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Abstract Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Abstract Background Parkinson’s disease is incurable, and the rate of progression varies meaning that people face a long future with an unpredictable condition that can significantly influence their quality of life. To date, much of the international research has focused on measuring and describing quality of life in Parkinson’s from a quantitative perspective. Given its multidimensional nature, the present study aims to explore the concept using a qualitative approach so factors influencing self-reported quality of life can be understood in greater depth. Methods Using a qualitative descriptive approach, people with Parkinson’s disease who were survey participants in the first phase of a mixed methods study exploring factors influencing health-related quality of life were invited to participate in semi-structured interviews. Eighteen participants with high (n = 6), average (n = 6), and low (n = 6) health-related quality of life (PDQ-39 SI scores) were purposively invited to participate in this study. Audio recordings were transcribed and thematically analysed using Braun and Clarke’s steps (familiarisation, generating initial codes, searching for themes, reviewing, defining, naming themes, and producing the report). Results Thematic analysis revealed four overarching themes; ‘Living an interrupted life,’ ‘Striving for ‘I’ in independence,’ ‘Unravelling identities, roles, and relationships’ and ‘Reconfiguring life’. These themes illuminated participants’ experiences of living with Parkinson’s disease and what influenced their overall quality of life. Conclusions These findings add to the international literature by helping to achieve a deeper understanding of what it means to live with Parkinson’s disease and how it influences quality of life. Participants experienced a range of fluctuating, and interconnected motor and non-motor symptoms. This finding draws attention to the impact of the often-unpredictable nature of the condition on the physical, functional, psychological, social, and spiritual dimensions of life. Quality of life was positively influenced by perceptions of independence and negative feelings of dependence. Being independent was associated with freedom to plan, autonomy of choice, and freedom from feeling stressed, strained, or fearful. Having a positive outlook, using problem-focused strategies, and participating in hobbies, holidays, work, and involvement in local community committees were perceived positively across interviews as accentuating social dimensions of life. Resourcing self-management strategies, advanced nursing roles, and developing personalised models of community support may assist healthcare professionals in meeting the unique needs of people with Parkinson’s disease thereby supporting quality of life.

Abstract Background De-escalation is often advocated to reduce harm associated with violence and use of restrictive interventions, but there is insufficient understanding of factors that influence de-escalation behaviour in practice. For the first time, using behaviour change and implementation science methodology, this paper aims to identify the drivers that will enhance de-escalation in acute inpatient and psychiatric intensive care mental health settings. Methods Secondary analysis of 46 qualitative interviews with ward staff (n = 20) and patients (n = 26) informed by the Theoretical Domains Framework. Results Capabilities for de-escalation included knowledge (impact of trauma on memory and self-regulation and the aetiology and experience of voice hearing) and skills (emotional self-regulation, distress validation, reducing social distance, confirming autonomy, setting limits and problem-solving). Opportunities for de-escalation were limited by dysfunctional risk management cultures/ relationships between ward staff and clinical leadership, and a lack of patient involvement in safety maintenance. Motivation to engage in de-escalation was limited by negative emotion associated with moral formulations of patients and internal attributions for behaviour. Conclusion In addition to training that enhances knowledge and skills, interventions to enhance de-escalation should target ward and organisational cultures, as well as making fundamental changes to the social and physical structure of inpatient mental health wards. Psychological interventions targeting negative emotion in staff are needed to increase motivation. This paper provides a new evidence-based framework of indicative changes that will enhance de-escalation in adult acute mental health inpatient and PICU settings.

Abstract Many analyses in particle and nuclear physics use simulations to infer fundamental, effective, or phenomenological parameters of the underlying physics models. When the inference is performed with unfolded cross sections, the observables are designed using physics intuition and heuristics. We propose to design targeted observables with machine learning. Unfolded, differential cross sections in a neural network output contain the most information about parameters of interest and can be well-measured by construction. The networks are trained using a custom loss function that rewards outputs that are sensitive to the parameter(s) of interest while simultaneously penalizing outputs that are different between particle-level and detector-level (to minimize detector distortions). We demonstrate this idea in simulation using two physics models for inclusive measurements in deep inelastic scattering. We find that the new approach is more sensitive than classical observables at distinguishing the two models and also has a reduced unfolding uncertainty due to the reduced detector distortions.

Abstract In recent years, demographers have parsed variation in survivorship into two distinct components: the shape and the pace of ageing. The pace of ageing is defined by measures of longevity such as mean life expectancy or maximum longevity, whereas measures of the shape of ageing attempt to classify different shapes of the survivorship curve. We recently published a paper pointing out that a commonly used discretization of a shape measure, Keyfitz' entropy, does not correctly classify survivorship curves into negatively and positively senescing curves (de Vries et al., 2023). In that paper, we also suggested an alternative, accurate discrete‐time version of Keyfitz' entropy. de Vries et al. (2023) ended with two open questions, both of which have been answered by Giaimo (2024) now: (1) Can a discrete‐time entropy measure of survivorship be generalized beyond age‐based population models? Giaimo (2024) introduce a new formula that achieves this. (2) Will a discretization of Keyfitz' derivation of his measure as the elasticity of lifespan to a uniform change in mortality lead to the same formula as a discretization of Keyfitz' result? Giaimo (2024) answers: no. Here, we briefly discuss the implications of the results obtained by Giaimo (2024), and the implementation of his new formula into the Rpackage Rage, which is widely used for comparative demographic studies. We showcase the strength of the new method by reanalysing a comparison of Keyfitz' entropy to another shape measure. We find that the comparison is significantly altered by using Giaimo's new Keyfitz' formula. This example strengthens Giaimo's (2004) words of warning in approaching discretizations with attentiveness.

Abstract DNA double-strand break repair by homologous recombination has a specialised role in meiosis by generating crossovers that enable the formation of haploid germ cells. This requires meiosis-specific MEILB2-BRME1, which interacts with BRCA2 to facilitate loading of recombinases onto resected DNA ends. Here, we report the crystal structure of the MEILB2-BRME1 2:2 core complex, revealing a parallel four-helical assembly that recruits BRME1 to meiotic double-strand breaks in vivo. It forms an N-terminal β-cap that binds to DNA, and a MEILB2 coiled-coil that bridges to C-terminal ARM domains. Upon BRCA2-binding, MEILB2-BRME1 2:2 complexes dimerize into a V-shaped 2:4:4 complex, with rod-like MEILB2-BRME1 components arranged at right-angles. The β-caps located at the tips of the MEILB2-BRME1 limbs are separated by 25 nm, allowing them to bridge between DNA molecules. Thus, we propose that BRCA2 induces MEILB2-BRME1 to function as a DNA clamp, connecting resected DNA ends or homologous chromosomes to facilitate meiotic recombination.

Abstract The capacity to perceive tactile input at the fingertips, referred to as tactile sensitivity, is known to diminish with age due to regressive changes to mechanoreceptor density and morphology. Sensitivity is measured as perceptual responses to stimuli of varying intensity. Contrary to traditional sensitivity monitoring instruments, smartphones are uniquely suited for remote assessment and have shown to deliver highly calibrated stimuli along a broad spectrum of intensity, which may improve test reliability. The aim of this study was to evaluate a vibration-emitting smartphone application, the Vibratus App, as a mode of estimating tactile sensory thresholds in the aging adult. The peripheral nerve function of 40 neurologically healthy volunteers (ages 18–71) was measured using monofilaments, a 128-Hz tuning fork, the Vibratus App, and nerve conduction studies (NCS). Between group differences were analyzed to determine each measurement’s sensitivity to age. Spearman correlation coefficients depicted the associative strength between hand-held measurements and sensory nerve action potential (SNAP) amplitude. Inter-rater reliability of traditional instruments and the software-operated smartphone were assessed by intraclass correlation coefficient (ICC2,k ). Measurements taken with Vibratus App were significantly different between age groups (p

Abstract Desensitisation of the mu-opioid receptor (MOR) is proposed to underlie the initiation of opioid analgesic tolerance and previous work has shown that agonist-induced phosphorylation of the MOR C-tail contributes to this desensitisation. Moreover, phosphorylation is important for β-arrestin recruitment to the receptor, and ligands of different efficacies induce distinct phosphorylation barcodes. The C-tail 370TREHPSTANT379 motif harbours Ser/Thr residues important for these regulatory functions. 375Ser is the primary phosphorylation site of a ligand-dependent, hierarchical, and sequential process, whereby flanking 370Thr, 376Thr and 379Thr get subsequently and rapidly phosphorylated. Here we used GRK KO cells, phosphosite specific antibodies and site-directed mutagenesis to evaluate the contribution of the different GRK subfamilies to ligand-induced phosphorylation barcodes and β-arrestin2 recruitment. We show that both GRK2/3 and GRK5/6 subfamilies promote phosphorylation of 370Thr and 375Ser. Importantly, only GRK2/3 induce phosphorylation of 376Thr and 379Thr, and we identify these residues as key sites to promote robust β-arrestin recruitment to the MOR. These data provide insight into the mechanisms of MOR regulation and suggest that the cellular complement of GRK subfamilies plays an important role in determining the tissue responses of opioid agonists.

Abstract Destructive wildfire disasters are escalating globally, challenging existing fire management paradigms. The establishment of defensible space around homes in wildland and rural urban interfaces can help to reduce the risk of house loss and provide a safe area for residents and firefighters to defend the property from wildfire. Although defensible space is a well-established concept in fire management, it has received surprisingly limited scientific discussion. Here we reviewed guidelines on the creation of defensible space from Africa, Europe, North America, South America, and Oceania. We developed a conceptual model of defensible space framed around the key recommended approaches to mitigate fire attack mechanisms, which address fuel types, amount, and spatial distribution. We found that zonation within the defensible space is commonly recommended; reduction (or removal) of all fuels, and particularly dead plant material, is usually suggested in close (

Wastewater surveillance is an effective way to track the prevalence of infectious agents within a community and, potentially, the spread of pathogens between jurisdictions. We conducted a retrospective wastewater surveillance study of the 2022–23 influenza season in 2 communities, Detroit, Michigan, USA, and Windsor-Essex, Ontario, Canada, that form North America’s largest cross-border conurbation. We observed a positive relationship between influenza-related hospitalizations and the influenza A virus (IAV) wastewater signal in Windsor-Essex (ρ = 0.785; p

Abstract Tuning the properties of a pair of entangled electron and hole in a light-induced exciton is a fundamentally intriguing inquiry for quantum science. Here, using semiconducting hybrid perovskite as an exploratory platform, we discover that Nd2+-doped CH3NH3PbI3 (MAPbI3) perovskite exhibits a Kondo-like exciton-spin interaction under cryogenic and photoexcitation conditions. The feedback to such interaction between excitons in perovskite and the localized spins in Nd2+ is observed as notably prolonged carrier lifetimes measured by time-resolved photoluminescence, ~10 times to that of pristine MAPbI3 without Nd2+ dopant. From a mechanistic standpoint, such extended charge separation states are the consequence of the trap state enabled by the antiferromagnetic exchange interaction between the light-induced exciton and the localized 4 f spins of the Nd2+ in the proximity. Importantly, this Kondo-like exciton-spin interaction can be modulated by either increasing Nd2+ doping concentration that enhances the coupling between the exciton and Nd2+ 4 f spins as evidenced by elongated carrier lifetime, or by using an external magnetic field that can nullify the spin-dependent exchange interaction therein due to the unified orientations of Nd2+ spin angular momentum, thereby leading to exciton recombination at the dynamics comparable to pristine MAPbI3.

Abstract Background Post graduate master’s degree qualifications are increasingly required to advance allied health profession careers in education, clinical practice, leadership, and research. Successful awards are dependent on completion of a research dissertation project. Despite the high volume of experience gained and research undertaken at this level, the benefits and impact are not well understood. Our study aimed to evaluate the perceived impact and legacy of master’s degree training and research on allied health profession practice and research activity. Methods A cross-sectional online survey design was used to collect data from allied health professionals working in the United Kingdom who had completed a postgraduate master’s degree. Participants were recruited voluntarily using social media and clinical interest group advertisement. Data was collected between October and December 2022 and was analysed using descriptive statistics and narrative content analysis. Informed consent was gained, and the study was approved by the university research ethics committee. Results Eighty-four responses were received from nine allied health professions with paramedics and physiotherapists forming the majority (57%) of respondents. Primary motivation for completion of the master’s degree was for clinical career progression (n = 44, 52.4%) and formation of the research dissertation question was predominantly sourced from individual ideas (n = 58, 69%). Formal research output was low with 27.4% (n = 23) of projects published in peer reviewed journal and a third of projects reporting no output or dissemination at all. Perceived impact was rated highest in individual learning outcomes, such as improving confidence and capability in clinical practice and research skills. Ongoing research engagement and activity was high with over two thirds (n = 57, 67.9%) involved in formal research projects. Conclusion The focus of master's degree level research was largely self-generated with the highest perceived impact on individual outcomes rather than broader clinical service and organisation influence. Formal output from master’s research was low, but ongoing research engagement and activity was high suggesting master’s degree training is an under-recognised source for AHP research capacity building. Future research should investigate the potential benefits of better coordinated and prioritised research at master’s degree level on professional and organisational impact.

Abstract Background Low awareness of chronic conditions raises the risk of poorer health outcomes and may result in healthcare utilization and spending in response to symptoms of undiagnosed conditions. Little evidence exists, particularly from lower-middle-income countries, on the health and healthcare use of undiagnosed people with an indication of a condition. This study aimed to compare health (physical, mental, and health-related quality of life (HRQoL)) and healthcare (inpatient and outpatient visits and out-of-pocket (OOP) medical spending) outcomes of undiagnosed Sri Lankans with an indication of coronary heart disease (CHD), hypertension, diabetes, and depression with the outcomes of their compatriots who were diagnosed or had no indication of these conditions. Methods This study used a nationally representative survey of Sri Lankan adults to identify people with an indication of CHD, hypertension, diabetes, or depression, and ascertain if they were diagnosed. Outcomes were self-reported measures of physical and mental functioning (12-Item Short Form Survey (SF-12)), HRQoL (EQ-5D-5L), inpatient and outpatient visits, and OOP spending. For each condition, we estimated the mean of each outcome for respondents with (a) no indication, (b) an indication without diagnosis, and (c) a diagnosis. We adjusted the group differences in these means for socio-demographic covariates using ordinary least squares (OLS) regression for physical and mental function, Tobit regression for HRQoL, and a generalized linear model (GLM) for healthcare visits and OOP spending. Results An indication of each of CHD and depression, which are typically symptomatic, was associated with a lower adjusted mean of physical (CHD -2.65, 95% CI -3.66, -1.63; depression -5.78, 95% CI -6.91, -4.64) and mental functioning (CHD -2.25, 95% CI -3.38, -1.12; depression -6.70, 95% CI -7.97, -5.43) and, for CHD, more annual outpatient visits (2.13, 95% CI 0.81, 3.44) compared with no indication of the respective condition. There were no such differences for indications of hypertension and diabetes, which are often asymptomatic. Conclusions Living with undiagnosed CHD and depression was associated with worse health and, for CHD, greater utilization of healthcare. Diagnosis and management of these symptomatic conditions can potentially improve health partly through substitution of effective healthcare for that which primarily responds to symptoms.

Abstract Algal biomass is a viable source of chemicals and metabolites for various energy, nutritional, medicinal and agricultural uses. While stresses have commonly been used to induce metabolite accumulation in microalgae in attempts to enhance high-value product yields, this is often very detrimental to growth. Therefore, understanding how to modify metabolism without deleterious consequences is highly beneficial. We demonstrate that low-doses (1–5 Gy) of ionizing radiation in the X-ray range induces a non-toxic, hormetic response in microalgae to promote metabolic activation. We identify specific radiation exposure parameters that give reproducible metabolic responses in Chlorella sorokiniana caused by transcriptional changes. This includes up-regulation of >30 lipid metabolism genes, such as genes encoding an acetyl-CoA carboxylase subunit, phosphatidic acid phosphatase, lysophosphatidic acid acyltransferase, and diacylglycerol acyltransferase. The outcome is an increased lipid yield in stationary phase cultures by 25% in just 24 hours, without any negative effects on cell viability or biomass.

Summary: Ageing affects food choices, food-related life and the nutritional status of older people. The latter may be addressed through the targeted development of specific food products. For example, the development of protein-fortified foods could help older adults increase their protein consumption, thus contributing to the prevention of age-related diseases. This exploratory qualitative study focused on exploring the factors affecting the choice of protein-fortified foods amongst community-dwelling Irish adults ≥ 55 years of age. Sixteen community-dwelling adults (between 55 and 89 years) residing in Ireland were interviewed online in relation to their preferences and perceptions of these foods. Thematic analysis of the transcribed interviews revealed that the willingness to consume protein-fortified foods was low and that the interviewees generally preferred to consume foods naturally high in protein. However, if they had to consume protein-fortified foods, their choice and acceptance would depend on the product characteristics such as its sensory properties, functionality, composition, nutritional value and digestibility. Moreover, most of the interviewees would prefer to consume savoury (e.g. bread, soup) rather than sweet (e.g. pancake, ice cream) products. The study also revealed individual-related factors that affected acceptance of protein-fortified foods including sociodemographic characteristics (living situation), physiological factors (health issues), food-related life (diet and food habits) and food-related awareness (lack of information about protein). This preliminary qualitative study provides valuable information to help guide the development of protein-fortified foods acceptable by the target population.

Introduction: Recent policy changes in Washington State presented a unique opportunity to pair evidence-based interventions with first responder services to combat increasing opioid overdoses. However, little is known about how these interventions should be implemented. In partnership with the Research with Expert Advisors on Drug Use team, a group of academically trained and community-trained researchers with lived and living experience of substance use, we examined facilitators and barriers to adopting leave-behind naloxone, field-based buprenorphine initiation, and HIV and hepatitis C virus (HCV) testing for first responder programs. Methods: Our team completed semi-structured, qualitative interviews with 32 first responders, mobile integrated health staff, and emergency medical services (EMS) leaders in King County, Washington, from February–May 2022. Semi-structured interviews were recorded, transcribed, and coded using an integrated deductive and inductive thematic analysis approach grounded in community-engaged research principles. We collected data until saturation was achieved. Data collection and analysis were informed by the Consolidated Framework for Implementation Research. Two investigators coded independently until 100% consensus was reached. Results: Our thematic analysis revealed several perceived facilitators (ie, tension for change, relative advantage, and compatibility) and barriers (ie, limited adaptability, lack of evidence strength and quality, and prohibitive cost) to the adoption of these evidence-based clinical interventions for first responder systems. There was widespread support for the distribution of leave-behind naloxone, although funding was identified as a barrier. Many believed field-based initiation of buprenorphine treatment could provide a more effective response to overdose management, but there were significant concerns that this intervention could run counter to the rapid care model. Lastly, participants worried that HIV and HCV testing was inappropriate for first responders to conduct but recommended that this service be provided by mobile integrated health staff. Conclusion: These results have informed local EMS strategic planning, which will inform roll out of process improvements in King County, Washington. Future work should evaluate the impact of these interventions on the health of overdose survivors.

Abstract Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.

The current gold standard grafting material is autologous bone due to its osteoinductive and osteoconductive properties. Autograft harvesting results in donors site morbidity. Coral scaffolds offer a natural autograft alternative, sharing the density and porosity of human bone. This study investigated the biocompatibility and osteogenic potential of a novel, sustainably grown Pocillopora scaffold with human bone marrow-derived mesenchymal stromal cells (MSCs). The coral-derived scaffold displays a highly textured topography, with concavities of uniform size and a high calcium carbonate content. Large scaffold samples exhibit compressive and diametral tensile strengths in the range of trabecular bone, with strengths likely increasing for smaller particulate samples. Following the in vitro seeding of MSCs adjacent to the scaffold, the MSCs remained viable, continued proliferating and metabolising, demonstrating biocompatibility. The seeded MSCs densely covered the coral scaffold with organized, aligned cultures with a fibroblastic morphology. In vivo coral scaffolds with MSCs supported earlier bone and blood vessel formation as compared to control constructs containing TCP-HA and MSCs. This work characterized a novel, sustainably grown coral scaffold that was biocompatible with MSCs and supports their in vivo osteogenic differentiation, advancing the current repertoire of biomaterials for bone grafting.

Abstract Background Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 −/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 −/y rats. Methods To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 −/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 −/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Abstract The Aurignacian is the first European technocomplex assigned to Homo sapiens recognized across a wide geographic extent. Although archaeologists have identified marked chrono-cultural shifts within the Aurignacian mostly by examining the techno-typological variations of stone and osseous tools, unraveling the underlying processes driving these changes remains a significant scientific challenge. Scholars have, for instance, hypothesized that the Campanian Ignimbrite (CI) super-eruption and the climatic deterioration associated with the onset of Heinrich Event 4 had a substantial impact on European foraging groups. The technological shift from the Protoaurignacian to the Early Aurignacian is regarded as an archaeological manifestation of adaptation to changing environments. However, some of the most crucial regions and stratigraphic sequences for testing these scenarios have been overlooked. In this study, we delve into the high-resolution stratigraphic sequence of Grotta di Castelcivita in southern Italy. Here, the Uluzzian is followed by three Aurignacian layers, sealed by the eruptive units of the CI. Employing a comprehensive range of quantitative methods—encompassing attribute analysis, 3D model analysis, and geometric morphometrics—we demonstrate that the key technological feature commonly associated with the Early Aurignacian developed well before the deposition of the CI tephra. Our study provides thus the first direct evidence that the volcanic super-eruption played no role in this cultural process. Furthermore, we show that local paleo-environmental proxies do not correlate with the identified patterns of cultural continuity and discontinuity. Consequently, we propose alternative research paths to explore the role of demography and regional trajectories in the development of the Upper Paleolithic.

Abstract Background Intellectual disability services have and continue to experience changes in service provision. This has an implication for leadership in practice as the quality of leadership has a direct influence on staff practice and care provided. Aim To design, deliver, and evaluate a leadership programme for nurse and social care managers in Ireland. Design An accredited programme was designed based on evidence from literature, practice, and national expertise. A cross-sectional survey was used to collect information on the attitudes and behaviour of participants before commencing and after completing the programme. Data from the questionnaires were analysed using SPSS and open-ended questions were analysed using content analysis. Setting Intellectual disability services. Participants 102 participants completed the programme and survey. Methods Pre-post survey and reported using the CROSS guidelines. Results Participants’ expectations were rated highly, and all items scored higher in the post-survey. Qualitative data was overall positive regarding opportunities for more time to work through each aspect of the programme. The key learning was through the forum day where participants shared their group projects. Conclusions Overall, the programme was positively evaluated and through engaging with the programme participants’ perceptions moved from seeing leadership as mostly task-oriented to realising that qualities such as good communication, person-centredness, advocacy, supporting, role modelling, and empowering are key to leadership.

Abstract Postmortem CT (PMCT) has become increasingly accepted alongside skeletal surveys as a critical part of investigation in childhood deaths, either as part of a suite of non-invasive investigations through parental choice, or comprehensive evaluation in a forensic setting. Whilst CT image acquisition and protocols have been published and are relatively standardised, CT imaging reporting remains highly variable, largely dependent upon reporter experience and expertise. The main “risk” in PMCT is the over-interpretation of normal physiological changes on imaging as pathological, potentially leading to misdiagnosis or overdiagnosis of the disease. In this article, we present a pragmatic standardised reporting framework, developed over a decade of PMCT reporting in children in our institution, with examples of positive and negative findings, so that it may aid in the interpretation of PMCT images with those less experienced in paediatric findings and postmortem imaging. Critical relevance statement Standardised reporting using a common framework with a sound understanding of normal postmortem changes that occur in children are crucial in avoiding common reporting errors at postmortem CT. Key Points Familiarity with postmortem imaging is required for useful image reporting, and reporting standards vary. Understanding normal postmortem change from significant abnormalities requires training and experience. Following a template may remind reporters what to include and help improve performance. Graphical Abstract

Abstract Background Policymakers and researchers recommend supporting the capabilities of feedback recipients to increase the quality of care. There are different ways to support capabilities. We aimed to describe the content and delivery of feedback facilitation interventions delivered alongside audit and feedback within randomised controlled trials. Methods We included papers describing feedback facilitation identified by the latest Cochrane review of audit and feedback. The piloted extraction proforma was based upon a framework to describe intervention content, with additional prompts relating to the identification of influences, selection of improvement actions and consideration of priorities and implications. We describe the content and delivery graphically, statistically and narratively. Results We reviewed 146 papers describing 104 feedback facilitation interventions. Across included studies, feedback facilitation contained 26 different implementation strategies. There was a median of three implementation strategies per intervention and evidence that the number of strategies per intervention is increasing. Theory was used in 35 trials, although the precise role of theory was poorly described. Ten studies provided a logic model and six of these described their mechanisms of action. Both the exploration of influences and the selection of improvement actions were described in 46 of the feedback facilitation interventions; we describe who undertook this tailoring work. Exploring dose, there was large variation in duration (15–1800 min), frequency (1 to 42 times) and number of recipients per site (1 to 135). There were important gaps in reporting, but some evidence that reporting is improving over time. Conclusions Heterogeneity in the design of feedback facilitation needs to be considered when assessing the intervention’s effectiveness. We describe explicit feedback facilitation choices for future intervention developers based upon choices made to date. We found the Expert Recommendations for Implementing Change to be valuable when describing intervention components, with the potential for some minor clarifications in terms and for greater specificity by intervention providers. Reporting demonstrated extensive gaps which hinder both replication and learning. Feedback facilitation providers are recommended to close reporting gaps that hinder replication. Future work should seek to address the ‘opportunity’ for improvement activity, defined as factors that lie outside the individual that make care or improvement behaviour possible. Review registration The study protocol was published at: https://www.protocols.io/private/4DA5DE33B68E11ED9EF70A58A9FEAC02 .

Abstract Background Nursing homes and other long-term care services account for a disparate share of COVID-19 cases and casualties worldwide. During COVID-19 there is a distinct need to preserve a holistic view of the wellbeing of residents of nursing homes, be mindful of their rights as citizens, and to be aware of protecting residents from infection. The delivery of health and social care throughout a pandemic must remain person-centred and adhere to a human rights-based approach. Methods This study aimed to capture nursing home residents, their families and staff’s perspective of the nursing homes residents experience, approaches of staff and the nursing home environment. An online survey was distributed via stakeholder networks and online platforms across Ireland. This study was performed and reported in line with the Consensus-Based Checklist for Reporting of Survey Studies (CROSS). Results 25 residents, 42 family members and 51 staff completed the survey (n = 118). Across the domains measured all but one aspect scored above 50% (residents get up and go to bed when they want 41.5%) with the highest score of 89.1% scored for the nursing home is comfortable and well-kept. Results highlight evidence of positive experiences and endeavours to preserve social connections, residents were in a safe place cared for by staff who did their best in a difficult position and who went above and beyond their duty of care. However, some families reported poor communication, no internet connections, not enough phones or tablets, and that staff were busy and unable at times to assist residents who needed help using phones/tablets. Conclusion This study highlights the importance of human rights and how they ought to inform and shape the advancement of public health advice and policy documents. Overall, nursing home residents, their families and staff reported favourably on the study measures. However, issues pertaining to communication are essential and there is a need to address issues such as the provision of accurate timely information, communication infrastructure and resources, and inconsistencies in communications. Of note is that while healthcare professionals have a duty to uphold the rights of nursing home residents, they themselves have human rights which must also be protected and supported.

Abstract The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs—and perhaps other NPs—can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

Abstract Background The COVID-19 pandemic has profoundly impacted individuals, society, and healthcare organisations worldwide. Recent international research suggests that concerns, needs, and experiences of healthcare workers (HCWs) have evolved throughout the pandemic. This longitudinal qualitative study explored the evolving views and experiences of Victorian healthcare workers (HCWs) and organisational key personnel during the coronavirus disease (COVID-19) pandemic. Methods We recruited participants from the Coronavirus in Victorian Health and Aged care workers (COVIC-HA) study cohort. We conducted two rounds of semi-structured interviews with HCWs and organisational key personnel from three different healthcare settings (hospital, aged care and primary care) in Victoria, Australia, in May-July 2021 and May-July 2022. Data were analysed thematically using trajectory and recurrent cross-sectional approaches, guided by a temporal change framework. Results Twelve HCWs and five key personnel from various professional roles participated in interviews at both timepoints. Expected themes derived from mid-2021 interviews (navigating uncertainty, maintaining service delivery, and addressing staff needs) evolved over time. Concerns shifted from personal health and safety to workforce pressures, contributing to HCW burnout and fatigue and ongoing mental health support needs. New themes emerged from mid-2022 interviews, including managing ongoing COVID-19 impacts and supporting the healthcare workforce into the future. Clear and consistent communication, stable guidelines and forward-looking organisational responses were considered crucial. Conclusions Our longitudinal qualitative study highlighted the evolving impact of the COVID-19 pandemic on HCWs’ perceptions, health and wellbeing and uncovered long-term sector vulnerabilities. Analysing HCW experiences and key personnel insights over time and across different pandemic phases provided crucial insights for policymakers to protect the healthcare workforce. Findings emphasise the need for proactive strategies that prioritise HCWs’ wellbeing and workforce sustainability. Policy makers must invest in HCW health and wellbeing initiatives alongside healthcare system improvements to ensure resilience and capacity to meet future challenges. Trial registration This study was approved through the Victorian Streamlined Ethical Review Process (SERP: Project Number 68,086) and registered with ANZCTR (ACTRN12621000533897) on 6 May 2021.

Abstract Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson’s disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson’s disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

Abstract Background Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI). Methods Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21. Results Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p 50% (p

Abstract Background Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5’UTRs, correlates with gene dosage sensitivity. Results We investigate 5’UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5’UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5’UTR length and complexity. Genes that are most intolerant to LoF have longer 5’UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. Conclusions Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.

BackgroundIn robot-assisted laparoscopic prostatectomy surgery patients are tilted 30°–40° head-down. Knowledge of cerebral autoregulation and determinants of cerebral blood flow in this setting is limited, though postoperative cognitive impairment has been reported. This observational study describes the hemodynamic determinants of cerebral blood flow and dynamics of cerebral perfusion pressure during surgery in the Trendelenburg position and the correlations with postoperative cognition measures.Materials and methodsWe included patients scheduled for robot-assisted laparoscopic prostatectomy without known cerebrovascular disease. Cardiac index, mean arterial pressure, central venous pressure, optic nerve sheath diameter as a surrogate for intracranial pressure, ultrasound-measured internal carotid artery (ICA) blood flow and PaCO2 were recorded at six time points (awake, anesthetized, immediately after tilt, 1 h of tilt, just before end of tilt, and before emerging from anaesthesia). Comprehensive cognitive tests were performed before surgery and 10 and 180 days post-surgery. Data was evaluated using linear regression models.ResultsForty-four males with a mean age of 67 years were included. Duration of anesthesia was 226 min [IQR 201,266] with 165 min [134,199] in head-down tilt. ICA flow decreased after induction of anesthesia (483 vs. 344 ml/min) and remained lowered before increasing at return to horizontal position (331 vs. 407 ml/min). Cerebral perfusion pressure decreased after 1 h tilt (from 73 to 62 mmHg) and remained lowered (66 mmHg) also after return to horizontal position. Optic nerve sheath diameter increased from mean 5.8 mm to 6.4 mm during the course of surgery. ICA flow correlated positively with cardiac index (β 0.367. 1 L/min/m2 increase corresponding to 92 ml/min increased ICA flow). PaCO2 had a positive effect on ICA flow (β 0.145. 1 kPa increase corresponding to 49 ml/min increased ICA flow), while mean arterial pressure had a negative effect (β −0.203. 10 mmHg increase corresponding to a 29 ml/min decline in ICA flow). We found no evidence of postoperative cognitive dysfunction.ConclusionICA flow and cerebral perfusion pressure were significantly reduced during robot-assisted laparoscopic prostatectomy surgery. ICA flow positively correlated with cardiac index and PaCO2, but negatively with mean arterial pressure. Postoperative cognitive function was not impaired.

Rodent studies have shown that alternative splicing in neurons plays important roles in development and maturity, and is regulatable by signals such as electrical activity. However, rodent-human similarities are less well explored. We compared basal and activity-dependent exon splicing in cortical-patterned human ESC-derived neurons with that in cortical mouse ESC-derived neurons, primary mouse cortical neurons at two developmental stages, and mouse hippocampal neurons, focussing on conserved orthologous exons. Both basal exon inclusion levels and activity-dependent changes in splicing showed human-mouse correlation. Conserved activity regulated exons are enriched in RBFOX, SAM68, NOVA and PTBP targets, and centered on cytoskeletal organization, mRNA processing, and synaptic signaling genes. However, human-mouse correlations were weaker than inter-mouse comparisons of neurons from different brain regions, developmental stages and origin (ESC vs. primary), suggestive of some inter-species divergence. The set of genes where activity-dependent splicing was observed only in human neurons were dominated by those involved in lipid biosynthesis, signaling and trafficking. Study of human exon splicing in mouse Tc1 neurons carrying human chromosome-21 showed that neuronal basal exon inclusion was influenced by cis-acting sequences, although may not be sufficient to confer activity-responsiveness in an allospecific environment. Overall, these comparisons suggest that neuronal alternative splicing should be confirmed in a human-relevant system even when exon structure is evolutionarily conserved.

Abstract Our understanding of the similarity in trajectories of ecosystem changes during different directions of environmental change is limited. For example, do the dominant organisms exhibit the same responses to different directions of environmental change, that is, do they exhibit symmetric responses? Here, we explore whether such response symmetry is determined and controlled by the symmetry in the features of the underlying biological system (i.e., system symmetry), such as in the network and strength of biotic and abiotic processes, and in symmetry of the environmental change (i.e., environmental symmetry). For this exploration, we developed and used a simple mathematical model of a microbial ecosystem driven by mutual inhibition in which we could vary the amount of system and environmental symmetry. Our results show that perfect system and environmental symmetry indeed produce perfect response symmetry. Moreover, introducing asymmetry in biological systems or in the environment proportionally increases response asymmetry. These findings suggest using symmetries in ecosystem structure and interaction strength to better understand and predict similarities in degradation and restoration phases of environmental change.

Abstract Objective Sudden sensorineural hearing loss (SSNHL) is a rare presentation requiring timely diagnosis and treatment. Despite recommendations against obtaining computed tomography (CT) imaging of the head in clinical practice guidelines, this investigation is often completed in patients with sudden hearing loss. The aim of this study was to determine the proportion of patients undergoing CT imaging of the head for SSNHL at our center and identify predictive factors for the use of CT imaging. Methods Retrospective chart review of adult patients referred for SSNHL to two academic otology/neurotology practices between January 2018 and May 2021. Patient demographics, comorbid medical conditions, associated symptoms, location of initial presentation, audiologic results, and completed imaging studies were collected. Statistical analysis was performed with SPSS software. Results Ninety‐eight patients with audiologically confirmed SSNHL were included. Twenty‐two patients (22.4%) underwent CT imaging as an investigation for SSNHL. The presence of vertigo (odds ratio 6.90; 95% confidence interval 2.43, 19.56) and presentation to the emergency room (odds ratio 8.71; 95% confidence interval 3.02, 25.16) were significantly associated with undergoing CT imaging. These two variables were statistically significant independent predictors of CT imaging on multivariate regression analysis (p = .01, p = .001, respectively). Conclusion A significant proportion of patients with SSNHL undergo low‐yield CT imaging of the head, particularly patients presenting to the emergency room with vertigo. These results highlight an opportunity for focused education and quality improvement initiatives. Level of evidence: 4.

Abstract Skeletal muscle (SM) acts as a secretory organ, capable of releasing myokines and extracellular vesicles (SM‐EVs) that impact myogenesis and homeostasis. While age‐related changes have been previously reported in murine SM‐EVs, no study has comprehensively profiled SM‐EV in human models. To this end, we provide the first comprehensive comparison of SM‐EVs from young and old human primary skeletal muscle cells (HPMCs) to map changes associated with SM ageing. HPMCs, isolated from young (24 ± 1.7 years old) and older (69 ± 2.6 years old) participants, were immunomagnetically sorted based on the presence of the myogenic marker CD56 (N‐CAM) and cultured as pure (100% CD56+) or mixed populations (MP: 90% CD56+). SM‐EVs were isolated using an optimised protocol combining ultrafiltration and size exclusion chromatography (UF + SEC) and their biological content was extensively characterised using Raman spectroscopy (RS) and liquid chromatography mass spectrometry (LC‐MS). Minimal variations in basic EV parameters (particle number, size, protein markers) were observed between young and old populations. However, biochemical fingerprinting by RS highlighted increased protein (amide I), lipid (phospholipids and phosphatidylcholine) and hypoxanthine signatures for older SM‐EVs. Through LC‐MS, we identified 84 shared proteins with functions principally related to cell homeostasis, muscle maintenance and transcriptional regulation. Significantly, SM‐EVs from older participants were comparatively enriched in proteins involved in oxidative stress and DNA/RNA mutagenesis, such as E3 ubiquitin‐protein ligase TTC3 (TTC3), little elongation complex subunit 1 (ICE1) and Acetyl‐CoA carboxylase 1 (ACACA). These data suggest SM‐EVs could provide an alternative pathway for homeostasis and detoxification during SM ageing.

Objective This umbrella review synthesises evidence on the methods used to recruit and retain ethnically diverse participants and report and analyse variables related to ethnic diversity in randomised controlled trials.Design Umbrella review.Data sources Ovid MEDLINE, Ovid Embase, CINAHL, PsycINFO and Cochrane and Campbell Libraries for review papers published between 1 January 2010 and 13 May 2024.Eligibility criteria English language systematic reviews focusing on inclusion and reporting of ethnicity variables. Methodological quality was assessed using the AMSTAR 2 tool.Results Sixty-two systematic reviews were included. Findings point to limited representation and reporting of ethnic diversity in trials. Recruitment strategies commonly reported by the reviews were community engagement, advertisement, face-to-face recruitment, cultural targeting, clinical referral, community presentation, use of technology, incentives and research partnership with communities. Retention strategies highlighted by the reviews included frequent follow-ups on participants to check how they are doing in the study, provision of incentives, use of tailored approaches and culturally appropriate interventions. The findings point to a limited focus on the analysis of variables relevant to ethnic diversity in trials even when they are reported in trials.Conclusion Significant improvements are required in enhancing the recruitment and retention of ethnically diverse participants in trials as well as analysis and reporting of variables relating to diversity in clinical trials.PROSPERO registration number CRD42022325241.

IntroductionStartle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI.MethodsUsing silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation.ResultsOver time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9–13%). No significant neural activity for PPI was detected.DiscussionStartle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

Abstract Keloids are benign fibroproliferative tumours with a high recurrence rate of 20%–100%, therefore, multimodal treatment is recommended. We report the case of an exceptionally large facial keloid precipitated by a vicious cycle of chronic inflammation and mechanical skin traction and discuss the management challenges in a low resource setting. A 67‐year‐old man presented with a 10‐year history of a facial keloid that rapidly enlarged to 2,800 g in 2 years causing difficulties eating, speaking, dressing, head movements and breathing. He had multiple other smaller keloids, hypertension, HIV, and a keloid family history. Surgical excision of the keloid including the multiple sinuses and cysts of enclosed skin with growing hair found inside was performed. A posterior skin flap was used to achieve tension free closure and monthly triamcinolone injections commenced. Histology showed keloidal collagen bundles in a fibrotic background, foci of a lymphoplasmacytic infiltrate and multinucleated foreign body type giant cells consistent with chronic inflammation. CD34 and S100 immunohistochemistry were both negative, ruling out the differential diagnoses that included dermatofibroma. Recovery was uneventful and the patient was discharged after 2 weeks. Notably, radiotherapy was not available in our country. We report this unique case of an extremely large keloid to demonstrate the role of suppurative chronic inflammation and high skin tension in accelerated keloid growth. This case also highlights the severe global disparity in the availability of effective keloid treatment and the urgent need for access to radiotherapy services especially in Africa where keloid prevalence is highest.

BackgroundLow- and lower-middle-income countries account for a higher percentage of global epidemics and chronic diseases. In most low- and lower-middle-income countries, there is limited access to health care. The implementation of open-source electronic health records (EHRs) can be understood as a powerful enabler for low- and lower-middle-income countries because it can transform the way health care technology is delivered. Open-source EHRs can enhance health care delivery in low- and lower-middle-income countries by improving the collection, management, and analysis of health data needed to inform health care delivery, policy, and planning. While open-source EHR systems are cost-effective and adaptable, they have not proliferated rapidly in low- and lower-middle-income countries. Implementation barriers slow adoption, with existing research focusing predominantly on technical issues preventing successful implementation. ObjectiveThis interdisciplinary scoping review aims to provide an overview of contextual barriers affecting the adaptation and implementation of open-source EHR systems in low- and lower-middle-income countries and to identify areas for future research. MethodsWe conducted a scoping literature review following a systematic methodological framework. A total of 7 databases were selected from 3 disciplines: medicine and health sciences, computing, and social sciences. The findings were reported in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist. The Mixed Methods Appraisal Tool and the Critical Appraisal Skills Programme checklists were used to assess the quality of relevant studies. Data were collated and summarized, and results were reported qualitatively, adopting a narrative synthesis approach. ResultsThis review included 13 studies that examined open-source EHRs’ adaptation and implementation in low- and lower-middle-income countries from 3 interrelated perspectives: socioenvironmental, technological, and organizational barriers. The studies identified key issues such as limited funding, sustainability, organizational and management challenges, infrastructure, data privacy and protection, and ownership. Data protection, confidentiality, ownership, and ethics emerged as important issues, often overshadowed by technical processes. ConclusionsWhile open-source EHRs have the potential to enhance health care delivery in low- and lower-middle-income-country settings, implementation is fraught with difficulty. This scoping review shows that depending on the adopted perspective to implementation, different implementation barriers come into view. A dominant focus on technology distracts from socioenvironmental and organizational barriers impacting the proliferation of open-source EHRs. The role of local implementing organizations in addressing implementation barriers in low- and lower-middle-income countries remains unclear. A holistic understanding of implementers’ experiences of implementation processes is needed. This could help characterize and solve implementation problems, including those related to ethics and the management of data protection. Nevertheless, this scoping review provides a meaningful contribution to the global health informatics discipline.

Summary: Ubiquitination is an essential regulator of cell division. The kinase Polo-like kinase 1 (PLK1) promotes protein degradation at G2/M phase through the E3 ubiquitin ligase Skp1-Cul1-F box (SCF)βTrCP. However, the magnitude to which PLK1 shapes the mitotic proteome is uncharacterized. Combining quantitative proteomics with pharmacologic PLK1 inhibition revealed a widespread, PLK1-dependent program of protein breakdown at G2/M. We validated many PLK1-regulated proteins, including substrates of the cell-cycle E3 SCFCyclin F, demonstrating that PLK1 promotes proteolysis through at least two distinct E3 ligases. We show that the protein-kinase-A-anchoring protein A-kinase anchor protein 2 (AKAP2) is cell-cycle regulated and that its mitotic degradation is dependent on the PLK1/βTrCP signaling axis. Expression of a non-degradable AKAP2 mutant resulted in actin defects and aberrant mitotic spindles, suggesting that AKAP2 degradation coordinates cytoskeletal organization during mitosis. These findings uncover PLK1’s far-reaching role in shaping the mitotic proteome post-translationally and have potential implications in malignancies where PLK1 is upregulated.

Background: Transparency can build trust in the scientific process, but scientific findings can be undermined by poor and obscure data use and reporting practices. The purpose of this work is to report how data from the Adolescent Brain Cognitive Development (ABCD) Study has been used to date, and to provide practical recommendations on how to improve the transparency and reproducibility of findings. Methods: Articles published from 2017 to 2023 that used ABCD Study data were reviewed using more than 30 data extraction items to gather information on data use practices. Total frequencies were reported for each extraction item, along with computation of a Level of Completeness (LOC) score that represented overall endorsement of extraction items. Univariate linear regression models were used to examine the correlation between LOC scores and individual extraction items. Post hoc analysis included examination of whether LOC scores were correlated with the logged 2-year journal impact factor. Results: There were 549 full-length articles included in the main analysis. Analytic scripts were shared in 30 % of full-length articles. The number of participants excluded due to missing data was reported in 60 % of articles, and information on missing data for individual variables (e.g., household income) was provided in 38 % of articles. A table describing the analytic sample was included in 83 % of articles. A race and/or ethnicity variable was included in 78 % of reviewed articles, while its inclusion was justified in only 41 % of these articles. LOC scores were highly correlated with extraction items related to examination of missing data. A bottom 10 % of LOC score was significantly correlated with a lower logged journal impact factor when compared to the top 10 % of LOC scores (β=-0.77, 95 % −1.02, −0.51; p-value < 0.0001). Conclusion: These findings highlight opportunities for improvement in future papers using ABCD Study data to readily adapt analytic practices for better transparency and reproducibility efforts. A list of recommendations is provided to facilitate adherence in future research.

Battery technology is increasingly important for global electrification efforts. However, batteries are highly sensitive to small manufacturing variations that can induce reliability or safety issues. An important technology for battery quality control is computed tomography (CT) scanning, which is widely used for non-destructive 3D inspection across a variety of clinical and industrial applications. Historically, however, the utility of CT scanning for high-volume manufacturing has been limited by its low throughput as well as the difficulty of handling its large file sizes. In this work, we present a dataset of over one thousand CT scans of as-produced commercially available batteries. The dataset spans various chemistries (lithium-ion and sodium-ion) as well as various battery form factors (cylindrical, pouch, and prismatic). We evaluate seven different battery types in total. The manufacturing variability and the presence of battery defects can be observed via this dataset. This dataset may be of interest to scientists and engineers working on battery technology, computer vision, or both.

Estuarine ecosystems are threatened by numerous anthropogenic pressures. Fish assemblages are a dominant component of estuarine macrofauna and serve as indicators for the health of these transitional water ecosystems. Environmental DNA (eDNA) metabarcoding is increasingly used to assess the biodiversity of fishes in estuaries. However, there is a need to further establish how effective eDNA metabarcoding can be relative to conventional fish sampling methods across multiple estuaries and seasons. This study compared fish assemblages detected via eDNA metabarcoding of surface water samples to contemporary sampling with conventional fishing gears in three temperate estuaries (UK), during early summer and autumn. Most species caught by fishing were detected by eDNA. Species richness estimates from eDNA were two to ten times higher than estimates based on fishing, and included taxa of conservation importance and a non-native species. The eDNA assemblage composition was significantly different to the assemblage detected by seine nets. Importantly, eDNA methods could effectively discriminate between fish assemblages of different estuaries and seasons. Fish assemblages in estuaries are often not monitored due to resource constraints. The dynamic nature of estuaries may make fishing gear deployment difficult and inconsistent. The findings indicate that eDNA metabarcoding is suited to gathering large amounts of information on fish biodiversity, at a relatively low sampling effort, compared to established fishing methods. Therefore, eDNA shows promise as an assessment tool for fish assemblage structure and ecosystem health in estuarine environments, with application to statutory monitoring.

Over the last decade, a significant paradigm shift has been observed towards leveraging less invasive biological fluids—such as skin interstitial fluid (ISF), sweat, tears, and saliva—for health monitoring. This evolution seeks to transcend traditional, invasive blood-based methods, offering a more accessible approach to health monitoring for non-specialized personnel. Skin ISF, with its profound resemblance to blood, emerges as a pivotal medium for the real-time, minimally invasive tracking of a broad spectrum of biomarkers, thus becoming an invaluable asset for correlating with blood-based data. Our exploration delves deeply into the development of wearable molecular biosensors, spotlighting dermal sensors for their pivotal roles across both clinical and everyday health monitoring scenarios and underscoring their contributions to the holistic One Health initiative. In bringing forward the myriad challenges that permeate this field, we also project future directions, notably the potential of skin ISF as a promising candidate for continuous health tracking.Moreover, this paper aims to catalyse further exploration and innovation by presenting a curated selection of seminal technological advancements. Amidst the saturated landscape of analytical literature on translational challenges, our approach distinctly seeks to highlight recent developments. In attracting a wider spectrum of research groups to this versatile domain, we endeavour to broaden the collective understanding of its trajectory and potential, mapping the evolution of wearable biosensor technology. This strategy not only illuminates the transformative impact of wearable biosensors in reshaping health diagnostics and personalized medicine but also fosters increased participation and progress within the field. Distinct from recent manuscripts in this domain, our review serves as a distillation of key concepts, elucidating pivotal papers that mark the latest advancements in wearable sensors. Through presenting a curated collection of landmark studies and offering our perspectives on the challenges and forward paths, this paper seeks to guide new entrants in the area. We delineate a division between wearable epidermal and subdermal sensors—focusing on the latter as the future frontier—thereby establishing a unique discourse within the ongoing narrative on wearable sensing technologies.

Abstract The activity of many animals follows recurrent patterns and foraging is one of the most important processes in their daily activity. Determining movement in the search for resources and understanding temporal and spatial patterns in foraging has therefore long been central in behavioural ecology. However, identifying and monitoring animal movements is often challenging. In this study we assess the use of camera traps to track a very specific and small‐scale interactions focused on the foraging behaviour of Heliconiini butterflies. Data on floral visitation was recorded using marked individuals of three pollen‐feeding species of Heliconius (H. erato, H. melpomene and H. sara), and two closely related, non‐pollen feeding species (Dryas iulia and Dryadula phaetusa) in a large outdoor insectary. We demonstrate that camera traps efficiently capture individual flower visitation over multiple times and locations and use our experiments to describe some features of their spatial and temporal foraging patterns. Heliconiini butterflies showed higher activity in the morning with strong temporal niche overlap. Differences in foraging activity between males and females was observed with females foraging earlier than males, mirroring published field studies. Some flowers were more explored than others, which may be explained by butterflies foraging simultaneously affecting each other's flower choices. Feeding was grouped in short periods of intense visits to the same flower, which we refer to as feeding bouts. Heliconius also consistently visits the same flower, while non‐Heliconius visited a greater number of flowers per day and their feeding bouts were shorter compared with Heliconius. This is consistent with Heliconius having more stable long‐term spatial memory and foraging preferences than outgroup genera. More broadly, our study demonstrates that camera traps can provide a powerful tool to gather information about foraging behaviour in small insects such as butterflies. © 2024 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.

ABSTRACT Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the Arenaviridae family of the Bunyavirales order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the Arenaviridae family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K+) channels as important for LCMV infection, with pharmacological inhibition confirming K+ channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K+-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K+ channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K+ as a third LCMV entry requirement. K+ did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K+ mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K+ channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K+ channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K+ channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K+ is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.

Background The purpose of this study was to investigate the relationship between blood–brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. Methods and Results A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix Alzheimer's and cerebrovascular diseases and 55 controlparticipants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast‐enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion‐tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning. Vascular risk burden predicted BBB permeability (r=0.24, P