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Sleep disturbance is a prevalent and disabling comorbidity in Parkinsons disease (PD). We performed multi-night (n = 57) at-home intracranial recordings from electrocorticography and subcortical electrodes using sensing-enabled Deep Brain Stimulation (DBS), paired with portable polysomnography in four PD participants and one with cervical dystonia (clinical trial: NCT03582891). Cortico-basal activity in delta increased and in beta decreased during NREM (N2 + N3) versus wakefulness in PD. DBS caused further elevation in cortical delta and decrease in alpha and low-beta compared to DBS OFF state. Our primary outcome demonstrated an inverse interaction between subcortical beta and cortical slow-wave during NREM. Our secondary outcome revealed subcortical beta increases prior to spontaneous awakenings in PD. We classified NREM vs. wakefulness with high accuracy in both traditional (30 s: 92.6 ± 1.7%) and rapid (5 s: 88.3 ± 2.1%) data epochs of intracranial signals. Our findings elucidate sleep neurophysiology and impacts of DBS on sleep in PD informing adaptive DBS for sleep dysfunction.

Abstract The peroxidase (Per) reaction is a quick and inexpensive biosensor for the screening of environmental contaminants and wastewaters. The purpose of this study was to screen various municipal wastewaters before and after 7 different types of treatment processes using this sensor to identify potential sites under stress by urban pollution. The following wastewater samples before (influent) and after the commonly applied treatments (effluent) were tested using the Per activity test: advanced biofiltration, biofiltration, aerated lagoons, secondary aeration sludge, trickling filter, secondary membrane filtration, and primary. The influents and effluents were collected for 3 days and concentrated to 500 X on a reverse-phase (C18) extraction cartridge. The ethanol extracts were examined for dissolved organic carbon, plastic-like materials, polyaromatic hydrocarbons and polystyrene nanoplastics. The samples were then tested using the Per reaction alone and in the presence of DNA to detect DNA binding agents. The results show that population size tended to increase Per activity and 60% of the effluents decreased Per activity leading to H2O2 persistence and toxicity. More advanced treatments (biofiltration, membrane biofiltration, secondary aeration) produced stronger changes from the corresponding untreated influents corroborating their performance in reducing toxicity. The addition of DNA during the Per reaction revealed that population size had no influence and that 60% of treated effluents restored Per activity suggesting release of genotoxic compounds in the aquatic environment from treated wastewaters. The toxic implications of the continuous release of wastewaters in aquatic ecosystems are discussed in the light of emerging contaminants such as nanoplastics.

Abstract Ocean ecosystems have been subjected to anthropogenic influences for centuries, but the scale of past ecosystem changes is often unknown. For centuries, the European flat oyster (Ostrea edulis), an ecosystem engineer providing biogenic reef habitats, was a culturally and economically significant source of food and trade. These reef habitats are now functionally extinct, and almost no memory of where or at what scales this ecosystem once existed, or its past form, remains. The described datasets present qualitative and quantitative extracts from written records published between 1524 and 2022. These show: (1) locations of past flat oyster fisheries and/or oyster reef habitat described across its biogeographical range, with associated levels of confidence; (2) reported extent of past oyster reef habitats, and; (3) species associated with these habitats. These datasets will be of use to inform accelerating flat oyster restoration activities, to establish reference models for anchoring adaptive management of restoration action, and in contributing to global efforts to recover records on the hidden history of anthropogenic-driven ocean ecosystem degradation.

Abstract Background A dementia diagnosis can lead to a decline in cognitive, social, and physical health, but people with dementia can live meaningful lives and participate actively in society with psychosocial support. This single-arm, non-randomised feasibility study explored the feasibility and acceptability of a Comprehensive REsilience-building psychoSocial intervenTion (CREST) for people with dementia, their caregivers, General Practitioners (GPs), and the public. Methods Nine people with dementia and their primary caregivers living in the community (n = 9 dyads) completed the CREST intervention which had three components (cognitive stimulation therapy [CST], physical exercise, and dementia education). Quantitative secondary outcomes were assessed at baseline and following the 15-week intervention; qualitative interviews were conducted during and post-intervention. All study components were assessed against pre-defined criteria, to determine the feasibility of conducting a future definitive trial. Results Recruitment of people with dementia and their caregiver was a significant challenge and led to considerable delays to the onset and conduct of the intervention. Only 13% of eligible GP practices agreed to assist in recruitment and achieved a 6% enrolment rate; a community-based recruitment strategy proved more effective, yielding a 29% enrolment rate. However, once recruited, participants maintained high attendance and adherence to the content of each component with average adherence rates of 98% for CST, exercise sessions and caregiver education. Adherence to secondary exercise measures was lower, with home exercise diary completion at 37% and Fitbit wear adherence at 80% during the day and 67% at night. The people with dementia felt their concentration and fitness had improved over the 15-week intervention and particularly enjoyed the social aspects (e.g. group classes, exercising with partners from the community). Caregivers felt they had better knowledge and understanding following their education component and reported that the social aspects (interacting and sharing experiences with each other) were important. Overall, participants reported that the three components of the intervention were feasible and acceptable. In addition, the quantitative measures and health economic tools employed were feasible. However, the secondary elements of the exercise component (recording home exercise diaries and Fitbit use) were not considered feasible. Overall, pre-defined criteria for progression to a definitive intervention were fulfilled in terms of acceptability, retention and fidelity but not recruitment. Conclusion While overall, the CREST intervention was feasible and acceptable to participants, significant difficulties with recruitment of people with dementia and their caregiver through GP practices impacted the viability of delivering the intervention. Recruitment through community-based groups proved a more feasible option and further work is needed to overcome barriers to recruiting this cohort before a larger-scale trial can be conducted. Trial registration ISRCTN25294519.

Abstract Aim Relatives of patients who have experienced an out of hospital cardiac arrest (OHCA) experience confusion and distress during resuscitation. Clear information from ambulance clinicians and the opportunity to witness the resuscitation helps them navigate the chaotic scene. However, UK-based evidence concerning relatives’ experiences of unsuccessful resuscitation attempts and interactions with ambulance clinicians is lacking. This qualitative study explores those experiences to inform ambulance clinician practice. Methods Two ambulance services in the UK identified OHCA events attended by their clinicians within the previous two weeks. After a minimum of three months relatives of non-survivors of these events were invited to participate in either a remote or face-to-face interview. Interviews focussed on their experiences of the resuscitation attempt and interactions with ambulance clinicians, their feelings at the time, and their reflections on the event afterwards. Data were analysed using reflexive thematic analysis. Results Semi-structured interviews were conducted with 14 relatives of OHCA non-survivors. Thematic analysis identified four themes. Cardiac arrest is a traumatic event for relatives, with chaotic noisy scenes increasing their distress. Many described feelings symptomatic of Post-Traumatic Stress Disorder since the event. During resuscitation, participants needed information from clinicians about what was happening, and provided information about their relatives’ wishes. Participants needed reassurance from clinicians that everything possible was done to save their relative and were reassured when they could witness some of the resuscitation. Participants were surprised how long resuscitation seemed to last; some were distressed that it lasted so long. Conclusion Relatives’ experiences highlight two key challenges for ambulance clinicians: (1) being aware of the tension relatives feel between needing reassurance that the crew is doing everything to save the patient and wanting to avoid prolonged and ultimately futile resuscitation attempts; and (2) having ongoing conversations with those present to inform clinical decision-making whilst managing the resuscitation attempt.

Abstract Macrophages are pivotal innate immune cells which exhibit high phenotypic plasticity and can exist in different polarization states dependent on exposure to external stimuli. Numerous methods have been employed to simulate macrophage polarization states to test their function in vitro. However, limited research has explored whether these polarization methods yield comparable populations beyond key gene, cytokine, and cell surface marker expression. Here, we employ an unbiased comprehensive analysis using data organized through the all RNA-seq and ChIP-seq sample and signature search (ARCHS4) database, which compiles all RNAseq data deposited into the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA). In silico analyses were carried out demonstrating that commonly employed macrophage polarization methods generate distinct gene expression profiles in macrophage subsets that remained poorly described until now. Our analyses confirm existing knowledge on broad macrophage polarization, while expanding nuanced differences between M2a and M2c subsets, suggesting non-interchangeable stimuli for M2a polarization. Furthermore, we characterize divergent gene expression patterns in M1 macrophages following standard polarization protocols, indicating significant subset distinctions. Consequently, equivalence cannot be assumed among polarization regimens for in vitro macrophage studies, particularly in simulating diverse pathogen responses.

Abstract Background A significant issue with innovative problem-solving in healthcare is an existing deficiency in continuing education for many healthcare professionals, which hinders the successful implementation of inventive solutions and progress in the field. Educators play a crucial role in guiding students to cultivate the knowledge and skills necessary to confront these challenges, including problem solving, collaboration, and the use of rapidly advancing technologies. It is vital to design educational programs that empower and motivate students to develop the proficiency and knowledge they need to be effective problem solvers, collaborators, and cultivators of innovative solutions. This project aims to assess the implementation and effectiveness of a codesigned postgraduate university program for a multidisciplinary health workforce. Methods The Leading Health Services Innovation Project is a hybrid type 2 mixed method implementation trial of a codesigned Graduate Certificate in Health Services Innovation. In collaboration with a large tertiary and quaternary health service, we developed a codesign process to guide the project, with time quarantined to create space for two-way learning between health sector partners and healthcare academics. Qualitative interviews and quantitative surveys for primary users will evaluate the implementation strategies. The reach, effectiveness, adoption implementation, and maintenance (RE-AIM) framework will guide the evaluation and maintenance of the program. Results Integrating a codesign strategy complemented by a well-structured implementation and evaluation protocol that is a combination of implementation science theoretical frameworks (Knowledge to Action, Evidence-Based Co-design, RE-AIM) may lead to translational competence as a potential outcome. Anticipated outcomes The application, resourcing and commitment to codesigned tertiary-level learning and qualification will demonstrate the achievement of a contemporary and comprehensive postgraduate university degree program in health innovation management.

Abstract Background Older people with HIV (PWH) are at risk of polypharmacy (taking multiple medications). Most medications may be necessary and indicated to manage HIV (e.g., antiretroviral therapy [ART]) and HIV-associated comorbidities. However, some are potentially inappropriate medications (PIMs), defined as causing greater harm than benefit, which leads to medication overload. The objective of this study was to characterize polypharmacy (taking multiple medications) and medication overload (prescription of ≥ 1 PIMs) among older PWH. Methods This retrospective study included older PWH (aged ≥ 50 years old) attending the tertiary care HIV clinic at the McGill University Health Centre (Montreal, Canada), from June 2022–June 2023. Patient characteristics, medications, and select laboratory values (e.g., CD4 count, hemoglobin A1C) were entered into the MedSafer software identifying PIMs and classifying them according to risk of adverse drug event. We measured the prevalence of polypharmacy (≥ 5 medications prescribed, both including and excluding ART) and medication overload (≥ 1 PIMs). Multivariable logistic regression identified factors associated with medication overload. Results The study included 100 patients, with a median age of 59 years (IQR = 54–63; range 50–82); 42% female. Polypharmacy affected 89% of patients when including antiretroviral therapy (ART) and 60% when excluding ART. Medication overload was present in 58% of patients, and 37.4% of identified PIMs were classified as high-risk. Polypharmacy was the sole predictor of medication overload. Conclusion Older PWH are at significant risk of medication overload and receiving higher risk PIMs. Deprescribing PIMs in this population could improve medication appropriateness while reducing the risk of ADEs.

Abstract Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression.

Abstract Background The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes. Methods Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer. Results Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes. Conclusions Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.

Abstract Estimating accurate oil and gas methane emissions has been a global challenge, highlighted by a twofold discrepancy between atmospheric measurement-based estimates and emission inventories. The principle of continuous improvement in Canada’s National Inventory Report has led to an unstable baseline in recent years for tracking emission reduction progress. The gaps between previous inventory estimates and inversions exceeded 60%. Here we show that incorporating new source-resolved information derived from low-altitude aerial survey data has narrowed this gap by 80%, reducing the discrepancy to 10% for the 2010–2014 baseline. This study proposes a hybrid emission reporting framework, complemented by an ensemble inversion top-down method using continuous tower-based atmospheric measurements, to establish a stable baseline and provide independent verification. As the 2030 target year for emission reduction approaches, we report a significant 27% decline (19%–34%) in inverse oil and gas methane emissions from 2010 to 2022 in Alberta and Saskatchewan, Canada, and a 41% decline (26%–56%) as calculated using the 2024 official inventory.

Background and Purpose Cold beverage intake (carbonated drinks, fruit juice/drinks, and water) may be important population-level exposures relevant to stroke risk and prevention. We sought to explore the association between intake of these beverages and stroke. Methods INTERSTROKE is an international matched case-control study of first stroke. Participants reported beverage intake using food frequency questionnaires or were asked “How many cups do you drink each day of water?” Multivariable conditional logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations with stroke. Results We include 13,462 cases and 13,488 controls; mean age was 61.7±13.4 years and 59.6% (n=16,010) were male. After multivariable adjustment, carbonated beverages were linearly associated with ischemic stroke (OR 2.39 [95% CI 1.64–3.49]); only consumption once/day was associated with intracerebral hemorrhage (ICH) (OR 1.58 [95% CI 1.23–2.03]). There was no association between fruit juice/drinks and ischemic stroke, but increased odds of ICH for once/day (OR 1.37 [95% CI 1.08–1.75)] or twice/day (OR 3.18 [95% CI 1.69–5.97]). High water intake (>7 cups/day) was associated ischemic stroke (OR 0.82 [95% CI 0.68–0.99]) but not ICH. Associations differed by Eugeographical region—increased odds for carbonated beverages in some regions only; opposing directions of association of fruit juices/drinks with stroke in selected regions. Conclusion Carbonated beverages were associated with increased odds of ischemic stroke and ICH, fruit juice/drinks were associated with increased odds of ICH, and high water consumption was associated with reduced odds of ischemic stroke, with important regional differences. Our findings suggest optimizing water intake, minimizing fruit juice/drinks, and avoiding carbonated beverages.

Abstract Background A novel Complex REsilience-building psychoSocial intervenTion (CREST) targeted at people with dementia, their informal carers, general practitioners and the wider community with the aim of increasing resilience and strengthening the personal attributes or external assets of people with dementia living at home, in the community, was developed. It included three components: cognitive stimulation therapy (CST), physical exercise and dementia education. A non-randomised feasibility study was conducted of the CREST intervention, the aim of which was to inform the design of a future randomised controlled trial. This article presents the findings from the qualitative component of the CREST intervention feasibility study, describing the experience of the people with dementia and their caregivers who participated and the volunteer older adults who supported the intervention. Methods A descriptive qualitative research approach using semi-structured interviews was undertaken. Key stakeholders (people with dementia (n = 9), their caregivers (n = 9) and the volunteer older adults from the physical exercise component (n = 9)) were interviewed about the intervention and the perceived impact of their participation. Results The social aspect of the CREST intervention proved to be important for all three groups. Attendance remained high throughout the intervention. The people with dementia spoke positively about their participation in the CST and exercise components of the CREST intervention. The caregivers liked receiving coping strategies focused on how to communicate better with the person they cared for and how to better manage their own self-care and they liked the group element of the programme. The volunteer older adults supported the people with dementia in taking part in the exercise component, motivating them to do the exercises and helping with social interaction within the group. The volunteers gained exposure to the illness and as a result understood more about dementia and felt better equipped to communicate and deal with people with dementia. Conclusion Participation in the CREST intervention produced a positive impact on all three groups. The social element of the intervention was noted by everybody and was regarded as being beneficial. Qualitative insights emphasised the value of embedding qualitative research within feasibility studies to inform future intervention design. Further research should focus on conducting a full-scale randomised controlled trial to evaluate CREST’s effectiveness and explore its application to individuals with more advanced dementia. Trial registration ISRCTN25294519.

In this short intervention addressing the impact of crises on geographical knowledge practices, we, members of GenUrb (a multi-sited, longitudinal, partnered urban research project), ask, “what counts as crisis?”, sketching out epistemological and methodological points about our project's engagement with this call. We query the adeptness of dominant Eurocentric epistemologies in addressing crises, adopting the work of Bedour Alagraa, who places crises firmly within a historical–geographical colonial framing that conceptualizes crises not through rupture but through continuation. We illustrate the utility of this epistemological framing of crisis, honing in on the everyday violence that women continually experience, with our research in the cities of Cochabamba, Delhi, Georgetown, Ibadan, Ramallah, and Shanghai, showing that one in every two women participants had experienced intimate partner violence. We further ask what crises mean for the methodologies we adopt, specifically concerning questions of the co-production of knowledge and methods.

The COVID-19 pandemic has brought significant changes across society. This Delphi study aimed to gain expert consensus on challenges faced and resource needs for autistic children during the COVID-19 pandemic. Round 1 of the Delphi method employed semi-structured interviews with experts (N = 24) which were thematically analysed in order to identify needs, resource targets and resource development. In a follow-up Round 2 survey participants rated emergent need and resource in order of priority. Round 2 provided consensus on challenges faced with anxiety, routine and wellbeing ranked most important. Direction on resource design was also obtained. Consensus on the challenges and resources was achieved and is being integrated into a needs-based transition resources toolkit. Future studies could make use of the Delphi method to quickly gain consensus on focus of needs in other contexts and communities.

In recent times, the role of Early Childhood Education and Care (ECEC), as a public service within Irish society has been illuminated. In the twenty-first century, although crises may unfold on a global scale, the response from society is galvanised at local level. Amongst other functions, ECEC is ideally positioned to form part of a local response to unanticipated public crisis. However, ECEC in Ireland finds itself in a space of converging multiple crises such as high fees for parents, poor working conditions for staff, alongside concerns of how children experience provision. This article analyses the institutional systems from which ECEC has emerged by mapping several discursive 'regimes of truth', that have built up through Irish history. Exposure of multiple crises, such as fragmentation and the commodification of care are mapped to a neoliberal discourse set in a history of colonialism and religious doctrine. Pulling off the sticky plasters is painful, whilst facing multiple crises can lead to a state of exhaustion. However, guided by affirmative ethics this article aims to generate possible solutions, thereby proposing mechanisms for creating a more sustainable model of ECEC as a public service, embedded in an interconnective narrative of ethical care.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

BACKGROUND AND OBJECTIVES: Although dispositional optimism and pessimism have been prospectively associated with health outcomes, little is known about how these associations manifest in everyday life. This study examined how short-term optimistic and pessimistic expectations were associated with psychological and physiological stress processes. METHODS: A diverse sample of adults (N = 300) completed a 2-day/1-night ecological momentary assessment and ambulatory blood pressure (ABP) protocol at ∼45-minute intervals. RESULTS: Moments that were more optimistic than typical for a person were followed by moments with lower likelihood of reporting a stressor, higher positive affect (PA), lower negative affect (NA), and less subjective stress (SS). Moments that were more pessimistic than typical were not associated with any affective stress outcome at the following moment. Neither optimism nor pessimism were associated with ABP, and did not moderate associations between reporting a stressor and outcomes. DISCUSSION: These findings suggest that intraindividual fluctuations in optimistic and pessimistic expectations are associated with stressor appraisals.