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Undergraduate science degrees in South Africa seldom offer explicit courses focussing on improving the disciplinary writing skills required for effectively communicating scientific research. Similarly, most students entering the 'Honours' degree in Molecular Medicine at a South African university have not commonly been afforded opportunities to develop appropriate scientific writing and thinking skills. Aspiring to improve writing abilities, in 2017 we introduced a set of writing workshops involving iterative writing activities of scientific report sections with dialogic feedback from the facilitator. This study aimed to interrogate whether the workshops achieved the intended outcomes by conducting a post-course survey to ascertain the perceptions of the Molecular Medicine students. We also compared the grades awarded for the scientific reports in years before and since the implementation of the workshops. Students highlighted numerous ways that the workshops had improved their ability to write sections of a scientific report, while the average grade for the scientific report also increased significantly since the introduction of the workshops. These results reveal that the structure and activities of our workshops can teach scientific writing skills to early-postgraduate level bioscience students with relatively little disruption to the existing curriculum and help inform the format of future writing workshops.

Abstract Innovation in image-guided procedures has been driven by advances in robotic Cone Beam Computed Tomography (CBCT) systems. A fundamental challenge for CBCT imaging is metal artifacts arising from surgical tools and implanted hardware. Here, we outline how two universal non-circular imaging orbits, optimized for metal artifact reduction, can be implemented in real-time on clinical robotic CBCT systems. Demonstrating potential clinical utility, the universal orbits were implemented during a pedicle screw cervical spine fixation and hip arthroplasty performed on a porcine and ovine cadaver respectively. In both procedures, the universal non-circular orbits noticeably reduced the metal artifacts surrounding the implanted orthopedic hardware, revealing anatomy and soft tissue obscured in current conventional CBCT imaging. This work represents a key step in clinically translating universal orbits, unlocking high quality in-room procedural verification to increase broader use of robotic CBCT systems and reduce the occurrence of secondary corrective surgeries.

The US Food and Drug Administration recognizes the unmet medical need for antibacterial drugs to treat serious bacterial diseases caused by resistant pathogens for which effective therapies are limited or lacking. The agency also recognizes that designing and conducting clinical trials to assess the safety and efficacy of drugs to treat resistant infections is challenging, especially for drugs only active against a single or a few bacterial species, and that a more flexible development program might be appropriate. In this article, we discuss several regulatory considerations for flexible development programs for antibacterial drugs intended to meet an unmet medical need. As an example, we use the recent approval of sulbactam for injection and durlobactam for injection (XACDURO) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.

Abstract Beta vulgaris L. is a root vegetable that is consumed mainly as a food additive. This study aimed to describe the protective effect of B. vulgaris on Fe2+-mediated oxidative liver damage through in vitro, ex vivo, and in silico studies to establish a strong rationale for its protective effect. To induce oxidative damage, we incubated the livers of healthy male rats with 0.1 mM FeSO4 to induce oxidative injury and coincubated them with an aqueous extract of B. vulgaris root (BVFE) (15–240 µg/mL). Induction of liver damage significantly (p

Abstract The deposition of the amyloid-β (Aβ) peptide into amyloid fibrils is a hallmark of Alzheimer’s disease. Recently, it has been reported that some proteins can aggregate and form amyloids through an intermediate pathway involving a liquid-like condensed phase. These observations prompted us to investigate the phase space of Aβ. We thus explored the ability of Aβ to undergo liquid–liquid phase separation, and the subsequent liquid-to-solid transition that takes place within the resulting condensates. Through the use of microfluidic approaches, we observed that the 40-residue form of Αβ (Αβ40) can undergo liquid–liquid phase separation, and that accessing a liquid-like intermediate state enables Αβ40 to self-assemble and aggregate into amyloid fibrils through this pathway. These results prompt further studies to investigate the possible role of Αβ liquid–liquid phase separation and its subsequent aggregation in the context of Alzheimer’s disease and more generally on neurodegenerative processes.

Abstract Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0–37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70–150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.

Abstract Many studies use a reductionist approach to isolate the influence of one factor in childhood on multimorbidity rather than consider the combined effect of wider determinants. We explored how potential multiple early life determinants of multimorbidity can be characterised across three UK cohort studies. We used the National Child Development Study (NCDS), the 1970 British Cohort Study (BCS70), and the Aberdeen Children of the 1950s Study (ACONF) to identified early life variables that fit into 12 conceptualised domains of early life determinants of multimorbidity. Variables were assigned into 12 domains; principal component analysis reduced the dimensionality of the data and structured variables into subgroups. The data audit identified 7 domains in ACONF, 10 domains in NCDS and 12 domains in BCS70. Dominant components included maternal fertility histories within the prenatal, antenatal and birth domain, long-term illnesses within the child health domain, educational ability within the child education and health literacy domain, ethnicity within the demography domain, parental health behaviours within the transgenerational domain, housing within the socioeconomic domain and parental-child interactions within the parental-family domain. We demonstrated that if multiple large scale longitudinal studies are used, there is enough data available for researchers to consider conceptualising early life risk factors of multimorbidity across groups or domains. Such conceptualisation can help challenge the existing understanding of disease aetiology and develop new ideas for prevention of multimorbidity.

Abstract This paper presents the design and development of a coastal fisheries monitoring system that harnesses artificial intelligence technologies. Application of the system across the Pacific region promises to revolutionize coastal fisheries management. The program is built on a centralized, cloud-based monitoring system to automate data extraction and analysis processes. The system leverages YoloV4, OpenCV, and ResNet101 to extract information from images of fish and invertebrates collected as part of in-country monitoring programs overseen by national fisheries authorities. As of December 2023, the system has facilitated automated identification of over six hundred nearshore finfish species, and automated length and weight measurements of more than 80,000 specimens across the Pacific. The system integrates other key fisheries monitoring data such as catch rates, fishing locations and habitats, volumes, pricing, and market characteristics. The collection of these metrics supports much needed rapid fishery assessments. The system’s co-development with national fisheries authorities and the geographic extent of its application enables capacity development and broader local inclusion of fishing communities in fisheries management. In doing so, the system empowers fishers to work with fisheries authorities to enable data-informed decision-making for more effective adaptive fisheries management. The system overcomes historically entrenched technical and financial barriers in fisheries management in many Pacific island communities.

Abstract Intratumoral injections have the potential for enhanced cancer treatment efficacy while reducing costs and systemic exposure. However, intratumoral drug injections can result in substantial off-target leakage and are invisible under standard imaging modalities like ultrasound (US) and x-ray. A thermosensitive poloxamer-based gel for drug delivery was developed that is visible using x-ray imaging (computed tomography (CT), cone beam CT, fluoroscopy), as well as using US by means of integrating perfluorobutane-filled microbubbles (MBs). MBs content was optimized using tissue mimicking phantoms and ex vivo bovine livers. Gel formulations less than 1% MBs provided gel depositions that were clearly identifiable on US and distinguishable from tissue background and with minimal acoustic artifacts. The cross-sectional areas of gel depositions obtained with US and CT imaging were similar in studies using ex vivo bovine liver and postmortem in situ swine liver. The gel formulation enhanced multimodal image-guided navigation, enabling fusion of ultrasound and x-ray/CT imaging, which may enhance targeting, definition of spatial delivery, and overlap of tumor and gel. Although speculative, such a paradigm for intratumoral drug delivery might streamline clinical workflows, reduce radiation exposure by reliance on US, and boost the precision and accuracy of drug delivery targeting during procedures. Imageable gels may also provide enhanced temporal and spatial control of intratumoral conformal drug delivery.

Abstract Emotion studies have commonly reported impaired emotional processing in individuals with heightened anhedonic depressive symptoms, as typically measured by collecting single subjective ratings for a given emotional cue. However, the interindividual variation in moment-to-moment emotional reactivity, and associated time-varying brain networks recruitment as emotions are unfolding, remains unclear. In this study, we filled this gap by using the unique temporal characteristics of music to investigate behavioural and brain network dynamics as a function of anhedonic depressive symptoms severity. Thirty-one neurotypical participants aged 18–30 years completed anhedonic depression questionnaires and then continuously rated happy, neutral and sad pieces of music whilst undergoing MRI scanning. Using a unique combination of dynamic approaches to behavioural (i.e., emotion dynamics) and fMRI (i.e., leading eigenvector dynamics analysis; LEiDA) data analysis, we found that participants higher in anhedonic depressive symptoms exhibited increased recruitment of attentional networks and blunted emotional response to both happy and sad musical excerpts. Anhedonic depression mediated the relationship between attentional networks recruitment and emotional blunting, and the elevated recruitment of attentional networks during emotional pieces of music carried over into subsequent neutral music. Future studies are needed to investigate whether these findings could be generalised to a clinical population (i.e., major depressive disorder).

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

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

Abstract The preclinical study of atherosclerosis has traditionally centred around the use of small animal models, translating to large animal models, prior to first-in-man studies. We propose to disrupt this paradigm by designing an ex vivo pump perfused human limb model. The novel model consists of taking a freshly amputated limb and incorporating it into an ex situ pump-perfused bypass system (akin to extracorporeal membrane oxygenation), circulating warmed, oxygenated blood. The circuit incorporates an introducer sheath and guiding catheter for intravascular imaging and X-ray angiography. Regular monitoring is performed using blood gas analysis, aiming for physiological parameters. The model maintains oxygen saturations > 99% for the length of perfusion (up to 6-h). Clinical grade X-ray angiography, intravascular ultrasound and optical coherence tomography have been successfully performed. Indocyanine green, a near-infrared fluorescent dye that localises to atherosclerotic plaque, has been injected into the system and left to circulate for 90-min. Fluorescence reflectance imaging of the dissected arterial bed confirmed uptake in areas of calcific atherosclerotic plaque on intravascular imaging. This is the first demonstration of an ex vivo pump-perfused “living” limb experimental model of atherosclerosis, which shows promise for future studies in translational interventional imaging and molecular targeting.

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

Abstract Background Human carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an inhibitory cell surface protein that functions through homophilic and heterophilic ligand binding. Its expression on immune cells in human tumors is poorly understood. Methods An antibody that distinguishes human CEACAM1 from other highly related CEACAM family members was labeled with 159Tb and inserted into a panel of antibodies that included specificity for programmed cell death protein 1 (PD1) and PD-L1, which are targets of immunotherapy, to gain a data-driven immune cell atlas using cytometry by time-of-flight (CyTOF). A detailed inventory of CEACAM1, PD1, and PD-L1 expression on immune cells in metastatic lesions to lymph node or soft tissues and peripheral blood samples from patients with treatment-naive and -resistant melanoma as well as peripheral blood samples from healthy controls was performed. Results CEACAM1 is absent or at low levels on healthy circulating immune cells but is increased on immune cells in peripheral blood and tumors of melanoma patients. The majority of circulating PD1-positive NK cells, innate T cells, B cells, monocytic cells, dendritic cells, and CD4+ T cells in the peripheral circulation of treatment-resistant disease co-express CEACAM1 and are demonstrable as discrete populations. CEACAM1 is present on distinct types of cells that are unique to the tumor microenvironment and exhibit expression levels that are highest in treatment resistance; this includes tumor-infiltrating CD8+ T cells. Conclusions To the best of our knowledge, this work represents the first comprehensive atlas of CEACAM1 expression on immune cells in a human tumor and reveals an important correlation with treatment-resistant disease. These studies suggest that agents targeting CEACAM1 may represent appropriate partners for PD1-related pathway therapies.

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

Abstract Liver cancer ranks as the fifth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic efficacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An X-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.

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

BackgroundVirtual care is increasingly incorporated within routine health care settings to improve patient experience and access to care. A patient’s experience encompasses all the interactions an individual has with the health care system. This includes a greater emphasis on actively involving carers in the decisions and activities surrounding a patient’s health care. ObjectiveThis study aimed to investigate the variety of health care delivery challenges encountered in a virtual hospital and explore potential ways to improve the patient experience. MethodsFocusing on acute respiratory, this protocol outlines a mixed methods study exploring the patient experience of a virtual hospital in Australia, Royal Prince Alfred Virtual Hospital (rpavirtual). We will use an exploratory mixed methods approach comprising of secondary data analysis, observations, interviews, and co-design focus groups. Participants will include patients, their carers, and health care workers who are involved in the acute respiratory virtual hospital model of care. Together, the data will be triangulated to explore views and experiences of using this model of care, as well as co-designing recommendations for further improvement. ResultsFindings from this study will identify current barriers and facilitators to implementing virtual care, such as work-as-done versus work-as-imagined, equity of care, the role of carers, and patient safety during virtual care. As of August 2024, a total of 25 participants have been interviewed. ConclusionsThis protocol outlines a mixed methods case study on the acute respiratory model of care from Australia’s first virtual hospital, rpavirtual. This study will collect the experiences of patients, carers, and health care workers to co-design a series of recommendations to improve the patient experience. International Registered Report Identifier (IRRID)DERR1-10.2196/58683

Introduction There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.Methods and analysis MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0–6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.Ethics and dissemination The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numbers NCT03387670; ISRCTN82598726.

Introduction Men’s participation is imperative for improving antenatal care (ANC) access and mother and child health outcomes in sub-Saharan Africa (SSA). Research looking at improving men’s participation in ANC often focuses on their instrumental and psychosocial roles and on biomedical ANC systems. There is limited understanding of how context-specific cultural experiences of fatherhood influence men’s participation in ANC within broader communal support networks and across different ANC systems in SSA. Against this background, and to understand how local communities in SSA conceive men’s participation in ANC, a scoping review will be undertaken to synthesise existing literature around local cultural experiences of fatherhood and men’s participation in ANC in rural settings in SSA.Methods and analysis The classical scoping review methodology developed by Arksey and O’Malley will be used to conduct the scoping review described above. Empirical studies published between 1 January 2000 and 31 August 2024 will be systematically searched for in key online databases (eg, PubMed/MEDLINE, CINAHL, EMBASE, PsycINFO, Cochrane Library, African Index Medicus, African Journals Online) and grey literature (eg, reports from key organisations like UNICEF and the WHO). Literature reviews, personal opinion articles and theoretical or conceptual articles that do not systematically analyse data, and non-English texts, will be excluded. Data will be extracted from the included texts in the form of study characteristics, which will be analysed using descriptive statistics, and key issues to be analysed thematically.Ethics and dissemination No ethical approvals are needed for this scoping review since data will be abstracted from already-published literature and no additional data will be collected. The findings will be shared with policymakers, practitioners, researchers, students and local communities through peer-reviewed journal publication(s), conference presentations, public lectures and policy-focused stakeholder and community meetings in and outside SSA.

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

Abstract Background There is a high prevalence of mental illness in nursing home residents compared to older adults living in the community. This was highlighted in the most recent comprehensive systematic review on the topic, published in 2010. In the context of a rapidly aging population and increased numbers of older adults requiring residential care, this study aims to provide a contemporary account of the prevalence of mental illness among nursing home residents. Methods This protocol was prepared in line with the PRISMA-P 2015 Statement. Systematic searches will be undertaken across six electronic databases: PubMed, Embase, Web of Science, PsycNET, CINAHL, and Abstracts in Social Gerontology. Peer-reviewed studies published from 2009 onwards which report the prevalence of mental illness within nursing home populations will be included. Database searches will be supplemented by forward and backward citation searching. Titles and abstracts of records will be screened using a semi-automated process. The full text of selected records will be assessed to confirm inclusion criteria are met. Study selection will be recorded in a PRISMA flowchart. A pilot-tested form will be used to extract data from included studies, alongside the JBI Critical Appraisal Checklist for Studies Reporting Prevalence Data. A study characteristics and results table will be prepared to present key details from each included study, supported by a narrative synthesis. Random-effects restricted maximum likelihood meta-analyses will be performed to compute pooled prevalence estimates for mental illnesses represented in the identified studies. Heterogeneity will be assessed using Cochran’s Q and Higgins’ I 2 statistics. A Funnel plot and Egger’s test will be used to assess publication bias. The GRADE approach will be used to assess the quality of the body of evidence identified. Discussion The study will provide a comprehensive and contemporary account of the prevalence of mental illness among nursing home residents. Meta-analyses will provide robust prevalence estimates across a range of presentations. Key insights will be highlighted, including potential sources of heterogeneity. Implications for residents, researchers, care providers, and policymakers will be noted. Systematic review registration PROSPERO: CRD42023456226.

Abstract Background Sensory changes due to aging or disease can impact brain tissue. This study aims to investigate the link between glaucoma, a leading cause of blindness, and alterations in brain connections. Methods We analyzed diffusion MRI measurements of white matter tissue in a large group, consisting of 905 glaucoma patients (aged 49-80) and 5292 healthy individuals (aged 45-80) from the UK Biobank. Confounds due to group differences were mitigated by matching a sub-sample of controls to glaucoma subjects. We compared classification of glaucoma using convolutional neural networks (CNNs) focusing on the optic radiations, which are the primary visual connection to the cortex, against those analyzing non-visual brain connections. As a control, we evaluated the performance of regularized linear regression models. Results We showed that CNNs using information from the optic radiations exhibited higher accuracy in classifying subjects with glaucoma when contrasted with CNNs relying on information from non-visual brain connections. Regularized linear regression models were also tested, and showed significantly weaker classification performance. Additionally, the CNN was unable to generalize to the classification of age-group or of age-related macular degeneration. Conclusions Our findings indicate a distinct and potentially non-linear signature of glaucoma in the tissue properties of optic radiations. This study enhances our understanding of how glaucoma affects brain tissue and opens avenues for further research into how diseases that affect sensory input may also affect brain aging.

Abstract Globally, there has been a dramatic increase in the geriatric population. Sadly, this populace is highly prone to develop various ocular morbidities putting pressure on the strained eye care delivery system especially in low-income countries. Hence, the aim of this study was to determine the distribution of ocular morbidities among elderly. The study was a retrospective cross-sectional study conducted at Mzuzu Central Hospital in Malawi. We retrieved data from the hospital’s Ophthalmology out-patient registry from January 2021 to December 2021. We recruited all 970 elderly patients who visited the clinic during the period of study. Data entry and analysis was done employing SPSS (v.26). More males than females had ocular morbidities. Cataract 400 (41.2%) was the most prevalent ocular morbidity followed by glaucoma 189 (19.5%), pinguecula 48 (4.9%) and allergic conjunctivitis 43 (4.4%). Anterior segment eye diseases were common 714 (73.6%). The prevalence of cataract, glaucoma, refractive error and allergic conjunctivitis was significantly associated with sex (p

Abstract A plutonium-rich carbide, (U,Pu)(Al,Fe)3C3, was discovered in a hot particle from the Maralinga nuclear testing site in South Australia. The particle was produced between 1960 and 1963 and has been exposed to ambient conditions since then. The new phase belongs to a group of ternary carbides known as 'derivative-MAX phases'. It formed at high temperature within an explosion cloud via rapid eutectic crystallisation from a complex Al–Fe–U–Pu–C–O melt, and is the major Pu host in this particle. Despite signs of volume expansion due to radiation damage, (U,Pu)(Al,Fe)3C3 remains highly X-ray crystalline 60 years after its formation, with no evidence of Pu leaching from the crystals. Our results highlight that the high-energy conditions of (sub-)critical explosions can create unexpected species. Even micro-particles of a derivative-MAX phase can effectively retain low-valence (metallic-like character) Pu under environmental conditions; the slow physical and chemical weathering of these particles may contribute to the slow release of radionuclides over decades, explaining constant low-levels of radionuclides observed in fauna. This study further suggests that rapidly quenched eutectic melts may be engineered to stabilise actinides in nuclear waste products, removing the need for hydrometallurgical processing.

Background: Hypertension remains one of the most important modifiable risk factors for stroke and heart disease. Anti-hypertensive medications are effective, but are often not used to maximum benefit. Sub-optimal dosing by prescribers and challenges with medication-taking for patients remain barriers to effective blood pressure control.Objectives: We aimed to systematically develop a theory-based complex intervention to support General Practitioners (GPs) and people with hypertension to maximise medication use to control blood pressure.Methods: We used the three-phase Behaviour Change Wheel (BCW) as the overarching intervention development framework. Collective Intelligence methodology was used to operationalise the stakeholder input to Phases 2 and 3 of the BCW. This took the form of a Collective Intelligence workshop with 19 stakeholders from diverse backgrounds including lived experience, general practice, nursing, pharmacy and health psychology. Techniques such as barrier identification, idea-writing and scenario-based design were used to generate possible intervention options. Intervention options were then selected and refined using the Acceptability, Practicability, Effectiveness, Affordability, Side-effects and Equity (APEASE) criteria and guidance from the MIAMI Public and Patient Involvement Panel.Results: The finalised MIAMI intervention consists of both GP and patient supports. GP supports include a 30-minute online training, information booklet and consultation guide (drop-down menu) embedded within the patient electronic health system. Patient supports include a pre-consultation plan, website, and a structured GP consultation with results from an Ambulatory Blood Pressure Monitor and urine chemical adherence test. The intervention components have been mapped to the intervention functions of the BCW and Behaviour Change Technique Ontology.Conclusion: Collective Intelligence offered a novel method to operationalise stakeholder input to Phases 2 and 3 of the BCW. The MIAMI intervention is now at pilot evaluation stage.

Background Barth syndrome is a rare, life-threatening X-linked recessive mitochondrial disorder of lipid metabolism primarily affecting males. Previous research suggests that bezafibrate may ameliorate cellular lipid abnormalities and reduce cardiac dysfunction in an animal model. Objectives Estimate the effect of bezafibrate on clinical, biochemical, and quality-of-life outcomes. Investigate whether within-participant clinical changes parallel in vitro changes in cardiolipin ratio/profile and mitochondrial morphology when each participant’s cells are cultured with bezafibrate. Investigate as for objective 2, culturing each participant’s cells with resveratrol. Describe the most feasible methods and standardised outcome measures to optimise the conduct of future trials and evaluations in Barth syndrome. Describe features of the research infrastructure which optimised recruitment, retention and communication with families and people with Barth syndrome. Describe the perceptions of participants and their families about the research and any important potential barriers to participation. Design Randomised, placebo-controlled, crossover trial of bezafibrate versus placebo. Setting NHS hospital providing UK-wide Barth Syndrome Service. Participants Males aged ≥ 6 years with a confirmed diagnosis of Barth syndrome with stable cardiac status, able to swallow tablets of bezafibrate/placebo. Exclusions were: hypersensitivity or allergy to bezafibrate or any component of bezafibrate; hepatic, liver or renal dysfunction; gallbladder disease; or recent deterioration in general health. Interventions Fifteen weeks of bezafibrate in one period and placebo in a second period, or vice versa (randomly allocated), with at least a 1-month washout between periods. Main outcome measures The primary outcome was peak VO2; secondary outcomes were cardiac function rest and exercise echocardiography and magnetic resonance imaging, cardiolipin ratio, quality of life, dynamic skeletal muscle P-magnetic resonance spectroscopy, mitochondrial studies and neutrophil counts, and adverse events. Outcomes were measured at baseline and the end of each period. Results Eleven males were studied; all attended all three assessments. There was no difference in peak VO2 between periods (0.66 ml/kg/min lower with bezafibrate than placebo, 95% confidence interval 2.34 to 1.03; p = 0.43). There was a trend towards a higher left ventricular ejection fraction with bezafibrate when measured by echocardiography but not magnetic resonance imaging, and better echocardiography-derived rest longitudinal and circumferential strain with bezafibrate. There was no difference in quality of life or cardiolipin ratio between periods. Skeletal muscle 31P magnetic resonance spectroscopy was performed cross-sectionally and showed a trend to higher Tau and lower Qmax indices in the bazafibrate group. Two participants had serious, expected adverse reactions when taking bezafibrate; otherwise, bezafibrate was well tolerated. Limitations The sample size was very small; the bezafibrate dose may have been too low or 15 weeks too short to observe an effect; measurements of mitochondrial content and membrane potential were highly variable; P-magnetic resonance spectroscopy was available only at the final assessment. Conclusions This study did not show significant improvement in the primary and secondary outcomes with bezafibrate treatment. Future work Elamipretide, studied in a small crossover trial in the USA, is another potential intervention which may be worth evaluating in an international study. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. Plain language summary Barth syndrome is a rare genetic syndrome with mutations in the tafazzin gene causing long-term effects in several organ systems, leading to significant lifelong comorbidities and a reduced quality of life. Barth syndrome shows an X-linked inheritance, hence it is almost exclusively present in males. Tafazzin gene mutations impair overall cell energy metabolism, and affected individuals show compromise of the immune system with a high risk for life-threatening infections, as well as cardiac dysfunction and cardiomyopathy, muscle and general fatigue, and generally reduced mobility also leading to psychological challenges and dysfunction. Currently, specific medical therapies are limited to symptomatic treatment, and drug therapies targeting the causative mitochondrial energy disturbance are urgently needed. This randomised controlled trial explored the use of oral bezafibrate, a licensed drug that can improve cell energy metabolism. Eleven male patients received either bezafibrate or a placebo for 4 months. Exercise capacity by cardiopulmonary exercise testing on a cycle ergometer, as the primary outcome measurement, as well as cardiac function by echocardiography and magnetic resonance imaging, and cellular anatomy and function by in vitro assays and microscopy, were measured before and after this 4-month period. Bezafibrate did not significantly improve exercise capacity, cardiac function or the cellular metabolism, although several cardiac function parameters showed slight improvements with bezafibrate treatment. No significant adverse effects were recorded. The limitations of the trial were its low participant number and the relatively short duration of the drug treatment phase. The trial did prove that complex randomised controlled drug trials are feasible in people with rare diseases. Adherence was good, with parents reporting few difficulties with pill swallowing. The qualitative interviews also found that the study was acceptable to participants and the burden of participating not too onerous. We hope the research can provide a template for future studies. Scientific summary Introduction Barth syndrome is a very rare, life-threatening, X-linked recessive genetic disease almost exclusively affecting young males, caused by abnormal lipids in mitochondria. The tafazzin gene (TAZ) encodes tafazzin, a phospholipid acyltransferase. Tafazzin transfers unsaturated fatty acids with acyl chains from phospholipids to monolysocardiolipin (MLCL) and regulates remodelling and maturation of cardiolipin, a phospholipid located exclusively in the inner mitochondrial membrane. Mature tetralinoleoyl-cardiolipin (L4-CL) is essential in the mitochondrial membrane for maintaining mitochondrial membrane potential, structural integrity of electron transport chain complexes and mitochondrial cristae architecture. Cardiolipin is a major constituent of inner mitochondrial membranes, and the major effects of the aberrant gene are on muscular tissues. Cardiac and skeletal manifestations of Barth syndrome are thought to result from impaired formation of respiratory chain super-complexes. TAZ mutations decrease L4-CL and increase intermediate species of MLCL, resulting in a marked increase in the MLCL : L4-CL ratio, which provides a highly sensitive and specific biochemical test for Barth syndrome. Barth syndrome is characterised by many gene mutations and profound phenotypic variability between affected patients within families and those in different families. The disease carries many risks and problems for its sufferers, as well as major healthcare costs. Almost one-third (30%) of living UK patients have undergone cardiac transplantation. Several patients who have died due to cardiac rejection or post-transplant lymphoproliferative disease had previously undergone cardiac transplantation. Other patients who have died deteriorated too fast to undergo transplantation or died of complications while awaiting transplantation. Neutropenia is another life-threatening issue. Two-thirds of UK patients are treated with granulocyte colony-stimulating factor by subcutaneous injection. Managing neutropenia in this disease is challenging, since patients have highly variable neutrophil counts, which prevents administration of a consistent daily dose and requires repeated blood counts and physician oversight. Exercise intolerance, lethargy and fatigue are universal, interfering with daily life, schoolwork and play and often necessitating use of a wheelchair. Patients cannot perform strenuous or demanding jobs. Many have major feeding problems from infancy through to adult life; for example, requiring feeding via gastrostomies. There can be rapid deterioration during periods of stable health despite expert medical care. Ventricular arrhythmia (tachycardia or fibrillation) affects 10% of adolescents and can cause sudden cardiac death at any time. There are no specific treatments for Barth syndrome. There is no evidence that standard medications for cardiomyopathy ameliorate long-term poor outcomes. Treatment is multidisciplinary and currently limited to treating intercurrent bacterial infections, bone marrow support, physiotherapy, nutritional support, management of heart failure and arrhythmia, and consideration for heart transplantation. Experiments using lymphoblasts from patients with Barth syndrome show that either bezafibrate or resveratrol can partially normalise the deranged cardiolipin ratio. This may be important, since some patients with Barth syndrome who lack neutropenia and tend to have good exercise tolerance have cardiolipin ratios intermediate between those of typical patients and normal individuals. Bezafibrate also improved left ventricular function and showed other benefits at supraphysiological doses in a TAZ knockdown mouse model. This trial was motivated by the need for disease-specific therapy to prevent morbidity, mortality, psychological distress, and disruption of quality of life (QoL) in affected patients and their families. An effective therapy also has the potential to generate savings for the NHS. Bezafibrate is a lipid-lowering drug used in adults and children, with a good safety record in long-term use. These characteristics made it a candidate for investigation. Bezafibrate has been reported to significantly ameliorate a mitochondrial myopathy in adults and shown promising results in several animal/human cellular models of mitochondrial disease. Several of the laboratory assays and clinical investigations proposed in this study were also considered potentially important beyond the scope of this specific study, to assess associations between genotype and phenotype and for future evaluations of therapies in Barth syndrome. Objectives Estimate the effect on clinical, biochemical and QoL outcome measures of bezafibrate compared to placebo. Investigate whether clinical improvements parallel in vitro changes in cardiolipin ratio and mitochondrial morphology in each participant’s cells when cultured with bezafibrate. Investigate whether clinical improvements and culture findings with bezafibrate parallel in vitro changes in each participant’s cells when exposed to resveratrol in laboratory culture. Describe the most feasible methods and standardised outcome measures for future trials. Describe features of the research infrastructure which optimised recruitment, retention and communication with participants and families. Describe participants’ and their families’ perceptions of research and important potential barriers to participation. Methods Study design and participants CARDIOlipin MANipulation trial (CARDIOMAN) was a double-blind, placebo-controlled crossover randomised trial. Treatment was given in two 15-week periods with a minimum of 1 month’s washout period between these when no treatment was given. Twenty-six males and one female with the disease were alive in the UK when the trial was designed. Males aged ≥ 6 years in the UK diagnosed with Barth syndrome were eligible. Exclusion criteria were: hypersensitivity to bezafibrate or component of the investigational medicinal product (IMP), photoallergic or phototoxic reaction to fibrate, unstable cardiac condition, cardiac chamber shortening fraction < 25% or significant decrease in shortening fraction in the preceding year, atrial or ventricular arrhythmia not stabilised by treatment, inability to swallow the IMP, hepatic dysfunction, renal impairment (creatinine clearance < 90 ml/min), gallbladder disease, recent unspecified significant deterioration in general health, prisoners and adults lacking capacity to provide informed consent. Randomisation and masking Participants were randomised to receive either bezafibrate then placebo, or the reverse order. Allocations were generated in advance by the Bristol Trials Centre and provided to the trial pharmacy which dispensed the IMP. All investigators, members of the research team (apart from pharmacy) and participants remained blind to treatment allocation. Intervention and procedures The intervention IMP was bezafibrate taken orally as 100-mg tablets. Children aged 6–9 years started on 100 mg once daily for the first 4 weeks and, if well tolerated, increased to 100 mg twice daily for the remaining 11 weeks. Children aged 10–17 years started on 200 mg once daily for the first 4 weeks and, if well tolerated, increased to 200 mg twice daily for the remaining 11 weeks. Adults (≥ 18 years) took 200 mg twice daily throughout. The comparator IMP was placebo taken orally as visually identical tablets and manufactured to be as similar as possible in taste and smell to the intervention. The IMP was prescribed at the start of the first period and again at the end of the first period for the second period. Outcomes All in vivo outcomes except magnetic resonance spectroscopy (MRS) were assessed three times: at baseline and in the final week of each treatment phase. The primary outcome measure was peak oxygen consumption on bicycle ergometry [peak volume of oxygen (VO2)]. Secondary outcomes were: MLCL/L4-CL ratio and cardiolipin profile in blood cells; phosphocreatine (PCr)/adenosine 5’ triphosphate (ATP) ratio in cardiac muscle on 31P MRS; skeletal muscle oxidative function/on 31P MRS; QoL [age-appropriate Pediatric Quality of Life Inventory (PedsQLTM) questionnaires]; absolute neutrophil count; amino acid expression (serum arginine and cysteine); cardiac function [left and right ventricular function: left ventricular ejection fraction (LVEF%), right ventricular ejection fraction (RVEF%); and 2-D longitudinal and circumferential strain at rest, peak exercise and after recovery]; mitochondrial size and number in lymphocytes; mitochondrial area in lymphocytes and as a proportion of cytoplasm area; mitochondrial function and cristae organisation in lymphocytes/neutrophils; arrhythmia profile from 12-lead electrocardiogram at rest and during exercise. Qualitative research methods explored participants’ and families’ experiences of the different interventions. Adverse events Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from participants from the time of consent until 1 month after the final period. Participants’ general practitioners were asked to inform the research team of suspected AEs. Participants were asked questions about SAEs/AEs at each research clinic visit and in monthly phone calls, including during the washout period. SAEs were reviewed by the Chief Investigator, who decided whether the SAE was related to bezafibrate. Statistical analysis A total of 20 males aged ≥ 6 years were potentially eligible. The sample size was dictated by the number of eligible boys willing to take part. The primary analysis estimated the difference in mean peak VO2 between placebo and bezafibrate periods (two-tailed 5% significance level). A sample size of 12 participants allowed the trial to detect a difference of 0.90 (within subject) standard deviations with 80% power. The statistical analysis plan (SAP) prespecified that all analyses should be conducted according to the intention-to-treat (ITT) principle. The ITT population comprised all participants and periods, according to the randomised allocations. The safety population comprised all randomised participants, according to the treatment received in each period, who received at least one dose of IMP. All statistical tests were two-sided and used a 5% significance level, except for interactions that used a 10% significance level. Treatment effects were estimated with 95% confidence intervals (CIs). No formal adjustment was made for multiple testing. The treatment effect for the primary outcome was analysed using mixed linear regression models, adjusting for period (fixed effect; exploring interactions where necessary) and participants (random effects). Model assumptions were tested using standard methods, and the carry-over effect was estimated by including treatment order. Treatment effects for continuously scaled secondary outcomes (prespecified in the SAP) were estimated and tested using the same methods. Results There was no statistically significant difference between bezafibrate and placebo in peak VO2, which was 0.66 ml/kg/min lower (95% CI −2.34 to 1.03; p = 0.43) with bezafibrate. There was a borderline statistically significant increase in LVEF% using echocardiography (3.72%, 95% CI −0.26% to 7.69%; p = 0.065) but no evidence of a difference when using magnetic resonance imaging (MRI) (0.15%, 95% CI −3.21% to 3.51%; p = 0.926). There was also no difference for RVEF% between bezafibrate and placebo (0.32, 95% CI −2.32 to 2.96; p = 0.801). Longitudinal and circumferential strain at rest were better (lower) with bezafibrate than with placebo; differences were –1.67 (95% CI −3.11 to −0.22; p = 0.026) and −2.72 (95% CI −5.03 to −0.40; p = 0.024) respectively. There was no difference in diastolic ratio at rest between bezafibrate and placebo, and no differences in strain or diastolic ratio at peak exercise or after 2 minutes’ recovery. All participants had sinus rhythm at rest and during exercise for all three time points. Magnetic resonance spectroscopy was only performed after the second period for 10 participants. PCr/ATP ratio in cardiac muscle was not collected. Cross-sectionally (five vs. five participants), MRS appeared to increase Tau and reduce Qmax parameters with bezafibrate compared to placebo. Monolysocardiolipin/L4-CL ratio did not differ between bezafibrate and placebo but deteriorated in the second period (20% higher, 95% CI 3% to 40%; p = 0.024). Neutrophil count also showed no difference between bezafibrate and placebo but increased in the second period (2.26, 95% CI 0.08 to 4.45; p = 0.043). Plasma cysteine increased with bezafibrate (32% higher, 95% CI 8% to 62%; p = 0.001) but plasma arginine did not (25% higher, 95% CI −10% to 72%; p = 0.180). Mitochondrial outcomes on blood samples did not show marked differences and were not formally compared. Quality-of-life scores were transformed to a 0–100 scale (higher being better). Bezafibrate had no effect on core (−3.41, 95% CI −8.67 to 1.86; p = 0.192) or fatigue (1.71, 95% CI −6.28 to 9.71; p = 0.659) QoL scores. Emerging themes identified in qualitative interviews were classified as overarching, related to lived experience with Barth syndrome, and trial participation and conduct. Participants and families were pleased to take part in the trial, viewing participation as ‘giving back’ to the medical community. No participant withdrew, and the trial was not perceived to be too onerous for families. Participating in the research gave both individuals and families a sense of responsibility for their condition, partly driven by appreciation for the Barth Syndrome Service and staff expertise. Monolysocardiolipin/L4-CL ratio in vitro was estimated from samples of cells incubated with control, bezafibrate or resveratrol. Each drug reduced the MLCL/L4-CL ratio, largely by increasing intermediate cardiolipin species, and more so with resveratrol than with bezafibrate. Ratios were nevertheless profoundly abnormal in comparison to patients with intermediate Barth phenotypes. Discussion Main findings: study results There was no clinically important or statistically significant improvement in peak VO2 with bezafibrate compared to placebo. There were inconsistent findings for LVEF% by method of measurement; echocardiography showed a borderline improvement that cardiac MRI did not demonstrate. Longitudinal and circumferential strain measurements were better at rest with bezafibrate, but not at peak exercise. There were no clinically important or statistically significant improvements in core or fatigue QoL domains. Plasma cysteine was significantly improved with bezafibrate treatment. Plasma arginine also increased but not significantly. Neutrophil count was unaffected and there was no significant change in cardiolipin ratio in participants’ blood with bezafibrate. There were no significant period effects except for MLCL/L4-CL ratio and neutrophil count, both increased in the second period. In vitro incubation of Epstein–Barr virus-transformed patient lymphoblasts with either bezafibrate or resveratrol resulted in improved MLCL/L4-CL ratios, an effect that was more profound with resveratrol. Treatment with this drug also resulted in a more obvious increase in intermediate MLCL species. Strengths and limitations Strengths of the trial are: randomisation and placebo blinding; crossover design; excellent retention; completeness of the data, good adherence and IMP tolerance. There were several limitations. The sample size (outside our control) was very small, and interpretation of effects for many secondary outcomes was challenging. Longer treatment duration or a higher bezafibrate dose might have produced better outcomes. Bezafibrate may have induced adverse reactions in some participants, inadvertently causing unblinding. The group of participants randomised to receive bezafibrate first was older than the group randomised to the opposite order, which may explain period effects. The electron microscopic and mitochondrial assessments proved problematic and were not completed in vitro. Measurements of mitochondrial content and membrane potential were highly variable. Amino acid levels were not assayed after fasting. Echocardiography images during exercise testing were often suboptimal. Lessons for the future Magnetic resonance spectroscopy in children is still exploratory, and protocols need to be better validated, but it is considered very promising as a potential objective functional outcome. Cardiolipin profile is not a good outcome for research, although it is appropriate for diagnosis because the Barth cardiolipin profile is so extremely different from a normal profile. Electron microscopy measurements of mitochondria should not be considered as outcomes in future trials. Peak VO2 should be the preferred current primary outcome because it is resistant to bias compared to other functional outcomes. Conclusion The trial did not show a significant treatment effect for the primary outcome, peak VO2. Some secondary outcomes such as systolic function measured by echocardiography and amino acid levels provided some evidence of benefit. The trial provided insights about trial methods and conduct in the context of a very rare paediatric disease that should inform future studies. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information.

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

Objective This study aims to create a national ethnicity spine based on all available ethnicity records in linkable anonymised electronic health record and administrative data sources.Design A longitudinal study using anonymised individual-level population-scale ethnicity data from 26 data sources available within the Secure Anonymised Information Linkage Databank.Setting The national ethnicity spine is created based on longitudinal national data for the population of Wales-UK over 22 years (between 2000 and 2021).Procedure and participants A total of 46 million ethnicity records for 4 297 694 individuals have been extracted, harmonised, deduplicated and made available within a longitudinal research ready data asset.Outcome measures (1) Comparing the distribution of ethnicity records over time for four different selection approaches (latest, mode, weighted mode and composite) across age bands, sex, deprivation quintiles, health board and residential location and (2) distribution and completeness of records against the ONS census 2011.Results The distribution of the dominant group (white) is minimally affected based on the four different selection approaches. Across all other ethnic group categorisations, the mixed group was most susceptible to variation in distribution depending on the selection approach used and varied from a 0.6% prevalence across the latest and mode approach to a 1.1% prevalence for the weighted mode, compared with the 3.1% prevalence for the composite approach. Substantial alignment was observed with ONS 2011 census with the Latest group method (kappa=0.68, 95% CI (0.67 to 0.71)) across all subgroups. The record completeness rate was over 95% in 2021.Conclusion In conclusion, our development of the population-scale ethnicity spine provides robust ethnicity measures for healthcare research in Wales and a template which can easily be deployed in other trusted research environments in the UK and beyond.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

How is the information-processing architecture of the human brain organised, and how does its organisation support consciousness? Here, we combine network science and a rigorous information-theoretic notion of synergy to delineate a ‘synergistic global workspace’, comprising gateway regions that gather synergistic information from specialised modules across the human brain. This information is then integrated within the workspace and widely distributed via broadcaster regions. Through functional MRI analysis, we show that gateway regions of the synergistic workspace correspond to the human brain’s default mode network, whereas broadcasters coincide with the executive control network. We find that loss of consciousness due to general anaesthesia or disorders of consciousness corresponds to diminished ability of the synergistic workspace to integrate information, which is restored upon recovery. Thus, loss of consciousness coincides with a breakdown of information integration within the synergistic workspace of the human brain. This work contributes to conceptual and empirical reconciliation between two prominent scientific theories of consciousness, the Global Neuronal Workspace and Integrated Information Theory, while also advancing our understanding of how the human brain supports consciousness through the synergistic integration of information.

Introduction Mild traumatic brain injury (mTBI) is a leading cause of morbidity and mortality, with approximately 1 out of 200 people each year sustaining an mTBI in Europe. There is a growing awareness that recovery may take months or years. However, the exact time frame of recovery remains ill-defined in the literature. This systematic review aims to record the range of outcome measures used for mTBI and understand the time to recovery for different outcomes.Methods and analysis This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guideline. A prespecified literature search for articles in the English language will be conducted from database inception to the date of searches using MEDLINE and EMBASE. A trial search was conducted on 5 October 2023 with refinement of the search criteria following this. For each study, screening of the title, abstract and full text, as well as data extraction, will be done by two reviewers, with an adjudicating third reviewer if required. The risk of bias will be assessed using the Cochrane risk of bias tool for clinical trials and the Newcastle Ottawa score for cohort studies. The primary outcome is the time to resolution of symptoms in mTBI patients who have a full recovery, using any validated outcome measure. Results will be categorised by symptom groups, including but not limited to post-concussive symptoms, mental health, functional recovery and health-related quality of life. For mTBI patients who do not recover, this review will also explore the time to the plateau of symptoms and the sequelae of these symptoms. Where possible, meta-analysis will be undertaken, with a narrative review undertaken when this is not possible. Subgroup analyses of patients aged over 64 years, and patients with repetitive head injury, are planned.Ethical review and dissemination Ethical review is not required, as no original data will be collected. Results will be disseminated through peer-reviewed publications and academic conferences.PROSPERO registration number CRD42023462797.

Biodiversity genomics research requires reliable organismal identification, which can be difficult based on morphology alone. DNA-based identification using DNA barcoding can provide confirmation of species identity and resolve taxonomic issues but is rarely used in studies generating reference genomes. Here, we describe the development and implementation of DNA barcoding for the Darwin Tree of Life Project (DToL), which aims to sequence and assemble high quality reference genomes for all eukaryotic species in Britain and Ireland. We present a standardised framework for DNA barcode sequencing and data interpretation that is then adapted for diverse organismal groups. DNA barcoding data from over 12,000 DToL specimens has identified up to 20% of samples requiring additional verification, with 2% of seed plants and 3.5% of animal specimens subsequently having their names changed. We also make recommendations for future developments using new sequencing approaches and streamlined bioinformatic approaches.

Objective To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH).Design Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial.Setting UK secondary care.Participants 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122).Interventions Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery).Main outcome measures In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists.Results In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be −£5520 (95% CI −£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be −£4536 (95% CI −£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE.Conclusions In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant).Ethics Ethical approval for the trial was obtained from the North West—Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076).Trial registration number ISRCTN87370545.

Abstract Many nocturnally active fireflies use precisely timed bioluminescent patterns to identify mates, making them especially vulnerable to light pollution. As urbanization continues to brighten the night sky, firefly populations are under constant stress, and close to half of the species are now threatened. Ensuring the survival of firefly biodiversity depends on a large-scale conservation effort to monitor and protect thousands of populations. While species can be identified by their flash patterns, current methods require expert measurement and manual classification and are infeasible given the number and geographic distribution of fireflies. Here we present the application of a recurrent neural network (RNN) for accurate automated firefly flash pattern classification. Using recordings from commodity cameras, we can extract flash trajectories of individuals within a swarm and classify their species with an accuracy of approximately seventy percent. In addition to its potential in population monitoring, automated classification provides the means to study firefly behavior at the population level. We employ the classifier to measure and characterize the variability within and between swarms, unlocking a new dimension of their behavior. Our method is open source, and deployment in community science applications could revolutionize our ability to monitor and understand firefly populations.

Abstract Concussion is commonly characterized by a cascade of neurometabolic changes following injury. Magnetic Resonance Spectroscopy (MRS) can be used to quantify neurometabolites non-invasively. Longitudinal changes in neurometabolites have rarely been studied in pediatric concussion, and fewer studies consider symptoms. This study examines longitudinal changes of neurometabolites in pediatric concussion and associations between neurometabolites and symptom burden. Participants who presented with concussion or orthopedic injury (OI, comparison group) were recruited. The first timepoint for MRS data collection was at a mean of 12 days post-injury (n = 545). Participants were then randomized to 3 (n = 243) or 6 (n = 215) months for MRS follow-up. Parents completed symptom questionnaires to quantify somatic and cognitive symptoms at multiple timepoints following injury. There were no significant changes in neurometabolites over time in the concussion group and neurometabolite trajectories did not differ between asymptomatic concussion, symptomatic concussion, and OI groups. Cross-sectionally, Choline was significantly lower in those with persistent somatic symptoms compared to OI controls at 3 months post-injury. Lower Choline was also significantly associated with higher somatic symptoms. Although overall neurometabolites do not change over time, choline differences that appear at 3 months and is related to somatic symptoms.

Abstract Background Distributed Medical Education (DME), a decentralized model focused on smaller cities and communities, has been implemented worldwide to bridge the gap in psychiatric education. Faculty engagement in teaching activities such as clinical teaching, supervision, and examinations is a crucial aspect of DME sites. Implementing or expanding DME sites requires careful consideration to identify enablers that contribute to success and barriers that need to be addressed. This study aims to examine enablers, barriers, and factors influencing psychiatrists' willingness to start or continue participating in teaching activities within Dalhousie University's Faculty of Medicine DME sites in two provinces in Atlantic Canada. Methodology This cross-sectional study was conducted as part of an environmental scan of Dalhousie Faculty of Medicine’s DME programs in Nova Scotia (NS) and New Brunswick (NB), Canada. In February 2023, psychiatrists from seven administrative health zones in these provinces anonymously participated in an online survey. The survey, created with OPINIO, collected data on sociodemographic factors, practice-related characteristics, medical education, and barriers to teaching activities. Five key outcomes were assessed, which included psychiatrists' willingness to engage in (i) clinical training and supervision, (ii) lectures or skills-based teaching, (iii) skills-based examinations, (iv) training and supervision of Canadian-trained psychiatrists, and (v) training and supervision of internationally trained psychiatrists. The study employed various statistical analyses, including descriptive analysis, chi-square tests, and logistic regression, to identify potential predictors associated with each outcome variable. Results The study involved 60 psychiatrists, primarily male (69%), practicing in NS (53.3%), with international medical education (69%), mainly working in outpatient services (41%). Notably, 60.3% lacked formal medical education training, yet they did not perceive the lack of training as a significant barrier, but lack of protected time as the main one. Despite this, there was a strong willingness to engage in teaching activities, with an average positive response rate of 81.98%. The lack of protected time for teaching/training was a major barrier reported by study participants. Availability to take the Royal College of Physicians and Surgeons of Canada Competency by Design training was the main factor associated with psychiatrists' willingness to participate in the five teaching activities investigated in this study: willingness to participate in clinical training and supervision of psychiatry residents (p = .01); provision of lectures or skills-based teaching for psychiatry residents (p < .01); skills-based examinations of psychiatry residents (p < .001); training/supervision of Canadian-trained psychiatrists (p < .01); and training and supervision of internationally trained psychiatrists (p < .01). Conclusion The study reveals a nuanced picture regarding psychiatrists' engagement in teaching activities at DME sites. Despite a significant association between interest in formal medical education training and willingness to participate in teaching activities, clinicians do not consider the lack of formal training as a barrier. Addressing this complexity requires thoughtful strategies, potentially involving resource allocation, policy modifications, and adjustments to incentive structures by relevant institutions.

Glucose has been shown to shorten lifespan in Caenorhabditis elegans. The connection of glucose to stress resistance in C. elegans, however, appears to be complex. We have shown glucose to be protective against heat stress early in adulthood (1-day-old adults), in both wild-type (WT, N2 strain) animals and those with a mutation in the gene encoding the C. elegans insulin receptor, daf-2. The protection conferred by 1 day on high glucose continues in mid-life (7-day-old adults) for daf-2, but not for WT. Mid-life and late-life stress following 7 or 13 days on high glucose shows glucose enrichment to be neutral or detrimental for recovery from heat stress in both strains. These results were also observed for animals exposed to sorbitol instead of glucose, suggesting the osmotic stress conferred by high concentrations of carbohydrate to be the basis of the resistance to heat stress.

Abstract Idiopathic Pulmonary Fibrosis (IPF) is a devastating form of respiratory disease with a life expectancy of 3–4 years. Inflammation, epithelial injury and myofibroblast proliferation have been implicated in disease initiation and, recently, epithelial-fibroblastic crosstalk has been identified as a central driver. However, the ability to interrogate this crosstalk is limited due to the absence of in vitro models that mimic physiological conditions. To investigate IPF dysregulated cross-talk, primary normal human bronchial epithelial (NHBE) cells and primary normal human lung fibroblasts (NHLF) or diseased human lung fibroblasts (DHLF) from IPF patients, were co-cultured in direct contact at the air–liquid interface (ALI). Intercellular crosstalk was assessed by comparing cellular phenotypes of co-cultures to respective monocultures, through optical, biomolecular and electrical methods. A co-culture-dependent decrease in epithelium thickness, basal cell mRNA (P63, KRT5) and an increase in transepithelial electrical resistance (TEER) was observed. This effect was significantly enhanced in DHLF co-cultures and lead to the induction of epithelial to mesenchymal transition (EMT) and increased mRNA expression of TGFβ-2, ZO-1 and DN12. When stimulated with exogenous TGFβ, NHBE and NHLF monocultures showed a significant upregulation of EMT (COL1A1, FN1, VIM, ASMA) and senescence (P21) markers, respectively. In contrast, direct NHLF/NHBE co-culture indicated a protective role of epithelial-fibroblastic cross-talk against TGFβ-induced EMT, fibroblast-to-myofibroblast transition (FMT) and inflammatory cytokine release (IL-6, IL-8, IL-13, IL-1β, TNF-α). DHLF co-cultures showed no significant phenotypic transition upon stimulation, likely due to the constitutively high expression of TGFβ isoforms prior to any exogenous stimulation. The model developed provides an alternative method to generate IPF-related bronchial epithelial phenotypes in vitro, through the direct co-culture of human lung fibroblasts with NHBEs. These findings highlight the importance of fibroblast TGFβ signaling in EMT but that monocultures give rise to differential responses compared to co-cultures, when exposed to this pro-inflammatory stimulus. This holds implications for any translation conclusions drawn from monoculture studies and is an important step in development of more biomimetic models of IPF. In summary, we believe this in vitro system to study fibroblast-epithelial crosstalk, within the context of IPF, provides a platform which will aid in the identification and validation of novel targets.

Abstract Football has one of the highest incidence rates of mild traumatic brain injury (mTBI) among contact sports; however, the effects of repeated sub-concussive head impacts on brain structure and function remain under-studied. We assessed the association between biomarkers of mTBI and structural and functional MRI scans over an entire season among non-concussed NCAA Division I linemen and non-linemen. Concentrations of S100B, GFAP, BDNF, NFL, and NSE were assessed in 48 collegiate football players (32 linemen; 16 non-linemen) before the start of pre-season training (pre-camp), at the end of pre-season training (pre-season), and at the end of the competitive season (post-season). Changes in brain structure and function were assessed in a sub-sample of 11 linemen and 6 non-linemen using structural and functional MRI during the execution of Stroop and attention network tasks. S100B, GFAP and BDNF concentrations were increased at post-season compared to pre-camp in linemen. White matter hyperintensities increased in linemen during pre-season camp training compared to pre-camp. This study showed that the effects of repeated head impacts are detectable in the blood of elite level non-concussed collegiate football players exposed to low-moderate impacts to the heads, which correlated with some neurological outcomes without translating to clinically-relevant changes in brain anatomy or function.

Abstract Background Issues relating to equality, diversity, and inclusion (EDI) significantly impact on medical student achievement and wellbeing. Interventions have been introduced at curricular and organisational levels, yet progress in addressing these issues remains limited. Timely evaluation is needed to assess effectiveness of interventions, and to explore issues and interactions in learning environments impacting on student experience. We introduced an anonymous question concerning students’ experiences of EDI into routine online student feedback questionnaires, to scope the nature of ongoing issues and develop greater understanding of students’ experiences in our programme environment. Ecological systems theory, which conceptualizes learning as a function of complex social interactions, determined by characteristics of individual learners and their environment, provides a framework for understanding. Methods Free-text responses regarding experiences of EDI gathered over 20 months from all programme years (n = 760) were pooled for analysis, providing a holistic overview of experiences in the learning environment. A counting exercise identified broad categories reported by students. Content analysis of the qualitative dataset was undertaken. Bronfenbrenner’s ecological systems theory was applied as a framework to demonstrate interdependencies between respondents’ experiences and environments, and associated impacts. Results Three hundred and seventy-six responses were received relating to wide-ranging EDI issues, most frequently gender or ethnicity. Responses mapped onto all areas of the ecological systems model, with frequent links between subsystems, indicating considerable complexity and interdependencies. Interpersonal interactions and associated impacts like exclusion were frequently discussed. Differential experiences of EDI-related issues in medical school compared to clinical settings were reported. Impacts of institutional leadership and wider societal norms were considered by respondents. Respondents discussed their need for awareness of EDI with reference to future professional practice. Conclusions Implementation of a regular free-text evaluation question allowed data-gathering across cohorts and throughout several stages of the curriculum, illuminating student experience. Connections established demonstrated intersectionality, and how environment and other factors interact, impacting on student experiences. Students experience EDI-related issues on multiple levels within the educational environment, with consequent impacts on learning. Any successful approach towards tackling issues and promoting equity of opportunity for all requires multi-level actions and widespread culture change. Students can offer fresh and distinct perspectives regarding change needed, to complement and diversify perspectives provided by staff and organisational leadership. Student voice should be enabled to shape change.

Abstract Background Ehlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments. Results Skin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts. Conclusion Together, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.

Abstract Biological phenotypes in patients with the acute respiratory distress syndrome (ARDS) have previously been described. We hypothesized that the trajectory of PaO2/FIO2 ratio could be used to identify phenotypes of ARDS. We used a retrospective cohort analysis of an ARDS database to identify latent classes in the trajectory of PaO2/FIO2 ratio over time. We included all adult patients admitted to an intensive care unit who met the Berlin criteria for ARDS over a 4-year period in tertiary adult intensive care units in Manitoba, Canada. Baseline demographics were collected along with the daily PaO2/FIO2 ratio collected on admission and on days 1–7, 14 and 28. We used joint growth mixture modeling to test whether ARDS patients exhibit distinct phenotypes with respect to both longitudinal PaO2/FIO2 ratio and survival. The resulting latent classes were compared on several demographic variables. In our study group of 209 patients, we found that four latent trajectory classes of PaO2/FIO2 ratio was optimal. These four classes differed in their baseline PaO2/FIO2 ratio and their trajectory of improvement during the 28 days of the study. Despite similar baseline characteristics the hazard for death for the classes differed over time. This difference was largely driven by withdrawal of life sustaining therapy in one of the classes. Latent classes were identified in the trajectory of the PaO2/FIO2 ratio over time, suggesting the presence of different ARDS phenotypes. Future studies should confirm the existence of this finding and determine the cause of mortality differences between classes.

Abstract Background Involving patient and community stakeholders in clinical trials adds value by ensuring research prioritizes patient goals both in conduct of the study and application of the research. The use of stakeholder committees and their impact on the conduct of a multicenter clinical trial have been underreported clinically and academically. The aim of this study is to describe how Study Advisory Committee (SAC) recommendations were implemented throughout the Emergency Medicine Palliative Care Access (EMPallA) trial. EMPallA is a multi-center, pragmatic two-arm randomized controlled trial (RCT) comparing the effectiveness of nurse-led telephonic case management and specialty, outpatient palliative care of older adults with advanced illness. Methods A SAC consisting of 18 individuals, including patients with palliative care experience, members of healthcare organizations, and payers was convened for the EMPallA trial. The SAC engaged in community-based participatory research and assisted in all aspects from study design to dissemination. The SAC met with the research team quarterly and annually from project inception to dissemination. Using meeting notes and recordings we completed a qualitative thematic analysis using an iterative process to develop themes and subthemes to summarize SAC recommendations throughout the project’s duration. Results The SAC convened 16 times between 2017 and 2020. Over the course of the project, the SAC provided 41 unique recommendations. Twenty-six of the 41 (63%) recommendations were adapted into formal Institutional Review Board (IRB) study modifications. Recommendations were coded into four major themes: Scientific, Pragmatic, Resource and Dissemination. A majority of the recommendations were related to either the Scientific (46%) or Pragmatic (29%) themes. Recommendations were not mutually exclusive across three study phases: Preparatory, execution and translational. A vast majority (94%) of the recommendations made were related to the execution phase. Major IRB study modifications were made based on their recommendations including data collection of novel dependent variables and expanding recruitment to Spanish-speaking patients. Conclusions Our study provides an example of successful integration of a SAC in the conduct of a pragmatic, multi-center RCT. Future trials should engage with SACs in all study phases to ensure trials are relevant, inclusive, patient-focused, and attentive to gaps between health care and patient and family needs. Trial Registration: Clinicaltrials.gov Identifier: NCT03325985, 10/30/2017.

Abstract Background Academic publishing is a cornerstone of scholarly communications, yet is unfortunately open to abuse, having given rise to ‘predatory publishers’– groups that employ aggressive marketing tactics, are deficient in methods and ethics, and bypass peer review. Preventing these predatory publishers from infiltrating scholarly activity is of high importance, and students must be trained in this area to increase awareness and reduce use. The scope of this issue in the context of medical students remains unknown, and therefore this sought to examine the breadth of the current literature base. Methods A rapid scoping review was undertaken, adhering to adapted PRISMA guidelines. Six databases (ASSIA, EBSCO, Ovid, PubMed, Scopus, Web of Science) were systematically searched for content related to predatory publishing and medical students. Results were single-screened, facilitated by online reviewing software. Resultant data were narratively described, with common themes identified. Results After searching and screening, five studies were included, representing a total of 1338 students. Two predominant themes– understanding, and utilisation– of predatory publishers was identified. These themes revealed that medical students were broadly unaware of the issue of predatory publishing, and that a small number have already, or would consider, using their services. Conclusion There remains a lack of understanding of the threat that predatory publishers pose amongst medical students. Future research and education in this domain will be required to focus on informing medical students on the issue, and the implication of engaging with predatory publishers.

Abstract It has been suggested that conscious experience is linked to the richness of brain state repertories, which change in response to environmental and internal stimuli. High-level sensory stimulation has been shown to alter local brain activity and induce neural synchrony across participants. However, the dynamic interplay of cognitive processes underlying moment-to-moment information processing remains poorly understood. Using naturalistic movies as an ecological laboratory model of the real world, here we investigate how the processing of complex naturalistic stimuli alters the dynamics of brain network interactions and how these in turn support information processing. Participants underwent fMRI recordings during movie watching, scrambled movie watching, and resting. By measuring the phase-synchrony between different brain networks, we analyzed whole-brain connectivity patterns. Our finding revealed distinct connectivity patterns associated with each experimental condition. We found higher synchronization of brain patterns across participants during movie watching compared to rest and scrambled movie conditions. Furthermore, synchronization levels increased during the most engaging parts of the movie. The synchronization dynamics among participants were associated with suspense; scenes with higher levels of suspense induced greater synchronization. These results suggest that processing the same high-level information elicits common neural dynamics across individuals, and that whole-brain functional connectivity tracks variations in processed information and subjective experience.

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that causes high fetal and neonatal mortality rates in ruminants and sometimes severe to fatal complications like encephalitis and hemorrhagic fever in humans. There is no licensed RVF vaccine for human use while approved livestock vaccines have suboptimal safety or efficacy. We designed self-amplifying RNA (saRNA) RVF vaccines and assessed their humoral immunogenicity in mice. Plasmid DNA encoding the Rift Valley fever virus (RVFV) medium (M) segment consensus sequence (WT consensus) and its derivatives mutated to enhance cell membrane expression of the viral surface glycoproteins n (Gn) and c (Gc) were assessed for in vitro expression. The WT consensus and best-expressing derivative (furin-T2A) were cloned into a Venezuelan equine encephalitis virus (VEEV) plasmid DNA replicon and in vitro transcribed into saRNA. The saRNA was formulated in lipid nanoparticles and its humoral immunogenicity in BALB/c mice was assessed. High quantities of dose-dependent RVFV Gn IgG antibodies were detected in the serum of all mice immunized with either WT consensus or furin-T2A saRNA RVF vaccines. Significant RVFV pseudovirus-neutralizing activity was induced in mice immunized with 1 µg or 10 µg of the WT consensus saRNA vaccine. The WT consensus saRNA RVF vaccine warrants further development.