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In the medical diagnostics domain, pathology and histology are pivotal for the precise identification of diseases. Digital histopathology, enhanced by automation, facilitates the efficient analysis of massive amount of biopsy images produced on a daily basis, streamlining the evaluation process. This study focuses in Stain Color Normalization (SCN) within a Whole-Slide Image (WSI) cohort, aiming to reduce batch biases. Building on published graphical method, this research demonstrates a mathematical population or data-driven method that optimizes the dependency on the number of reference WSIs and corresponding aggregate sums, thereby increasing SCN process efficiency. This method expedites the analysis of color convergence 50-fold by using stain vector Euclidean distance analysis, slashing the requirement for reference WSIs by more than half. The approach is validated through a tripartite methodology: 1) Stain vector euclidean distances analysis, 2) Distance computation timing, and 3) Qualitative and quantitative assessments of SCN across cancer tumors regions of interest. The results validate the performance of data-driven SCN method, thus potential to enhance the precision and reliability of computational pathology analyses. This advancement is poised to enhance diagnostic processes, therapeutic strategies, and patient prognosis.

Abstract This study aimed to assess the human health risks associated with groundwater consumption in Abakaliki Metropolis using Water Quality Index (WQI) and HERisk code. Groundwater samples (n = 32) obtained from boreholes were analysed for pH, Zn, Pb. Fe, Cr and NO3 to evaluate both non-carcinogenic and carcinogenic health risks. The average concentrations of these parameters, except Pb (0.02 mg/L) and Cr (0.06 mg/L), were within permissible limits. The distribution of the average concentrations of the parameters followed the order: Zn > Cr > Fe > NO3 > Pb. The WQI ranged from 0.15 to 505.67 classifying 12.50% of the water samples as excellent sources of drinking water, 9.38% as good, 9.38% as poor, 12.50% as very poor and 56.25% unfit for drinking. The HERisk code revealed significant non-carcinogenic and carcinogenic health risks exceeding safety limits (

Abstract Background Several new treatments have recently been shown to have heart and kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, it is unclear how the different molecular pathways affected by the therapies may overlap. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone in mice with comorbid diabetes, focusing on the regulation of expression of the glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor (GIPR) and glucagon receptor (GCGR), which are targets of approved or investigational therapies in diabetes. Methods Male C57BL/6J mice were fed a high fat diet for 26 weeks. Twelve weeks into the high fat diet feeding period, mice received an intraperitoneal injection of streptozotocin before being followed for the remaining 14 weeks (DMHFD mice). After 26 weeks, mice were fed a high fat diet containing finerenone (100 mg/kg diet) or high fat diet alone for a further 2 weeks. Cell culture experiments were performed in primary vascular smooth muscle cells (VSMCs), NRK-49 F fibroblasts, HK-2 cells, and MDCK cells. Results DMHFD mice developed albuminuria, glomerular mesangial expansion, and diastolic dysfunction (decreased E/A ratio). Glp1r and Gcgr were predominantly expressed in arteriolar VSMCs and distal nephron structures of mouse kidneys respectively, whereas Gipr was the predominant of the three transcripts in mouse hearts. Kidney Glp1r and Gcgr and cardiac Gipr mRNA levels were reduced in DMHFD mice and this reduction was negated or attenuated with finerenone. Mechanistically, finerenone attenuated upregulation of the profibrotic growth factor Ccn2 in DMHFD kidneys, whereas recombinant CCN2 downregulated Glp1r and Gcgr in VSMCs and MDCK cells respectively. Conclusions Through its anti-fibrotic actions, finerenone reverses Glp1r and Gcgr downregulation in the diabetic kidney. Both finerenone and GLP-1R agonists have proven cardiorenal benefits, whereas receptor co-agonists are approved or under development. The current findings provide preclinical rationale for the combined use of finerenone with the GLP-1R agonist family. They also provide mechanism of action insights into the potential benefit of finerenone in people with diabetes for whom GLP-1R agonists or co-agonists may not be indicated.

Abstract Two-dimensional (2D) electron systems are promising for investigating correlated quantum phenomena. In particular, 2D oxides provide a platform that can host various quantum phases such as quantized Hall effect, superconductivity, or magnetism. The realization of such quantum phases in 2D oxides heavily relies on dedicated heterostructure growths. Here we show the integer quantum Hall effect achieved in chemical vapor deposition grown Bi2O2Se - a representative member of a more accessible oxide family. A single or few subband 2D electron system can be prepared in thin films of Bi2O2Se, where the film thickness acts as the key subband design parameter and the occupation is determined by the electric field effect. This oxide platform exhibits characteristic advantages in structural flexibility due to its layered nature, making it suitable for scalable growth. The unique small mass distinguishes Bi2O2Se from other high-mobility oxides, providing a new platform for exploring quantum Hall physics in 2D oxides.

Abstract CNS tumours encompass a diverse group of neoplasms with significant morbidity and mortality. The SHH signalling pathway plays a critical role in the pathogenesis of several CNS tumours, including gliomas, medulloblastomas and others. By influencing cellular proliferation, differentiation and migration in CNS tumours, the SHH pathway has emerged as a promising target for therapeutic intervention. Current strategies such as vismodegib and sonidegib have shown efficacy in targeting SHH pathway activation. However, challenges such as resistance mechanisms and paradoxical effects observed in clinical settings underscore the complexity of effectively targeting this pathway. Advances in gene editing technologies, particularly CRISPR/Cas9, have provided valuable tools for studying SHH pathway biology, validating therapeutic targets and exploring novel treatment modalities. These innovations have paved the way for a better understanding of pathway dynamics and the development of more precise therapeutic interventions. In addition, the identification and validation of biomarkers of SHH pathway activation are critical to guide clinical decision making and improve patient outcomes. Molecular profiling and biomarker discovery efforts are critical steps towards personalised medicine approaches in the treatment of SHH pathway-associated CNS tumours. While significant progress has been made in understanding the role of the SHH pathway in CNS tumorigenesis, ongoing research is essential to overcome current therapeutic challenges and refine treatment strategies. The integration of molecular insights with advanced technologies and clinical expertise holds great promise for developing more effective and personalised therapies for patients with SHH pathway-driven CNS tumours. Graphical Abstract

Abstract Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. We developed a network medicine methodology via integrating human brain multi-omics data to prioritize drug targets and repurposable treatments for ALS. We leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on human brain expression quantitative trait loci (QTL) (eQTL), protein QTL (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Using a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in known ALS pathobiological pathways. Applying network proximity analysis of predicted ALS-associated genes and drug-target networks under the human protein-protein interactome (PPI) model, we identified potential repurposable drugs (i.e., Diazoxide and Gefitinib) for ALS. Subsequent validation established preclinical evidence for top-prioritized drugs. In summary, we presented a network-based multi-omics framework to identify drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

Abstract Background The NOTACS trial will assess the efficacy, safety and cost-effectiveness of high-flow nasal therapy (HFNT) compared to standard oxygen therapy (SOT) on the outcomes of patients after cardiac surgery. Methods/design NOTACS is an adaptive, international, multicentre, parallel group, randomised controlled trial, with a pre-planned interim sample size re-estimation (SSR). A minimum of 850 patients will be randomised 1:1 to receive either HFNT or SOT. The primary outcome is days alive and at home in the first 90 days after the planned surgery (DAH90), with a number of secondary analyses and cost-effectiveness analyses also planned. The interim SSR will take place after a minimum of 300 patients have been followed up for 90 days and will allow for the sample size to increase up to a maximum of 1280 patients. Results This manuscript provides detailed descriptions of the design of the NOTACS trial and the analyses to be undertaken at the interim and final analyses. The main purpose of the interim analysis is to assess safety and to perform a sample size re-estimation. The main purpose of the final analysis is to examine the safety, efficacy and cost-effectiveness of HFNT compared to SOT on the outcomes of patients after cardiac surgery. Discussion This manuscript outlines the key features of the NOTACS statistical analysis plan and was submitted to the journal before the final analysis in order to preserve scientific integrity under an adaptive design framework. A previous version of this SAP was published prior to the interim analysis (Dawson, 2022). The NOTACS SAP closely follows published guidelines for the content of SAPs in clinical trials (Gamble, 2017). Trial registration ISRCTN14092678 . (13 May 2020).

Abstract Stony coral tissue loss disease (SCTLD) has swept through Florida reefs and caused mass mortality of numerous coral species. In the wake of these losses, efforts are underway to propagate coral species impacted by SCTLD and promote population recovery. However, numerous knowledge gaps must be addressed to effectively grow, outplant, and restore populations of the slower growing, massive species that were lost. Here, we used sexual recruits of Diploria labyrinthiformis spawned in captivity to understand how conditioning, coral size, and nutritional status at outplanting affect coral survivorship, growth, and susceptibility to predation. We found that ex situ conditioning with supplemental feeding increased coral growth rates, resulting in larger sized corals at the time of outplanting. In turn, these corals had higher growth rates in the field and a lower probability of being removed by predators than outplants that were conditioned in in situ nurseries. Additionally, we found that coral size was an important predictor of survivorship, suggesting that hastening the speed at which young corals grow and outplanting larger juveniles can improve restoration outcomes. Taken together, our results suggest that providing supplemental food to corals at ex situ facilities confers benefits that could help restore populations of massive coral species impacted by SCTLD.

Abstract Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

Objective: Our primary research objective was to assess the population uptake and contact tracer utilisation of the Bluetooth function of the New Zealand Covid Tracer App (NZCTA) throughout the pandemic. Methods: We adopted a retrospective cohort study design using all diagnosed COVID-19 community cases from December 12, 2020 to February 16, 2022. Results: At its height, more than 60% of the eligible population had the Bluetooth function of NZCTA activated. However, only an estimated 2.2% of the population was able to fully participate. Cases managed by the national case investigation service were 17 times (aRR 17.54, 95%CI: 13.02-23.90) and 9 times (aRR 9.27, 95%CI: 6.91, 12.76) more likely to generate a Bluetooth token than cases managed by local public health units during the Delta and Omicron periods, respectively. Conclusions: The Bluetooth functionality of the NZCTA likely had a low impact on the pandemic response in NZ despite its exceptionally high levels of public uptake. The primary reason for the lack of impact was the low utilisation by contact tracers. Implications for public health: The results highlight the need for greater consultation and collaboration with the public health sector during the development and implementation of digital contact tracing tools.

Abstract Introduction This study is a prospective, randomized, subject/evaluator-masked clinical trial in a single-center clinical setting. The purpose of the study is to compare the clinical performance of Tecnis Symfony Optiblue IOL (models ZXR00V and ZXW150) with violet light filter (VLF) and manufacturing improvements versus Tecnis Symfony IOL (models ZXR00 and ZXT150) with ultraviolet light filter (UVF) in patients undergoing cataract surgery. Methods Patients with cataracts aged ≥ 22 years were randomly assigned 1:1 to bilateral implantation with ZXR00V/ZXW150 (VLF group) or ZXR00/ZXT150 (UVF group). Key endpoints at 6 months postoperative included patient reported nighttime dysphotopsia symptoms, 25% low contrast visual acuity with glare, and patient satisfaction. Results Sixty patients were implanted with ZXR00V/ZXW150 (30) or ZXR00/ZXT150 (30). At 6 months, the VLF group did not show a statistically significant differences in mean monocular photopic uncorrected distance visual acuity (UCDVA), best-corrected distance visual acuity (BCDVA), uncorrected near visual acuity (UCNVA) (40 cm), or distance-corrected near visual acuity (DCNVA) (40 cm) compared to the UVF group. At 1 month, patients in the VLF group reported significantly less difficulty due to halo (p = 0.016) and starburst (p = 0.028) symptoms. By the 6 months, dysphotopsia complaints were no longer significantly different between the groups. Although the VLF group trended toward better low contrast visual acuity and patient satisfaction, statistical significance was not reached. Conclusions Managing the patients’ expectations is key to achieving success. At the 1-month visit the patients who reported dysphotopsia complaints in the VLF group had significantly less difficulty with starbursts and halos as compared to the UVF group. By the 6-month visit, there was no significant difference between the two groups in the difficulty with starbursts and halos. Trial Registration ClinicalTrials.gov identifier, NCT06567834.

Abstract Population screening for breast cancer (BC) is currently offered in the UK for women aged 50 to 71 with the aim of reducing mortality. There is additional screening within the national programme for women identified as having a very high risk of BC. There is growing interest in further risk stratification in breast screening, which would require a whole population risk assessment and the subsequent offer of screening tailored to the individual’s risk. Some women would be offered more intensive screening than others or no screening. This might provide a better balance of screening benefits and harms for each individual than the current population age-based programme alone. The UK National Screening Committee (UK NSC) is considering using decision-analytic and other models to evaluate different risk stratification screening strategies and identify remaining gaps in evidence. This paper reports the proceedings of a UK NSC workshop where experts in the field discussed both risk prediction models, as well as decision-analytic models providing a benefit-harm analysis/economic evaluation of risk-stratified screening programmes (see Table 1). The aim of the meeting was to present and discuss the current work of experts, including some data which had not been published at the time of the meeting, to inform the UK NSC. The workshop was not intended to present a balanced evaluation of how to deliver screening in future. Areas for further work identified included methods for comparing models to assess accuracy, the optimum risk assessment tools, the digital screening infrastructure, acceptability of stratification, choice of screening test and reducing inequalities. A move to risk stratification of the whole programme would require a careful phased introduction with continuing assessment of real-world evidence during deployment.

Abstract Background Sympathetic nervous system hyperactivity and chronic intermittent nocturnal hypoxia in individuals with obstructive sleep apnea (OSA) predispose them to microvascular impairment, which may contribute to increased daytime muscle fatigue. This study aimed to assess microvascular reactivity of the skeletal muscle, examine fatigability, and determine the relationship between fatigability and microvascular reactivity in adults with OSA. Methods Twenty-six participants were allocated into two groups—those with OSA and those without i.e. non-OSA. Each group comprised of 13 individuals who underwent an arterial occlusion test on their non-dominant leg. The percentage change of maximal hyperemic response (MHR) and the time to achieve MHR (tM) of both the total myoglobin/hemoglobin (∆[Hbtot]) and the oxygenated myoglobin/hemoglobin (∆[HbO2]) signals from near-infrared spectroscopy were calculated to examine microvascular reactivity. In addition, a 10-min walk test was performed to assess performance and perceived fatigability. Results The OSA group demonstrated a reduced in ∆[Hbtot]MHR (150.9 ± 16.2% vs. 235.8 ± 72.7%, p = 0.006), ∆[HbO2]MHR (131.4 ± 8% vs. 161.7 ± 10.6%, p = 0.001) and increased ∆[Hbtot]tM (80.5 ± 13.1 s vs. 47.7 ± 9.9 s, p

Abstract Background Helicopter Emergency Medical Services (HEMS) in the United Kingdom (UK) deliver enhanced care to high-acuity, critically ill and injured patients. To enable patients to meet the HEMS team who treated them, many services within the UK have developed or are in the process of developing a Patient and Family Aftercare Service (PFAS). This study aims to evaluate whether the introduction of PFAS mitigates anxiety associated with patient aftercare visits. Methods A service evaluation of anxiety in HEMS team members before and after patient aftercare visits were conducted. The study was carried out between 1 September 2023, and 31 October 2023, and patient visits were undertaken between March 2022 and July 2023. An electronic survey was distributed to the respondents who provided informed consent for participation. The survey comprised the validated generalised anxiety disorder anxiety scale (GAD-7) and five additional contextualised statements developed through the wider PFAS. Anonymised data were collected using REDCap, a secure electronic database and was analysed in R programming. Free-text comments were reported by content analysis, placed into themes, and discussed with a narrative to complement the quantitative analysis. Results Of the 33 recipients, 25 completed the questionnaire. Between the pre- and post-aftercare visits, a statistically significant difference was found between scores for GAD-7 (0.004, p

Background: Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models. Methods: A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR. Results: KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered. Conclusion: Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.

Abstract Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Abstract The colloid cellular automata do not imitate the physical structure of colloids but are governed by logical functions derived from them. We analyze the space-time complexity of Boolean circuits derived from the electrical responses of colloids-specifically ZnO (zinc oxide, an inorganic compound also known as calamine or zinc white, which naturally occurs as the mineral zincite), proteinoids (microspheres and crystals of thermal abiotic proteins), and their combinations in response to electrical stimulation. To extract Boolean circuits from colloids, we send all possible configurations of two-, four-, and eight-bit binary strings, encoded as electrical potential values, to the colloids, record their responses, and infer the Boolean functions they implement. We map the discovered functions onto the cell-state transition rules of cellular automata-arrays of binary state machines that update their states synchronously according to the same rule-creating the colloid cellular automata. We then analyze the phenomenology of the space-time configurations of the automata and evaluate their complexity using measures such as compressibility, Shannon entropy, Simpson diversity, and expressivity. A hierarchy of phenomenological and measurable space-time complexity is constructed.

Abstract Background The Dohne Merino sheep was introduced to Australia from South Africa in the 1990s. It was primarily used in crosses with the Merino breed sheep to improve on attributes such as reproduction and carcass composition. Since then, this breed has continued to expand in Australia but the number of genotyped and phenotyped purebred individuals remains low, calling into question the accuracy of genomic selection. The Australian Merino, on the other hand, has a substantial reference population in a separate genomic evaluation (MERINOSELECT). Combining these resources could fast track the impact of genomic selection on the smaller breed, but the efficacy of this needs to be investigated. This study was based on a dataset of 53,663 genotypes and more than 2 million phenotypes. Its main objectives were (1) to characterize the genetic structure of Merino and Dohne Merino breeds, (2) to investigate the utility of combining their evaluations in terms of quality of predictions, and (3) to compare several methods of genetic grouping. We used the ‘LR-method’ (Linear Regression) for these assessments. Results We found very low Fst values (below 0.048) between the different Merino lines and Dohne breed considered in our study, indicating very low genetic differentiation. Principal component analysis revealed three distinct groups, identified as purebred Merino, purebred Dohne, and crossbred animals. Considering the whole population in the reference led to the best quality of predictions and the largest increase in accuracy (from ‘LR-method’) from pedigree to genomic-based evaluations: 0.18, 0.14 and 0.16 for yearling fibre diameter (YFD), yearling greasy fleece weight (YGFW) and yearling liveweight (YWT), respectively. Combined genomic evaluations showed higher accuracies than the evaluation based on the Dohne reference only (accuracies increased by 0.16, 0.06 and 0.07 for YFD, YGFW, and YWT, respectively). For the combined genomic evaluations, metafounder models were more accurate than Unknown Parent Groups models (accuracies increased by 0.04, 0.04 and 0.06 for YFD, YGFW and YWT, respectively). Conclusions We found promising results for the future transition of the Dohne breed from pedigree to genomic selection. A combined genomic evaluation, with the MERINOSELECT evaluation in addition to using metafounders, is expected to enhance the quality of genomic predictions for the Dohne Merino breed.

Abstract The integration of artificial intelligence (AI) into healthcare systems within low-middle income countries (LMICs) has emerged as a central focus for various initiatives aiming to improve healthcare access and delivery quality. In contrast to high-income countries (HICs), which often possess the resources and infrastructure to adopt innovative healthcare technologies, LMICs confront resource limitations such as insufficient funding, outdated infrastructure, limited digital data, and a shortage of technical expertise. Consequently, many algorithms initially trained on data from non-LMIC settings are now being employed in LMIC contexts. However, the effectiveness of these systems in LMICs can be compromised when the unique local contexts and requirements are not adequately considered. In this study, we evaluate the feasibility of utilizing models developed in the United Kingdom (a HIC) within hospitals in Vietnam (a LMIC). Consequently, we present and discuss practical methodologies aimed at improving model performance, emphasizing the critical importance of tailoring solutions to the distinct healthcare systems found in LMICs. Our findings emphasize the necessity for collaborative initiatives and solutions that are sensitive to the local context in order to effectively tackle the healthcare challenges that are unique to these regions.

Abstract The increasing use of machine learning, with its significant computational and environmental costs, has motivated the exploration of unconventional computing substrates. Liquid substrates, such as colloids, are of particular interest due to their ability to conform to various shapes while exhibiting complex dynamics resulting from the collective behaviour of the constituent colloidal particles. This study explores the potential of using a PEDOT:PSS colloidal suspension as a physical reservoir for reservoir computing in spoken digit recognition. Reservoir computing uses high-dimensional dynamical systems to perform tasks with different substrates, including physical ones. Here, a physical reservoir is implemented that encodes temporal data by exploiting the rich dynamics inherent in colloidal suspensions, thus avoiding reliance on conventional computing hardware. The reservoir processes audio input encoded as spike sequences, which are then classified using a trained readout layer to identify spoken digits. Evaluation across different speaker scenarios shows that the colloidal reservoir achieves high accuracy in classification tasks, demonstrating its viability as a physical reservoir substrate.

Abstract Background Osteoporotic fractures signal severely compromised bone strength and are associated with a greatly increased risk of refracture. Despite the availability of effective and safe medications that reduce fracture risk, 70–80% of patients are inadequately investigated or treated for osteoporosis following an initial fracture, constituting a significant ‘osteoporosis care gap’. Optimal methods of bridging this gap with primary care at the forefront of secondary fracture prevention remain undetermined. This protocol describes a cluster randomised controlled trial to evaluate the effectiveness of a novel integrated model of secondary fracture prevention and management in primary care. Methods The cluster randomised controlled trial involves multiple branches of a community-based radiology provider (CRP), a hospital-based secondary fracture prevention program (SFPP) and numerous primary care practices in metropolitan Sydney that refer to either the CRP or SFPP. Using natural language processing tools, patients diagnosed with a potential osteoporotic fracture will be identified by automatically screening radiology reports generated at the CRP or SFPP. The primary care practices that these patients attend will be randomised (1:1) to either the intervention or usual care. The intervention consists of (i) electronic and fax alerts informing the practice/primary care physician that their patient has been diagnosed with a potential osteoporotic fracture; (ii) provision of osteoporosis management guidelines and (iii) follow-up surveys at 4 weeks and 6 months. Practices in the usual care (control) group will receive no alerts and provide usual care. The primary outcome is the proportion of patients undergoing a bone density scan and/or filling a prescription for osteo-protective pharmacotherapy within 3 months of the initial diagnostic imaging report. Secondary outcomes are the proportion of patients: (i) undergoing an osteoporosis-related blood test within 3 months of the initial diagnostic imaging report; (ii) initiated on a chronic disease management plan within 3 months of the diagnostic report, and (iii) filling a second prescription for osteo-protective pharmacotherapy within 9 months post initial diagnostic imaging report. Outcomes will be obtained through de-identified linked data from Medical Benefits Schedule and Pharmaceutical Benefits Scheme held by the Australian Institute of Health and Welfare. Discussion This is the first randomised trial to integrate case-detection of potential osteoporotic fractures in a hospital and community setting with direct alerts to the patient’s primary care provider. This study will determine whether such an intervention is effective in improving investigation and/or treatment rates of osteoporosis in patients with a potential osteoporotic fracture. Trial registration This study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12623000658617p.

Abstract The risk of developing posttraumatic stress symptoms following exposure to traumatic events is well documented, however, emerging research also lends support to the potential development of growth in some people. Rumination and memory have been identified as important factors in post-trauma outcomes, yet, current research in this area is limited, particularly in the context of a multidimensional view of rumination (i.e., intrusive and deliberate rumination) and metamemory beliefs. This study explored the association between rumination styles, beliefs about memory, and posttraumatic stress symptoms and posttraumatic growth. Participants (N = 151) who experienced a traumatic event completed relevant measures online. Path analysis showed that intrusive rumination was significantly related to higher levels of posttraumatic stress symptoms (β = 0.19, p

Abstract Background Despite Africa’s significant infectious disease burden, it is underrepresented in global vaccine clinical trials. While this trend is slowly reversing, it is important to recognize and mitigate the challenges that arise when conducting vaccine clinical trials in this environment. These challenges stem from a variety of factors peculiar to the population and may negatively impact adverse event collection and reporting if not properly addressed. Methods As a team of clinical researchers working within the MRCG (Medical Research Council Unit The Gambia), we have conducted 12 phase 1 to 3 vaccine trials over the past 10 years. In this article, we discuss the challenges we face and the strategies we have developed to improve the collection and reporting of adverse events in low-income settings. Outcome. Healthcare-seeking behaviors in the Gambia are influenced by spiritual and cultural beliefs as well as barriers to accessing orthodox healthcare; participants in trials may resort to non-orthodox care, reducing the accuracy of reported adverse events. To address this, trial eligibility criteria prohibit self-treatment and herbal product use during trials. Instead, round-the-clock care is provided to trial participants, facilitating safety follow-up. Constraints in the healthcare system in the Gambia such as limitations in diagnostic tools limit the specificity of diagnosis when reporting adverse events. To overcome these challenges, the Medical Research Council Unit maintains a Clinical Services Department, offering medical care and diagnostic services to study participants. Sociocultural factors, including low literacy rates and social influences, impact adverse event collection. Solicited adverse events are collected during home visits on paper-based or electronic report forms. Community engagement meetings are held before each study starts to inform community stakeholders about the study and answer any questions they may have. These meetings ensure that influential members of the community understand the purpose of the study and the risks and benefits of participating in the trial. This understanding makes them more likely to support participation within their communities. Conclusion Conducting ethical vaccine clinical trials in resource-limited settings requires strategies to accurately collect and report adverse events. Our experiences from the Gambia offer insights into adverse event collection in these settings.

The advent of serial crystallography has rejuvenated and popularized room-temperature X-ray crystal structure determination. Structures determined at physiological temperature reveal protein flexibility and dynamics. In addition, challenging samples (e.g. large complexes, membrane proteins and viruses) form fragile crystals that are often difficult to harvest for cryo-crystallography. Moreover, a typical serial crystallography experiment requires a large number of microcrystals, mainly achievable through batch crystallization. Many medically relevant samples are expressed in mammalian cell lines, producing a meager quantity of protein that is incompatible with batch crystallization. This can limit the scope of serial crystallography approaches. Direct in situ data collection from a 96-well crystallization plate enables not only the identification of the best diffracting crystallization condition but also the possibility for structure determination under ambient conditions. Here, we describe an in situ serial crystallography (iSX) approach, facilitating direct measurement from crystallization plates mounted on a rapidly exchangeable universal plate holder deployed at a microfocus beamline, ID23-2, at the European Synchrotron Radiation Facility. We applied our iSX approach on a challenging project, autotaxin, a therapeutic target expressed in a stable human cell line, to determine the structure in the lowest-symmetry P1 space group at 3.0 Å resolution. Our in situ data collection strategy provided a complete dataset for structure determination while screening various crystallization conditions. Our data analysis reveals that the iSX approach is highly efficient at a microfocus beamline, improving throughput and demonstrating how crystallization plates can be routinely used as an alternative method of presenting samples for serial crystallography experiments at synchrotrons.

Introduction This study investigated the effect of foot muscle energy technique (MET) on nerve conduction velocity (NCV) and isometric muscle strength in patients with type 2 diabetic neuropathy (DN). Methods Forty-four patients were randomly assigned to either the MET group (group A) or the conventional physical therapy program group (group B). Electrophysiological measurements, including peroneal and tibial motor NCV studies, and isometric muscle strength using a toe strength dynamometer, were conducted. The assessment period ranged from April to November 2022, with measurements taken before the first session and after 4 weeks of treatment. Results Significant improvements were observed in post-treatment peroneal motor NCV ( p < 0.001), tibial motor NCV ( p < 0.001), and isometric muscle strength ( p < 0.001) in group A, but not in group B. Conclusions MET enhances motor NCV and isometric muscle strength in patients with type 2 DN.

Abstract This work studies domain walls between chirally-separated vacua in supersymmetric Yang-Mills theory (SYM) on ℝ3 × 𝕊1 in the semiclassical limit. For all gauge groups we explicitly find the electric fluxes of all BPS domain walls and fully characterize the representation that they form under the global symmetry of SYM. We compute the characters of these representations formed by the semiclassical domain walls. We also compute these characters for the worldvolume TQFTs appearing in the literature for SU(N) and Sp(N) gauge groups. We find complete agreement between the two computations, providing thus a dynamical test of the proposed worldvolume TQFTs. We also propose a new worldvolume TQFT for E 6 domain walls, subjecting it to the same tests. Finally, we study deconfinement of quarks on domain walls for all gauge groups. We show that for all gauge groups confining strings (stable in the abelianized regime) can end on domain walls, regardless of whether or not the group has a center.

Abstract Background Preclinical technical feasibility study of robot-assisted microinvasive glaucoma surgery using a novel ophthalmic robot-assisted surgery system. Methods Feasibility was assessed in synthetic eye models in two stages: Stage I, nonimplantable robot-assisted goniotomy; and Stage II, robot-assisted stent implantation using a trabecular bypass stent. Robot-assisted interventions were subsequently compared to the manual approach. Results Stage I: Two surgeons completed 10 trials each of ab-interno sectoral goniotomy with and without robotic assistance for at least 3 clock hours using a standard goniotomy knife and more than 10 clock hours of extended goniotomy using a flexible, guided goniotomy instrument. Stage II: Trabecular bypass stent deployment was successfully achieved in 100% of the attempts with and without robotic assistance. Surgical time was recorded and compared between the robotic-assisted and the manual approach. Conclusions A system for robot-assisted microinvasive glaucoma surgery can successfully achieve implantable and nonimplantable interventions in the anterior segment. This is the first known demonstration of the feasibility of robot-assisted glaucoma surgery.

Abstract Disruption of retinal vasculature is linked to various diseases, including diabetic retinopathy and macular degeneration, leading to vision loss. We present here a novel algorithmic approach that generates highly realistic digital models of human retinal blood vessels, based on established biophysical principles, including fully-connected arterial and venous trees with a single inlet and outlet. This approach, using physics-informed generative adversarial networks (PI-GAN), enables the segmentation and reconstruction of blood vessel networks with no human input and which out-performs human labelling. Segmentation of DRIVE and STARE retina photograph datasets provided near state-of-the-art vessel segmentation, with training on only a small (n = 100) simulated dataset. Our findings highlight the potential of PI-GAN for accurate retinal vasculature characterization, with implications for improving early disease detection, monitoring disease progression, and improving patient care.

ABSTRACT Bacterial cells secrete extracellular vesicles (EVs), the function of which is a matter of intense investigation. Here, we show that the EVs secreted by the human pathogen Streptococcus pneumoniae (pneumococcus) are associated with bacterial DNA on their surface and can deliver this DNA to the transformation machinery of competent cells. These findings suggest that EVs contribute to gene transfer in Gram-positive bacteria and, in doing so, may promote the spread of drug resistance genes in the population.IMPORTANCEThis work extends our understanding of horizontal gene transfer and the roles of extracellular vesicles in pneumococcus. This bacterium serves as the model for transformation, a process by which bacteria can take up naked DNA from the environment. Here, we show that extracellular vesicles secreted by the pneumococcus have DNA on their surface and that this DNA can be imported by the transformation machinery, facilitating gene transfer. Understanding EV-mediated gene transfer may provide new avenues to manage the spread of antibiotic drug resistance.

IntroductionSickle cell disease (SCD) is a genetic blood disorder caused by a mutation in the HBB gene, which encodes the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin S (HbS), causing red blood cells to deform into a sickle shape. These deformed cells can block blood flow, leading to complications like chronic hemolysis, anemia, severe pain episodes, and organ damage. SCD genotypes include HbSS, HbSC (HbC is an abnormal variant of hemoglobin), and HbS/β-thalassemia. Sickle cell trait (SCT), HbAS, represents the carrier state, while other hemoglobin variants include HbCC, HbAC, and the normal HbAA. Over 7.5 million people worldwide live with SCD, with a high mortality rate in sub-Saharan Africa, including Ghana. Despite its prevalence, SCD is underdiagnosed and poorly managed, especially in children. Characterized by intravascular hemolysis, SCD leads to oxidative stress, endothelial activation, and systemic inflammation. Identifying circulating blood biomarkers indicative of organ damage and systemic processes is vital for understanding SCD and improving patient management. However, research on biomarkers in pediatric SCD is limited and few have been identified and validated. This study explores specific circulating biomarkers in pediatric SCD in Ghana (West Africa), hypothesizing that inflammatory and neuronal injury markers in children with SCD could predict disease outcomes.MethodsClinical data were collected from 377 children aged 3–8 years with various Hb genotypes, including SCD and SCT, at Korle-Bu Teaching Hospital in Accra, Ghana (2021–2022). A total of 80 age- and sex-matched subjects were identified. A cross-sectional study utilized a multiplexed immunoassay procedure to evaluate serum biomarkers, including cytokines, chemokines, vascular injury markers, systemic inflammation markers, cell-free heme scavengers, brain-derived neurotrophic factor (BDNF), and angiogenic factors.ResultsElevated levels of BDNF, Ang-2, CXCL10, CCL11, TNF-α, IL-6, IL-10, IL12p40, ICAM-1, VCAM-1, Tie-2, and VEGFA were observed in HbSS subjects, correlating with hemoglobin level, leukocyte, and erythrocyte counts. Heme scavengers like HO-1, hemopexin, and haptoglobin also correlated with these parameters. ROC and AUC analyses demonstrated the potential of these biomarkers in predicting SCD outcomes.ConclusionThese findings suggest that there are significant differences between biomarker expression among the different genotypes examined. We conclude that a predictive algorithm based on these biomarkers could be developed and validated through longitudinal assessment of within-genotype differences and correlation of the data with disease severity or outcomes. With such a tool one can enhance SCD management and improve patient outcomes. This approach may pave the way for personalized interventions and better clinical care for pediatric SCD patients.

ABSTRACT Detection of multiple pneumococcal serotype carriage can enhance monitoring of pneumococcal vaccine impact, particularly among high-burden childhood populations. We assessed methods for identifying co-carriage of pneumococcal serotypes from whole-genome sequences. Twenty-four nasopharyngeal samples were collected during community carriage surveillance from healthy children in Blantyre, Malawi, which were then serotyped by microarray. Pneumococcal DNA from culture plate sweeps were sequenced using Illumina MiSeq, and genomic serotyping was carried out using SeroCall and PneumoKITy. Their sensitivity was calculated in reference to the microarray data. Local maxima in the single-nucleotide polymorphism (SNP) density distributions were assessed for their correspondence to the relative abundance of serotypes. Across the 24 individuals, the microarray detected 77 non-unique serotypes, of which 42 occurred at high relative abundance (>10%) (per individual, median, 3; range, 1–6 serotypes). The average sequencing depth was 57X (range: 21X–88X). The sensitivity of SeroCall for identifying high-abundance serotypes was 98% (95% CI, 0.87–1.00), 20% (0.08–0.36) for low abundance (

Low-grade inflammation and pathological endochondral ossification are key processes underlying the progression of osteoarthritis, the most prevalent joint disease worldwide. In this study, we employed a multi-faceted approach, integrating publicly available datasets, in silico analyses, in vitro experiments and in vivo models to identify new therapeutic candidates targeting these processes. Data mining of transcriptomic datasets identified EPHA2, a receptor tyrosine kinase associated with cancer, as being linked to both inflammation and endochondral ossification in osteoarthritis. A computational model of cellular signaling networks in chondrocytes predicted that in silico activation of EPHA2 in healthy chondrocytes increases inflammatory mediators and induces hypertrophic differentiation, a hallmark of endochondral ossification. We then evaluated the effect of EPHA2 inhibition using the tyrosine kinase inhibitor ALW-II-41-27 in cultured human chondrocytes from individuals with osteoarthritis, demonstrating significant reductions in both inflammation and hypertrophy. Additionally, systemic subcutaneous administration of ALW-II-41-27 in a mouse osteoarthritic model attenuated joint degeneration by reducing local inflammation and pathological endochondral ossification. Collectively, this study demonstrates a novel drug discovery pipeline that integrates computational, experimental, and animal models, paving the way for the development of disease-modifying treatments for osteoarthritis.

Abstract Mohs surgeons' fallibility is an important topic to explore. There are no studies on the role of cognitive biases in heuristic decision‐making within Mohs micrographic surgery (MMS) as a contributing factor in mistakes or errors of clinical judgement. We reviewed established cognitive biases applied to heuristics during the pre‐operative, intraoperative and reconstruction stages of MMS, and recommend conscious cognitive bias mitigating strategies for Mohs surgeons. Clinical errors/incidents may be reframed as opportunities to learn and develop, rather than evidence of competency or status. These experiences offer the opportunity to sharpen skills within metacognition and allow for more cognizant Mohs surgeons. We highly recommend all Mohs surgeons develop in‐depth knowledge and maintain awareness of cognitive biases throughout clinical practice, to enhance clinical performance.

Objective: Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood. Methods: To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions. Results: We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets. Conclusions: These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.

The increasing capabilities of AI pose new risks and vulnerabilities for organizations and decision makers. Several trustworthy AI frameworks have been created by U.S. federal agencies and international organizations to outline the principles to which AI systems must adhere for their use to be considered responsible. Different trustworthy AI frameworks reflect the priorities and perspectives of different stakeholders, and there is no consensus on a single framework yet. We evaluate the leading frameworks and provide a holistic perspective on trustworthy AI values, allowing federal agencies to create agency-specific trustworthy AI strategies that account for unique institutional needs and priorities. We apply this approach to the Department of Veterans Affairs, an entity with largest health care system in US. Further, we contextualize our framework from the perspective of the federal government on how to leverage existing trustworthy AI frameworks to develop a set of guiding principles that can provide the foundation for an agency to design, develop, acquire, and use AI systems in a manner that simultaneously fosters trust and confidence and meets the requirements of established laws and regulations.

We previously reported an ability of low-intensity vibration (LIV) to improve selected biomarkers of bone turnover and gene expression and reduce osteoclastogenesis but lacking of evident bone accrual. In this study, we demonstrate that a prolonged course of LIV that initiated at 2 weeks post-injury and continued for 8 weeks can protect against bone loss after SCI in rats. LIV stimulates bone formation and improves osteoblast differentiation potential of bone marrow stromal stem cells while inhibiting osteoclast differentiation potential of marrow hematopoietic progenitors to reduce bone resorption. We further demonstrate that the combination of LIV and RANKL antibody reduces SCI-related bone loss more than each intervention alone. Our findings that LIV is efficacious in maintaining sublesional bone mass suggests that such physical-based intervention approach would be a noninvasive, simple, inexpensive and practical intervention to treat bone loss after SCI. Because the combined administration of LIV and RANKL inhibition better preserved sublesional bone after SCI than either intervention alone, this work provides the impetus for the development of future clinical protocols based on the potential greater therapeutic efficacy of combining non-pharmacological (e.g., LIV) and pharmacological (e.g., RANKL inhibitor or other agents) approaches to treat osteoporosis after SCI or other conditions associated with severe immobilization.

As circular business activity is a pivotal component of the European Green Deal, this study examines its impact on economic prosperity by examining how the model influences income levels. The investigation spans a panel of 27 European Union (EU) member countries from 2014 to 2023, factoring in the income effect of consumption footprint and public trust in governing institutions. Based on the system Generalized Method of Moments (GMM) estimators of the dynamic panel model, the results reveal that circular business activities enhance economic well-being. However, the interaction effect of consumption footprint limits the full potential of this enhancing effect. Moreover, as public confidence in government institutions improves, so does economic well-being. This perspective underscores the pivotal role of trust in bolstering the economic benefits of circular business activities, leading to more robust societal conditions. Overall, the study suggests that while circular business activities can improve economic well-being, efficient management of the consumption footprint is crucial for optimization. Its policy implication emphasizes balancing economic aspects with social, institutional, and environmental elements to enhance individual well-being. Thus, the findings contribute to the literature and provide valuable policy insights into circular economy models, opening up avenues for future consideration.

Climate change adaptation requires proactive development of adaptive planning strategies. To implement such strategies, it is crucial to identify indicators that can monitor and signal approaching adaptation thresholds. While existing research has focused on physical and hazard-based indicators, addressing social and economic indicators is essential for informed decision-making. This research aims to fill this gap by compiling 298 economic indicators across six categories: fiscal factors for central, regional, and local governments; financial system indicators; indicators for industries, businesses, and public organisations; and indicators for identifying socially vulnerable populations due to climate change. Derived from previous studies and the national climate change risk assessment framework, these indicators aim to provide policymakers at all levels and communities with a ready-to-use toolbox for monitoring climate change economic risks. Additionally, the research identifies measurable indicators as well as those that cannot currently be measured but could potentially be quantified. Future work involves further analysis and mapping of these indicators to form a cohesive set warning of the need for adaptation measures, aiming to equip decision-makers with tools to address the economic impacts of climate change.

Purpose Providers who treat patients with psoriasis are unevenly distributed across the United States, with more in urban than rural areas. This retrospective claims analysis characterized disparities in access to care for US patients with psoriasis using data from the STATinMED database.Materials and methods Patients (≥18 years) had ≥1 claim with a psoriasis diagnosis and ≥1 claim for advanced psoriasis therapy (apremilast or biologics) between January 2015 and December 2019. Access to psoriasis care was determined using the proportion of patients with 0, 1–2, 3–4, or ≥5 providers in their local area.Results Overall, 179,688 patients were included in the analysis, 80.0% in urban areas. The access ratio was highest for internal medicine physicians (97.1 per 1000 patients) and lowest for dermatologists (4.4 per 1000 patients) and family practice physicians (3.9 per 1000 patients). In urban areas, 41% of patients had access to ≥5 dermatologists versus 7% in rural areas. Whereas 2% of patients in urban areas sought care outside of their local area, 75% in rural areas did so. Use of advanced therapies was low in all states (

As the global ambition is directed at net-zero 2050 amidst energy intensity-efficiency targets, the advanced economies, such as the United States of America (USA) has been consistently charged with more target-driven commitments. Considering this, the current study finds the influence of commercial, industrial, and household energy intensities on both the economic and environmental indicators. A set of cointegration approaches was employed to evaluate the long-run and short-run relationship between covariates and carbon emission over the period 1974–2019. Empirical findings reveal that all the covariates are positive and significantly related to carbon emissions. For instance, the emission of carbon dioxide is worsened by economic growth in both the short- and long-run. Additionally, intense use of energy across the commercial, household, and industrial sectors is responsible for an increase in environmental degradation arising from the emission of carbon emission. Importantly, environmental degradation that is attributed to energy intensity is far more (twice) in the commercial sector and household sector, than in the industrial sector. Regarding the economic aspects, there is statistical evidence that research and development expenditure in energy efficiency improves economic growth while higher energy intensities in the commercial and industrial sectors are detrimental to economic expansion. As a policy, the study suggests that the share of renewable or clean energy technology in the country’s energy mix should be significantly increased to over-turn the undesirable economic, environmental, and global warming-related issues in the United States. Other few directions for policy implication were addressed.

Bacteria frequently colonize niches by forming multicellular communities called biofilms. To explore new territories, cells exit biofilms through an active process called dispersal. Biofilm dispersal is essential for bacteria to spread between infection sites, yet how the process is executed at the single-cell level remains mysterious due to the limitations of traditional fluorescent proteins, which lose functionality in large, oxygen-deprived biofilms. To overcome this challenge, we developed a cell-labeling strategy utilizing fluorogen-activating proteins (FAPs) and cognate far-red dyes, which remain functional throughout biofilm development, enabling long-term imaging. Using this approach, we characterize dispersal at unprecedented resolution for the global pathogen Vibrio cholerae. We reveal that dispersal initiates at the biofilm periphery and approximately 25% of cells never disperse. We define novel micro-scale patterns that occur during dispersal, including biofilm compression during cell departure and regional heterogeneity in cell motions. These patterns are attenuated in mutants that reduce overall dispersal or that increase dispersal at the cost of homogenizing local mechanical properties. Collectively, our findings provide fundamental insights into the mechanisms of biofilm dispersal, advancing our understanding of how pathogens disseminate. Moreover, we demonstrate the broad applicability of FAPs as a powerful tool for high-resolution studies of microbial dynamics in complex environments.

IntroductionGenomics is a lifespan competency that is important for improving health outcomes for individuals, families, and communities. Nurses play a key role in genomic healthcare and realizing the potential of the genomic era.MethodsWe aimed to chart the current state of genomics in nursing by conducting a systematic scoping review of the literature in four databases (2012–2022). We categorized included articles using the Cochrane Collaboration outcome domains/sub-domains and identify key topical areas.ResultsOf 8532 retrieved articles, we identified 67 articles on ‘consumer-oriented outcomes’ (patient and family) for analysis. Identified articles primarily centered on themes of genetic testing and screening. Most studies reported non-interventional studies 39/67 (58%) and more than half were from the U.S.A. 34/67 (51%). Six of nine subdomains were reported on. The “patient involvement in care” subdomain was the most commonly reported subdomain (17/67, 25%) while “treatment outcomes” had the fewest reports (5/67, 8%). Overall, consumers (i.e., patients and families) had high satisfaction with nurse-led interventions.DiscussionSynthesizing findings revealed key knowledge gaps and unmet patient informational needs around genetic testing and decision support. There are opportunities for interprofessional collaboration between nursing and genetic counseling to meet the mounting demand for genomic healthcare and develop more person-centered approaches to genetic counseling and decisional support. Findings support the need for interventional studies and enhanced focus on implementation for nurses to improve consumer-oriented outcomes.

ABSTRACT Bats are known to host zoonotic viruses, including henipaviruses that cause high fatality rates in humans (Nipah virus and Hendra virus). However, the determinants of zoonotic spillover are generally unknown, as the ecological and demographic drivers of viral circulation in bats are difficult to ascertain without longitudinal data. Here we analyse serological data collected from African straw‐coloured fruit bats (Eidolon helvum) in Ghana over the course of 2 years and across four sites, comprising three wild roosts and one captive colony. We focus on antibody affinity to five henipavirus antigens: Ghanaian bat henipavirus (GhV), Nipah virus (NiV), Hendra virus (HeV), Mojiang virus (MojV) and Cedar virus (CedV). In the wild roosts, we detected seasonal variations in henipavirus antibody binding, possibly associated with bat life‐history cycles and migration patterns. In the captive colony, we identified increases in antibody affinity levels among pregnant bats, suggesting possible shifts in the immune system during pregnancy. These bats then pass maternal antibodies to their pups, which wane before antibody affinity levels rise later in life following initial infections and/or reactivation of latent infections. These results improve our understanding of the links between bat ecology and viral circulation, including for GhV, a locally‐circulating African henipavirus.

Introduction A literature review provides a synthesis on a selection of papers about a specific topic. This is used by health practitioners in critical care as in other specialities when making clinical practice decisions. The task of knowledge transfer through the review process of scientific papers involves a variety of methodologies with differing expectations on the quality and rigour that is applied. Exploration on the types of review methodologies selected by the authors of critical care literature may reveal the extent that choice of methodology has on how papers are selected and appraised may influence evidence-based practice recommendations. This scoping review aims to systematically map the breadth of current literature with the objective of identifying the types of review methodologies used by interdisciplinary authors synthesising the literature in adult critical care.Methods and analysis Arksey and O’Malley’s approach in conducting a scoping review will be followed and use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review guidelines in the reporting of findings. Papers with diverse review methodologies will be identified by searching four electronic databases (CINAHL/EBSCO, MEDLINE/PubMed, Scopus and Embase). Grey literature will be excluded due to the clinical nature of the review question. Search results will be reviewed independently by two researchers based on title and abstract followed by full-text papers that meet inclusion criteria. Characteristics of review methodologies will be collected and analysed using a tool developed by the interdisciplinary research team.Ethics and dissemination This scoping review will provide an overview of the types of review methodologies most often undertaken with the interdisciplinary research team synthesising the quality of critical care literature. Scrutiny will be applied to the review methodologies selected, the challenges faced and current trends in the transfer of knowledge towards evidence-based practice. The results will be disseminated by publication through a peer-reviewed journal and by presentation as a part of conference proceedings. Ethics approval is not applicable for this scoping review.

Summary: Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer’s disease (AD). Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42–85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer’s Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.

Summary: Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.