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Decades of previous efforts to develop renal-sparing polyene antifungals were misguided by the classic membrane permeabilization model1. Recently, the clinically vital but also highly renal-toxic small-molecule natural product amphotericin B was instead found to kill fungi primarily by forming extramembraneous sponge-like aggregates that extract ergosterol from lipid bilayers2-6. Here we show that rapid and selective extraction of fungal ergosterol can yield potent and renal-sparing polyene antifungals. Cholesterol extraction was found to drive the toxicity of amphotericin B to human renal cells. Our examination of high-resolution structures of amphotericin B sponges in sterol-free and sterol-bound states guided us to a promising structural derivative that does not bind cholesterol and is thus renal sparing. This derivative was also less potent because it extracts ergosterol more slowly. Selective acceleration of ergosterol extraction with a second structural modification yielded a new polyene, AM-2-19, that is renal sparing in mice and primary human renal cells, potent against hundreds of pathogenic fungal strains, resistance evasive following serial passage in vitro and highly efficacious in animal models of invasive fungal infections. Thus, rational tuning of the dynamics of interactions between small molecules may lead to better treatments for fungal infections that still kill millions of people annually7,8 and potentially other resistance-evasive antimicrobials, including those that have recently been shown to operate through supramolecular structures that target specific lipids9.

Wellbeing is fundamental to an individual's ability to function and live well. Maori have some of the worst wellbeing statistics in New Zealand (Chalmers & Williams, 2018). From a te ao Maori perspective mana (power, authority) and kaitiakitanga (guardianship) encapsulate the critical relationships inherent in Maori understandings of wellbeing. These relationships highlight the interconnectedness and interdependence of humans with the people, places and things in their worlds, and the responsibilities associated with these people, places and things. This article discusses findings from a Teaching and Learning Research Initiative funded project, Te Whakapumautia te mana: Enhancing Mana Through Kaitiakitanga (2020-2021), and outlines implications for early childhood education (ECE) from the findings. The aim of the project was to investigate ways that ECE provides mokopuna (grand/child/ren) opportunities to recognise mana and understand ways to attain mana through being kaitiaki (guardians) of themselves, others and their environment, thereby contributing to a collective sense of wellbeing. The article focuses on kaiako (teacher/s) understandings of mana and kaitiakitanga and how they are currently reflected in contemporary ECE services.

Abstract It has recently been shown that KAT8, a genome-wide association study candidate risk gene for Parkinson’s Disease, is involved in PINK1/Parkin-dependant mitophagy. The KAT8 gene encodes a lysine acetyltransferase and represents the catalytically active subunit of the non-specific lethal epigenetic remodelling complex. In the current study, we show that contrary to KAT5 inhibition, dual inhibition of KAT5 and KAT8 via the MG149 compound inhibits the initial steps of the PINK1-dependant mitophagy process. More specifically, our study shows that following mitochondrial depolarisation induced by mitochondrial toxins, MG149 treatment inhibits PINK1-dependant mitophagy initiation by impairing PINK1 activation, and subsequent phosphorylation of Parkin and ubiquitin. While this inhibitory effect of MG149 on PINK1-activation is potent, MG149 treatment in the absence of mitochondrial toxins is sufficient to depolarise the mitochondrial membrane, recruit PINK1 and promote partial downstream recruitment of the autophagy receptor p62, leading to an increase in mitochondrial delivery to the lysosomes. Altogether, our study provides additional support for KAT8 as a regulator of mitophagy and autophagy processes.

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents.

Identification and sharing of lessons is a key aspect of emergency preparedness, resilience and response (EPRR) activity in the national health service (NHS) in England (NHS England, 2022). The overall intent of the lessons identification and implementation process is to improve readiness and response to future major incidents and emergencies, such that, wherever possible, patient harm is minimised and staff well-being is maximised.In this commentary, we draw on international literature to outline some of the major challenges in healthcare organisations to learning from major incidents and emergencies. We describe our experience of identifying lessons and set out the approach used by NHS England (London) to identifying lessons from the NHS response to the Covid-19 pandemic in the capital. We describe the knowledge garnered in our organisation about learning methods during the Covid-19 pandemic. The commentary considers the different approaches to identifying lessons, and the subsequent challenges of learning and implementation. This paper places its focus on the learning processes followed rather than what was learned as a result. It also explores whether the learning process undertaken by NHS England (London) demonstrates the hallmarks of a learning organisation.

The gauging of free surface flows in waterways provides the foundation for monitoring and managing the water resources of built and natural environments. A significant body of literature exists around the techniques and benefits of optical surface velocimetry methods to estimate flows in waterways without intrusive instruments or structures. However, to date, the operational application of these surface velocimetry methods has been limited by site configuration and inherent challenging optical variability across different natural and constructed waterway environments. This work demonstrates a significant advancement in the operationalisation of non-contact stream discharge gauging applied in the computer vision stream gauging (CVSG) system through the use of methods for remotely estimating water levels and adaptively learning discharge ratings over time. A cost-effective stereo camera-based stream gauging device (CVSG device) has been developed for streamlined site deployments and automated data collection. Evaluations between reference state-of-the-art discharge measurement technologies using DischargeLab (using surface structure image velocimetry), Hydro-STIV (using space–time image velocimetry), acoustic Doppler current profilers (ADCPs), and gauging station discharge ratings demonstrated that the optical surface velocimetry methods were capable of estimating discharge within a 5 %–15 % range between these best available measurement approaches. Furthermore, results indicated model machine learning approaches leveraging data to improve performance over a period of months at the study sites produced a marked 5 %–10 % improvement in discharge estimates, despite underlying noise in stereophotogrammetry water level or optical flow measurements. The operationalisation of optical surface velocimetry technology, such as CVSG, offers substantial advantages towards not only improving the overall density and availability of data used in stream gauging, but also providing a safe and non-contact approach for effectively measuring high-flow rates while providing an adaptive solution for gauging streams with non-stationary characteristics.

Abstract Myeloma patients presenting with renal failure continue to have a poor prognosis despite significant advances in anti‐myeloma therapy. MERIT was a randomised clinical trial (RCT), set up to evaluate if mechanical reduction of elevated free light chain levels (FLC) would result in clinical benefit. Completion of the planned seven plasma exchanges (PEs) in the first 14 days failed to show, for the exchange group, a greater reduction in FLC or any improvement in dialysis independence at 100 days or subsequently. To improve prognosis for these patients requires earlier diagnosis and prompt anti‐myeloma therapy with effectiveness guided by frequent FLC monitoring.

Objectives There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic.Methods The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2–5) and high grade (≥G3) infections.Results In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2–8), 23.4% of patients experienced ≥1 any grade (G2–5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16–75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (

Application of the [1,2]-Wittig rearrangement and cyclisation approach to 3-arylphthalides has been evaluated for the synthesis of three bioactive natural products. While this is successful in the case of crycolide, providing the second synthesis of this compound, the more sterically demanding targets isopestacin and cryphonectric acid prove not to be amenable to this approach, with the 2,6-disubstituted aryl groups causing the failure of the rearrangement and alkylation steps, respectively. Direct oxidation of the substituted benzhydrols resulting from [1,2]-Wittig rearrangement using MnO2 provides a new route to 3-aryl-3-hydroxyisoindolinones, and this method has been used in the synthesis of two 3-aryl-3-benzyloxyisoindolinone anticancer agents. [ABSTRACT FROM AUTHOR]

Summary: This Good Practice Paper provides recommendations for the use of advanced imaging for earlier diagnosis and morbidity prevention in multiple myeloma. It describes how advanced imaging contributes to optimal healthcare resource utilisation by in newly diagnosed and relapsed myeloma, and provides a perspective on future directions of myeloma imaging, including machine learning assisted reporting. [ABSTRACT FROM AUTHOR]

Purpose: In recent times, many universities have been pressured to become heavily involved in university branding. The purpose of this paper is to investigate students' perceptions of different international universities (brands) in terms of important university attributes, including the country in which the university's main campus is located and educational programs are designed (COD) and the method by which the educational services are distributed internationally (DM). Design/methodology/approach: Using a conjoint simulation procedure, this paper predicts the impact that university attributes have on Malaysian and Chinese students' preferences for international universities. Findings: The results suggest that, although COD and DM are important factors, the extent to which these factors dominate student preference differs significantly across students according to nationality. Research limitations/implications: The simulation suggests how international universities can improve their branding strategies, and highlights the need to understand students' preferences when developing marketing strategies. Originality/value: Past research has compared the importance of university attributes across countries from the perspective of students, but failed to assess this issue in the light of existing university brands (at an institutional or country level). Such knowledge can provide an indication of student preferences and competitive performance, which are of great interest to education marketers. The present study predicts the impact of various university attributes on Malaysian and Chinese students' preferences for specific international universities (brands) in four different countries, and changes in preference that occur when the style of delivery or course suitability is altered.