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1. Introduction | ill | RECRUITMENT | The author (Barbara D’Amen) carried out the project activities and contributed to the writing of the article as a researcher at the Centre for Socio-Economic Research on Ageing, National Institute of Health and Science on Ageing (IRCCS INRCA). Since 15 January 2023, she has been a researcher at the Italian National Institute of Statistics (ISTAT), Via Cesare Balbo 39, 00184 Rome, Italy.Young carers provide a substantial amount of care to family members and support to friends, yet their situation has not been actively addressed in research and policy in many European countries or indeed globally. Awareness of their situation by professionals and among children and young carers themselves remains low overall. Thus, young carers remain a largely hidden group within society. This study reports and analyses the recruitment process in a multi-centre intervention study offering psychosocial support to adolescent young carers (AYCs) aged 15–17 years. A cluster-randomised controlled trial was designed, with recruitment taking place in Italy, the Netherlands, Slovenia, Sweden, Switzerland and the United Kingdom exploiting various channels, including partnerships with schools, health and social services and carers organisations. In total, 478 AYCs were recruited and, after screening failures, withdrawals and initial dropouts, 217 were enrolled and started the intervention. Challenges encountered in reaching, recruiting and retaining AYCs included low levels of awareness among AYCs, a low willingness to participate in study activities, uncertainty about the prevalence of AYCs, a limited school capacity to support the recruitment; COVID-19 spreading in 2020–2021 and related restrictions. Based on this experience, recommendations are put forward for how to better engage AYCs in research.Young carers are children and young people (<18 years old) who provide regular and substantial care to ill or disabled family members [Previous research has brought attention to the difficulty of unequivocally stating whether a young person is providing regular and/or substantial care (thus to be considered as a young carer) or not. In this respect, it is more appropriate to consider care activities provided by young individuals in the light of a continuum of care ranging from caring about the person to caring for the person, as opposed to a binary condition (i.e., being a young carer or not) [Low awareness and preparedness by formal and educational services, as well as the challenges related to defining young carers, lead to a range of problems when researchers and practitioners aim to identify young carers for research or providing support [In general terms, reaching young carers and involving them in research is complex [Furthermore, selective participation mechanisms exist for recruitment, due to the following: structural factors, e.g., a lower likelihood that a sub-group of the target population with certain demographic or socio-economic characteristics are considered, found or concretely involved by researchers in a study, and agency-related factors, e.g., a lower likelihood of a certain sub-group to be interested and willing to participate in a research study. These mechanisms usually produce biases based on the fact that people from lower socio-economic status, minority groups, rural areas or with poorer health are less likely to be invited and ultimately be involved in research [Phelps [Among young carers, a specific sub-group of adolescent young carers (AYCs) aged 15–17 years are an under-investigated target group. This age group of adolescents deserves more attention in research, since they find themselves in a delicate, transitionary phase between childhood and adulthood [The aim of this article is to report and analyse the recruitment process in an intervention study designed to provide psychosocial support to adolescent young carers (AYCs) aged 15–17 years in six European countries. The intervention study was conducted within the broader “Psychosocial support for promoting the mental health and well-being among adolescent young carers (AYCs) in Europe” project (ME-WE), funded by the European Union under the Horizon 2020 programme (grant agreement no. 754702) [ | PMC10049644 |
2. Materials and Methods | The ME-WE project included a wide range of quantitative and qualitative research, co-design and knowledge translation activities dealing with the phenomenon of AYCs in Europe. Below, we describe, review and critique the methods and recruitment-related aspects of the trial evaluating the newly designed psychosocial intervention for AYCs. An overview of the ME-WE project, activities carried out and results is available elsewhere [ | PMC10049644 | ||
2.1. Design | The ME-WE psychosocial intervention was designed as a cluster-randomised controlled trial (C-RCT) design, with a two (arm) by three (times) repeated measures factorial design [Clusters consisted of AYCs attending the same school (in Slovenia, Sweden and Switzerland) or living in the same geographical area (e.g., neighbourhood) (in Italy, the Netherlands and the UK). Clusters were randomised to the ME-WE intervention or wait-list control arm using an online number generator. To achieve a certain degree of blinding, AYCs were informed that the study aimed to investigate the effects of different support strategies on AYCs’ well-being and were not offered detailed information about the respective other trial arm during the study.Outcomes were measured at the individual level. Primary outcomes were psychological flexibility; mindfulness skills; resilience; subjective mental and physical health; quality of life; impact of caring; and social support. Secondary outcomes were self-reported school, training or work experience performance and attendance. Control variables included caring activities, overall amount of caring and likes and dislikes of caring. The outcomes for the ME-WE intervention arm were compared with the wait-list control arm from the baseline (pre-intervention) through post-intervention and 3-month follow-up (3MFU). After the 3MFU, participants in the wait-list control arm were offered the same programme as the intervention arm.The ME-WE C-RCT was registered as a trial in 2019 (ClinicalTrials.gov Identifier: NCT04114864).More details on the intervention design are described elsewhere [ | PMC10049644 | ||
2.2. Intervention | activity/ies | SESSION | The ME-WE primary prevention intervention was developed by refining the existing DNA-V protocol [Participants of clusters allocated to the ME-WE intervention arm attended seven weekly 2 h group sessions, with a follow-up meeting after 3 months from the end of the intervention. Groups were comprised of 2 to 9 AYCs (with the exception of Switzerland and Slovenia where individual interventions were held with one participant; in addition, in Slovenia there was one group with 23 participants). Group dynamics represent an important part of the intervention. To facilitate a proxy of group dynamics, the facilitators were instructed to also step into the participant role in cases where groups were small.All sessions had a similar structure (objectives, ice-breaker, central activity/ies and final activity). After a first introductory session regarding the DNA-V model, sessions 2, 3 and 4 introduced the main concepts used. Session 5 dealt with values and values-oriented action and session 6 focused on attaining psychological flexibility and self-compassion (i.e., the ability to approach personal suffering and failures with openness and awareness, showing self-kindness [Two different methods were originally followed in the delivery of the ME-WE intervention (that is, prior to the COVID-19 pandemic): a fully face-to-face approach (adopted by Italy, Slovenia and UK), and a blended approach that combined face-to-face and online sessions delivered via video-conferencing tools and a dedicated ME-WE mobile app (adopted by Sweden, Switzerland and the Netherlands) which was co-designed with AYCs at earlier stages of the ME-WE European project.It was originally planned that AYCs in the control group would perform ice-breaker and team-building activities during three meetings organised to correspond with the three assessment points with the aim of collecting outcome measures data.The interventions were carried out in the six countries during the period June 2019–March 2021. | PMC10049644 |
2.3. Ethics Approval and Informed Consent | The study protocol and related documentation were assessed and approved/expert opinions were provided (in accordance with national legislation) by competent ethics committees in each of the six countries during 2019. All participants were engaged in the study on a voluntary basis in accordance with the Declaration of Helsinki [All participants were provided with a plain-language statement describing the general purpose of the study. They were informed about the voluntary nature of their participation and their right to withdraw from the study at any time without having to provide a reason and without any adverse consequences. Information letters and informed consent forms were handed over to AYCs, one set for themselves and, when required by legislation, one set for their parents or legal guardians, to be returned later on. Written self-consent was obtained from participant AYCs and, when required by legislation, also from their parents or legal guardians. In Sweden and Switzerland, parental consent is not a legal requirement for young people aged 15–17 years. For 14-year-olds (see Data were processed in compliance with both national laws on data protection and the EU General Data Protection Regulation (GDPR) 2016/679 to guarantee the respondents’ confidentiality and privacy.The amendments introduced due to the COVID-19 pandemic received formal ethical approvals and/or detailed opinions (as appropriate according to national legislation) from the previously consulted ethics review boards in all six countries. They were informed that, due to the COVID-19 situation, it was necessary to adapt the methodological approach by replacing all personal meetings (group sessions) of the intervention with online meetings (see For more details, see the Institutional Review Board Statement at the end of the article.Ethics issues, especially those concerning the implementation of the intervention during the pandemic, were also carefully monitored by the project’s external International Advisory and Ethics Board (IAEB) until the project end. | PMC10049644 | ||
2.4. Sample | During the study protocol preparation, we conducted an average sample size estimation for each country (considering the cluster-level randomisation) [The minimum total sample sizes obtained from this procedure were as follows ( | PMC10049644 | ||
2.5. Inclusion and Exclusion Criteria | a disability | RECRUITMENT | To be eligible for the study, the following inclusion criteria were established: (1) aged between 15 and 17 years at the recruitment stage; (2) caring for family member(s) (e.g., parents, siblings, grandparents) or significant other(s) (e.g., friends, schoolmates or neighbours) with a disability, chronic physical and/or mental health condition or substance use issue and/or problems related to old age [In response to the COVID-19 pandemic and to boost the recruitment of AYCs, the Swedish Ethical Review Authority and the Vrije University Amsterdam Research Ethics Review Committee approved the target group to be expanded from 15–17 years to 14–17 years. In the UK, the competent research ethics committee approved the target group to be expanded to 14–18-year-olds. | PMC10049644 |
2.6. Compassionate Cases | RECRUITMENT | All participating countries allowed participants who did not meet the inclusion criteria to attend the ME-WE groups. They were identified as AYCs during recruitment and were interested in participating in the intervention. They expressed a need for support, but no alternatives for support other than the ME-WE-groups were available for them at that particular time or place. During the COVID-19 pandemic, the issue of compassionate use became more relevant as almost all regular support for young people was or remained cancelled due to the pandemic restrictions.In most of the cases they had not met the inclusion criteria as a consequence of their age, i.e., being 14 or 18 years old. In the UK and Sweden, those on psychotropic medication and those either in current receipt of a psychotherapeutic intervention or mental health counselling or planning to receive such therapies during the course of the ME-WE C-RCT study were also deemed compassionate cases.Access to the ME-WE groups was allowed on a case-by-case assessment. National Clinical Trial Managers (CTMs) requested permission for inclusion from the project’s CTM and Ethics, Gender and Data Manager (EGDM). Informed consent procedures were applied as standard in this C-RCT study for AYCs aged 15–17. Furthermore, for participants below the age of 15, informed consent of a parent or guardian was obtained. Compassionate cases might have completed the evaluation questionnaires at any of the three assessment points, but their data were excluded from the formal evaluation of the intervention. | PMC10049644 | |
2.7. Recruitment | RECRUITMENT | The recruitment of AYCs was carried out between April 2019 and September 2020. All countries employed cluster-targeted recruitment methods aimed to reach a convenience sample. The efforts were invested to overcome the known difficulties to reach and involve AYCs, especially in countries where there is no formal recognition of their role. Thus, convenience approaches were designed in each country, based on the specific context (e.g., availability and willingness to support the study by schools, health and social services and non-profit organisations), by the leading research partner organisation. The recruitment of AYCs was performed in either schools only (in Slovenia, Sweden and Switzerland) or geographical areas (in Italy, the Netherlands and UK) by also partnering with, in addition to schools, community-based service organisations (e.g., community health and social service agencies and organisations, youth welfare agencies, carer-related or disease-specific non-governmental organisations (NGOs) and young carers charities). In Sweden, a large school campaign was conducted. In Slovenia and Switzerland, recruitment was expanded from initially targeting schools to dormitories and campuses, respectively, as well as to a wider range of additional stakeholders (i.e., from the health and the social sectors, including NGOs). In Italy, the majority of participants were identified and recruited with the mediation of a public or private health or social care service and through condition-specific associations and NGOs working with young persons. The UK differed from the other ME-WE partner countries because they have a widespread network of young carers support services already in place. Thus, recruitment efforts in the UK focused firstly on recruiting appropriate young carers projects to the ME-WE study and secondly on recruiting AYCs to take part in the study. A variety of recruitment methods were adopted by the research teams in each country. Among these, the collaboration with local stakeholders (e.g., school staff, professionals from health and social sectors) was fundamental in order to promote the participation in the study among young people [A screening interview (either in person or via telephone) against eligibility criteria was conducted by the research team in every country. During the screening, the AYCs were given the opportunity to ask questions regarding the project. In the UK, AYCs and their parents/legal guardians took part in a screening call with the ME-WE group member and the UK Clinical Trial Manager. Sweden and Switzerland endeavoured to turn to the randomisation of individual participants, since their recruitment method did not pose a risk for spill-over effects. As outlined above, due to COVID-related interruptions and a slowing down of the recruitment of trial participants, Sweden and Switzerland launched national social media recruitment campaigns. In Sweden, the recruitment was supplemented with advertising via short films on social media and further information through the project’s website. In Switzerland, recruitment was also expanded with the development of a social media strategy, through blogs, websites, newsletters and social media, including the creation of a new Instagram account and using paid promotions. Following the COVID-19 pandemic outbreak, recruitment and enrolment were performed remotely in the six countries. Screening interviews to assess the eligibility of participants were carried out exclusively by telephone or video-conferencing applications (e.g., Zoom, Microsoft Teams). Written parental (or guardian) consent and self-consent to be involved in the study were collected by email or recorded (by video-conferencing applications). | PMC10049644 | |
2.8. Adaptation of Study Protocols | The COVID-19 pandemic posed (from March 2020 onwards) considerable challenges to the trial study in all six countries. Largely due to ethical considerations put forward by the project’s International Advisory and Ethics Board (IAEB), namely the possibility to continue to offer support to AYCs during the pandemic via their participation in the ME-WE project, combined with more pragmatic concerns to avoid costly trial closures, deviations from the original study protocol were considered unavoidable by the research team. Amendments to the study protocols were prepared and submitted for approval to competent local ethics committees. To comply with the restrictions and precautionary measures introduced at national levels, the study was virtualised, to include remote enrolment, screening, consent and data collection, as well as a fully online delivery of the ME-WE intervention [Partners amended the original study protocol in the second half of 2020, which involved a few changes to the intervention delivery, while the core contents of the intervention remained the same. Specifically, the fully face-to-face method, planned for Italy, Slovenia and the UK was replaced by online sessions using secure video-conferencing instruments, allowing for visual presentations of participants and session materials (e.g., Zoom, Microsoft Teams). In addition, the prior “blended delivery approach” in use in Sweden, Switzerland and the Netherlands and including a combination of face-to-face and online sessions supported by an app developed ad hoc for the project and co-designed with AYCs was replaced solely by online meetings using the ME-WE mobile app and supported with the Zoom video-conferencing system. | PMC10049644 | ||
2.9. CONSORT Flowchart | The Consolidated Standard of Reporting Trials (CONSORT) 2010 statement extended to cluster trials was followed in this study [ | PMC10049644 | ||
3. Results | PMC10049644 | |||
3.1. Recruitment Process in the Six Countries | RECRUITMENT | There were considerable difficulties in recruiting AYCs to the trial. Below, we present a summary of recruitment efforts and outcomes for each country. | PMC10049644 | |
3.1.1. Italy | RECRUITMENT | Initially, in Italy, researchers attempted to recruit AYCs in high schools and municipalities but without success, due to the low level of visibility of AYCs. Thus, it was decided to try to engage AYCs with the mediation of public or private health and/or social care services and through condition-specific associations and NGOs working with young persons. In this case, it was a trusted professional that took the initial contact with the parents/guardians to ask for permission and then invited the AYC to participate. Following this, a member of the research staff further contacted the parents and the AYC to provide all the necessary details, respond to questions and organise the collection of the consent forms before proceeding to the screening. The majority of participants were identified in this way. A minority of participants contacted the research team after having found leaflets or online information about the project. In this case, after an initial contact with the AYC, a phone contact with the parents/guardians was sought to provide all the information, secure consent and eventually organise the logistics of the group. The recruitment process took place mostly before the COVID-19 pandemic, while some participants were recruited later but following the same process (i.e., with the mediation of trusted professionals). | PMC10049644 | |
3.1.2. The Netherlands | RECRUITMENT | In the Netherlands, the recruitment was carried out through schools and care support centres. The first wave of recruitment involved the following: (a) A total of nine schools (three high schools and six schools in vocational education) entered the study, of which six schools in vocational education cancelled participation before the start of the intervention (such cancellations were due to the timing of the intervention in the schools’ calendar, so that it was too close to the examination period, which would have meant students being too stressed with studying for exams and not having time for participating in the ME-WE intervention); (b) A total of 19 informal care support centres were approached. Of these, four support centres accepted to take part in the study by contributing to recruitment efforts, but two of them dropped out before the start of the intervention. In March 2020, immediately prior to the COVID-19 outbreak in this country, a second wave of recruitment was initiated: 17 care support centres were engaged, of which 13 centres dropped out before the start of the intervention. In June 2020, recruitment was conducted online by the care support centres using social media posts, at (online) activities during the Dutch National Week of the Young Carer (1–7 June 2020) and through inviting young carers on their contact lists. | PMC10049644 | |
3.1.3. Slovenia | disability | RECRUITMENT | In Slovenia, the recruitment strategy was built on liaising with high schools as well as with non-governmental organisations and care services dedicated to the disability and mental health fields concerning young people and adults. The majority of the recruitment was carried out via school presentations and direct recruitment within classrooms during the first wave and in the second wave the same approach was applied in student dormitories (these are institutional facilities for students that prefer to stay at the place of school during week days, for instance if they live in remote areas and would otherwise have to commute to school). The COVID-19 pandemic led to the need for recruitment in the third and fourth waves to move to online platforms used by schools to communicate with students. During the second and fourth wave, schools also directly recruited participants via school advisors. COVID-19 hindered the recruitment of participants especially for the intervention groups. | PMC10049644 |
3.1.4. Sweden | RECRUITMENT | In Sweden, a school campaign was conducted, which reached out to 1081 students and 354 school staff in twelve schools. In the first intervention wave, Sweden adopted a blended delivery approach. In the second wave, with COVID-19 restrictions underway, all recruitment was conducted via advertisements and videos on social media, reaching out to over 100,000 young people and professionals. With these considerable efforts and resources, the research team was able to recruit a few potential participants per week, but if the young people had to wait for joining a group they dropped out. The priority was therefore to create and start groups as soon as possible, and a decision was made to wait with the control group to make sure that there would be at least some groups in Sweden. During the pandemic, Sweden adopted a fully online approach with the use of the ME-WE mobile app and supported by the Zoom video-conferencing system. | PMC10049644 | |
3.1.5. Switzerland | RECRUITMENT, RECRUITMENT | In Switzerland, recruitment was initially entirely and directly through schools. Recruitment was expanded in December 2019, and whilst it continued through the schools (with additional direct recruitment on school campuses), recruitment also took place through a wider range of additional stakeholders from the health and the social sectors, including NGOs. Recruitment was also expanded with the development of a social media strategy. In total, 24 schools participated, thanks to a robust effort of approaching 590 stakeholders and 27 schools (through presentations, emails, phone calls, fliers and posters in schools, as well as contacts and meetings with school directors, staff and educational departments), which covered an estimated 16,000 young people. During the COVID-19 pandemic, recruitment activities on school campuses became restricted and then cancelled altogether. The focus of the recruitment therefore shifted further to phone calls and email communications via the schools and additional stakeholders and linked to social media recruitment. | PMC10049644 | |
3.1.6. United Kingdom | STRUCK, RECRUITMENT | In the UK, there were two waves of recruitment. In the first wave, Carers Trust (a UK-based charity) led the recruitment of the young carers projects to the study through its network of young carers support services. Carers Trust sent out informational leaflets to its network of hundreds of young carers projects across England. Three network partners were chosen because of their interest and perceived ability to achieve the target sample size. They were tasked with finding schools that would permit the ME-WE sessions to take place. Before COVID-19 struck, 13 schools were recruited for participation. However, once the pandemic started, the UK research team moved to an online mode of delivery. In Spring 2020, the team decided to expand its recruitment effort and performed an outreach to its wider network partners in England to find other organisations willing to take part in the project. A final total of eight young carers projects were recruited to participate in the study. | PMC10049644 | |
3.2. Recruitment Results | RECRUITMENT | There were considerable differences in recruitment outcomes across countries. A large number of screen failures (young people who, among those screened, did not match with the screening criteria) are noted in the Netherlands and Slovenia, and these countries, together with Sweden, also recorded a prominent number of withdrawals (“Final sample sizes” in Numbers of completed evaluation assessments at each assessment point per study arm per country considered in the quantitative analysis are shown in | PMC10049644 | |
3.3. Target Sample Size vs. Final Sample Size: Challenges | RECRUITMENT | Due to difficulties in the recruitment process, recruitment to the control groups was often delayed and thus they contain a smaller number of AYCs than the intervention group/s. Additionally, the amount of reported data from the control groups differs between the countries, making a comparison more difficult. As can be seen from The methodological limitations of the study include the recruitment difficulties, screen failures and high levels of dropouts, both prior to the group start (e.g., in Sweden and Switzerland), as well as during the intervention (e.g., in Slovenia and the UK). While acknowledging all the challenges and efforts put in place, it should be recognised as a limitation that the number of participants to the study was lower than originally expected and that this influenced the power of the quantitative analysis results. The total final sample size (107 in the intervention group and 106 in the control group) was less than half of the original target sample size (263 in the intervention group and 263 in the control group) required to perform in-depth statistical analyses. Although the amended study protocols accommodated smaller sample sizes, the methodological limitation remains.The recruitment process proved to be challenging in all partner countries, for a variety of reasons common to many of the countries involved, in addition to the COVID-19 pandemic: Low levels of awareness and invisible young carers (in Italy, the Netherlands, Sweden and Slovenia) imply significant efforts in engaging relevant stakeholders, as it requires a prior time investment in raising awareness on the issue of young carers and on the need to support them before being able to engage stakeholders in the recruitment process.Uncertainty about the prevalence of AYCs (in Italy, the Netherlands and Sweden): The prevalence of young people recognised as young carers in partner countries (between 6 and 8%) was an estimation, which brought uncertainty about where and how to approach AYCs in the society. The recruitment channels used made it necessary to reach a very high number of young people in order to have the opportunity to recruit the target number of AYCs.Willingness of AYCs to participate in the study (in Italy, the Netherlands, Slovenia and Switzerland): Many partners underlined that it is challenging to convince participants in the age range of this study to participate in this research, both because of a lack of recognition of themselves as carers and because of their reluctance to participate in activities where they have to expose themselves and their emotions. In Switzerland, for example, some AYCs who dropped out from the intervention reported that they preferred to use their (limited) free time for other types of activities, e.g., sport.Limited capacity of schools (including school staff) to participate in a research project (in the Netherlands, Sweden, Switzerland and the UK): The involvement of schools, while strategic in most of the countries involved, proved to be challenging. On the one hand, the decision-making processes in schools can be complicated and often require approvals from different levels of the organisation. On the other hand, schools and teachers are often involved in a variety of projects and activities, which does not allow them much time to dedicate to other actions, such as externally funded research, such as the ME-WE project. The COVID-19 pandemic posed further challenges to school staff, who needed to prioritise other things ahead of the ME-WE project. | PMC10049644 | |
3.4. Mitigation Measures Implemented | RECRUITMENT | Project partners implemented several measures along the recruitment process, aimed at mitigating the abovementioned challenges and the risk of involving too few participants: Extra efforts in communication activities: All partners implemented additional communication activities to reach-out to a larger number of potentially interested young carers, through online channels (e.g., social networks) as well as being physically present in schools or in other places where young people commonly gather.Involvement of more stakeholders/partner organisations, as well as former young carers and young people: All partners identified and involved other organisations (e.g., non-profit organisations) and stakeholders (e.g., former young carers) that could help them to reach out to AYCs, engage them through the organisation of meetings and involve young people as research assistants in recruitment.Logistical measures: Many partners worked to provide as much logistic support as possible to their participants. This meant both scheduling sessions at times and places that could make it easier for young carers to attend and providing transportation to meeting venues.Organisational measures: Some partners executed contingency measures to help catch up with initial delays, such as running two sessions per week instead of one.Methodological adaptation: A mixed-method process evaluation was ultimately adopted with the engagement of stakeholders in all six partner countries. This allowed the project research team to complement quantitative information on the impact of the intervention together with a deeper understanding of the challenges encountered during the recruitment and implementation of the ME-WE intervention in each country. | PMC10049644 | |
4. Discussion | RECRUITMENT | The recruitment of participants for the ME-WE trial study has certainly proved that AYCs are a hard-to-reach target group for researchers and practitioners. A lower number of participants were recruited and fully engaged, despite the significant recruitment efforts that were made and additional efforts spent. In order to approach AYCs and ask them to participate in the study, the first challenge was to identify them in the general population. This task was carried out in partnership with local non-profit organisations, as well as institutional services such as schools and social care. In addition, recruitment campaigns (e.g., through social media) were implemented in some cases, targeting children and young people. Since in most countries the phenomenon of AYCs Is not formally recognised and both practitioners have low awareness about this target group and AYCs themselves have low self-awareness of their role, there was a need to train field workers about the issue and to understand with them the best channels to exploit for recruitment. The identification of AYCs was difficult due to all these factors and resulted in a limited number of AYCs being approached (n = 478, 90.9% of the total target sample size) and involved in the study after screening, compassionate cases and withdrawals (n = 260, 49.4% of the total target sample size).The second challenge was to keep AYCs interested while waiting for their ME-WE group to start and subsequently to keep them engaged in the study until the end. Despite a high retention rate (82% of those starting the study), a further reduction (18%) in AYC cases available for the quantitative analysis occurred, leading to a total final number of 217 cases (41.3% of the total target sample size). However, in some countries there was a higher number of dropouts (especially in Slovenia and the UK), which suggests that specific problems were faced during the intervention implementation. The need to fill in online surveys with a relatively large battery of sensitive questions might have deterred some AYCs from participating in the evaluation. Furthermore, the long waiting period of 3 months after the end of the intervention may have contributed to reducing the AYCs motivation to complete the questionnaire at T2.Overall, the ME-WE trial study was conducted in specific and highly challenging times under COVID-19 restrictions of physical and social distancing and periodic lockdowns in most participating countries. The COVID-19 restrictions led to a temporary complete halt of the recruitment process in all six countries, thus leaving partners to endorse social media campaigns (Switzerland, Sweden), which were based on an individual recruitment strategy. The delivery of the intervention itself was severely hindered by the outbreak of the COVID-19 pandemic, as the Netherlands and Slovenia were in the field during the first lockdown period that affected Europe. The intervention was moved fully online; however, there was a long pause in Slovenia, for example, in waiting for all intervention materials to be adjusted to an online delivery, which resulted in increased dropout rates. Due to the transition to online platforms during lockdown, some participants were unable to continue participating owing to technical barriers (see the ethical considerations below). The recruitment barriers prevented partners from reaching sufficient sample sizes and, consequently, it was not feasible to perform a complete quantitative analysis both at the national level as well as the cross-national level.The restricted age group (15–17 years) that was targeted could have been another limiting factor to identifying AYCs. Minors in this group are in a transition phase of their personal development from childhood to adulthood and may be subject to a variety of social influences (e.g., perceived social stigma of attending a psychosocial support intervention), as well as practical constraints (e.g., limited time to attend the intervention sessions due to school, family and social and care commitments). Moreover, as AYCs are more likely to come from socially disadvantaged groups, family circumstances and other issues may have prevented some from joining in and finding sufficient time and resources to dedicate to such a project.Moreover, in general, the study design of interventions such as the one proposed by the ME-WE project deserves careful consideration. RCTs are widely used in medical and health-related research, especially for drug discovery and efficacy evaluation, but their use in social research with psychosocial interventions such as the ME-WE intervention are far less common. The reasons include ethical considerations but also practicalities of the process and how to conduct rigorous (reliable) RCTs in social/community settings with a “hard to reach” and invisible group such as AYCs, where professionals and other gatekeepers have little awareness of the “target group” [Despite recruitment challenges and study limitations (some explained also in Hanson and colleagues [As a result of the impact of the COVID-19 pandemic on the study, the ME-WE intervention model, which was originally designed for a face-to-face approach and a blended face-to-face and app approach, was shown to be adaptable and well functioning in a fully online approach [The mixed-methods evaluation ultimately implemented relies on a robust and sufficient amount of quantitative and qualitative data. These latter ones suggest some evidence of promising results that can shape future interventions and further research in this field. Although, due to several methodological limitations, the data should be interpreted with caution, the results suggest some positive impacts. Despite all the challenges faced in the course of the project, the ME-WE model provided a benefit to the mental health and overall well-being of the AYCs, as expressed by the AYCs through their own first-hand accounts. | PMC10049644 | |
5. Conclusions | influencer, ’ interests | EVENT, RECRUITMENT | Drawing from the lessons learned from the recruitment process in our study and inputs received by stakeholders during the project (the IAEB and the Eurocarers Young Carers Working Group), we developed a set of recommendations and practical suggestions for researchers and practitioners dealing with AYCs, which may help them to better approach, involve and retain AYCs in future research studies: Time schedule and setting: Have the intervention at school and during school hours but also consider having it in a different setting that is not identifiable as dedicated to a psychosocial intervention. The venue should avoid being too formal, as this might scare off participants. It should rather be a place that can take the pressure away. Adapt the time schedule and setting to the needs and preferences of the participants’ situation. Provide food and snacks.Young-people-friendly and appropriate remuneration: Make agreements with local service providers/NGOs (as appropriate according to the local context where the research is taking place) and encourage them to offer pro bono fun activities (e.g., bowling or cinema tickets, as appropriate in the specific country context). Alternatively, build in a small budget line within proposed action grants/research proposals focusing on the topic of young carers to be able to appropriately remunerate participant YCs for their time and efforts in a study and as a way of respecting and thanking them for their involvement in the research.Logistics: Provide AYCs with as much practical help as possible to attend (e.g., pick them up and offer rides home, using accessible venues and offering technical devices for online meetings (such as headphones if needed)).Organisation: In light of the COVID-19 experience and of the difficulties encountered in keeping AYCs engaged, use a blended approach—in person and online—for planning the AYCs intervention. This blended approach could also promote the participation of AYCs with a high burden of care activities and/or school commitments.Communication: Use online tools; have a YouTube influencer or another famous person (ideally with young caring experience) sponsoring the intervention; or, when going to schools to raise awareness on young carers and to present the project, focus more on the relationship aspect. When presenting in a country with low levels of public awareness on young carers, specific attention should be paid to clearly communicating about the target group for intervention, while trying to keep a positive and empowering attitude towards AYCs. On a practical note, provide AYCs with reminders of upcoming sessions and check with AYCs that they are able to attend, and, if not, how they could be supported to attend.Create trust and build positive relationships: The key is to take the fear away and to let young carers trust the intervention team. It is suggested to envisage a session n. 0, that is a preliminary meeting before the actual start of the intervention. This session would simply be an opportunity for young carers to meet the intervention team, build relationships and break the fear and they could invite their friends to this session. This most likely could consist of a fun activity, e.g., a gathering with music and food. A session 0 would also help to build trust and good relationships with AYCs from the beginning.Flexible participation: It is important to enable AYCs to participate to the best of their situation. For example, if they attend online from settings with restricted privacy (other family members present), taking related precautions such as switching off their camera and writing their responses in the chat as appropriate. In the event of absence from a session, there is a need to follow up with the missing AYC/s and facilitate their continuation in the intervention by offering a missed session/s at another suitable date and time. In order to maintain the interest of recruited AYCs, keep in touch with them regularly during the waiting period between the screening interview and the start of the intervention. This also applies to the period between the end of the intervention and the evaluation follow-ups, taking adequate precautions for avoiding affecting the investigated long-term effects of the intervention.Network of key stakeholder groups: It would be valuable to use a 6-12 months period in the design to build a network of key stakeholder groups, such as professionals, representatives from civil societies and young people themselves that have direct contact with youth/young carers. For instance, in some countries a network of carers organisations could already be in place, but in others contacts with schools and/or care support centres might need to be established and several meetings at different levels (managements, teachers, mentors, etc.) are necessary before schools take a decision to participate or not.Design: Consider using a design with different waves, so that one school could hold two different intervention groups (in two consecutive school years). This could increase the willingness of schools to participate, because there is a pay off in the second year (efficiency of delivery, knowledge on the procedures, etc).Improving recruitment: It is useful to offer training and promotional materials for schools, carer organisations and health and social services. By having them “on board” the chances to recruit participants are likely to be higher.Co-designed intervention: Since a psychoeducational intervention may make young carers feel “different” or “wrong” in comparison with their peers, it is suggested to further tailor the ice-breaking activities around the young participants’ interests and capabilities. For example, if young participants are keen on the arts, they could agree to produce a short theatre piece or song about their caring experience. | PMC10049644 |
Author Contributions | Conceptualisation, E.H., L.M., F.B., L.B., G.C. and V.H.; methodology, G.C., L.B., E.H., L.M. and V.H.; validation, G.C., L.B., E.H., L.M. and V.H.; formal analysis, E.H., L.M., F.B., L.B., G.C. and V.H.; investigation, E.H., L.B., G.C., V.H., I.B., F.L., R.H., R.B., S.S., M.S., B.D., Y.d.J., T.B., N.d.J., A.L., D.P., E.G., A.W., V.M. and L.M.; resources, E.H. and L.M.; data curation, G.C., L.B., E.H., L.M. and V.H.; writing—original draft preparation, F.B., E.H., L.B., G.C., V.H., I.B., F.L., S.B., R.H., R.B., S.S., M.S., B.D., Y.d.J., N.d.J., A.L., D.P., E.G. and A.W.; writing—review and editing, F.B., E.H., L.B., G.C., V.H., I.B., F.L., R.H., R.B., S.S., M.S., B.D., Y.d.J., T.B., N.d.J., A.L., D.P., E.G., A.W., V.M., S.B. and L.M.; visualisation, E.H., F.B., L.M., G.C., V.H. and I.B.; supervision, E.H., L.M., G.C. and L.B.; project administration, E.H., F.B. and L.M.; funding acquisition, E.H., F.B., L.M., S.B., V.H., L.B., S.S. and M.S. All authors have read and agreed to the published version of the manuscript. | PMC10049644 | ||
Institutional Review Board Statement | This study was conducted in accordance with the Declaration of Helsinki. Formal ethics approvals (and amendments, due to COVID-19 insurgence) were obtained from the ethical review boards of the University of Bologna (Italy) (116994; 144521), University of Ljubljana (Slovenia) (20 August 2019; 20 April 2020; 20 August 2020), Vrije Universiteit Amsterdam (the Netherlands) (ERB/19-08-02; ERB/20-04-01) and University of Sussex (United Kingdom) (ER/FML24/5; ER/FML24/6) and from the Swedish Ethical Review Authority (2019-04285; 2020-03057). According to the National Human Research Act, the Ethics Committee of the Zürich Canton (Switzerland) deemed formal ethical approval unnecessary (2019-00995). However, detailed opinions were duly sought and gained by SKF accordingly. This study was registered at clinicaltrials.gov (trial registration number: NCT04114864). | PMC10049644 | ||
Informed Consent Statement | Written informed consent was obtained from all subjects involved in the clinical study. | PMC10049644 | ||
Data Availability Statement | The ME-WE project reports, deliverables and outputs are publicly accessible in the project website: | PMC10049644 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10049644 | ||
References | RECRUITMENT | CONSORT flow diagram for the original study protocol.Minimum composition of the national sample size (initial estimation).Recruitment of participants to the ME-WE trial for each partner country.* Total number of young persons who applied to the study and were screened. This number includes participants with informed consent (with an exception of a few participants in Switzerland and the Netherlands—they are included in this number but excluded from the analysis). Number of AYCs participating in the intervention, number of compassionate cases, number of dropouts and final sample size per study arm and per country.Description of the recruitment waves by country for the intervention group: time and type of delivery, number of groups delivered and total number of participants per wave and per country.* Last session conducted online.Description of the recruitment waves by country for the control: time of delivery with total number of participants per wave and per country.Number of completed evaluation assessments at baseline (T0), post-intervention (T1) and follow-up (T2) for each country as included in the quantitative analysis.Final target sample size and final sample size. | PMC10049644 | |
Background | BTV | Mechanical ventilation during general anesthesia may impair airway mucosal function. This study aimed to investigate the effect of pressure-controlled ventilation-volume guaranteed (PCV-VG) on bronchial mucus transport velocity (BTV) in patients during laparoscopic surgery for gynecological oncology compared with volume controlled ventilation (VCV). | PMC10658982 | |
Methods | PNEUMOPERITONEUM | 66 patients undergoing elective a laparoscopic surgery for gynecological oncology. The patients were randomized into two group receiving either PCV-VG or VCV. a drop of methylene blue was placed on the surface of the airway mucosa under the bronchoscopeand, then the distance the dye movement was measured after 2, 4, and 6 min. Outcomes were assessed at T0 (5 min after endotracheal intubation and before initiation of pneumoperitoneum), T1 and T2 (1 and 2 h after stabilization of pneumoperitoneum respectively). BTV at T0, T1 and T2 was the primary outcome. Secondary outcomes included heart rate (HR), mean arterial pressure (MAP), body temperature, end | PMC10658982 | |
Results | 64 patients were included in the analysis. The median [interquartile range] BTV was significantly lower in VCV group at T1 and T2 that at T0 ( | PMC10658982 | ||
Conclusions | PCV-VG | PCV-VG is more suitable for patients undergoing laparoscopic surgery for gynecological oncology than VCV since it can protect mucociliary clearance function. | PMC10658982 | |
Trial registration | This trial is registered on | PMC10658982 | ||
Keywords | PMC10658982 | |||
Background | Airway mucosa is the most important natural defense system in the body and is considered the first line of defense of the respiratory system [Pressure-controlled ventilation-volume guaranteed (PCV-VG) mode utilizes a decelerating flow and constant pressure to achieve volume control and pressure control. It has thus been widely used in clinical practice [To bridge this data gap, in this study, we used bronchial mucus transport velocity (BTV) to quantify mucociliary clearance [ | PMC10658982 | ||
Methods | PMC10658982 | |||
Study design | This was a single-center, prospective, patient and observer-blinded, randomized- controlled trial. This study was reported following the CONSORT reporting guidelines [ | PMC10658982 | ||
Study population | atopy, tumor | RESPIRATORY DISEASE, MAY, TUMOR, ATOPY | First, all patients scheduled to undergo elective laparoscopic gynecologic tumor resection at the First Affiliated Hospital of Medical College, Shihezi University, China, from 12 October 2022 to 13 May 2023, were recruited. Next, only patients aged 40–75 years and met the American Society of Anesthesiologists’ (ASA) physical status I-II were included in the study. Patients with a history of respiratory disease, surgery, smoking, or recent use of drugs that can affect BTV (adrenergic receptor antagonists, hormones, anticholinergic drugs, theophylline, and catecholamines) predicted airway difficulty, and atopy were excluded from the study. | PMC10658982 |
Anesthesia procedures | patients-Dash | MUSCLE RELAXATION | The patients were not administered preoperative medications. Electrocardiogram, pulse oximetry, non-invasive blood pressure, and Bispectral Index Sensor (BIS, Aspect Medical Systems, Newton, MA, USA) were used to monitor all patients-Dash 3000 monitor, GE Company, Madison, USA. Anesthesia was induced using a bolus containing 0.05 mg/kg midazolam, 1 mg/kg propofol, 0.3 mg/kg sufentanil, and 1.5 mg/kg rocuronium after insertion of a peripheral intravenous cannula induction (unified model). Anesthesia was maintained through intravenous infusion of 50–150 ug/(kg·min) propofol and 0.05–0.1 g/kg· min remifentanil to maintain BIS within 40–60 and the mean arterial pressure within 20% of the pre-induction value. The patients also received intravenous injection of 0.7 mg/kg vecuronium to maintain muscle relaxation during anesthetization. Tracheal intubation was performed after muscle release. The cuff was inflated with 10 mL of air. The pressure of the tracheal intubation CUF was maintained at 20–30 cmH | PMC10658982 |
Study intervention | PNEUMOPERITONEUM | The patients received ventilation using the same type of Anesthesia Machine (Datex-Ohmeda-Avance CS2, GE Company, Madison, USA) after induction of anesthesia and intubation. Anesthesia machine parameters were similar under the two modes (VT; 8 ml /kg, inspiratory/expiratory ratio (I/E); 1:2, positive end-expiratory pressure (PEEP); 0, inspiratory fresh gas flow rate; 2.0 L/min with an inspired oxygen fraction (Fio2) of 0.4 in an oxygen-air. and respiratory rate (RR); initially set at 12 breath/min). Subsequently, RR was adjusted to maintain an end-tidal CO2 pressure (ETCO2) of 35–40 mmHg. The peak inspiratory pressure (PIP) and pneumoperitoneum pressure were set at 40cmH | PMC10658982 | |
Measurements | BTV | SECONDARY, PNEUMOPERITONEUM | The respiratory circuit was disconnected at T0, T1, and T2 time points as described by Seo H and Kim SH et al. [Method for measuring bronchial mucus transport velocity (BTV). Data were collected at the following time points:Baseline; 5 min after endotracheal intubation and before initiation of the pneumoperitoneum (T0)Post pneumoperitoneum (1 h after complete COPost pneumoperitoneum (2 h after complete COBTV at T0, T1 and T2 was the primary outcome. The secondary outcomes included heart rate (HR), mean arterial pressure (MAP), body temperature, PETCO2, VT, PIP, mean inspiratory pressure (P mean), respiratory rate (RR), and dynamic compliance (CDyn) at T0, T1, and T2. | PMC10658982 |
Sample size | PASS 15 Power Analysis and Sample Size Software (2017NCSS, LLC. Kaysville, Utah, USA) was used to determine the minimum number of samples. For BTV, a minimum number of 16 patients per group was required to detect a difference of at least 5.0 mm/min with a two-tailed alpha error of 0.05 and desired power of 80% (according to the data (mean, standard deviation) of a previous investigation) [ | PMC10658982 | ||
Randomization and blinding | PCV-VG | The 66 subjects were divided into two groups (1:1) using SPSS 26.0 software program (IBM SPSS Statistics, Chicago, Illinois, USA). and computer random number method. 33 pairs of numbers (1 or 2) were randomly generated, where 1 and 2 corresponded to the PCV-VG and VCV groups, respectively. The intervention methods adopted for PCV-VG or VCV groups were stored in opaque envelopes numbered 1 to 66 in the order in which they were produced. An anesthesiologist blinded to the study opened the envelope and determined the ventilation mode (PCV-VG or VCV). Fibrescope was performed by a senior and experienced anesthesiologist blinded to the study. A nurse who was blinded to the study recorded the data. The parameters of the anesthesia machine were covered using an opaque cloth during the bronchoscopy operation to ensure the operator was blinded to the study. | PMC10658982 | |
Statistical analyses | cancer | CANCER, PNEUMOPERITONEUM | Normal distribution of data was assessed using the Shapiro-Wilktest test. The equality of group variances was evaluated using the homogeneity of variance test (Levene statistic). Two independent samples t-tests were used to analyze data for age, height, BMI, weight, anesthesia time, pneumoperitoneum time, forced expiratory volume in 1st second (FEV1), and forced vital capacity (FVC). Fisher’s exact test was used to compare the ASA physical status and cancer types. The data of HR, MAP, body temperature, V | PMC10658982 |
Discussion | BTV, throat | PNEUMOPERITONEUM | In this study, both VCV and PCV-VG ventilation modes inhibited BTV in patients during laparoscopic surgery for gynecological oncology, and the degree of inhibition increased with increasing pneumoperitoneum time. The degree of BTV inhibition was not significantly different between the two groups at 1 h after pneumoperitoneum. However, the degree of BTV inhibition was significantly less in the PCV-VG group than in VCV group at 2 h after pneumoperitoneum. In addition, VT was similar for both modes indicating that PCV-VG could deliver a preset ventilation volume to the patients. To the best of our knowledge, this is the first study to evaluate the effect of PCV-VG mode on BTV in patients during laparoscopic surgery.Similarly, an animal study of Piccin VS comparing the effects of four mechanical ventilation strategies (normal volume ventilation, low volume ventilation, high volume ventilation, and high-pressure ventilation) on the mucociliary system [Jung Min Lee et al. [Although mechanical ventilation is widely used in intubated patients with various medical and surgical conditions, its direct effect on BTV in patients undergoing anesthesia is unknown. In this study, fiberscope was used to locate, map, and measure BTV. This method compares with the radioactive aerosol inhalation lung scanning method, nasal saccharin transport time test, and other methods for determining and evaluating BTV. Besides, it is a relatively accurate and non-invasive measurement method [However, this study has some limitations. First, the movement trajectory of methylene blue dye on the airway surface of most patients under general anesthesia was not an absolute straight line but showed an irregular curve. This indicates that although the total swing direction of the airway surface cilia is toward the direction of throat, each swing does not always go in a straight line [ | PMC10658982 |
Acknowledgements | We would like to express our sincere gratitude to all the participants for theirsupport and contribution to this research. We greatly appreciate the assistancefrom all the surgical and operating room members of First Affiliated Hospital, Shihezi University for their support in conducting this study. | PMC10658982 | ||
Authors’ contributions | Chao Deng and Tao Xu developed the concept and drafted the manuscript; Chao Deng and XK Wang performed the experiments and data acquisition; DF Gu contributed to the literature research and data analysis; T Xu revised the manuscript. All have read the final version of this paper and have agreed with this submission. | PMC10658982 | ||
Funding | This research was conducted with financial support from a research scholarship supported though funding from Science and Technology Bureau (No.2022ZD037). | PMC10658982 | ||
Availability of data and materials | The datasets used and analyzed during the current study are available from the corresponding author on request. | PMC10658982 | ||
Declarations | PMC10658982 | |||
Ethics approval and consent to participate | This study was approved by the Research Ethics Board of The First Affiliated Hospital of Shihezi University School of Medicine (Shihezi, China) and is registered on | PMC10658982 | ||
Consent for publication | Not applicable. | PMC10658982 | ||
Competing interests | The authors declare no competing interests. | PMC10658982 | ||
References | PMC10658982 | |||
Abstract | PMC10109340 | |||
Objective | MULTIPLE SCLEROSIS (MS) | This study aimed to evaluate safety (infusion‐related reactions [IRRs]) and patient satisfaction (patient‐reported outcomes [PROs]) for at‐home ocrelizumab administration for patients with multiple sclerosis (MS). | PMC10109340 | |
Methods | ADVERSE EVENTS, DISEASE | This open‐label study included adult patients with an MS diagnosis who had completed a ≥ 600‐mg ocrelizumab dose, had a patient‐determined disease steps score of 0 to 6 and had completed PROs. Eligible patients received a 600‐mg ocrelizumab home‐based infusion over 2 h, followed by 24‐h and 2‐week post‐infusion follow‐up calls. IRRs and adverse events (AEs) were documented during infusions and follow‐up calls. PROs were completed before and 2 weeks post infusion. | PMC10109340 | |
Results | fatigue, grogginess, itch, mild/moderate | Overall, 99 of 100 expected patients were included (mean [SD] age, 42.3 [7.7] years; 72.7% female; 91.9% White). The mean (SD) infusion time was 2.5 (0.6) hours, and 75.8% of patients completed their ocrelizumab infusion between 2 to 2.5 h. The IRR incidence rate was 25.3% (95% CI: 16.7%, 33.8%)—similar to other shorter ocrelizumab infusion studies—and all AEs were mild/moderate. In total, 66.7% of patients experienced AEs, including itch, fatigue, and grogginess. Patients reported significantly increased satisfaction with the at‐home infusion process and confidence in the care provided. Patients also reported a significant preference for at‐home infusion compared with prior infusion center experiences. | PMC10109340 | |
Interpretation | IRRs and AEs occurred at acceptable rates during in‐home infusions of ocrelizumab over a shorter infusion time. Patients reported increased confidence and comfort with the home infusion process. Findings from this study provide evidence of the safety and feasibility of home‐based ocrelizumab infusion over a shorter infusion period. | PMC10109340 | ||
Introduction | MULTIPLE SCLEROSIS (MS), DISEASE | Treatment for multiple sclerosis (MS) often requires routine and long‐term care for optimal disease management, including the administration of disease‐modifying therapies (DMTs) by intravenous (IV) infusion.Ocrelizumab is a recombinant, humanized monoclonal antibody that selectively targets CD20‐expressing B cells and is approved for the treatment of both relapsing (RMS) and primary progressive (PPMS) forms of MS.A number of recent clinical studies have evaluated the safety of shorter infusion times for patients with MS who received ocrelizumab treatment.The safety and benefit of the reduced infusion time for ocrelizumab has been established; however, limited data are available for the safety of home‐based infusions, especially in MS. The aim of this study was to develop and investigate a feasible and safe home infusion model, as well as to gain insights into the patient experience, for those who receive at‐home infusions of ocrelizumab and are monitored by telehealth visits for translation into routine clinical practice. | PMC10109340 | |
Methods | PMC10109340 | |||
Trial design | ADVERSE EVENT, RECRUITMENT | This was an open‐label, single‐arm, nonrandomized study to evaluate the safety and patient experience of ocrelizumab infusion over a 2‐h period via home‐based infusion (NCT04650321). The similarly designed Phase IIIb, open‐label SaROD study of accelerated ocrelizumab infusions was used as a historical control.Eligible patients were contacted by study research coordinators and screened for potential study recruitment, then provided preliminary electronic consent through a telehealth visit (Fig. Study design. AE, adverse event; CBC, complete blood count; CMP, comprehensive metabolic panel; Ig, immunoglobulin; IRR, infusion‐related reaction; PRO, patient‐reported outcome; UCH, University of Colorado Health. Patient vitals, IRRs and any AEs were documented throughout the infusion process. Following the home infusion, research coordinators called the participants within 24 h to follow‐up on any additional AEs that they may have experienced. Electronic PRO forms similar to those completed prior to home infusion were sent a week later to assess the patient's experience with the home infusion and to reassess their general health. A final telehealth study visit was conducted with a research coordinator 2 weeks after the home infusion to collect any additional ocrelizumab‐related AEs and to close the study.This study was conducted in accordance with the current US Food and Drug Administration Good Clinical Practices and local ethical and legal requirements. All study participants provided informed consent via electronic signature prior to participation in the study. | PMC10109340 | |
Patient population | In this study, participant selection was designed to reflect real‐world patients with MS who receive ocrelizumab. Enrollment occurred on a rolling basis over a 12‐month period from active patients of the Rocky Mountain MS Center (RMMSC) at the University of Colorado Anschutz Medical Campus until the target population of 100 patients was met for the intention‐to‐treat population (ITT).Eligible patients included adults aged 18 to 55 years who: (1) had a diagnosis of RMS or PPMS as defined by the 2017 McDonald criteria;Patients were excluded from participation in this study if they experienced a serious IRR ( | PMC10109340 | ||
Outcome measures | Cancer | ADVERSE EVENT, DISEASE, DISEASE CHARACTERISTIC, APPENDIX, CANCER | Data collected at screening and pre‐infusion visits consisted of patient demographics (age, sex, race, and ethnicity) and clinical disease characteristics (type of MS, disease duration, DMT type, DMT duration, PDDS score, and number of prior ocrelizumab infusions). Infusion procedure variables documented during the infusion included pre‐infusion medications, time to complete the infusion, ocrelizumab dose (mg and mL).The primary outcome was the proportion of patients with IRRs in this study, and in the SaROD historical comparator cohort 1. The SaROD cohort 1 study enrolled patients who had completed ≥1 dose of 600‐mg ocrelizumab according to the US label prior to study screening, then received an additional dose of ocrelizumab 600 mg over the shorter infusion time, as planned with our study design. Severity of IRRs was determined using the Common Terminology Criteria for Adverse Events developed by the National Cancer Institutes and utilized in the OPERA I and II studies.Secondary outcomes included PRO measures of patient experiences with home infusion and number of patient‐reported adverse events (AEs) (Supporting information Appendix | PMC10109340 |
Statistical analysis | DISEASE CHARACTERISTIC | Descriptive statistics were used to summarize patient demographics, clinical disease characteristics, infusion procedure variables and AEs for the ITT population. Controls were limited to available historic data from the SaROD study.The frequencies and proportions of IRRs for the primary outcome were summarized descriptively. The 95% confidence intervals were calculated for IRR proportions; exact methods were used as necessary. Descriptive statistics and 95% confidence intervals for the mean were calculated for the PROs. PRO data were not available for the historical controls. When applicable, pre‐post infusion comparisons of PROs were performed. For continuous or scale outcomes, paired | PMC10109340 | |
Results | PMC10109340 | |||
Patient demographics and disease characteristics | RRMS | DISEASE, MULTIPLE SCLEROSIS, DISEASE CHARACTERISTIC | Between August 2020 and February 2021 medical charts were reviewed for 925 eligible patients with MS, and 312 patients were contacted by the study team (Fig. Patient identification and attrition.A total of 99 patients with MS were included in the ITT population in this home infusion cohort study. The mean (SD, range) age was 42.3 (7.7, 25.7–55.5) years, and most patients were female (72.7%) and White (91.9%) (Table Patient demographics and disease characteristics by study cohort.DMT, disease‐modifying therapy; EDSS, Expanded Disability Status Scale; IQR, interquartile range; MS, multiple sclerosis; PDDS, patient‐determined disease steps; PPMS, primary progressive MS; RRMS, relapsing–remitting MS.Data presented at [The mean (SD) disease duration and number of prior infusions was 70.1 (346.9) months and 5.6 (1.9) infusions, respectively (Table | PMC10109340 |
Summary of at‐home ocrelizumab infusion procedures | The majority of patients received acetaminophen (94.9%), methylprednisolone (89.9%) and diphenhydramine (88.9%) prior to their ocrelizumab infusion (Table Infusion procedure by study cohort.One patient switched to 25 mg of diphenhydramine due to a prior reaction with the 50‐mg dose.Longer infusion times may have been a result of mechanical and other interruptions. | PMC10109340 | ||
Overall, only 25.3% (95% CI: 16.7%, 33.8%) of patients experienced an IRR of any grade during the at‐home ocrelizumab infusion. These IRRs were 18.2% Grade 1 (95% CI: 10.6%, 25.8%) and 7.1% Grade 2 (95% CI: 2.9%, 14.0%); no IRRs were classified as ≥Grade 3 (95% CI: 0.0%, 3.7%) (Fig. Frequency of infusion‐related reactions experienced with home infusion by grade.IRR frequency by study cohort.IRR, infusion‐related reaction. | PMC10109340 | |||
Patient‐reported | ADVERSE EVENT | Among these patients, a total of 174 AEs were reported, and 66.7% of patients experienced an AE with at‐home ocrelizumab infusion (Fig. Post‐infusion (A) patient‐reported AEs and (B) most common patient‐reported AEs. AE, adverse event; GI gastrointestinal. | PMC10109340 | |
Patient experience with home‐based ocrelizumab treatment | Patients reported favorable scores across PRO measures of their at‐home infusion experience, compared to their prior infusion experience at an infusion center. Significant improvements from were reported following a home for overall experience with the at‐home infusion process (The (A) overall patient experience with ocrelizumab home infusion, (B) patient experience with nurses during home infusion and (C) patient preference for infusion location. | PMC10109340 | ||
Discussion | DISEASE, RECRUITMENT | This open‐label, single‐arm, nonrandomized study is among the first to assess the safety of the at‐home infusion of ocrelizumab. Leveraging the shorter infusion regimen, at‐home administration did not increase the incidence of IRRs compared with the SaROD trial of the shorter infusion protocol for administering ocrelizumab, and no cases of severe or life‐threatening IRRs were experienced, which highlights the safety of at‐home infusions. Overall, patients reported increased confidence and comfort during home infusions through PROs administered pre‐ and post‐infusion compared with their last infusion received at an infusion center.Our study is among the first to evaluate home infusion for the administration of ocrelizumab, and findings from this cohort provide evidence of the safety, feasibility and patient satisfaction that can be achieved with at‐home infusions. Our study supports the use of home infusions as another safe and efficient alternative option for administering ocrelizumab to stable MS patients. Limited data on the administration of at‐home infusions are available, which highlights the importance of these study findings as providers of MS patients find newer ways to administer ocrelizumab. It is important to note that available studies in other DMTs and antibiotic treatment administration have shown comparable safety and efficacy with at‐home treatments compared with standard clinical settings. In a pilot crossover clinical study, patients with MS were randomized to receive usual care or home infusions of natalizumab, and were then switched to receive the alternate treatment.The mean infusion time achieved in this study was 2.5 h, which is consistent with the historical control data of 2.4 h reported in the SaROD study.The findings from this study are also unique because they provide valuable insights into the patient experience with at‐home infusion treatments through PRO questionnaires. The increased use of PRO scales in clinical studies enhances our understanding of patients' feelings about the treatment experience, their interactions with healthcare providers and circumstances that may influence their adherence to treatment. A survey study of patients with MS who received treatment at an infusion center reported that 83% of patients who received natalizumab or ocrelizumab had to take time off work or study for treatment infusions, and 60% responded that they would consider home‐based infusions.The results presented here should be interpreted within the context of the study limitations. Patient recruitment methods from a single center may limit the generalizability of these results for the overall MS population. The outcomes from this study were also only evaluated for a single home‐based infusion experience; therefore, further studies over longer periods that include multiple infusions should be conducted to extend these results. Historical control data were also used for comparison in the present study, which may introduce bias, although the SaROD study had similar characteristics in terms of sex, race, age and MS disease type. Studies that include direct comparison arms are needed; nevertheless, the findings of this study are consistent with and comparable to similar prior studies. Additionally, some of the PRO questionnaires included in this report are not validated; however, they do include very specific questions tailored to the home‐based infusion process that can provide valuable insights that established PROs may not address. While there are study limitations to consider, the findings presented here add useful evidence for the use of home‐based infusion therapy. Future studies that are designed to specifically address safety and efficacy concerns regarding at‐home infusions can further substantiate our findings.Overall, the findings presented in this study demonstrate the safety and feasibility of at‐home infusions for patients with MS. We report IRR and overall AE incidence rates comparable to those reported in other clinical studies involving home‐based infusions. This study also provides positive PRO data regarding the patient experience with at‐home ocrelizumab infusions and reveals factors that contribute to patient treatment satisfaction with infusion therapy. The reduction in time spent undergoing treatment through at‐home infusions can increase convenience and patient satisfaction, as well as positively impact treatment adherence without compromising the clinical benefit. | PMC10109340 | |
Author Contributions | PMC10109340 | |||
Conflict of Interest Statement | PMC10109340 | |||
Funding Information | INTERACTIONS | NIH funding was provided by CTSA grants UL1 TR002535, KL2 TR002534, and TLI TR002533. This study was sponsored by F. Hoffmann‐La Roche Ltd and Genentech, Inc. Support for third‐party writing assistance, furnished by Charli Dominguez, PhD, CMPP, of Health Interactions, Inc, was provided by F. Hoffmann‐La Roche Ltd. | PMC10109340 | |
Supporting information |
Click here for additional data file. | PMC10109340 | ||
Acknowledgements | We thank the patients and their families who participated in this study. We also acknowledge the Adult Clinical and Translational Research Center (CTRC) Nursing services at the Colorado Clinical and Translational Sciences Institute (CCTSI). | PMC10109340 | ||
Data Availability Statement | The datasets generated and/or analyzed during the current study are not publicly available as this study involved the merging of data from several different sources (patient‐reported outcomes, laboratory outcomes, telehealth visit data) and different electronic systems (home infusion center, academic medical center) but are available from the corresponding author on reasonable request. | PMC10109340 | ||
References | PMC10109340 | |||
Background | Cell salvage reduces allogenic blood transfusion requirements in surgery. We present a pilot study exploring the impact of anticoagulant choice, citrate or heparin, on the quality of cell salvaged blood in adults undergoing coronary artery bypass grafting (CABG). | PMC10082980 | ||
Materials and methods | inflammation | INFLAMMATION | Elective on pump CABG patients were randomly allocated to citrate or heparin anticoagulation. We measured red blood cell characteristics and inflammation in both the blood collection reservoir and the washed red blood cell concentrate. Postoperatively, the level of biomarkers and the coagulation profile in the peripheral blood as well as the transfusion requirements of allogenic blood products were studied. | PMC10082980 |
Results | Thirty eight patients were included, 19 in the citrate group and 19 in the heparin group. Baseline characteristics were similar. In the washed red blood cell concentrate, Mean Hb (g/dl) and Ht (%) were lower in the citrate group [Hb: 18.1 g/dL (SD 1.3) vs. 21.1 (1.6), | PMC10082980 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13019-023-02246-w. | PMC10082980 | ||
Keywords | PMC10082980 | |||
Background | blood loss | BLOOD LOSS, ADVERSE EFFECTS, BLOOD | Allogenic blood transfusion, a necessary tool in managing perioperative blood loss, has several adverse effects. Perioperative allogenic blood transfusion, even when limited in volume, is associated with postoperative morbidity, increased length of stay and so cost, and mortality in both general and cardiac surgery [Blood collected in the cell saver blood collection reservoir (BCR) can be used to study the effects of heparin vs. citrate directly on inflammatory parameters in red blood cells collected from the surgical field. To our knowledge, only one clinical study by Mortelmans et al. compared the effects of these anticoagulants in CS [ | PMC10082980 |
Methods | intraoperative bleeding, blood loss, neoplasia, infection, hemolysis | BLOOD LOSS, NEOPLASIA, CHRONIC INFLAMMATORY DISEASE, INFECTION, BLOOD, HEMOLYSIS, INTRAOPERATIVE BLEEDING | This single center pilot study (NCT02674906) was performed in the operating room and the mixed medical-surgical ICU of Ziekenhuis Oost Limburg (ZOL), Genk, Belgium, a 805-bed non-university teaching hospital. This study was approved by the local ethics committee and written informed consent was obtained prior to surgery from the patient or legal representative. After consent, patients were randomized preoperatively either to a citrate anticoagulant group or a heparin anticoagulant group for cell salvage. During CABG, the perfusionist and anaesthesiologist were unblinded for the anticoagulation regimen used. Blinding was complete for the patient, as well as personnel in the intensive care unit (ICU) and ward.Adult patients undergoing elective on-pump CABG were considered eligible for inclusion. Elective surgery was defined as planned at least 24 h before surgery. Off-pump CABG, urgent procedures, use of vasoactive medication prior to surgery, infection treated with antimicrobial therapy, chronic inflammatory disease, immune suppressive drug treatment, active neoplasia, renal replacement therapy, or use of extracorporeal membrane oxygenation (ECMO) were exclusion criteria. In addition, we excluded patients who had massive intraoperative bleeding that could not be safely managed while collecting study data. Patients could be excluded at any time if the inclusion criteria were no longer met or when exclusion criteria appeared. Patients were randomized using randomly generated treatment allocations within sealed opaque envelopes.CS is a procedure to collect blood lost in the surgical field for reuse. Blood is collected in cell saver blood collection reservoir (BCR), where it is mixed with an anticoagulant, either citrate or heparinized saline. The collected blood-anticoagulant mixture is processed by filtering, after which it is drawn into a centrifuge. Isotonic saline solution is added to the centrifuge bowl as washing fluid. The centrifugal procedure separates red blood cells, which are denser and are propelled against the outer wall of the bowl, while less dense plasma moves towards the centre of the bowl where it is deposited in a waste bag. Waste products, including white blood cells, platelets, plasma, anticoagulant, fat, clotting factors, and free plasma haemoglobin are collected in the waste fluid. The washed red blood cell concentrate (WRBC) is collected in a separate bag.Anaesthesia, cardiopulmonary bypass and cell salvage procedures were all executed according to the standard protocol used in our institution (see Additional file Washed red blood cell concentrate (WRBC) was transfused per-operatively or immediately post-operatively. If there was ongoing blood loss, the standard hospital protocol was applied to manage this; if there was necessity for allogenic blood transfusion, this was administered irrespective of the type of anticoagulant used (the ICU ward and the intensivist were blinded to the anticoagulant group).The standard protocol left transfusion at the discretion of the board certified anesthesiologist and/or ICU staff member; a Hb < 8 g/dl in the peripheral blood is in our protocol considered the threshold for allogenic blood transfusion in this type of patients.We collected baseline characteristics of patients before CABG. We measured effects of the specific anticoagulation protocol on quality of WRBC, and at various time points inflammatory parameters and variables of hemolysis and coagulation.On one hand, the quality of WRBC was analysed by measuring hemoglobin (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), free hemoglobin (fHb), iron, thrombocytes, white blood cell (WBC) count and differentiation in WRBC compared to Hb and Hct in the BCR. Inflammatory parameters were analysed by measuring levels of interleukin (IL)-6, IL-8, IL-10 and myeloperoxidase (MPO) at baseline, in the BCR (in the blood-anti-coagulant mixture before processing) and in peripheral blood of the patient (taken from the arterial catheter in place) at two time points; Firstly, when the patient was successfully weaned from cardiopulmonary bypass, protamine had been given and when the WRBC had not yet been transfused. Secondly, in the ICU, 2–3 h post transfusion of WRBC, but before extubation or allogenic blood transfusion.The impact after transfusion of WRBC was evaluated, apart from measuring inflammatory parameters, by measuring fHB, iron, transferrin, ferritin, haptoglobin, hepcidin, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), rotational thromboelastometry (ROTEM) in peripheral blood of the patient (taken from the arterial catheter), at the same two time points before and after transfusion of WRBC. Furthermore, blood loss in thoracic drains and transfusion requirements over the first 24 postoperative hours were compared between groups.For determining the levels of interleukins and MPO, validated and commercially available assays were used: IL-6: Electrochemiluminescence immunoassay, (Elecsys Il-6 on Cobas e801); IL-8: human IL-8 ELISA kit (cat.no. KHC0081), Thermo Fischer Scientific; IL-10: human IL-10 ELISA kit (cat. No BMS215-2) Thermo Fischer Scientific; MPO: Myeloperoxidase ELISA kit (ref: KT-890) Epitope Diagnostics, inc. All assays were performed according to the manufacturers’ instructions, with internal quality controls and participation to external quality control programs.Statistics were performed using SPSSA sample size of 34 achieves 80% power to detect a difference of 2 g/dl in Hb, a primary outcome parameter, using a two-tailed two sample t-test at a 0.05 level of significance. Equal sized groups and a standard deviation of 2 was assumed. | PMC10082980 |
Results | Over a 3 month study period, a total of 38 patients were included, 19 patients in each group. There were no significant differences in baseline characteristics, including fasting lipid profiles, between the groups, apart from a higher lymphocyte count in the citrate exposed patients (of citrate group) (Table Panel A. Baseline Characteristics as mean (SD) or median (25–75%)Euroscore is a validated score to evaluate the risk of cardiac surgery (Nashef et al. EuroSCORE II. Eur J Cardio-thorac. 2012) [Bold value < than 0.05 i.e. statistically significant | PMC10082980 | ||
The quality of WRBC | WRBC from patients in the citrate group had lower Hb, Ht and RBC count compared to heparin exposed patients (Table WBC counts did not differ between groups in WRBC. WBC differentiation showed a higher count and percentage for lymphocytes, monocytes and eosinophils in the citrate group (see Table | PMC10082980 | ||
Inflammatory parameters | In the BCR, despite no difference at baseline, the anti-inflammatory marker IL-10 was significantly higher in the citrate group [203.70 (108.98–411.42) vs 108.10 (60.00–176.71) Before WRBC transfusion, there were no significant differences in inflammatory parameters between the groups (see Additional file Results in patients after WRBC transfusion, reported as mean (SD) or median (25–75%)Bold value < than 0.05 i.e. statistically significant | PMC10082980 | ||
The impact after transfusion of WRBC | Free Hb, iron, ferritin, haptoglobin and hepcidin did not differ between the groups, both before and after WRBC transfusion. There was no difference in aPTT, PT, INR and ROTEM analysis before and after WRBC transfusion between groups. Both intra-operatively and post-operatively there was no difference between the groups in the need for transfusion of allogenic blood products (Packed Cells, Thrombocytes, Fresh Frozen Plasma) and total blood volume lost during the first 24 post-operative hours was comparable (see Table Intra- and post-operative allogenic blood product tranfusion and blood lossFor readability, volumes of tranfusion products are given as mean (SD). | PMC10082980 | ||
Cell salvage volumes | There were no significant differences between study groups in total fluid volume collected in BCR, ATBR, incubation time, waste fluid and washing fluid. Although the volume of WRBC was higher in the citrate group this difference was not significant. The significant difference in Ht in WRBC between groups (see Table No significant differences were noted in fluid volume or type, administered before, during and after cardiopulmonary bypass. Intraoperative diuresis was not significantly different between the groups. The total heparin dose during cardiopulmonary bypass was not significantly different between the groups (Citrate group: mean heparin dose: 32,361 (11,776) IU, heparin group: 36,711 (13,087), | PMC10082980 | ||
Discussion | blood loss, hemolysis, postoperative bleeding | HYPOTONIC, BLOOD LOSS, POSTOPERATIVE BLEEDING, FRAGILITY, BLOOD, HEMOLYSIS, INFLAMMATORY RESPONSE | In this trial comparing the effects of differing anticoagulant regimens (citrate or heparin) on cell salvage in adult patients undergoing elective pump CABG, small but relevant differences were observed between the two groups. WRBC had a significantly lower hematocrit and higher MCV and a larger residual thrombocyte count in the citrate group. There were also differences in WBC differentiation between groups. In the collecting bowl (before the cell salvage washing procedure but after treatment with anti-coagulant) IL-10 was significantly higher in the citrate group. After WRBC transfusion in the patients, there were no differences in interleukin blood levels between the groups, but MPO was significantly higher in patients in the heparin group. Both intra-operatively and post-operatively, this did not result in differences in transfusion of allogenic blood products or blood loss. Washed red blood cell concentrates in both groups met the quality guidelines published by the American Association of Blood Banks [We believe the differences in MCV and MCHC can be attributed to a number of factors. ACD-A is hypotonic (400–440 mOsm/kg, sodium content 214–234 mEq/l) and acidic (pH 4.5–5.5). Both have been implicated in increased MCV, the latter especially when ACD-A concentrations are relatively high [Since ACD-A is a hypotonic solution, the osmotic effect on red blood cells would increase with increasing ATBR. However, the ATBR and incubation time of blood in the BCR was comparable in both groups. Consecutive washing cycles could possibly have an impact on WRBC quality but the volume of red blood cells washed twice and the proportion of patients per study group whose red blood cells were washed twice, were again comparable between groups.During the washing cycle, the centrifuged volume of red blood cells at which the cell saver sensor detects the buffy coat will have been comparable between the groups. In the citrate group because of the larger MCV, there are therefore fewer red blood cells. This can explain the lower Hb, but not the lower Ht, in the citrate group (since the MCH was comparable between the groups). The same cell saver device was used in all patients but can be expected to deliver a comparable Ht of WRBC in both groups, only when MCV is similar. A larger MCV, with a comparable MCH, may have caused a less efficient centrifugal movement of RBC in the citrate groups during washing. This may have led to a more dilute WRBC, which would also explain why the volume of WRBC in the citrate group was higher (though not significantly), although the total volume of fluid in the BCR was comparable between the groups. Since the product of Hb and the volume of WRBC was comparable between the study groups, the total amount of autologous Hb transfused in both groups was comparable, which argues against significant differences in hemolysis between groups. Fortunately, the quality guidelines for perioperatively salvaged RBCs, published by the American Association of Blood Banks (AABB), were met in both groups (Hct > 50%, Hb > 15 g/dl, fHb < 1.0 g/dl) [There was a significantly lower residual thrombocyte count in the WRBC in the heparin group. This could be an effect of more pronounced thrombocyte activation in the heparin group. Both in vitro [The inflammatory response elicited by cardiac surgery is characterized by a significant release of both pro- and anti-inflammatory cytokines [Interpretation of the differences found in WBC differentiation in the washed RBC concentrate is difficult because of minimal baseline differences in WBC differentiation, though the effects of citrate versus heparin as described above, especially the differing effects on polymorphonuclear degranulation, could play a role.Undoubtedly this pilot study has a number of limitations; primarily it is a small, single center study, despite which findings are statistically robust. The larger anticoagulant priming volume could cause early hemolysis when ATBR was highest, but this was masked by the washing process. A blood smear and quantification of osmotic fragility might have added reinforcing data. Heparin was given systemically in both study groups. Despite equivalent doses in both groups, a supra-additive effect of systemic heparin with heparinized saline in the heparin group cannot be excluded totally. Differences in blood loss during the first 24 h, may have been nullified by the standard algorithm for the treatment of postoperative bleeding and the effect of differing techniques and outcomes between surgeons could be a possible confounding factor. Furthermore, blinding was not complete until the patient left the operating room. | PMC10082980 |
Conclusion | BLOOD, RESIDUAL | This study comparing citrate vs. heparin in cell salvage in adults undergoing coronary artery bypass grafting (CABG) found significant differences in the washed red blood cell concentrates: Hb and Hct were lower in the citrate group and the washed red blood cells had a higher MCV and lower MCHC. Residual trombocyte count was higher in the citrate group. Despite these differences, WRBC concentrates in both groups met the quality guidelines published by the American Association of Blood Banks. There were no differences in the necessity for transfusion of allogenic blood products intraoperatively and postoperatively nor in coagulation parameters. Higher IL-10 was found in the citrate group in the BCR, higher myeloperoxidase (MPO) in heparin group patients after WRBC infusion a possible reflection of a proinflammatory effect of heparin compared to citrate anticoagulation.It has been speculated that intraoperative use of hemo-adsorption therapy may alleviate the hyperinflammatory response triggered by cardiopulmonary bypass during cardiac surgery, though as yet little evidence exists for a decrease in proinflammatory cytokines [ | PMC10082980 | |
Author contributions | MVT | WB: Conception and design of the study; the acquisition of data and data analysis, interpretation of data; drafting of and substantive revision of the manuscript. MVT: Design of study, the acquisition of data and data analysis; drafting of and substantive revision of the manuscript. MB: Design of study, the acquisition of data. MS: The acquisition of data and data analysis. PDV: Design of study, the acquisition of data. MVL: The acquisition of data and data analysis. EH: Design of the study, interpretation of data, substantive revision of the manuscript. PGJ: Conception and design of the study, interpretation of data; drafting of and substantive revision of the manuscript. All authors read and approved the final manuscript. | PMC10082980 | |
Funding | None. | PMC10082980 | ||
Availability of data and materials | The datasets during and/or analysed during the current study available from the corresponding author on reasonable request. | PMC10082980 | ||
Declarations | PMC10082980 | |||
Ethics approval and consent to participate | The study protocol was approved by the local institutional review board (Commissie Medische Ethiek, Ziekenhuis Oost‐Limburg, approval. Written informed consent to participate in the study was obtained prior to surgery from the patient or legal representative. | PMC10082980 |
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