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Abstract Intracranial pressure (ICP) is a physiological parameter that conventionally requires invasive monitoring for accurate measurement. Utilising multivariate predictive models, we sought to evaluate the utility of non-invasive, widely accessible MRI biomarkers in predicting ICP and their reversibility following cerebrospinal fluid (CSF) diversion. The retrospective study included 325 adult patients with suspected CSF dynamic disorders who underwent brain MRI scans within three months of elective 24-h ICP monitoring. Five MRI biomarkers were assessed: Yuh sella grade, optic nerve vertical tortuosity (VT), optic nerve sheath distension, posterior globe flattening and optic disc protrusion (ODP). The association between individual biomarkers and 24-h ICP was examined and reversibility of each following CSF diversion was assessed. Multivariate models incorporating these radiological biomarkers were utilised to predict 24-h median intracranial pressure. All five biomarkers were significantly associated with median 24-h ICP (p

Abstract By 2050, 1 in 4 people worldwide will be living with hearing impairment. We propose a digital Speech Hearing Screener (dSHS) using short nonsense word recognition to measure speech-hearing ability. The importance of hearing screening is increasing due to the anticipated increase in individuals with hearing impairment globally. We compare dSHS outcomes with standardized pure-tone averages (PTA) and speech-recognition thresholds (SRT). Fifty participants (aged 55 or older underwent pure-tone and speech-recognition thresholding. One-way ANOVA was used to compare differences between hearing impaired and hearing not-impaired groups, by the dSHS, with a clinical threshold of moderately impaired hearing at 35 dB and severe hearing impairment at 50 dB. dSHS results significantly correlated with PTAs/SRTs. ANOVA results revealed the dSHS was significantly different (F(1,47) = 38.1, p

Abstract There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer’s disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.

Abstract Background Past research suggests that low testosterone levels relate to poorer cognitive function and higher Alzheimer’s disease (AD) risk; however, these findings are inconsistent and are mostly derived from male samples, despite similar age-related testosterone decline in females. Both animal and human studies demonstrate that testosterone’s effects on brain health may be moderated by apolipoprotein E ε4 allele (APOE-ε4) carrier status, which may explain some previous inconsistencies. We examined how testosterone relates to cognitive function in older women versus men across healthy aging and the AD continuum and the moderating role of APOE-ε4 genotype. Methods Five hundred and sixty one participants aged 55–90 (155 cognitively normal (CN), 294 mild cognitive impairment (MCI), 112 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who had baseline cognitive and plasma testosterone data, as measured by the Rules Based Medicine Human DiscoveryMAP Panel were included. There were 213 females and 348 males (self-reported sex assigned at birth), and 52% of the overall sample were APOE-ε4 carriers. We tested the relationship of plasma testosterone levels and its interaction with APOE-ε4 status on clinical diagnostic group (CN vs. MCI vs. AD), global, and domain-specific cognitive performance using ANOVAs and linear regression models in sex-stratified samples. Cognitive domains included verbal memory, executive function, processing speed, and language. Results We did not observe a significant difference in testosterone levels between clinical diagnostic groups in either sex, regrardless of APOE-ε4 status. Across clinical diagnostic group, we found a significant testosterone by APOE-ε4 interaction in females, such that lower testosterone levels related to worse global cognition, processing speed, and verbal memory in APOE-ε4 carriers only. We did not find that testosterone, nor its interaction with APOE-ε4, related to cognitive outcomes in males. Conclusions Findings suggest that low testosterone levels in older female APOE-ε4 carriers across the aging-MCI-AD continuum may have deleterious, domain-specific effects on cognitive performance. Although future studies including additional sex hormones and longitudinal cognitive trajectories are needed, our results highlight the importance of including both sexes and considering APOE-ε4 carrier status when examining testosterone’s role in cognitive health.

Introduction Successful organ transplantation in patients with end-stage organ failure improves long-term survival, improves quality of life and reduces costs to the NHS. Despite an increase in the number of deceased organ donors over the last decade, there remains a considerable shortfall of suitable organs available for transplantation. Over half of UK donors are certified dead by neurological criteria following brain stem compression, which leads to severe physiological stress in the donor, combined with a hyperinflammatory state. Brain stem death-related dysfunction is an important reason for poor organ function and hence utilisation. For example, more than 30% of donation after brain stem death cardiac transplant recipients need short-term mechanical cardiac support, reflecting donor heart dysfunction.A small, randomised study previously showed improved outcomes for cardiac transplant recipients if the donor was given simvastatin. SIGNET takes inspiration from that study and hypothesises a potential reduction in damage to the heart and other organs during the period after diagnosis of death and prior to organ retrieval in donors that receive simvastatin.Methods and analysis SIGNET is a multicentre, single-blind, prospective, group sequential, randomised controlled trial to evaluate the benefits of a single high dose of simvastatin given to potential organ donors diagnosed dead by neurological criteria on outcomes in all organ recipients. The trial will run across a minimum of 89 UK sites with a recruitment target of 2600 donors over 4 years.Ethics and dissemination SIGNET received a favourable opinion from the London, Queen Square Research Ethics Committee (Ref: 21/LO/0412) and following approval of substantial amendment 1 in January 2023, the current protocol is version 2 (7 December 2022). Substantial amendment 1 clarified consent procedures and added additional sites and prescribers. Findings from the study will be publicly available and disseminated locally and internationally through manuscript publications in peer-reviewed journals and conference presentations at national and international platforms.Trial registration number ISRCTN11440354

Introduction Traumatic pneumothoraces are present in one of five victims of severe trauma. Current guidelines advise chest drain insertion for most traumatic pneumothoraces, although very small pneumothoraces can be managed with observation at the treating clinician’s discretion. There remains a large proportion of patients in whom there is clinical uncertainty as to whether an immediate chest drain is required, with no robust evidence to inform practice. Chest drains carry a high risk of complications such as bleeding and infection. The default to invasive treatment may be causing potentially avoidable pain, distress and complications. We are evaluating the clinical and cost-effectiveness of an initial conservative approach to the management of patients with traumatic pneumothoraces.Methods and analysis The CoMiTED (Conservative Management in Traumatic Pneumothoraces in the Emergency Department) trial is a multicentre, pragmatic parallel group, individually randomised controlled non-inferiority trial to establish whether initial conservative management of significant traumatic pneumothoraces is non-inferior to invasive management in terms of subsequent emergency pleural interventions, complications, pain, breathlessness and quality of life. We aim to recruit 750 patients from at least 40 UK National Health Service hospitals. Patients allocated to the control (invasive management) group will have a chest drain inserted in the emergency department. For those in the intervention (initial conservative management) group, the treating clinician will be advised to manage the participant without chest drain insertion and undertake observation. The primary outcome is a binary measure of the need for one or more subsequent emergency pleural interventions within 30 days of randomisation. Secondary outcomes include complications, cost-effectiveness, patient-reported quality of life and patient and clinician views of the two treatment options; participants are followed up for 6 months.Ethics and dissemination This trial received approval from the Wales Research Ethics Committee 4 (reference: 22/WA/0118) and the Health Research Authority. Results will be submitted for publication in a peer-reviewed journal.Trial registration number ISRCTN35574247.

Introduction More than 170 countries have implemented disability-targeted social protection programmes, although few have been rigorously evaluated. Consequently, a non-randomised controlled trial is being conducted of a pilot ‘cash-plus’ programme implemented by UNICEF Laos and the Laos government for children with disabilities in the Xiengkhouang Province in Laos. The intervention combines a regular cash transfer with provision of assistive devices and access for caregivers to a family support programme.Methods and analysis The non-randomised controlled trial will involve 350 children with disabilities across 3 districts identified by programme implementers as eligible for the programme (intervention arm). Implementers have also identified approximately 180 children with disabilities in neighbouring districts, who would otherwise meet eligibility criteria but do not live in the project areas (control arm). The trial will assess the impact of the programme on child well-being (primary outcome), as well as household poverty, caregiver quality of life and time use (secondary outcomes). Baseline data are being collected May–October 2023, with endline 24 months later. Analysis will be intention to treat. A complementary process evaluation will explore the implementation, acceptability of the programme, challenges and enablers to its delivery and mechanisms of impact.Ethics and dissemination The study has received ethical approval from the London School of Hygiene and Tropical Medicine and the National Ethics Committee for Health Research in Laos. Informed consent and assent will be taken by trained data collectors. Data will be collected and stored on a secure, encrypted server and its use will follow a detailed data management plan. Findings will be disseminated in academic journals and in short briefs for policy and programmatic actors, and in online and in-person events.Trial registration number ISRCTN80603476.

Abstract Optical motion capture (OMC) is considered the best available method for measuring spine kinematics, yet inertial measurement units (IMU) have the potential to collect data outside the laboratory. When combined with musculoskeletal modeling, IMU technology may be used to estimate spinal loads in real-world settings. To date, IMUs have not been validated for estimates of spinal movement and loading during both walking and running. Using OpenSim Thoracolumbar Spine and Ribcage models, we compare IMU and OMC estimates of lumbosacral (L5/S1) and thoracolumbar (T12/L1) joint angles, moments, and reaction forces during gait across six speeds for five participants. For comparisons, time series are ensemble averaged over strides. Comparisons between IMU and OMC ensemble averages have low normalized root mean squared errors ( 0.5 for 91% of comparisons), suggesting signals are similar in magnitude and trend. As expected, joint moments and reaction forces are higher during running than walking for IMU and OMC. Relative to OMC, IMU overestimates joint moments and underestimates joint reaction forces by 20.9% and 15.7%, respectively. The results suggest using a combination of IMU technology and musculoskeletal modeling is a valid means for estimating spinal movement and loading.

Abstract Background Creative methods/practices have been highlighted as helpful to develop more collaborative, equitable research partnerships between researchers and communities/public-participants. We asked artist partners to design four online workshops, one on each research priority area: school environments and mental health; wellbeing within the Somali community; air pollution; health data. We aimed to understand whether creative processes can enable public-participants and researcher- participants to meet in a neutral space to discuss a research theme and begin to build collaborative relationships through more equal engagement. Ideas could be taken forwards with seed funding, providing opportunity for collaboration to continue beyond initial workshops. Methods Different artist partners designed and facilitated four workshops. Evaluation data was collected on each workshop using participatory observation and fieldnotes, alongside chatlog data, and one-to-one interviews with 21 workshop participants, providing a contextually rich, comparative evaluation across four diverse workshops. Analysis was thematically driven. Results Artist partners took different approaches to designing workshops. The workshops began with introductory games and activities, and there was less emphasis on introductions of people’s roles, with the intention to avoid hierarchical dynamics. Whilst public-participants enjoyed this, some researchers found it challenging and reported confusions over their workshop roles. Disrupting usual practice and challenging norms was not always an easy experience. There were examples where emergent, co-created knowledge was enabled. However, it was more challenging to facilitate longer-term collaborative research projects from the workshops due to different stakeholder priorities, and lack of staff time/ less sense of ownership for further work. Conclusions Creative activities can influence and impact the types of conversations between public-participants and researchers in a way that changes and challenges power dynamics, shifting towards public-participant driven discussion. Whilst deconstructing hierarchies is important, supporting researchers is key so that any discomfort can be productive and experienced as a vital part of co-production. Longer term collaborative research projects were limited, highlighting a need for facilitation beyond initial workshops, and a sense of ownership from workshop participants to take things forwards. Workshops like these may lend themselves well to research prioritisation. However, taking community-led ideas forwards within research funding landscapes remains challenging.

Background Compared with multiple-inhaler triple therapy (MITT), single-inhaler triple therapy (SITT) with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) demonstrated improved lung function and meaningful improvements in chronic obstructive pulmonary disease (COPD) Assessment Test score. This real-world study compared the effectiveness of switching patients with COPD in England from MITT to once-daily SITT with FF/UMEC/VI by evaluating rates of COPD exacerbation, healthcare resource use (HCRU) and associated direct medical costs.Methods Retrospective cohort pre-post study using linked primary care electronic health record and secondary care administrative datasets. Patients diagnosed with COPD at age ≥35 years, with smoking history, linkage to secondary care data and continuous GP registration for 12 months pre-switch and 6 months post-switch to FF/UMEC/VI were included. Index date was the first initiation of an FF/UMEC/VI prescription immediately following MITT use from 15 November 2017 to 30 September 2019. Baseline was 12 months prior to index, with outcomes assessed 6/12 months pre-switch and post-switch, and stratified by prior COPD exacerbation status.Results We included 2533 patients (mean [SD] age: 71.1 [9.9] years; 52.1% male). In the 6 months post-switch, there were significant decreases in the proportion of patients experiencing ≥1 moderate-to-severe (36.2%–28.9%), moderate only (24.4%–19.8%) and severe only (15.4%–11.8%) COPD exacerbation (each, p

Introduction Emerging evidence suggests improved quality of life, reduced symptom burden and lower health services costs when integrated palliative care and cancer care are implemented. Integrated palliative care aims to achieve care continuity by integrating organisational, administrative and clinical services involved in patient care networks. However, integrated palliative care for cancer is not common practice. This project, therefore, aims to understand how integrated palliative care and cancer care works in different healthcare settings (inpatient/outpatient), and for which groups of people (at what stage of the cancer journey), so we can develop guidance for optimal delivery.Methods and analysis We will conduct a realist synthesis to develop a programme theory of how integrated palliative care in cancer works, for whom and in what contexts to achieve improved symptom management and quality of life for patients and their families.This realist synthesis will follow the five stages outlined by Pawson: (1) locating existing theories, (2) searching for evidence, (3) article selection, (4) extracting and organising data and (5) synthesising the evidence and drawing conclusions. We will work closely with our expert stakeholder group, which includes health and social care professionals providing palliative care and oncology; management and policy groups and members of the public and patients. We will adhere to RAMESES quality standards for undertaking a realist synthesis.Ethics and dissemination Ethics approval for this project is not required.The realist synthesis will develop a programme theory that provides clarity on the optimal delivery of palliative care for adults with cancer. We will use the programme theory to coproduce guidance and user-friendly outputs, working with stakeholders to inform delivery of best practice. Findings will inform further research in integrated palliative care and cancer. Stakeholder engagement will assist in the dissemination of our findings.PROSPERO registration number CRD42023389791.

Background In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), histopathological assessment of affected tissue is often necessary for diagnosis and assessment of disease extent. There is a requirement for validated non-invasive biomarkers to avoid the need for serial tissue biopsies.Methods A systematic review of scientific databases from 2012 until present was performed to identify studies fulfilling the inclusion criteria. Studies were assessed for quality using the Strengthening the Reporting of Observational Studies in Epidemiology checklist for cohort, case–control and cross-sectional studies and the Risk of Bias Assessment tool for Non-randomised Studies, or the Cochrane Risk of Bias tool 2.0 for randomised controlled trials. A descriptive synthesis of the data for non-invasive (blood-based or urinary) biomarkers of AAV-related disease activity and organ damage was performed.Results Twenty-two high quality studies were included. These articles reported the value of blood-based and urinary biomarkers including anti-neutrophil cytoplasmic antibodies, immune cells, complement factors, gene expression profiles, cytokines, chemokines and other proteins in the assessment of disease activity and/or organ damage in patients with AAV. Many of these biomarkers involve the alternative complement pathway, neutrophil activation and macrophage activation.Conclusion This is the first contemporary systematic review synthesising the value of non-invasive biomarkers of AAV-related disease activity and organ damage. The incorporation of individual markers in combined biomarker profiles might enhance clinical decision-making. Many unmet needs were identified; few studies involve oeosinophilic granulomatosis with polyangiitis and patients with childhood-onset AAV. Further validation of the candidate biomarkers is warranted in large prospective studies to bridge the existing knowledge gaps and apply precision health to systemic vasculitis.

Objective Management of chronic obstructive pulmonary disease (COPD) with inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) improves lung function and health status and reduces COPD exacerbation risk versus monotherapy. This study described treatment use, healthcare resource utilisation (HCRU), healthcare costs and outcomes following initiation of single-device ICS/LABA as initial maintenance therapy (IMT).Design Retrospective cohort study.Setting Primary care, England.Data sources Linked data from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics datasets.Participants Patients with COPD and ≥1 single-device ICS/LABA prescription between July 2015 and December 2018 were included.Primary and secondary outcome measures Treatment pathways, COPD-related HCRU and healthcare costs, COPD exacerbations, time to triple therapy, medication adherence (proportion of days covered ≥80%) and indexed treatment time to discontinuation. Data for patients without prior maintenance therapy history (IMT users) and non-triple users were assessed over a 12-month follow-up period.Results Of 13 451 new ICS/LABA users, 5162 were IMT users (budesonide/formoterol, n=1056; beclomethasone dipropionate/formoterol, n=2427; other ICS/LABA, n=1679), for whom at 3 and 12 months post-index, 45.6% and 39.4% were still receiving any ICS/LABA. At >6 to ≤12 months, the proportion of IMT users with ≥1 outpatient visit (10.1%) and proportion with ≥1 inpatient stay (12.6%) had increased from those at 3 months (9.0% and 7.4%, respectively). Inpatient stays contributed most to total COPD-related healthcare costs. For non-triple IMT users, at 3 and 12 months post-index, 4.5% and 13.7% had ≥1 moderate-to-severe COPD exacerbation. Time to triple therapy initiation and time to discontinuation of index medication ranged from 45.9 to 50.2 months and 2.3 to 2.8 months between treatments. Adherence was low across all time points (21.5–27.6%). Results were similar across indexed therapies.Conclusions In the year following treatment initiation, ICS/LABA adherence was poor and many patients discontinued or switched therapies, suggesting that more consideration and optimisation of treatment is required in England for patients initiating single-device ICS/LABA therapy.

Background: Malnutrition is a significant and prevalent issue in hospital settings, associated with increased morbidity and mortality, longer hospital stays, higher readmission rates, and greater healthcare costs. Despite the potential impact of nutritional interventions on patient outcomes, there is a paucity of research focusing on their economic evaluation in the hospital setting. This study aims to fill this gap by conducting a cost–consequence analysis (CCA) of nutritional interventions targeting malnutrition in the hospital setting. Methods: We performed a CCA using data from recent systematic reviews and meta-analyses, focusing on older adult patients with or at risk of malnutrition in the hospital setting. The analysis included outcomes such as 30-day, 6-month, and 12-month mortality; 30-day and 6-month readmissions; hospital complications; length of stay; and disability-adjusted life years (DALYs). Sensitivity analyses were conducted to evaluate the impact of varying success rates in treating malnutrition and the proportions of malnourished patients seen by dietitians in SingHealth institutions. Results: The CCA indicated that 28.15 DALYs were averted across three SingHealth institutions due to the successful treatment or prevention of malnutrition by dietitians from 1 April 2021 to 31 March 2022, for an estimated 45,000 patients. The sensitivity analyses showed that the total DALYs averted ranged from 21.98 (53% success rate) to 40.03 (100% of malnourished patients seen by dietitians). The cost of implementing a complex nutritional intervention was USD 218.72 (USD 104.59, USD 478.40) per patient during hospitalization, with additional costs of USD 814.27 (USD 397.69, USD 1212.74) when the intervention was extended for three months post-discharge and USD 638.77 (USD 602.05, USD 1185.90) for concurrent therapy or exercise interventions. Conclusion: Nutritional interventions targeting malnutrition in hospital settings can have significant clinical and economic benefits. The CCA provides valuable insights into the costs and outcomes associated with these interventions, helping healthcare providers and policymakers to make informed decisions on resource allocation and intervention prioritization.

Abstract The tropical rock lobster, Panulirus ornatus, is a commercially important aquaculture species exhibiting complex social interactions in laboratory culture, including cannibalism of moulting conspecifics. Cannibalism of soft-shelled post-moult stage individuals is a major limitation during the juvenile stage of culture. Not limited to P. ornatus, cannibalism is widespread across farmed decapods, limiting stocking densities in crab, freshwater crayfish, and prawn species. To understand the mechanisms driving this behaviour and reduce its prevalence, we have investigated the role of chemoreception via the aesthetasc-bearing region of the lateral antennular flagellum, in the recognition of conspecific moulting cues. Differential expression analysis of several tissues in P. ornatus shows an upregulation of 70 ionotropic receptor isoforms, including co-receptors (IR25a and IR93a) and divergent receptors (IR4, IR7, and IR21a) in the aesthetasc-bearing region of the antennules. Deafferentation of the aesthetascs via deionised water exposure prevents juveniles from responding to conspecific moulting cues in a two-current choice flume, suggesting chemoreception, possibly olfaction, plays a role in identifying moulting juveniles. This is the first step in understanding the mechanisms via which cannibalism is triggered in juvenile P. ornatus culture. Further work in this area will help discover means to limit cannibalism in laboratory and commercial culture.

Abstract African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC–MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

BackgroundUniversity students typically face acute financial pressure, which can adversely impact mental health, wellbeing, and academic outcomes. This scoping review of qualitative and quantitative studies aimed to identify distinct money-management behaviours, and psychological determinants, to inform future interventions.MethodsTwo electronic databases were searched for observational studies focusing on money-management behaviours and their correlates (in quantitative studies) or reflections on experiences of such behaviours (qualitative studies). Of 789 unique papers identified, 12 papers, reporting 10 distinct studies (six quantitative, two qualitative, two mixed-methods), were entered into review. We inductively categorised all behaviours and psychological correlates, and narratively synthesised findings.ResultsWe documented 15 distinct money-management behaviours, which fitted five higher-order categories: budgeting, saving (i.e., building funds), spending, borrowing, and settling debts. Twenty-two distinct potential correlates were observed, which fitted six categories: personality characteristics, financial beliefs and knowledge, attitudes, affective responses, self-efficacy and control, and social influences. Financial beliefs and knowledge, attitudes, self-efficacy and control, and social support from parents and peers were generally associated with 'better' money management practices.ConclusionHeterogeneity in behaviours and correlates studied precluded definitive conclusions. Future studies should more comprehensively adopt theories and concepts from behavioural science, to distinguish between different money-management behaviours, identify which behaviours have most impact on students, and establish which specific determinants are most related to which money-management behaviours.

Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective. Funding: Swedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.

BackgroundYouth who experience traumatic events are at a substantially higher risk of engaging in substance use and sexual risk behaviors and problems (eg, HIV acquisition) than their non–trauma-exposed counterparts. Evidence-based substance use and risky sexual behavior prevention may reduce the risk of these outcomes. Trauma-focused mental health treatment provides a window of opportunity for the implementation of such preventive work with these youth. However, overburdened clinicians face challenges in adding prevention content while implementing evidence-based treatments. Mobile health (mHealth) tools can help reduce this burden in delivering prevention curricula. Trauma-Informed Prevention for Substance Use and Risky Sexual Behavior (TIPS) is an mHealth app that was developed to aid trauma-focused cognitive behavioral therapy (TF-CBT) clinicians in the implementation of an evidence-based risk behavior prevention curriculum. ObjectiveThe goal of this paper is to describe the rationale for and development of the TIPS app and present the results of a mixed methods approach for the initial evaluation of its usability. MethodsParticipants included clinicians (n=11), adolescents (n=11), and caregivers (n=10) who completed qualitative interviews and an adapted version of the Website Analysis and Measurement Inventory. ResultsIn total, 4 overarching themes emerged from the participants’ answers to the qualitative interview questions, demonstrating a generally positive response to the app. The themes were (1) strength of app content, (2) suggestions about app content, (3) esthetics and usability, and (4) benefits to the patient and session implementation. Clinicians, adolescents, and caregivers all agreed that the content was very relevant to adolescents and used examples and language that adolescents could relate to. All 3 groups also discussed that the content was comprehensive and addressed issues often faced by adolescents. All 3 groups of users made suggestions about the esthetics, which mostly comprised suggestions to change the font, color, or pictures within the app. Of all the groups, adolescents were most positive about the esthetics and usability of the app. Results from the Website Analysis and Measurement Inventory further illustrated the users’ favorable reaction to the TIPS app, with 100% (11/11) of clinicians, 100% (10/10) of caregivers, and most adolescents (7/11, 64%) selecting strongly agree or somewhat agree to the following statement: “This app has much that is of interest to me.” Adolescents generally found the app easier to use than did caregivers and clinicians. ConclusionsThe TIPS app shows promise as an mHealth tool for TF-CBT clinicians to integrate evidence-based substance use, risky sexual behavior, and HIV prevention during treatment. Future research, including a randomized controlled trial comparing TF-CBT implementation with and without the inclusion of the app, is necessary to evaluate the feasibility and efficacy of the app in reducing the risk of substance use and risky sexual behavior among trauma-exposed adolescents. Trial RegistrationClinicalTrials.gov NCT03710720; https://clinicaltrials.gov/study/NCT03710720

Ribosome biogenesis is a vital and highly energy-consuming cellular function occurring primarily in the nucleolus. Cancer cells have an elevated demand for ribosomes to sustain continuous proliferation. This study evaluated the impact of existing anticancer drugs on the nucleolus by screening a library of anticancer compounds for drugs that induce nucleolar stress. For a readout, a novel parameter termed ‘nucleolar normality score’ was developed that measures the ratio of the fibrillar center and granular component proteins in the nucleolus and nucleoplasm. Multiple classes of drugs were found to induce nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Each class of drugs induced morphologically and molecularly distinct states of nucleolar stress accompanied by changes in nucleolar biophysical properties. In-depth characterization focused on the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that regulates RNA Pol II. Multiple CDK substrates were identified in the nucleolus, including RNA Pol I– recruiting protein Treacle, which was phosphorylated by CDK9 in vitro. These results revealed a concerted regulation of RNA Pol I and Pol II by transcriptional CDKs. Our findings exposed many classes of chemotherapy compounds that are capable of inducing nucleolar stress, and we recommend considering this in anticancer drug development.

Introduction Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (

Introduction Hearing loss is a common chronic health condition and adversely affects communication and social function resulting in loneliness, social isolation and depression. We know little about the patient experience of living with hearing loss and their views on the quality of the audiology service. In this study, we will develop and validate the first patient-reported experience measure (PREM) to understand patients’ experiences of living with hearing loss and their healthcare interactions with audiology services.Methods and analysis We will develop the PREM in three phases: (1) development of PREM prototype (items/statements) derived from previous qualitative work and narrative review, (2) cognitive interview testing of the PREM prototype using a ‘think aloud’ technique to examine the acceptability and comprehensibility of the tool and refine accordingly and (3) psychometric testing of the modified PREM with 300 participants to assess the reliability and validity of the tool using Rasch analyses with sequential item reduction. Eligible participants will be young people and adults aged 16 years and over who have hearing loss. Participants will be recruited from three clinical sites located in England (Bath, Bristol) and Scotland (Tayside) and non-clinical settings (eg, lip-reading classes, residential care settings, national charity links, social media).Ethics and dissemination The study was approved by the West of Scotland Research Ethics Service (approval date: 6 May 2022; ref: 22/WS/0057) and the Health Research Authority and Health and Care Research Wales (HCRW) Approval (approval date: 14 June 2022; IRAS project ID: 308816). Findings will be shared with our patient and public involvement groups, academics, audiology communities and services and local commissioners via publications and presentations. The PREM will be made available to clinicians and researchers without charge.

Stories can be a powerful method of exploring complexity, and the factors affecting everyday physical activity within a modern urban setting are nothing if not complex. The first part of our How Do You Move? study focused on the communication of physical activity guidelines to under-served communities. A key finding was that adults especially wanted physical activity messages to come from ‘everyday people, people like us’. This finding also reflects a wider move to use more relatable imagery in health promotion campaigns. Using a portrait vignette approach to create monologues, we set out to explore the experiences of people from diverse backgrounds living in Bristol, all of whom took part in varied leisure time physical activities but would also be considered to lead ‘normal’ lives. We aim to demonstrate that stories of such ‘experts by experience’ can contribute to how physical activity is perceived and elucidate the complex interplay of barriers and enablers in everyday experiences of physical activity.

Abstract Across the human body, skeletal muscles have a broad range of biomechanical roles that employ complex proprioceptive control strategies to successfully execute a desired movement. This information is derived from peripherally located sensory apparatus, the muscle spindle and Golgi tendon organs. The abundance of these sensory organs, particularly muscle spindles, is known to differ considerably across individual muscles. Here we present a comprehensive data set of 119 muscles across the human body including architectural properties (muscle fibre length, mass, pennation angle and physiological cross-sectional area) and statistically test their relationships with absolute spindle number and relative spindle abundance (the residual value of the linear regression of the log-transformed spindle number and muscle mass). These data highlight a significant positive relationship between muscle spindle number and fibre length, emphasising the importance of fibre length as an input into the central nervous system. However, there appears to be no relationship between muscles architecturally optimised to function as displacement specialists and their provision of muscle spindles. Additionally, while there appears to be regional differences in muscle spindle abundance, independent of muscle mass and fibre length, our data provide no support for the hypothesis that muscle spindle abundance is related to anatomical specialisation.

Introduction: Malnutrition is a widespread and intricate issue among hospitalized adults, necessitating a wide variety of nutritional strategies to address its root causes and repercussions. The primary objective of this study is to systematically categorize nutritional interventions into simple or complex, based on their resource allocation, strategies employed, and predictors of intervention complexity in the context of adult malnutrition in hospital settings. Methods: A conceptual evaluation of 100 nutritional intervention studies for adult malnutrition was conducted based on data from a recent umbrella review (patient population of mean age > 60 years). The complexity of interventions was categorized using the Medical Research Council 2021 Framework for Complex Interventions. A logistic regression analysis was employed to recognize variables predicting the complexity of interventions. Results: Interventions were divided into three principal categories: education and training (ET), exogenous nutrient provision (EN), and environment and services (ES). Most interventions (66%) addressed two or more of these areas. A majority of interventions were delivered in a hospital (n = 75) or a hospital-to-community setting (n = 25), with 64 studies being classified as complex interventions. The logistic regression analysis revealed three variables associated with intervention complexity: the number of strategies utilized, the targeted areas, and the involvement of healthcare professionals. Complex interventions were more likely to be tailored to individual needs and engage multiple healthcare providers. Conclusions: The study underlines the importance of considering intervention complexity in addressing adult malnutrition. Findings advocate for a comprehensive approach to characterizing and evaluating nutritional interventions in future research. Subsequent investigations should explore optimal balances between intervention complexity and resource allocation, and assess the effectiveness of complex interventions across various settings, while considering novel approaches like telehealth.

Objectives To adapt the content and functionalities of Brain Health PRO, a web-based multidomain program designed to increase dementia literacy, to the context and needs of users, providers and community organisations across Québec, Canada.Design Five consecutive qualitative co-creation focus group sessions 30–90 min in duration each, exploring potential barriers and facilitators to usability, accessibility, comprehensibility, participant recruitment and retention.Setting Virtual meetings.Participants A 15-member team based in Québec and Ontario, Canada, consisting of 9 researchers (including a graduate student and the project coordinator), representing occupational therapy, sensory rehabilitation, neuropsychology, psychology, health science and research methods, 3 informal caregivers of older adults living with cognitive decline and 3 members of the Federation of Quebec Alzheimer Societies.Data analysis Session recordings were summarised through both qualitative description and thematic analysis.Results The synthesised recommendations included adjustments around diversity, the complexity and presentation styles of the materials, suggestions on refining the web interface and the measurement approaches; it influenced aspects of participant recruitment, retention efforts and engagement with the content of Brain Health PRO.Conclusions Co-creation in dementia prevention research is important because it involves collaboration between researchers, community support and service providers, and persons with lived experience as care providers, in the design and implementation of clinical studies. This approach helps to ensure that the content and presentation of educational material is relevant and meaningful to the target population and those involved in its delivery, and it leads to a greater understanding of their needs and perspectives.

Maintaining a healthy body weight requires an exquisite balance between energy intake and energy expenditure. To understand the genetic and environmental factors that contribute to the regulation of body weight, an important first step is to establish the normal range of metabolic values and primary sources contributing to variability. Energy metabolism is measured by powerful and sensitive indirect calorimetry devices. Analysis of nearly 10,000 wild-type mice from two large-scale experiments revealed that the largest variation in energy expenditure is due to body composition, ambient temperature, and institutional site of experimentation. We also analyze variation in 2329 knockout strains and establish a reference for the magnitude of metabolic changes. Based on these findings, we provide suggestions for how best to design and conduct energy balance experiments in rodents. These recommendations will move us closer to the goal of a centralized physiological repository to foster transparency, rigor and reproducibility in metabolic physiology experimentation.

Abstract Fully shaped, morphologically standardized bone tools are generally considered reliable indicators of the emergence of modern behavior. We report the discovery of 23 double-beveled bone tools from ~ 80,000–60,000-year-old archaeological layers at Sibudu Cave in KwaZulu-Natal, South Africa. We analyzed the texture of use-wear on the archaeological bone tools, and on bone tool replicas experimentally used in debarking trees, processing rabbit pelts with and without an ochre compound, digging in sediment in and outside a cave, and on ethnographic artefacts. Debarking trees and digging in humus-rich soil produce use-wear patterns closely matching those observed on most Sibudu tools. This tool type is associated with three different Middle Stone Age cultural traditions at Sibudu that span 20,000 years, yet they are absent at contemporaneous sites. Our results support a scenario in which some southern African early modern human groups developed and locally maintained specific, highly standardized cultural traits while sharing others at a sub-continental scale. We demonstrate that technological and texture analyses are effective means by which to infer past behaviors and assess the significance of prehistoric cultural innovations.

Introduction Worldwide, hearing loss is a significant public health issue and one of the most common chronic health conditions experienced by older adults. Hearing loss is associated with communication difficulties, social withdrawal, isolation and lower quality of life. Although hearing aid technology has improved significantly, the workload of managing hearing aids has increased. The aim of this qualitative study is to develop a novel theory of people’s lived experience of hearing loss across the lifespan.Methods Eligible participants will be young people and adults aged 16 years and above who have a hearing loss and carers/family members of people with a hearing loss. This study will use individual, in-depth face-to-face or online interviews. With participants’ permission, interviews will be audio-recorded and transcribed verbatim. A grounded theory approach to concurrent data gathering and analysis will develop grouped codes and categories and link these to provide a novel theory to describe the experience of hearing loss.Ethics and dissemination The study was approved by the West of Scotland Research Ethics Service (approval date: 6 May 2022 ref: 22/WS/0057) and the Health Research Authority and Health and Care Research Wales Approval (approval date: 14 June 2022; IRAS project ID: 308816). The research will inform the development of a Patient Reported Experience Measure to improve the information and support given to patients. Findings will be disseminated through peer-reviewed articles and at academic conferences, as well as to our patient and public involvement groups, healthcare professionals, audiology services and local commissioners.

Introduction Aboriginal and Torres Strait Islander peoples are the First Peoples of Australia. Since settler colonisation, Aboriginal and Torres Strait Islander peoples have experienced disparities in health outcomes, including cancer, when compared with non-Indigenous Australians, including higher cancer incidence and mortality rates, and lower participation in cancer screening programmes. Data to monitor and improve outcomes are limited.Aims, method and analysis The Kulay Kalingka Study will be a national cohort study aiming to understand Aboriginal and Torres Strait Islander people’s beliefs about cancer and experiences with cancer care and treatment, and to improve experiences and outcomes. It will be nested within the Mayi Kuwayu Study, a national community-controlled cohort study of Aboriginal and Torres Strait Islander people (n>11 000), with supplementary in-community recruitment.Mayi Kuwayu Study participants aged ≥18 years who consented to being recontacted, and a diversity of local community members will be invited to participate through completing a questionnaire relevant to their cancer status, aiming to recruit 2800 participants without prior doctor-diagnosed cancer and 700 with a cancer diagnosis.This community-driven data will enable monitoring and reporting of national trends over time and will guide national cancer control research, policy and clinical care, to improve outcomes for Aboriginal and Torres Strait Islander peoples.Ethics and dissemination The Kulay Kalingka Study has ethics approval from Australian Institute of Aboriginal and Torres Strait Islander Studies (#EO324-20220414 and REC-0121) and the Australian National University (#2022/465). The Kulay Kalingka Study is being developed with Aboriginal and Torres Strait Islander communities, following the Maiam nayri Wingara Indigenous Data Sovereignty Collective principles. Meaningful, accessible and culturally adapted study findings will be disseminated to Aboriginal and Torres Strait Islander communities through activities including community workshops, reports and feedback sheets, and in other ways as determined by the community. We will also return data to participating communities.

The oral cavity is a niche for diverse microbes, including viruses. Members of the Herpesviridae family, comprised of dsDNA viruses, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an ssRNA virus, are among the most prevalent viruses infecting the oral cavity, and they exhibit clinical manifestations unique to oral tissues. Viral infection of oral mucosal epithelia triggers an immune response that results in prolonged inflammation. The clinical and systemic disease manifestations of HHV have been researched extensively, and several recent studies have illuminated the relationship between HHV and oral inflammatory diseases. Burgeoning evidence suggests the oral manifestation of SARS-CoV-2 infection includes xerostomia, dysgeusia, periodontal disease, mucositis, and opportunistic viral and bacterial infections, collectively described as oral post-acute sequelae of COVID-19 (PASC). These diverse sequelae could be a result of intensified immune responses initially due to the copious production of proinflammatory cytokines: the so-called “cytokine storm syndrome”, facilitating widespread oral and non-oral tissue damage. This review explores the interplay between HHV, SARS-CoV-2, and oral inflammatory diseases such as periodontitis, endodontic disease, and peri-implantitis. Additionally, the review discusses proper diagnostic techniques for identifying viral infection and how viral diagnostics can lead to improved overall patient health.

Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. The existing data suggest that early diagnosis and intervention can improve ASD outcomes. The causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. There is an increasing recognition that ASD might be associated with oxidative stress through several mechanisms including abnormal metabolism (lipid peroxidation) and the toxic buildup of reactive oxygen species (ROS). Glutathione acts as an antioxidant, a free radical scavenger and a detoxifying agent. This open-label pilot study investigates the tolerability and effectiveness of oral supplementation with OpitacTM gluthathione as a treatment for patients with ASD. The various aspects of glutathione OpitacTM glutathione bioavailability were examined when administered by oral routes. The absorption of glutathione from the gastrointestinal tract has been recently investigated. The results of this case series suggest that oral glutathione supplementation may improve oxidative markers, but this does not necessarily translate to the observed clinical improvement of subjects with ASD. The study reports a good safety profile of glutathione use, with stomach upset reported in four out of six subjects. This article discusses the role of the gut microbiome and redox balance in ASD and notes that a high baseline oxidative burden may make some patients poor responders to glutathione supplementation. In conclusion, an imbalance in redox reactions is only one of the many factors contributing to ASD, and further studies are necessary to investigate other factors, such as impaired neurotransmission, immune dysregulation in the brain, and mitochondrial dysfunction.

Abstract Whether sentinel lymph node biopsy (SLNB) should be performed in patients with microinvasive breast cancer (MIBC) has been a matter of debate over the last decade. MIBC has a favorable prognosis and while metastasis to the axilla is rare, it can impact treatment recommendations. In this study we evaluated clinical and histological features in both MIBC and background DCIS including ER, PR, and HER-2, number of foci of MIBC, the extent of the DCIS, nuclear grade, presence of comedo necrosis, as well as surgical procedures, adjuvant treatment and follow up to identify variables which predict disease free survival (DFS), as well as the factors which influence clinical decision making. Our study included 72 MIBC patients with a mean patient follow-up time of 55 months. Three patients with MIBC had recurrence, and two deceased, leaving five patients in total with poor long-term outcomes and a DFS rate of 93.1%. Performing mastectomy, high nuclear grade, and negativity for ER and HER-2 were found to be associated with the use of SLNB, although none of these variables were found to be associated with DFS. One positive lymph node case was discovered following SLNB in our study. This suggests the use of SLNB may provide diagnostic information to some patients, although these are the anomalies. When comparing patients who had undergone SLNB to those which had not there was no difference in DFS. Certainly, the use of SLNB in MIBC is quite the conundrum. It is important to acknowledge that surgical complications have been reported, and traditional metrics used for risk assessment in invasive breast cancer may not hold true in the setting of microinvasion.

Abstract Adiponectin, encoded by ADIPOQ, is an insulin-sensitizing, anti-inflammatory, and renoprotective adipokine that activates receptors with intrinsic ceramidase activity. We identified a family harboring a 10-nucleotide deletion mutation in ADIPOQ that cosegregates with diabetes and end-stage renal disease. This mutation introduces a frameshift in exon 3, resulting in a premature termination codon that disrupts translation of adiponectin’s globular domain. Subjects with the mutation had dramatically reduced circulating adiponectin and increased long-chain ceramides levels. Functional studies suggest that the mutated protein acts as a dominant negative through its interaction with non-mutated adiponectin, decreasing circulating adiponectin levels, and correlating with metabolic disease.

Abstract Background The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Methods Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Results Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Conclusions Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

Abstract Stroke survivors often exhibit gait dysfunction which compromises self-efficacy and quality of life. Muscle Synergy Analysis (MSA), derived from electromyography (EMG), has been argued as a method to quantify the complexity of descending motor commands and serve as a direct correlate of neural function. However, controversy remains regarding this interpretation, specifically attribution of MSA as a neuromarker. Here we sought to determine the relationship between MSA and accepted neurophysiological parameters of motor efficacy in healthy controls, high (HFH), and low (LFH) functioning stroke survivors. Surface EMG was collected from twenty-four participants while walking at their self-selected speed. Concurrently, transcranial magnetic stimulation (TMS) was administered, during walking, to elicit motor evoked potentials (MEPs) in the plantarflexor muscles during the pre-swing phase of gait. MSA was able to differentiate control and LFH individuals. Conversely, motor neurophysiological parameters, including soleus MEP area, revealed that MEP latency differentiated control and HFH individuals. Significant correlations were revealed between MSA and motor neurophysiological parameters adding evidence to our understanding of MSA as a correlate of neural function and highlighting the utility of combining MSA with other relevant outcomes to aid interpretation of this analysis technique.

Abstract Background According to international guidelines, Human Papillomavirus (HPV) DNA tests represent a valid alternative to Pap Test for primary cervical cancer screening, provided that they guarantee balanced clinical sensitivity and specificity for cervical intraepithelial neoplasia grade 2 or more (CIN2+) lesions. The study aimed to assess whether HPV Selfy (Ulisse BioMed – Trieste, Italy), a full-genotyping HPV DNA test that detects and differentiates 14 high-risk HPV (HR-HPV) types, meets the criteria for primary cervical cancer screening described in the international guidelines, on clinician-collected as well as on self-collected samples. Methods For each participant woman, consecutively referring to Azienda Sanitaria Universitaria Giuliano Isontina (Trieste, Italy) and CRO—National Cancer Institute (Aviano, Italy) for the cervical cancer screening program, the following samples were tested: (a) a clinician-collected cervical specimen, analyzed with the reference test (Hybrid Capture®2 test, HC2) and HPV Selfy; and (b) a self-collected vaginal sample, analyzed with HPV Selfy. Enrolled women were also asked to fulfill a questionnaire about self-sampling acceptability. As required by guidelines, a non-inferiority test was conducted to compare the clinical performance of the test under evaluation with its reference test. Results HPV Selfy clinical sensitivity and specificity resulted non-inferior to those of HC2. By analysis of a total of 889 cervical liquid-based cytology samples from a screening population, of which 98 were from women with CIN2+, HPV Selfy showed relative sensitivity and specificity for CIN2+ of 0.98 and 1.00 respectively (non-inferiority score test: P = 0.01747 and P = 0.00414, respectively); the test reached adequate intra- and inter-laboratory reproducibility. Moreover, we demonstrated that the performance of HPV Selfy on self-collected vaginal samples was non-inferior to the performance obtained on clinician-collected cervical specimen (0.92 relative sensitivity and 0.97 relative specificity). Finally, through HPV Selfy genotyping, we were able to describe HPV types prevalence in the study population. Conclusions HPV Selfy fulfills all the requirements of the international Meijer’s guidelines and has been clinically validated for primary cervical cancer screening purposes. Moreover, HPV Selfy has also been validated for self-sampling according to VALHUDES guidelines. Therefore, at date, HPV Selfy is the only full-genotyping test validated both for screening purposes and for self-sampling. Trial registration ASUGI Trieste n. 16008/2018; CRO Aviano n.17149/2018

Active matter systems can generate highly ordered structures, avoiding equilibrium through the consumption of energy by individual constituents. How the microscopic parameters that characterize the active agents are translated to the observed mesoscopic properties of the assembly has remained an open question. These active systems are prevalent in living matter; for example, in cells, the cytoskeleton is organized into structures such as the mitotic spindle through the coordinated activity of many motor proteins walking along microtubules. Here, we investigate how the microscopic motor-microtubule interactions affect the coherent structures formed in a reconstituted motor-microtubule system. This question is of deeper evolutionary significance as we suspect motor and microtubule type contribute to the shape and size of resulting structures. We explore key parameters experimentally and theoretically, using a variety of motors with different speeds, processivities, and directionalities. We demonstrate that aster size depends on the motor used to create the aster, and develop a model for the distribution of motors and microtubules in steady-state asters that depends on parameters related to motor speed and processivity. Further, we show that network contraction rates scale linearly with the single-motor speed in quasi-one-dimensional contraction experiments. In all, this theoretical and experimental work helps elucidate how microscopic motor properties are translated to the much larger scale of collective motor-microtubule assemblies.

The proprioceptive system is essential for the control of coordinated movement, posture, and skeletal integrity. The sense of proprioception is produced in the brain using peripheral sensory input from receptors such as the muscle spindle, which detects changes in the length of skeletal muscles. Despite its importance, the molecular composition of the muscle spindle is largely unknown. In this study, we generated comprehensive transcriptomic and proteomic datasets of the entire muscle spindle isolated from the murine deep masseter muscle. We then associated differentially expressed genes with the various tissues composing the spindle using bioinformatic analysis. Immunostaining verified these predictions, thus establishing new markers for the different spindle tissues. Utilizing these markers, we identified the differentiation stages the spindle capsule cells undergo during development. Together, these findings provide comprehensive molecular characterization of the intact spindle as well as new tools to study its development and function in health and disease.

Introduction Cardiovascular events are a major cause of mortality following successful kidney transplantation.Arteriovenous fistulas (AVFs) are considered the best option for haemodialysis, but may contribute to this excess mortality because they promote adverse cardiac remodelling and ventricular hypertrophy. This raises the question whether recipients with a well-functioning kidney transplant should undergo elective AVF ligation.Methods and analysis The COBALT feasibility study is a multicentre interventional randomised controlled trial (RCT) that will randomise renal transplant patients with stable graft function and a working AVF on a 1:1 basis to standard care (continued conservative management) or to AVF ligation. All patients will perform cardiopulmonary exercise testing (CPET) on recruitment and 6 months later. Daily functioning and quality of life will be additionally assessed by questionnaire completion and objective measure of physical activity. The primary outcome—the proportion of approached patients who complete the study (incorporating rates of consent, receipt of allocated intervention and completion of both CPETs without withdrawal)—will determine progression to a full-scale RCT. Design of the proposed RCT will be informed by an embedded qualitative assessment of participant and healthcare professional involvement.Ethics and dissemination This study has been approved by the East Midlands—Derby Research Ethics Committee (22/EM/0002) and the Health Research Authority. The results of this work will be disseminated academically through presentation at national and international renal meetings and via open access, peer-reviewed outputs. Existing networks of renal patient groups will also be used to disseminate the study findings to other key stakeholders.Trial registration number ISRCTN49033491.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) community transmission was eliminated in Australia from 1/11/2020 to 30/6/2021, allowing evaluation of surveillance system performance in detecting novel outbreaks, including against variants of concern (VoCs). This paper aims to define system requirements for coronavirus disease 2019 (COVID-19) surveillance under future transmission and response scenarios, based on surveillance system performance to date. Methods This study described and evaluated surveillance systems and epidemiological characteristics of novel outbreaks based on publicly available data, and assessed surveillance system sensitivity and timeliness in outbreak detection. These findings were integrated with analysis of other critical COVID-19 public health measures to establish future COVID-19 management requirements. Results Twenty-five epidemiologically distinct outbreaks and five distinct clusters were identified in the study period, all linked through genomic sequencing to novel introductions from international travellers. Seventy percent (21/30) were detected through community testing of people with acute respiratory illness, and 30% (9/30) through quarantine screening. On average, 2.07% of the State population was tested in the week preceding detection for those identified through community surveillance. From 17/30 with publicly available data, the average time from seeding to detection was 4.9 days. One outbreak was preceded by unexpected positive wastewater results. Twenty of the 24 outbreaks in 2021 had publicly available sequencing data, all of which identified VoCs. A surveillance strategy for future VoCs similar to that used for detecting SARS-CoV-2 would require a 100–1000-fold increase in genomic sequencing capacity compared to the study period. Other essential requirements are maintaining outbreak response capacity and developing capacity to rapidly engineer, manufacture, and distribute variant vaccines at scale. Conclusions Australia’s surveillance systems performed well in detecting novel introduction of SARS-CoV-2 while community transmission was eliminated; introductions were infrequent and case numbers were low. Detection relied on quarantine screening and community surveillance in symptomatic members of the general population, supported by comprehensive genomic sequencing. Once vaccine coverage is maximised, future COVID-19 control should shift to detection of SARS-CoV-2 VoCs, requiring maintenance of surveillance systems and testing all international arrivals, alongside greatly increased genomic sequencing capacity. Effective government support of localised public health response mechanisms and engagement of all sectors of the community is crucial to current and future COVID-19 management.

Abstract Objective Menopausal status impacts risk for many health outcomes. However, factors including hysterectomy without oophorectomy and Menopausal Hormone Therapy (MHT) can mask menopause, affecting reliability of self-reported menopausal status in surveys. We describe a step-by-step algorithm for classifying menopausal status using: directly self-reported menopausal status; MHT use; hysterectomy; oophorectomy; intervention timing; and attained age. We illustrate this approach using the Australian 45 and Up Study cohort (142,973 women aged ≥ 45 years). Results We derived a detailed seven-category menopausal status, able to be further consolidated into four categories (“pre-menopause”/“peri-menopause”/“post-menopause”/“unknown”) accounting for participants’ ages. 48.3% of women had potentially menopause-masking interventions. Overall, 93,107 (65.1%), 9076 (6.4%), 17,930 (12.5%) and 22,860 (16.0%) women had a directly self-reported “post-menopause”, “peri-menopause”, “pre-menopause” and “not sure”/missing status, respectively. 61,464 women with directly self-reported “post-menopause” status were assigned a “natural menopause” detailed derived status (menopause without MHT use/hysterectomy/oophorectomy). By accounting for participants’ ages, 105,817 (74.0%) women were assigned a “post-menopause” consolidated derived status, including 15,009 of 22,860 women with “not sure”/missing directly self-reported status. Conversely, 3178 of women with directly self-reported “post-menopause” status were assigned “unknown” consolidated derived status. This algorithm is likely to improve the accuracy and reliability of studies examining outcomes impacted by menopausal status.

Abstract Background The World Health Organization’s (WHO) 25X25 goal aims for a 25% relative reduction in premature death due to four non-communicable diseases (NCD4)—cancer, cardiovascular disease, chronic respiratory diseases and diabetes—by 2025 compared to 2010. This study aimed to quantify the premature mortality in the Australian population due to NCD4, quantify the variation in mortality rates by age and sex, predict the premature mortality due to NCD4 in 2025 and evaluate the progress towards the WHO 25X25 goal. Methods A population-based study using cause-specific mortality data of all deaths which occurred in Australia from 2010 to 2016 and registered up to 2017, for adults aged 30–69 years, was conducted. Age-specific and age-standardised mortality rates (ASMR) and probability of death for NCD4 were calculated for each year. ASMRs in 2016 were calculated for men and women. Deaths and the probability of death in 2025 were predicted using Poisson regression based on data from 2006 to 2016. To assess the progress against the WHO 25X25 goal, the relative reduction in the probability of death from NCD4 conditions in 2025 compared to 2010 was calculated. Results ASMRs for NCD4 decreased from 2010 to 2016, except for diabetes which increased on average by 2.5% per year. Across sociodemographic factors, ASMRs were highest in males and increased with age. The projected probability of premature death in 2025 was 7.36%, equivalent to a relative reduction of 25.16% compared to 2010 levels. Conclusions Premature mortality due to cancer, cardiovascular disease, respiratory diseases and diabetes declined in Australia from 2010 to 2016. This trend is consistent across age groups and by sex, and higher mortality rates were observed in males and at older ages. Nationally, if the current trends continue, we estimate that Australia will achieve a 25.16% relative reduction in premature deaths due to NCD4 in 2025 compared to 2010, signifying substantial progress towards the WHO 25X25 goal. Concerted efforts will need to continue to meet the 25X25 goal, especially in the context of the COVID-19 pandemic.

Opioid use among pregnant and postpartum women and people (PPWP) has significant health repercussions. This study explores how substance-use behaviors may vary by stage in recovery among PPWP with opioid use disorder (OUD). We recruited 29 PPWP with OUD. “High-risk” participants self-identified as “not being engaged in treatment” or “new or early in their recovery” (n = 11); “low-risk” participants self-identified as being “well-established” or “in long-term recovery” (n = 18). Participants were queried regarding sociodemographic, mental health, and drug-misuse factors; urine drug screens were collected at baseline. Univariate group comparisons between high-risk and low-risk PPWP were conducted. High-risk PPWP were more likely to self-identify as non-Hispanic African American and more likely to report current opioid use, other illicit drugs, and tobacco. High-risk PPWP had higher opioid cravings versus low-risk PPWP. High-risk PPWP were more likely to screen positive on urine tests for non-opioid drugs and on concurrent use of both non-opioid drugs and opioids versus low-risk participants. PPWP earlier in recovery are at higher-risk for opioid and other illicit drug misuse but are willing to disclose aspects of their recent use. PPWP early in recovery are an ideal population for interventions that can help facilitate recovery during the perinatal period and beyond.

With the development of economy and society, the consumption of fossil energy is gradually increasing. In order to solve the current energy dilemma, Natural gas hydrate (NGH) is considered as an ideal alternative energy. At the same time, solid fluidization exploitation is an ideal method. However, in the process of that, sand and hydrate ore bodies enter the closed pipeline together, which will block the pipeline and increase the difficulty of exploitation. Therefore, the pre-separation of sand by hydrocyclone plays an important role in solid fluidization exploitation. In this study, the numerical simulation method was used to study the internal flow field characteristics of the hydrocyclone, and the effects of different flow rate, different flow ratio, different sand content and different particle diameter on the phase distribution were investigated. The results show that: at the same axial position, the increase of flow rate and sand content makes the sand phase more distributed at the edge of the flow field. Under the same working conditions, the sand gradually migrates to the center of the flow field with the increase of the axial distance. By calculation, it is obtained that under the optimum working condition of the flow rate is 4.83m3/h, the flow ratio is 20%, the sand content is 20%, and sand diameter is 80μm, the maximum Es is 22.1% and the minimum is 86.1%. Finally, a comprehensive analysis of the hydrocyclone in this study shows that this hydrocyclone is only applicable to rough pre-separation of sand in the process of solid fluidization exploitation. Through the study of the internal flow field characteristics and phase distribution law of the hydrocyclone, this study provides a reference for the practical engineering application of sand phase pre-separation in the solid fluidization exploitation of NGH.

Firearm deaths continue to be a major public health problem, but the number of non-fatal firearm injuries and the characteristics of patients and injuries is not well known. The American College of Surgeons Committee on Trauma, with support from the National Collaborative on Gun Violence Research, leveraged an existing data system to capture lethal and non-lethal injuries, including patients treated and discharged from the emergency department and collect additional data on firearm injuries that present to trauma centers. In 2020, Missouri had the 4th highest firearm mortality rate in the country at 23.75/100,000 population compared to 13.58/100,000 for the US overall. We examined the characteristics of patients from Missouri with firearm injuries in this cross-sectional study. Of the overall 17,395 patients, 1,336 (7.7%) were treated at one of the 11 participating trauma centers in Missouri during the 12-month study period. Patients were mostly male and much more likely to be Black and uninsured than residents in the state as a whole. Nearly three-fourths of the injuries were due to assaults, and overall 7.7% died. Few patients received post-discharge services.