT) cells which recognize metabolites derived from the riboflavin biosynthesis pathway complexed to the MHC-I-like molecule, MR1. To investigate the biosynthesis and function of riboflavin and its pathway intermediates in mycobacterial metabolism and physiology, we constructed conditional knockdowns (hypomorphs) in riboflavin biosynthesis and utilization genes in Mycobacterium smegmatis (Msm) and Mtb by inducible CRISPR interference. Using this comprehensive panel of hypomorphs, we analyzed the impact of gene silencing on viability, on the transcription of (other) riboflavin pathway genes, on the levels of the pathway proteins, and on riboflavin itself. Our results revealed that (i) despite lacking a canonical transporter, both Msm and Mtb assimilate exogenous riboflavin when supplied at high concentration; (ii) there is functional redundancy in lumazine synthase activity in Msm; (iii) silencing of ribA2 or ribF is profoundly bactericidal in Mtb; and (iv) in Msm, ribA2 silencing results in concomitant knockdown of other pathway genes coupled with RibA2 and riboflavin depletion and is also bactericidal. In addition to their use in genetic validation of potential drug targets for tuberculosis, this collection of hypomorphs provides a useful resource for future studies investigating the role of pathway intermediates in MAIT cell recognition of mycobacteria., Importance: The pathway for biosynthesis and utilization of riboflavin, precursor of the essential coenzymes, FMN and FAD, is of particular interest in the flavin-rich pathogen, Mycobacterium tuberculosis (Mtb), for two important reasons: (i) the pathway includes potential tuberculosis (TB) drug targets and (ii) intermediates from the riboflavin biosynthesis pathway provide ligands for mucosal-associated invariant T (MAIT) cells, which have been implicated in TB pathogenesis. However, the riboflavin pathway is poorly understood in mycobacteria, which lack canonical mechanisms to transport this vitamin and to regulate flavin coenzyme homeostasis. By conditionally disrupting each step of the pathway and assessing the impact on mycobacterial viability and on the levels of the pathway proteins as well as riboflavin, our work provides genetic validation of the riboflavin pathway as a target for TB drug discovery and offers a resource for further exploring the association between riboflavin biosynthesis, MAIT cell activation, and TB infection and disease., Competing Interests: The authors declare no conflict of interest.

Hypersensitivity reactions to anticancer drugs include treatment-limiting toxicity. Standard drug desensitisation offers temporary tolerance and hence requires repetition. We used omalizumab, an anti-immunoglobulin E antibody, to overcome immediate and delayed hypersensitivity reactions to various anticancer drugs. Seven of the eight patients in the current study successfully resumed the desired anticancer drug regimen without standard desensitisation. No safety issues from omalizumab were observed., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Widespread fragmentation and degradation of habitats make organisms increasingly vulnerable to declines in population size. Immigration is a key process potentially affecting the rescue and persistence of populations in the face of such pressures. Field research addressing severe demographic declines in the context of immigration among interconnected local populations is limited owing to difficulties in detecting such demographic events and the need for long-term monitoring of populations. In a 17-subpopulation metapopulation of the butterfly, Parnassius smintheus , all adults observed in two adjacent patches were removed over eight consecutive generations. Despite this severe and long-term reduction in survival and reproduction, the targeted populations did not go extinct. Here, we use genetic data to assess the role of immigration versus in situ reproduction in allowing the persistence of these populations. We genotyped 471 samples collected from the targeted populations throughout the removal experiment at 152 single nucleotide polymorphisms. We found no reduction in the genetic diversity of the targeted populations over time, but a decrease in the number of loci in Hardy-Weinberg equilibrium, consistent with a high level of immigration from multiple surrounding populations. Our results highlight the role of connectivity and movement in making metapopulations resilient to even severe and protracted localized population reductions., Competing Interests: We declare we have no competing interests., (© 2024 The Author(s).)

Type 2 diabetes (T2D) is posing a serious public health concern with a considerable impact on human life and health expenditures worldwide. The disease develops when insulin plasma level is insufficient for coping insulin resistance, caused by the decline of pancreatic β-cell function and mass. In β-cells, the lipotoxicity exerted by saturated free fatty acids in particular palmitate (PA), which is chronically elevated in T2D, plays a major role in β-cell dysfunction and mass. However, there is a lack of human relevant in vitro model to identify the underlying mechanism through which palmitate induces β-cell failure. In this frame, we have previously developed a cutting-edge 3D spheroid model of β-like cells derived from human induced pluripotent stem cells. In the present work, we investigated the signaling pathways modified by palmitate in β-like cells derived spheroids. When compared to the 2D monolayer cultures, the transcriptome analysis (FDR set at  0.1) revealed that the 3D spheroids upregulated the pancreatic markers (such as GCG, IAPP genes), lipids metabolism and transporters (CD36, HMGSC2 genes), glucose transporter (SLC2A6). Then, the 3D spheroids are exposed to PA 0.5 mM for 72 h. The differential analysis demonstrated that 32 transcription factors and 135 target genes were mainly modulated (FDR set at  0.1) including the upregulation of lipid and carbohydrates metabolism (HMGSC2, LDHA, GLUT3), fibrin metabolism (FGG, FGB), apoptosis (CASP7). The pathway analysis using the 135 selected targets extracted the fibrin related biological process and wound healing in 3D PA treated conditions. An overall pathway gene set enrichment analysis, performed on the overall gene set (with pathway significance cutoff at 0.2), highlighted that PA perturbs the citrate cycle, FOXO signaling and Hippo signaling as observed in human islets studies. Additional RT-PCR confirmed induction of inflammatory (IGFBP1, IGFBP3) and cell growth (CCND1, Ki67) pathways by PA. All these changes were associated with unaffected glucose-stimulated insulin secretion (GSIS), suggesting that they precede the defect of insulin secretion and death induced by PA. Overall, we believe that our data demonstrate the potential of our spheroid 3D islet-like cells to investigate the pancreatic-like response to diabetogenic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA., Methods: Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings., Results: rhApoJ-treated APP23 presented fewer cortical CMBs (50-300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036)., Conclusions: Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation., (© 2024. The Author(s).)

The ultraviolet (UV) photodissociation dynamics of the 1-methylallyl (1-MA) radical were studied using the high- n Rydberg atom time-of-flight (HRTOF) technique in the wavelength region of 226-244 nm. The 1-MA radicals were produced by 193 nm photodissociation of the 3-chloro-1-butene and 1-chloro-2-butene precursor. The 1 + 1 REMPI spectrum of 1-MA agrees with the previous UV absorption spectrum in this wavelength region. Quantum chemistry calculations show that the UV absorption is mainly attributed to the 3 p z Rydberg state (perpendicular to the allyl plane). The H atom photofragment yield (PFY) spectrum of 1-MA from 3-chloro-1-butene displays a broad peak around 230 nm, while that from 1-chloro-2-butene peaks at ∼236 nm. The translational energy distributions of the H atom loss product channel, P ( E T )'s, show a bimodal distribution indicating two dissociation pathways in 1-MA. The major pathway is isotropic in product angular distribution with β ∼ 0 and has a low fraction of average translational energy in the total excess energy, ⟨ f T ⟩, in the range of 0.13-0.17; this pathway corresponds to unimolecular dissociation of 1-MA after internal conversion to form 1,3-butadiene + H. The minor pathway is anisotropic with β ∼ -0.23 and has a large ⟨ f T ⟩ of ∼0.62-0.72. This fast pathway suggests a direct dissociation of the methyl H atom on a repulsive excited state surface or the repulsive part of the ground state surface to form 1,3-butadiene + H. The fast/slow pathway branching ratio is in the range of 0.03-0.08.

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, highly prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation. Here, we show that sTDP43 is created as a byproduct of TDP43 autoregulation and cleared by nonsense mediated RNA decay (NMD). The sTDP43-encoding transcripts that escape NMD can lead to toxicity but are rapidly degraded post-translationally. Circumventing these regulatory mechanisms by overexpressing sTDP43 results in neurodegeneration in vitro and in vivo via N-terminal oligomerization and impairment of flTDP43 splicing activity, in addition to RNA binding-dependent gain-of-function toxicity. Collectively, these studies highlight endogenous mechanisms that tightly regulate sTDP43 expression and provide insight into the consequences of aberrant sTDP43 accumulation in disease.

Objectives: Ultrasonic (US) cutting of cartilage in orthopaedic surgery has received little attention despite its potential to reduce chondrocyte death which could enhance cartilage repair. We aimed to investigate whether an ultrasonically-vibrating scalpel to cut human articular cartilage could reduce chondrocyte death, and to determine if hyper-osmolarity could provide chondroprotection during the procedure., Methods: A scalpel (no. 15) was mounted on an ultrasonic transducer to resonate at 35 ​kHz with 30 ​μm vibrational displacement. Thirty-six fresh human femoral cartilage samples were divided into four groups based on ultrasonic activation (US or non-US) and saline osmolarity (300 or 600 mOsm/L). Cell viability was assessed using a live/dead cell assay and analysed quantitatively by confocal microscopy. Histology illustrated tissue surface changes at the cut site., Results: The overall chondrocyte death percentage at both the US and non-US cut sites showed comparable results (p ​> ​0.05) in both osmolarities. However, the zone of chondrocyte death was reduced by 31 ​± ​5% and 36 ​± ​6%, respectively, when comparing US cutting at 300 mOsm/L and 600 mOsm/L to the control group (non-US cutting; 300 mOsm/L) (p ​< ​0.05). The width of the cut was consistent at both sites, regardless of the method of cutting., Conclusion: Cutting human cartilage with US in the presence of 300 or 600 mOsm/L media was chondroprotective compared to normal (non-US) scalpel cutting in 300 mOsm/L medium. These results suggest chondroprotection can be achieved while cutting using a US scalpel and raised osmolarity, potentially improving cartilage regeneration and repair following injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International (OARSI).)

Chloride (Cl - ) is traditionally categorized as an antagonist of nitrate (NO 3 - ) because Cl - hinders plant NO 3 - transport and accumulation. However, we have recently defined Cl - as a beneficial macronutrient for higher plants, due to specific functions that lead to more efficient use of water, nitrogen (N) and CO 2 under optimal N and water supply. When accumulated in leaves at macronutrient levels, Cl - promotes growth through osmotic, physiological, metabolic, anatomical and cellular changes that improve plant performance under optimal NO 3 - nutrition. Nitrate over-fertilization in agriculture can adversely affect crop yield and nature, while its deficiency limits plant growth. To study the relationship between Cl - nutrition and NO 3 - availability, we have characterized different physiological responses such as growth and yield, N-use efficiency, water status, photosynthesis, leaf anatomy, pigments and antioxidants in tomato plants treated with or without 5 mM Cl - salts and increasing NO 3 - treatments (3-15 mM). First, we have demonstrated that 5 mM Cl - application can reduce the use of NO 3 - in the nutrient solution by up to half without detriment to plant growth and yield in tomato and other horticultural plants. Second, Cl - application reduced stress symptoms and improved plant growth under low-NO 3 - conditions. The Cl - -dependent resistance to low-N stress resulted from: more efficient use of the available NO 3 - ; improved plant osmotic and water status regulation; improved stomatal conductance and photosynthetic rate; and better antioxidant response. We proposed that beneficial Cl - levels increase the crop ability to grow better with lower NO 3 - requirements and withstand N deficiency, promoting a more sustainable and resilient agriculture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: In the past two decades, researchers have published mortality and morbidity rates in patients with very low hemoglobin levels declining blood transfusion. The clinical knowledge and tools available for the management of patients who decline transfusions have grown since these publications. The aim of our study was to provide a further update on outcomes associated with severe anemia in these patients., Study Design and Methods: A retrospective observational study of patients declining allogeneic blood transfusions with nadir hemoglobin levels ≤8 g/dL treated at The Institute for Blood Management, HELIOS Klinikum Gotha, Germany. Outcomes were in-hospital mortality within 30 days and composite morbidity or mortality, with morbidity events defined as acute myocardial infarction, cardiac failure, wound infection, arrhythmia, and pneumonia., Results: Between June 2008 and June 2021, The Institute for Blood Management treated 2841 admissions of which 159 (5.6%) recorded nadir hemoglobin levels ≤8 g/dL. Of these, five (3.1%) patients died in hospital within 30 days, including four (4.8%) patients admitted for surgical procedures and one (1.4%) medical admission. There was a significant increase in the unadjusted proportion of composite morbidity or mortality events with severity of nadir hemoglobin, with each gram decrease in hemoglobin associated with a 1.48 (95% confidence interval = 1.05-2.09; p = .025) times increase., Conclusion: Our comparatively lower proportion of patients reaching hemoglobin levels ≤8 g/dL and lower mortality rates suggest outcomes in patients with severe anemia is modifiable with the application of current patient blood management and bloodless medicine and surgery strategies., (© 2024 AABB.)

The origin of rupture segmentation along subduction zone megathrusts and linkages to the structural evolution of the subduction zone are poorly understood. Here, regional-scale seismic imaging of the Cascadia margin is used to characterize the megathrust spanning ~900 km from Vancouver Island to the California border, across the seismogenic zone to a few tens of kilometers from the coast. Discrete domains in lower plate geometry and sediment underthrusting are identified, not evident in prior regional plate models, which align with changes in lithology and structure of the upper plate and interpreted paleo-rupture patches. Strike-slip faults in the lower plate associated with oblique subduction mark boundaries between regions of distinct lower plate geometry. Their formation may be linked to changes in upper plate structure across long-lived upper plate faults. The Juan de Fuca plate is fragmenting within the seismogenic zone at Cascadia as the young plate bends beneath the heterogeneous upper plate resulting in structural domains that coincide with paleo-rupture segmentation.