Protocol of the pilot study to test and evaluate the iCARE tool: a machine learning-based e-platform tool to make health prognoses and support decision-making for the care of older persons with complex chronic conditions

Introduction
The provision of optimal care for older adults with complex chronic conditions (CCCs) poses significant challenges due to the interplay of multiple medical, pharmacological, functional and psychosocial factors. To address these challenges, the I-CARE4OLD project, funded by the EU-Horizon 2020 programme, developed an advanced clinical decision support tool—the iCARE tool—leveraging large longitudinal data from millions of home care and nursing home recipients across eight countries. The tool uses machine learning techniques applied to data from interRAI assessments, enriched with registry data, to predict health trajectories and evaluate pharmacological and non-pharmacological interventions. This study aims to pilot the iCARE tool and assess its feasibility, usability and impact on clinical decision-making among healthcare professionals.

Methods and analysis
A minimum of 20 participants from each of the seven countries (Italy, Belgium, the Netherlands, Poland, Finland, Czechia and the USA) participated in the study. Participants were general practitioners, geriatricians and other medical specialists, nurses, physiotherapists and other healthcare providers involved in the care of older adults with CCC. The study design involved pre-surveys and post-surveys, tool testing with hypothetical patient cases and evaluations of predictions and treatment recommendations. Two pilot modalities—decision loop and non-decision loop—were implemented to assess the effect of the iCARE tool on clinical decisions. Descriptive statistics and bivariate and multivariate analysis will be conducted. All notes and text field data will be translated into English, and a thematic analysis will be performed. The pilot testing started in September 2024, and data collection ended in January 2025. At the time this protocol was submitted for publication, data collection was complete but data analysis had not yet begun.

Ethics and dissemination
Ethical approvals were granted in each participating country before the start of the pilot. All participants gave informed consent to participate in the study. The results of the study will be published in peer-reviewed journals and disseminated during national and international scientific and professional conferences and meetings. Stakeholders will also be informed via the project website and social media, and through targeted methods such as webinars, factsheets and (feedback) workshops. The I-CARE4OLD consortium will strive to publish as much as possible open access, including analytical scripts. Databases will not become publicly available, but the data sets used and/or analysed as part of the project can be made available on reasonable request and with the permission of the I-CARE4OLD consortium.

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Influence of context on engagement with COVID-19 testing: a scoping review of barriers and facilitators to testing for healthcare workers, care homes and schools in the UK

Objective
The UK government’s response to the COVID-19 pandemic included a ‘test, trace and isolate’ strategy. Testing services for healthcare workers, care homes and schools accounted for the greatest spend and volume of tests. We reviewed relevant literature to identify common and unique barriers and facilitators to engaging with each of these testing services.

Design
Scoping review.

Search strategy
PubMed, Scopus and the WHO COVID-19 Research Database were searched for evidence published between 1 January 2020 and 7 November 2022. This was supplemented by evidence identified via free-text searches on Google Scholar and provided by the UK Health Security Agency (UKHSA).

Data extraction and synthesis
Data were extracted by a team of reviewers and synthesised thematically under the broad headings of perceptions, experiences, barriers and facilitators to engaging with the COVID-19 testing programme.

Results
This study included 40 sources, including 17 from projects that informed UKHSA’s decisions during the pandemic. Eight themes emerged and were used to categorise barriers and facilitators to engaging with the testing services for healthcare workers, care homes and schools: (1) perceived value, (2) trust in the tests and public bodies, (3) importance of infrastructure, (4) impact of media and social networks, (5) physical burden of the test, (6) perceived capability to undertake testing, (7) importance of relevant information and 8) consequences of testing.

Conclusions
Universal barriers and facilitators to engagement with the testing programme related to the core elements of each testing service, such as uncomfortable specimen collection and the influence of media and peers; these could be mitigated or leveraged to increase engagement across settings. However, the individuals involved, perceptions of value and available resources differed across services, leading to unique experiences between settings. Thus, consideration of context is crucial when designing and implementing a testing programme in response to a pandemic.

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Association between herpes simplex virus 1 and dementia: a systematic review protocol

Introduction
Herpes simplex virus 1 (HSV-1) infects approximately two-thirds of the global population under the age of 50 years. Although widely prevalent, the possible implications of HSV-1 in neurodegenerative diseases, especially dementia and Alzheimer’s disease, remain poorly understood. This review seeks to elucidate this association and explore the potential benefits of preventing or treating herpesvirus infections on dementia risk. The goal is to enhance our understanding of HSV-1’s potential role in dementia, which could inform the development of future therapeutic interventions for these conditions.

Methods and analysis
PubMed, Embase (Elsevier/Ovid), Web of Science, Scopus, Global Health, PsycInfo, Cochrane Library and Clinicaltrials.gov will be searched from the inception of each respective database. Studies that have HSV-1 as an exposure and dementia, or its subtypes, as a primary outcome will be included. Two researchers will independently screen titles, abstracts and full texts, with discrepancies resolved by a third researcher. Systematic data extraction from eligible studies will be performed using a standardised template. Risk of bias of individual studies will be assessed with the Cochrane Collaboration approach. We will assess the overall quality of cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Statistical analysis will employ a random effects model, and heterogeneity will be determined with Cochrane’s Q test and assessed using I2. Studies will be grouped by population subgroups and dementia subtypes when possible to explore nuances in results. We will consider performing meta-regression if heterogeneity remains after subgroup analyses. All statistical analyses will be conducted using Stata V.18 software (College Station, Texas, USA).

Ethics and dissemination
No ethical approval is required since data will be collected from existing studies. The review will be disseminated through peer-reviewed publication and at national and international conferences.

PROSPERO registration number
CRD42024516789.

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Hypoxic Preconditioning Enhances the Potential of Mesenchymal Stem Cells to Treat Neonatal Hypoxic-Ischemic Brain Injury

Stroke, Ahead of Print. BACKGROUND:Neonatal hypoxic-ischemic (HI) brain injury is one of the leading causes of long-term neurological morbidity in newborns. Current treatment options for HI brain injury are limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are under development. The current study aimed to test the potency of hypoxic preconditioning of MSCs to enhance the therapeutic efficacy in a mouse model of neonatal HI injury.METHODS:HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured under hypoxic (hypoxic-preconditioned MSCs [HP-MSCs], 1% O2) or normoxic-control (normoxic-preconditioned MSCs, 21% O2) conditions for 24 hours before use. At 10 days after HI, HP-MSCs, normoxic-preconditioned MSCs, or vehicle were intranasally administered. Gold nanoparticle–labeled MSCs were used to assess MSC migration 24 hours after intranasal administration. At 28 days post-HI, lesion size, sensorimotor outcome, and neuroinflammation were assessed by hematoxylin and eosin staining, cylinder rearing task, and IBA1 staining, respectively. In vitro, the effect of HP-MSCs was studied on transwell migration, neural stem cell differentiation and microglia activation, and the MSC intracellular proteomic content was profiled using quantitative LC-MS/ms.RESULTS:Intranasally administered HP-MSCs were superior to normoxic-preconditioned MSCs in reducing lesion size and sensorimotor impairments post-HI. Moreover, hypoxic preconditioning enhanced MSC migration in an in vitro set-up, and in vivo to the lesioned hemisphere after intranasal application. In addition, HP-MSCs enhanced neural stem cell differentiation into more complex neurons in vitro but had similar anti-inflammatory effects compared with normoxic-preconditioned MSCs. Lastly, hypoxic preconditioning led to elevated abundances of proteins in MSCs related to extracellular matrix remodeling.CONCLUSIONS:This study shows for the first time that hypoxic preconditioning enhanced the therapeutic efficacy of MSC therapy in a mouse model of neonatal HI brain injury by increasing the migratory and neuroregenerative capacity of MSCs.

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Digital health intervention to optimise heart failure management after hospital discharge in Brazil (OPT-HF): a randomised clinical trial protocol

Introduction
Guideline-directed medical therapy (GDMT) for heart failure (HF) reduces adverse events, but is underused. Global barriers to GDMT optimisation include low frequency of visits, clinician inertia and poor patient knowledge, which may be mitigated by digital health interventions (DHI). In Brazil, low digital literacy and reduced access to technology may compromise these potential DHI’s beneficial effects. Our objective is to develop and test the effectiveness of a DHI to optimise GDMT in patients recently hospitalised for HF in the Brazilian public health system (Sistema Único de Saúde (SUS)).

Methods and analysis
This is a randomised, controlled, multicentre, parallel-group, clinical trial in which 154 patients being discharged from an HF-related hospitalisation will be randomised. Inclusion criteria are ≥18 years of age, reduced ejection fraction HF (EF

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Group cognitive behavioural therapy for insomnia compared with treatment as usual for sleep problems in psychiatric care (the SIP trials): a protocol for a pragmatic, randomised controlled trial

Introduction
Insomnia is prevalent in psychiatric populations and may contribute to maintain and exacerbate psychiatric symptoms. Cognitive behavioural therapy for insomnia (CBTi) is the treatment of choice also for insomnia comorbid to psychiatric illness. However, patients are rarely offered CBTi in psychiatric outpatient clinics. The aim of this randomised controlled trial is to investigate whether CBTi delivered in groups in a psychiatric outpatient clinic is superior to treatment as usual (TAU).

Methods and analysis
In the Sleep in Psychiatric Care trial, 60 patients with moderate to severe psychiatric illness who meet the criteria for insomnia disorder will be recruited from an outpatient psychiatric clinic in Norway. The patients will be randomised (1:1) either to group-based CBTi (Sleep School Wake Up for Insomnia; SSWU-I) or to a wait list (WL) while they are all receiving TAU for their psychiatric disorder. SSWU-I will comprise five bi-weekly sessions, each lasting 120 min, hence the treatment period is 8 weeks. Assessment will be conducted at baseline (T1) and after 8 weeks (T2). The primary outcome will be self-rated insomnia symptoms using the Insomnia Severity Index and the Bergen Insomnia Scale. Secondary outcomes include measures of symptoms of dysfunctional beliefs and attitudes about sleep, depression, anxiety, fatigue, problems with work and social adjustment and well-being. Mixed model analyses will be conducted to test the hypotheses.

Ethics and dissemination
Ethical approval has been granted by the Regional Committee for Medical and Health Research Ethics, in Western Norway (REK 2020/66304). Findings will be published in peer-reviewed journals and presented at research conferences and in relevant media. The results may document the need for specific sleep-directed treatments in psychiatric clinics as a way of treating insomnia disorder as well as to alleviate psychiatric symptoms.

Trial registration number
NCT04463498.

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QbTest for ADHD assessment and medication management: a mixed-methods systematic review of impact on clinical outcomes and patient, carer and clinician experiences

Objectives
To explore patient, carer and clinician experiences of the QbTest and its impact on patient outcomes for attention deficit hyperactivity disorder (ADHD) diagnosis and medication management.

Design
Mixed-methods systematic review.

Data sources
MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov and WHO ICTRP (from inception to September 2024).

Study selection
Primary studies, of any design, that evaluated any version of the QbTest (QbMini

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Development of FastFrail–a rapid frailty screening tool for medical calls: a development study based on cross-sectional data from an urgent care centre in Norway

Objective
To develop a rapid screening tool for the identification of frailty in medical calls and other out-of-hospital acute care services.

Design
Development study based on cross-sectional data. A set of potential items were developed based on existing frailty tools and other relevant literature by a panel with geriatric and primary care expertise. The items and the Clinical Frailty Scale (CFS) were administered on a convenience sample of older urgent care patients. Further development of the tool was based on statistical analyses of this data material and final discussions in the panel.

Setting
Urgent care centre in Norway, data collected between January and August 2022.

Participants
All patients ≥70 years were eligible for inclusion, with the exception of patients triaged to the highest urgency level and patients not able to answer questions with no next of kin present.

Primary outcome
Potential items associated with frailty by CFS, measured by explained variance (adjusted R2 values from linear regression analyses).

Results
Nine potential items were developed and administered on 200 patients (59% female), of whom 48% were 70–79 years, 38% were 80–89 years and 14% were ≥90 years. The median CFS score was 4 (living with very mild frailty). Receiving help weekly, being homebound and using a walking aid were identified as strong indicators of frailty (adjusted R2 values 59%, 48% and 43%, respectively). Together these three factors could explain 74% of the variation in CFS scores.

Conclusions
Receiving help weekly, being homebound and using a walking aid are strong indicators of frailty among urgent care patients. We developed a frailty screening tool for medical calls—FastFrail—consisting of three simple, binary questions (yes/no) on these aspects. We hypothesise that FastFrail can supplement traditional symptom-based triage and enable more accurate assessment of older adults calling for acute medical help. We intend to test the tool in clinical practice.

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14,15-EET Maintains Mitochondrial Homeostasis to Inhibit Neuronal Pyroptosis After Ischemic Stroke

Stroke, Ahead of Print. BACKGROUND:Neuronal pyroptosis is involved in neuronal cell death and neurological damage after cerebral ischemia-reperfusion. 14,15-Epoxyeicosatrienoic acid (14,15-EET) can reduce neuronal loss induced by cerebral ischemia-reperfusion by regulating mitochondrial biological processes. However, it remains unclear how 14,15-EET regulates mitochondrial homeostasis, inhibits neuronal pyroptosis, and promotes neurological functional recovery after cerebral ischemia-reperfusion.METHODS:Mice with middle cerebral artery occlusion and reperfusion were used as an animal model to study the cerebral ischemia-reperfusion disease. The neurological function of mice was performed at 1, 3, and 5 days to test the therapeutic effects of 14,15-EET. Transmission electron microscope imaging and Nissl staining were used to analyze neuronal morphological structure, mitophagy, and neuronal pyroptosis. Western blot and transcriptome were used to detect the levels of mitophagy and neuronal pyroptosis signaling pathway–related molecules. HT22 cells were used in in vitro studies to detect the mechanism by which 14,15-EET reduces neuronal pyroptosis after oxygen-glucose deprivation/reoxygenation treatment.RESULTS:14,15-EET treatment reduced cerebral infarct volumes and improved neurological functional recovery in mice after cerebral ischemia-reperfusion. 14,15-EET treatment maintained the morphological structure of neurons in the ischemic penumbra area as well as the dendritic spine density in mice after cerebral ischemia-reperfusion. The upregulation of NLRP1 (NOD-like receptor thermal protein domain associated protein 1), IL (interleukin)-1β, caspase-1, and GSDMD (gasdermin D) induced by cerebral ischemia-reperfusion was inhibited, and the expression of mitophagy proteins Parkin and LC3B was increased by 14,15-EET treatment. Transcriptome profiling found that 14,15-EET exerts a neuroprotection role in promoting neural function recovery by activating the WNT (wingless-type MMTV integration site family) signaling pathway. We found that 14,15-EET upregulated the WNT pathway proteins such as WNT1, WNT3A, β-catenin, and p-GSK-3β (phosphorylation of glycogen synthase kinase 3β) in vivo and in vitro. The WNT signaling pathway inhibitor XAV-939 reduced the expression of mitophagy protein Parkin and upregulated the expression of caspase-1 and GSDMD in HT22 cells with oxygen-glucose deprivation/reoxygenation and 14,15-EET treatment.CONCLUSIONS:14,15-EET regulates mitochondrial homeostasis to inhibit neuronal pyroptosis, thereby promoting the recovery of neurological function in mice after cerebral ischemia-reperfusion. These results provide new ideas for maintaining mitochondrial homeostasis and inhibiting neuronal pyroptosis after cerebral ischemia-reperfusion.

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Randomised controlled trial of a nurse coordination intervention for people living with dementia and their carers: study protocol

Introduction
The multifaceted impact of dementia means that people living with dementia require multidisciplinary care across different services and settings; however, these care transitions pose a risk of fragmented care. Models that improve integration and coordination of care in the community are needed.

Methods and analysis
This randomised control trial will test the effectiveness and cost effectiveness of a dementia nurse-led intervention to: (1) increase days lived in the community at 12-month follow-up (primary outcome) among people living with dementia and (2) improve quality of life for people living with dementia and their carers, compared with usual care. Participants are recruited from several sources including private and public geriatric medicine clinics, carer support groups and self-referral. People living with dementia and their carers are randomised as a dyad to (1) usual care or (2) dementia nurse-led care-coordination. The dementia nurse will provide care coordination and direct support through a tailored, integrated and patient-centred approach. The needs of people living with dementia will be identified and addressed, with a focus on improving the management of comorbidities, risk reduction and symptoms. Carers will also receive support. The model for people living with dementia will focus on days lived in their community as the outcome variable. Differences between groups in quality of life at 12-month follow-up will be assessed using linear mixed effects regression. Analysis will follow the intention to treat principles. People living with dementia and carers’ data will be analysed separately and collectively for the economic study.

Ethics and dissemination
The trial has been approved by the Hunter New England Research Ethics Committee (2023/ETH01221) and the University of Newcastle Ethics Committee (R-2024–0021). Trial findings will be disseminated via peer-reviewed publications and conference presentations. If the intervention is effective, the research team aims to further implement the intervention as usual care within the participating services and beyond.

Trial registration number
The trial was prospectively registered via the Australian New Zealand Clinical Trials Registry: ACTRN12624000235505. Registration date: 11 March 2024.

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Pain management training for people with persistent pain and their informal carers (JOINT SUPPORT): multicentre randomised controlled feasibility trial with embedded qualitative study in English musculoskeletal services

Objectives
To assess the feasibility of conducting a pragmatic, multicentre randomised controlled trial (RCT) to test the clinical and cost-effectiveness of a pain management training intervention to support people with persistent musculoskeletal pain and their informal carers.

Design
Two-arm, multicentre, pragmatic, open, feasibility RCT with embedded qualitative study.

Setting
National Health Service (NHS) providers in four English hospitals.

Participants
Adults receiving NHS care for persistent musculoskeletal pain and their informal carers.

Intervention
Control: usual NHS care. Experimental: usual NHS care plus a carer-patient pain management training intervention (JOINT SUPPORT), comprising five, 1-hour, group-based sessions for patients and carers, delivered by trained physiotherapists or occupational therapists. Content included understanding pain, pacing, graded activity, fear avoidance, goal-setting, understanding the benefits of physical activity and medication management. This was re-enforced with a workbook. After the group-based sessions, patients and carers were supported through three telephone sessions.

Randomisation
Central randomisation was computer-generated (2:1 Experimental:Control), stratified by hospital and patient-participant age (≤65 years). There was no blinding.

Main outcome measures
Data collected at baseline and 3 months post-randomisation included screening logs, intervention logs, fidelity checklists and clinical outcomes on quality of life, physical and emotional outcomes, adverse events and resource use. Interviews with 14 patient-carer participants and six health professionals who delivered the intervention.

Results
A total of 76 participants (38 patients; 38 carers) were enrolled. Sixty per cent (312/480) of patients screened were eligible with 12% consenting to be randomised (38/312). Fifty-four per cent (13/24) of the experimental group reached minimal compliance with the JOINT SUPPORT intervention. There was no evidence of treatment contamination. For patient-participant outcomes, within-group differences from baseline to 3 months favoured the control group when assessed by EQ-5D and Generalised Self-Efficacy total score, but favoured the intervention group when assessed by numerical rating scale pain, fatigue and Centre for Epidemiologic Studies Depression Scaletotal score. Qualitative data demonstrated the acceptability of the trial design and JOINT SUPPORT intervention with modifications to improve trial processes.

Conclusions
The JOINT SUPPORT intervention was acceptable to patient-carer dyads and health professionals. Modifications to trial design, particularly enhanced recruitment strategies, are required.

Trial registration number
ISRCTN78169443.

Data availability statement
The data that support the findings of this study are available from the corresponding author (TS) on reasonable request. This includes access to the full protocol, anonymised participant-level dataset and statistical code.

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ReNeuWell mental well-being app: protocol for a randomised controlled trial

Introduction
The field of mental well-being interventions includes numerous studies of smartphone app-based programs, but there is a research-to-retail gap where many studies pertain to apps that are not publicly available, not used as standalone programs, or not tested in the general population, and many publicly available apps (or their proprietary in-app measures) have yet to be submitted to empirical testing. Furthermore, few well-being apps offer multicomponent interventions, despite such interventions having demonstrated efficacy outside the smartphone context. In response to these openings in the literature and marketplace, we have developed ReNeuWell, an iPhone app designed to measure the user’s mental well-being (via the validated Composure, Own-worth, Mastery, Positivity, Achievement and Satisfaction for Well-being (COMPAS-W) scale) and improve their well-being via a personalised, multicomponent program of activities informed by the peer-reviewed evidence base. This article describes the protocol for the preregistered randomised controlled trial (RCT) of ReNeuWell, to test the app in adult participants from the general population of Apple App Store users. It is hypothesised that ReNeuWell users will experience significant increases in mental well-being and decreases in mental distress over the 6–12-week trial period, relative to users of an active control version of the app.

Methods and analysis
The RCT will recruit participants from Apple Store users who choose to download ReNeuWell in the normal course of browsing the marketplace. Following consent, the app will randomly allocate participants to receive either the full version of the app or the active control version. The full version assesses the user’s well-being via the validated COMPAS-W scale, provides feedback on their well-being across six dimensions and creates a personalised schedule of daily positive psychology activities designed to enhance well-being along each dimension. Participants will be instructed to use the app for at least 10 min (at least one activity) per day for the first 6 weeks, and as they wish for the following 6 weeks. Trial outcomes will be measured via in-app surveys administered in weeks 1, 6 and 12. Data collection will begin when the app is officially launched on the Apple Store. Data will be analysed using linear mixed models to estimate condition-by-time interaction effects on the primary and secondary outcomes, and to assess whether any such effects are themselves moderated by other key variables.

Ethics and dissemination
This protocol has been approved by the Human Research Ethics Committee of the University of New South Wales (reference number: HC210302). Trial outcomes will be published in accordance with the preregistered protocol described here, both in the peer-reviewed literature and on the registry website.

Trial registration number
This protocol was preregistered with the Australian New Zealand Clinical Trials Registry (registration approved on 4 August 2021; trial ID number: ACTRN12621001014842p).

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Comparison of non-invasive and fluorescein tear film break-up time in a 65-year-old Norwegian population: a cross-sectional study

Objectives
Measurement of tear film stability is central in dry eye disease (DED) diagnosis. In this study, we aimed to compare the performance of two methods of tear film stability measurement: non-invasive tear break-up time (NIBUT) and fluorescein tear film break-up time (FTBUT).

Design
Cross-sectional study.

Setting and participants
The study involved 132 subjects of 65-year-old inhabitants of the Oslo region who were not seeking ophthalmic care.

Interventions
The participants underwent a battery of DED tests, including NIBUT measured on Oculus Keratograph 5M and a traditional method using fluorescein drops (FTBUT). Oculus Keratograph 5M measures two types of NIBUT:; appearance time of the first dry spot (NIBUTFirst) and average NIBUTAvg.

Results
74 participants (56%) were female and 58 were male (44%). Subjects presented with varying degrees of DED signs and symptoms. Mean values of NIBUTFirst and FTBUT from all the participants were significantly different (6.2±4.9 s vs 8.6±6.2 s, p

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