A strategic neurological research agenda for Europe: Towards clinically relevant and patient-centred neurological research priorities.

BACKGROUND AND PURPOSE: Neurological disorders constitute a significant portion of the global disease burden, affecting >30% of the world's population. This prevalence poses a substantial threat to global health in the foreseeable future. A lack of awareness regarding this high burden of neurological diseases has led to their underrecognition, underappreciation, and insufficient funding. Establishing a strategic and comprehensive research agenda for brain-related studies is a crucial step towards aligning research objectives among all pertinent stakeholders and fostering greater societal awareness. METHODS: A scoping literature review was undertaken by a working group from the European Academy of Neurology (EAN) to identify any existing research agendas relevant to neurology. Additionally, a specialized survey was conducted among all EAN scientific panels, including neurologists and patients, inquiring about their perspectives on the current research priorities and gaps in neurology. RESULTS: The review revealed the absence of a unified, overarching brain research agenda. Existing research agendas predominantly focus on specialized topics within neurology, resulting in an imbalance in the number of agendas across subspecialties. The survey indicated a prioritization of neurological disorders and research gaps. CONCLUSIONS: Building upon the findings from the review and survey, key components for a strategic and comprehensive neurological research agenda in Europe were delineated. This research agenda serves as a valuable prioritization tool for neuroscientific researchers, as well as for clinicians, donors, and funding agencies in the field of neurology. It offers essential guidance for creating a roadmap for research and clinical advancement, ultimately leading to heightened awareness and reduced burden of neurological disorders.

Inhalable dry powders of microRNA-laden extracellular vesicles prepared by thin-film freeze-drying.

Extracellular vesicles (EVs) are endogenous vesicles that comprise a variety of submicron vesicular structures. Among these, exosomes have been widely investigated as delivery systems for small and large molecules. Herein, the thin-film freeze-drying technology was utilized to engineer aerosolizable dry powders of miR-335-laden induced EVs (iEV-335) generated in B cells for potential delivery into the lung to treat primary lung cancer and/or pulmonary metastases. The size distribution, structure, and morphology of iEV-335 were preserved after they were subjected to thin-film freeze-drying with the proper excipients. Importantly, iEV-335, in liquid or reconstituted from thin-film freeze-dried powders, were equally effective in downregulating SOX4 gene expression in LM2 human triple-negative mammary cancer cells. The iEV-335 dry powder compositions showed mass median aerodynamic diameters (MMAD) of around 1.2 µm with > 60 % of the emitted doses had an MMAD of ≤ 3 µm, indicating that the powders can potentially achieve efficient deposition within the alveolar region following oral inhalation, which is desirable for treatment of primary lung cancer and pulmonary metastases. Overall, it is concluded that it is feasible to apply thin-film freeze-drying to prepare aerosolizable dry powders of iEVs for pulmonary delivery.

A Cognitive Occupation-Based programme for people with MS: acceptability, feasibility, and experiences of people with multiple sclerosis.

PURPOSE: COB-MS is an eight-session, Cognitive Occupation-Based programme for people with both MS and cognitive difficulty - designed to enhance cognition and daily functioning, through a combination of goal-setting, cognitive strategy engagement, group activities, home-practice activities and one-on-one sessions. This research aims to investigate the acceptability of COB-MS from the perspective of people living with MS, as well as the occupational therapists who facilitated the programme. MATERIALS AND METHODS: Two content analyses were conducted on interview data from (n = 11) COB-MS participants and (n = 8) COB-MS facilitators. Thematic analysis was also conducted on the participant interview data. RESULTS: Through a, primary, content analysis, participants reported that the COB-MS provided both a positive experience and quality resources. Qualitative improvement and utilisation of their learning beyond completion of the intervention were also identified. Four themes were identified via, secondary, thematic analysis: (1) Group interaction within COB-MS was vital; (2) Online COB-MS had positive and negative effects on participation; (3) COB-MS as a provider of clarity; and (4) Using learned strategies after the completion of COB-MS. Recommendations for future administration are provided. CONCLUSIONS: Findings suggest COB-MS acceptability, as well as appropriateness and feasibility, indicative of progression to a definitive trial in future research. TRIAL REGISTRATION: ISRCTN: ISRCTN11462710. Registered on 9 September 2019.

Cognitive difficulties associated with multiple sclerosis (MS) impact on daily life activities and are considered invisible MS symptoms. This invisibility and the lack of acknowledgement of such symptoms often adds to the distress experienced by people with MS.Occupational therapists are well-placed to address the daily-life impacts of cognitive difficulties in MS.The COB-MS is an occupation-focused intervention that aims to enhance daily function.The intervention was found to be well-accepted well by people with MS and occupational therapists and can feasibly be delivered in clinical practice.

Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): an update to the protocol for a feasibility cluster-randomised controlled trial.

BACKGROUND: Cognitive difficulties experienced by people with multiple sclerosis (MS) impact on quality of life and daily functioning, from childcare and work to social and self-care activities. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention to address the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. METHODS: Due to the impacts of COVID-19, trial activities that were planned for in-person delivery were completed remotely. One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment-as-usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The COB-MS intervention was planned for in-person delivery but was delivered online by occupational therapists to small groups of people with MS. The primary outcome measure is the Goal Attainment Scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention, 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants' perspectives will also be examined as part of the feasibility study. Data, due to be collected in-person, was collected online or by post. The original study design, including the statistical analysis plan, remains unchanged despite the shift to a remote trial conduct. DISCUSSION: Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. TRIAL REGISTRATION: ISRCTN ISRCTN11462710 . Registered on 9 September 2019 and updated on 23 September 2020 to account for changes outlined here.

Remote administration of BICAMS measures and the Trail-Making Test to assess cognitive impairment in multiple sclerosis.

Reliable remote cognitive testing could provide a safer assessment of cognitive impairment in multiple sclerosis (MS) during the COVID-19 pandemic and thereafter. Here we aimed to investigate the reliability and feasibility of administering Brief International Cognitive Assessment for MS (BICAMS) and the Trail-Making Test (TMT) to people with MS online. Between-group differences on BICAMS and the TMT were examined in a sample of 68 participants. Group 1 (N = 34) was tested in-person pre-pandemic. Group 2 was tested remotely. Within-group differences for in-person and virtual administrations were examined for Group 1. No significant differences between virtual and in-person administrations of the CVLT-II and SDMT were detected. BVMT-R scores were significantly higher for virtual administrations (M = 20.59, SD = 6.65) compared to in-person administrations (M = 16.35, SD = 6.05), possibly indicating inter-rater differences. Strong positive correlations were found for in-person and virtual scores within Group 1 on the CVLT-II (r = .84), SDMT (r = .85), TMT-A (r = .88), TMT-B (r = .76) and BVMT-R (r = .72). No significant differences between in-person and remote administrations of CVLT-II and SDMT in people living with MS were detected. Recommendations for future studies employing the TMT and BVMT-R online are provided.

A qualitative investigation of reasoning behind decisions to decline participation in a research intervention: A study-within-a-trial.

The current study-within-a-trial explored individuals' decisions to decline participation in research trialling a chronic illness-focused therapy (i.e. multiple sclerosis). Four themes were identified from seven semi-structured interviews with participation decliners and were confirmed by the host trial's Patient & Public Involvement (PPI) panel: acknowledgement of the value of research; 'fit' of the study; misinterpretation of participant information; and 'ignorance is bliss' - discussed in light of theory and research. This study-within-a-trial extends research on trial recruitment and participation decline; while also suggesting that PPI can be utilised in both a practical and impactful manner.

Assessment and Management of Cognitive and Psychosocial Difficulties for People with Multiple Sclerosis in Ireland: A National Survey of Clinical Practice.

Background: A recent survey of 109 healthcare professionals explored how UK healthcare professionals typically assess and treat multiple sclerosis (MS)-related cognitive impairment. Little is currently known about what constitutes usual care for cognitive impairment and psychosocial care for people with MS in Ireland. Aim: The aim of the current research was to survey healthcare professionals (HCPs) who work with people with MS, to understand current assessment and management of cognition and psychosocial care in people with MS in the Republic of Ireland. Methods: A cross-sectional survey design was used. Data were collected online through Microsoft forms and through postal responses. The original UK questionnaire was adapted, piloted, and distributed to Irish HCPs. Participants were qualified HCPs who work clinically with people with MS in the Republic of Ireland. Results: Ninety-eight HCPs completed the survey. Only 34% of those surveyed reported routine screening of cognition for people with MS within their services; approximately, 36% HCPs reported that they did not provide information or services in relation to cognition to people with MS and 39% reported not referring elsewhere when cognitive difficulties were suspected. Out of the 98 HCPs, 47% reported assessing mood difficulties as part of their services, with 14% unsure. In total, 70% of participants reported onward referral took place if mood difficulties were identified. The Montreal Cognitive Assessment was the most commonly administrated cognitive assessment. Cognitive intervention choices were found to be guided by clinical judgement in 75.5% of cases. Discussion. Despite the high importance placed on cognitive and psychosocial care, there is very little consistency in treatment and assessment across services for people with MS in Ireland.

Comparing the effects of a patient-designed-and-informed participant information leaflet in comparison with a standard, researcher-designed information leaflet on recruitment, retention and understanding: A study-within-a-trial.

Background and aim: The process of trial recruitment is vital, given its impact on resources, statistical power and the validity of findings. A participant information leaflet (PIL) is often the initial and primary source of information engaged by potential participants during recruitment. Research suggests that a variety of manipulations to a PIL can be made during its development to enhance understanding, readability and accessibility. In light of this, PIL-design led by Public and Patient Involvement (PPI) may also yield positive effects in this respect, as well as consent and retention. This study-within-a-trial (SWAT) compared the effects of a PPI-developed PIL with a standard, researcher-developed PIL on rates of consent, retention, decision certainty, understanding, readability, accessibility, likeability and decision to consent. Method: This SWAT used a double-blind, two-armed randomised design. The SWAT was conducted within a host trial of cognitive rehabilitation in multiple sclerosis. Results: A total of 234 people expressed interest in the trial, of which 94 were retained at 6-month follow up. Results revealed no effects on levels of consent and retention between the two PIL groups. Conclusions: These null effects provide interesting points of discussion and important implications for not only future research on PILs, but also for future research that involves recruitment to health-related interventions.

Exploring the impact of ineligibility on individuals expressing interest in a trial aimed at improving daily functioning regarding perceptions of self, research and likelihood of future participation.

BACKGROUND: Eligibility guidelines in research trials are necessary to minimise confounds and reduce bias in the interpretation of potential treatment effects. There is limited extant research investigating how being deemed ineligible for such trials might impact patients' perceptions of themselves and of research. Better understanding of the impact of patient ineligibility could enhance design and implementation of future research studies. METHODS: Eight semi-structured telephone interviews were conducted to explore the impact of ineligibility on self-perceptions; perceptions regarding the nature of research; and the likelihood of expressing interest in future research. Data were collected and analysed thematically through inductive, interpretive phenomenological analysis (IPA). RESULTS: Five themes emerged regarding the experience of being deemed ineligible: (1) Being deemed ineligible is emotion and reaction evoking; (2) 'Doing your bit': Helping others and increasing the value of research; (3) Communication of ineligibility; (4) Appreciation for those who express interest; and (5) Subsequent perceptions and attitudes towards research. CONCLUSIONS: The results suggest that being deemed ineligible can elicit negative emotional outcomes but is not likely to change perceptions of or attitudes towards research, possibly due to a desire to help similar others. Ineligibility can impact future participation in some cases, thus reducing the recruitment pool for subsequent research studies. Recommendations are provided to help minimise this risk. Advising of ineligibility in a personal way is recommended: with enhanced clarity regarding the reasoning behind the decision; providing opportunities to ask questions; and ensuring that appreciation for the patient's time and interest are communicated.

Twelve months into a feasibility trial: reflections on three experiences of public and patient involvement in research.

In this Open Letter we present reflections from three different perspectives on the integration of public and patient involvement (PPI) in a research trial. We reflect on the experience of having a patient employed as a contract researcher, with no prior research experience, on a feasibility trial of cognitive rehabilitation in multiple sclerosis. This Open Letter is written by the PPI research team member with reflections from a researcher on the trial and the principle investigator. We will discuss some of the changes made and the impacts that have been resulted from of PPI input into the trial. We focus on PPI involvement in participant recruitment, the development of trial material, integration of PPI along the research cycle, and collaboration. We hope that this Open Letter will encourage principle investigators and groups to include PPI members as part of the research team and help patients and members of the public understand what the experience of PPI members is like.

The Challenges for Labour Market Policy during the COVID-19 Pandemic.

The COVID-19 pandemic is having a dramatic economic impact in most countries. In the UK, it has led to sharp falls in labour demand in many sectors of the economy and to initial acute labour shortages in other sectors. Much more than in a typical downturn, the current crisis is not simply a general slowdown in economic activity but also a radical short-term shift in the mix of economic activities - of which an unknown, but possibly significant, amount will be persistent. The initial policy response has focused on cushioning the blow to families' finances and allowing the majority of workers and firms to resume their original activities once the crisis subsides. These are crucial priorities. But there should also be a focus on reallocating some workers, either temporarily if working in shut-down sectors or permanently by facilitating transitions to sectors and jobs offering better prospects and facing labour shortages. The phasing-out of the furlough subsidies, which is projected to happen in Autumn 2020, brings this into even sharper focus since the alternative for many workers will be unemployment. Active labour market policy will need to be front and centre.

COVID-19 and Inequalities.

This paper brings together evidence from various data sources and the most recent studies to describe what we know so far about the impacts of the COVID-19 crisis on inequalities across several key domains of life, including employment and ability to earn, family life and health. We show how these new fissures interact with existing inequalities along various key dimensions, including socio-economic status, education, age, gender, ethnicity and geography. We find that the deep underlying inequalities and policy challenges that we already had are crucial in understanding the complex impacts of the pandemic itself and our response to it, and that the crisis does in itself have the potential to exacerbate some of these pre-existing inequalities fairly directly. Moreover, it seems likely that the current crisis will leave legacies that will impact inequalities in the long term. These possibilities are not all disequalising, but many are.

An examination of the effects of a patient-designed-and-informed participant information sheet in comparison with a standard, researcher-designed information sheet on recruitment, retention and understanding: Protocol for a study-within-a-trial.

Background: This protocol describes a double-blind, randomised non-inferiority study-within-a-trial (SWAT), comparing the effects of a patient-designed-and-informed participant information sheet with a standard, researcher-designed participant information sheet on recruitment, retention, decision certainty, participant information sheet understanding and likeability. The SWAT is part of a larger trial that aims to evaluate the feasibility and preliminary efficacy of a cognitive occupation-based programme for people with MS (COB-MS) on cognitive and daily functioning for people with multiple sclerosis. Methods: During the study, 120 people with multiple sclerosis will be randomly allocated to one of the two groups, where they will either receive a standard participant information sheet or a patient-designed participant information sheet. Recruitment and retention will be analysed, as well as decision certainty, likability and understanding. Discussion: Results will provide recommendations for recruitment, consent and retention for future trials, as well as shed some light on the factors influencing the understanding and likeability of a trial's participant information sheet. Recommendations will also be made regarding patient and public involvement in developing and/or aiding the development of participant information sheets.  Registration: SWAT: Northern Ireland Hub for Trials Methodology Research SWAT Repository Store ( SWAT105). COB-MS trial: ISRCTN11462710.

Evaluating the feasibility and preliminary efficacy of a Cognitive Occupation-Based programme for people with Multiple Sclerosis (COB-MS): protocol for a feasibility cluster-randomised controlled trial.

BACKGROUND: Cognitive difficulties experienced by people with multiple sclerosis (MS) impact their quality of life and daily functioning, from childcare and work, to social and self-care activities. Despite the high prevalence of cognitive difficulties seen in MS, there is a lack of developed programmes that target cognition, while also supporting patients by helping them to function well in everyday life. The Cognitive Occupation-Based programme for people with MS (COB-MS) was developed as a holistic, individualised cognitive rehabilitation intervention. It addresses the wide-ranging symptoms and functional difficulties that present in MS, including the ability to maintain employment, social activities, home management and self-care. The aim of the current research is to evaluate the feasibility and preliminary efficacy of COB-MS for people with MS. The focus is on feasibility outcomes as well as functioning associated with cognitive difficulty and secondary outcomes related to cognition, fatigue and quality of life. METHODS: One hundred and twenty people with MS will be assigned to participate in either the COB-MS programme or a treatment as usual, wait-list control group as part of this single-blind, cluster-randomised controlled feasibility and preliminary efficacy trial of the COB-MS programme. The COB-MS group will participate in an eight-session occupational-based cognitive rehabilitation programme over 9 weeks. The primary outcome measure is the goal attainment scaling at 12 weeks. Participants will be assessed pre-intervention, post-intervention and at 12 weeks post-intervention and 6 months post-intervention. Qualitative evaluations of participants' perspectives will also be examined as part of the feasibility study. DISCUSSION: Results will provide recommendations for a future definitive trial of COB-MS, with respect to both feasibility and preliminary, clinical efficacy. In the event that results indicate efficacy, study findings will suggest that COB-MS requires consideration as a means of enhancing cognitive and daily functioning in people living with MS. TRIAL REGISTRATION: ISRCTN: ISRCTN11462710. Registered on 9 September 2019.

The long shadow cast by childhood physical and mental problems on adult life.

In this article we assess and compare long-term adult socioeconomic status impacts from having experienced psychological and physical health problems in childhood. To do so, we use unique prospective data from the British National Child Development Study, a continuing panel study of a cohort of 17,634 children born in Great Britain during a single week in March 1958. To date there have been nine waves for this birth cohort to monitor their physical, educational, and social development, during childhood (at birth and 7, 11, and 16 y) and adulthood (age 23, 33, 42, 46, and 50 y). Excellent contemporaneous information exists throughout childhood on physical and psychological health, captured by doctor and nurse-led medical examinations and detailed parental and teacher questionnaires. This information is combined with a wealth of contemporaneous information on adult health and economic experiences collected from cohort members. Information includes their economic circumstances (earnings, labor supply, and other sources of family income), physical and psychological health, and relationship status. Large effects are found due to childhood psychological problems on the ability of affected children to work and earn as adults and on intergenerational and within-generation social mobility. Adult family incomes are reduced by 28% by age 50 y, with sustained impacts on labor supply, marriage stability, and the conscientiousness and agreeableness components of the "Big Five" personality traits. Effects of psychological health disorders during childhood are far more important over a lifetime than physical health problems.

Determination of anions at trace levels in power plant water samples by ion chromatography with electrolytic eluent generation and suppression.

An ion chromatographic method was developed for the determination of nine inorganic and organic acid anions at sub- to low-microg/l levels in power plant water samples. In this method, samples were injected using a large-volume direct injection technique, the analyte anions were separated on a hydroxide-selective anion-exchange column using high-purity hydroxide eluents generated by an on-line electrolytic eluent generator and detected using the suppressed conductivity detection method. The method performance was evaluated by analyzing synthetic water samples containing additives encountered in the power plant water samples and four water samples from a fossil fuel power plant. The relative standard deviations of retention times of analyte ions separated on the hydroxide-selective anion-exchange column were less than 0.4%. The recoveries of analyte ions spiked into the synthetic water samples at concentrations of 0.13-1.0 microg/l were in the range of 70-120%. The method detection limits for analyte ions in deionized water were 0.0099, 0.0056, 0.019, 0.057, 0.0084, 0.023, 0.067, 0.037, and 0.079 microg/l for fluoride, acetate, formate, chloride, nitrite, sulfate, bromide, nitrate, and phosphate, respectively.