Experiences of health services for adults with cerebral palsy, their support people, and service providers.

AIM: To explore the experiences of health services among adults with cerebral palsy (CP) in Ireland, from the perspectives of adults with CP, their support people, and service providers. METHOD: A qualitative descriptive study design was used. In-depth semi-structured interviews were conducted between March and August 2021 with adults with CP, people who supported them, and health professionals. Thematic analysis was used to evaluate the data. RESULTS: Twenty-one adults with CP, seven support people (family carer[s], spouse or partner, or friend), and 15 service providers participated in the study. Adults had a mean age of 38 years 5 months (range 22-58 years) and were classified in Gross Motor Function Classification System levels I to V. Five themes were identified from the data: (1) access challenges in adult services; (2) knowledge and understanding of CP; (3) support people's role and care burden; (4) communication and interaction in adult services; and (5) health system challenges. CONCLUSION: Adults with CP in Ireland face multiple challenges accessing the health services they need. Services were reported to be inadequate, with limited resources and understanding of CP. Participants highlighted a need for system-level interventions, including enhanced training for health professionals to effectively meet the needs of adults with CP.

Transition from child to adult services for young people with cerebral palsy in Ireland: Influencing factors at multiple ecological levels.

AIM: To explore the factors that influence the process of transitioning from child to adult services in Ireland among young people with cerebral palsy, their parents, and service providers. METHOD: This study followed a qualitative descriptive approach. Semi-structured interviews were conducted with 54 participants, including young people with cerebral palsy aged 16 to 22 years (n = 13), their parents (n = 14), and service providers (n = 27). Data were analysed using the Framework Method. Findings were categorized using an ecological model across four levels: individual, microsystem, mesosystem, and exosystem. RESULTS: Limited awareness, preparation, and access to information hindered successful transition. Microsystem factors such as family knowledge, readiness, resilience, and health professional expertise influenced transition experience. Mesosystem factors encompassed provider-family interaction, interprofessional partnerships, and interagency collaboration between child and adult services. Exosystem factors included inadequate availability and distribution of adult services, limited referral options, coordination challenges, absence of transition policies, staffing issues, and funding allocation challenges. INTERPRETATION: Transition is influenced by diverse factors at multiple ecological levels, including interactions within families, between health professionals, and larger systemic factors. Given the complexity of transition, a comprehensive multi-level response is required, taking into account the interactions among individuals, services, and systems.

Understanding the use of digital technologies to provide disability services remotely during the COVID-19 pandemic; a multiple case study design.

BACKGROUND: Using digital technologies to provide services and supports remotely may improve efficiency and accessibility of healthcare, and support people with disabilities to live independently. This study aimed to explore the experience of using digital technologies to access and provide disability services and supports during the Covid-19 pandemic, from the perspective of people with disabilities, families and service providers. METHODS: Using a multiple case study design, we purposively sampled three cases based on service user characteristics and geographical reach of the service. We conducted semi-structured interviews with 40 service users and service providers. Topic guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR). Analysis followed a largely deductive approach, using the CFIR constructs as a coding framework. A summary memo was developed for each case. Influence and strength of each construct was rated to identify constructs that influenced implementation of digital technologies. Ratings were compared across services to identify facilitators and barriers to implementation. RESULTS: Service users and providers were positive about using digital technologies to access and provide disability services and supports remotely. Advantages over in-person delivery included reduced travel time, increased opportunity for peer support and peer learning, more choice and opportunity to participate in activities, and an enhanced sense of self while accessing services from the secure environment of their home. The urgency to identify new modes of service delivery to meet the needs of service users during Covid-19 was a strong facilitator but did not necessarily result in successful implementation. Other factors that were strong facilitators were the use of adaptations to enable service users to access the online service, service users' willingness to try the online service, service users' persistence when they encountered challenges, and the significant time and effort that service providers made to support service users to participate in the online service. Barriers to implementation included the complexity of accessing online platforms, poor design quality of online platforms, and organisations prioritising in-person delivery over online services. CONCLUSIONS: These findings may allow service providers to leverage facilitators that support implementation of online disability services and supports.

Transition to adult services experienced by young people with cerebral palsy: A cross-sectional study.

AIM: To assess if young people with cerebral palsy experience and health professionals provide practices that may improve transition from child to adult health services. METHOD: Seventy-five young people (31 females, 44 males; mean age 18 years 5 months [standard deviation 2 years 2 months]) and/or parents and 108 health professionals completed a questionnaire describing their experience or the provision of nine transition practices. RESULTS: The percentage of young people reporting each practice was: appropriate parent involvement (90%); promotion of health self-efficacy (37%); named worker who supports the transition process (36%); self-management support for physical health (36%); self-management support for mental health (17%); information about the transition process (24%); meeting the adult team (16%); and life skills training (16%). Post-discharge, 10% of young people reported that their general practitioner (GP) received a discharge letter. The percentage of health professionals reporting each practice was: promotion of health self-efficacy (73.2%); self-management support (73.2%); information (69%); consulting the parent and young person about parent involvement (63% and 66%); discharge letter to a GP (55%); life skills training (36%); named worker (35%); meeting the adult team (30%); and senior manager (20%). INTERPRETATION: Many young people did not experience practices that may improve the experience and outcomes of transition. Young people should be involved in the development and delivery of transition to ensure it meets their needs. WHAT THIS PAPER ADDS: Many young people with cerebral palsy (CP) do not receive support that may improve the experience of transition. Appropriate protocols and training for health professionals may improve the provision of transition and reduce inconsistency in care between and within organizations. Young people and their families should be involved in service design, delivery, and evaluation related to the transition to ensure it meets their needs.

Prevalence and incidence of chronic conditions among adults with cerebral palsy: A systematic review and meta-analysis.

AIM: To assess the prevalence and incidence of chronic conditions among adults with cerebral palsy (CP) and compare them to the prevalence and incidence among adults without CP. METHOD: We searched MEDLINE and Embase for studies reporting the prevalence or incidence of one or more chronic conditions among adults with CP. Two independent reviewers screened titles, abstracts, and full-text articles. Two independent reviewers extracted data relating to prevalence and incidence and appraised study quality. We performed random-effects meta-analyses to pool prevalence and incidence. RESULTS: We identified 69 studies; 65 reported the prevalence of 53 conditions and 13 reported the incidence of 21 conditions. At least 20% of adults had the following conditions: depression (21%); anxiety (21%); mood affective disorders (23%); asthma (24%); hypertension (26%); epilepsy (28%); urinary incontinence (32%); malnutrition (38%); and scoliosis (46%). Adults with CP were more likely to have type 2 diabetes, anxiety, bipolar disorder, depression, schizophrenia, hypertension, ischaemic heart disease, stroke, cerebrovascular disease, asthma, liver disease, osteoarthritis, osteoporosis, underweight, and chronic kidney disease than adults without CP. INTERPRETATION: These data from 18 countries, which provide an international perspective, may be used to promote awareness, identify targets for intervention, and inform the development of appropriate supports for adults with CP.

Safety, feasibility, acceptability and effects of a behaviour-change intervention to change physical activity behaviour among people with multiple sclerosis: Results from the iStep-MS randomised controlled trial.

BACKGROUND: There is limited information regarding the safety, feasibility and acceptability of behaviour-change interventions to increase physical activity (PA) and reduce sedentary behaviour among people with multiple sclerosis (MS). Prior to evaluating efficacy, it is important to identify problems with feasibility and acceptability, which may undermine effectiveness. OBJECTIVE: To examine the safety, feasibility and acceptability of a behaviour-change intervention to increase PA and reduce sedentary behaviour among people with MS. METHODS: Sixty people received a 3-month intervention or usual care. Fatigue, pain and adverse events (AEs) were assessed. Feasibility and acceptability were explored through focus groups with physiotherapists and interviews with participants. Fidelity to intervention content, delivery skills, programme receipt and programme task were assessed. RESULTS: There was no difference in AE rate between groups (p = 0.965). Fatigue and pain were not higher in the intervention group at 3 or 9 months. Therapists reported the intervention was feasible to deliver and fidelity was acceptable. Twenty-nine participants (97%) attended at least 75% of sessions. Participants found the intervention acceptable but suggested some amendments were required to intervention components. CONCLUSIONS: The intervention was safe, feasible and acceptable. Although modifications are required to intervention components, the intervention warrants further evaluation in a future trial.

Educating undergraduate occupational therapy and physiotherapy students in motivational interviewing: the student perspective.

BACKGROUND: Motivational Interviewing (MI) is an evidenced based talking therapy designed to affect client Health Behaviour Change. Previous research indicates that Allied Health Professionals (AHP) can effectively use the approach and training at pre-registration level has been piloted. However, student experiences of training is underexplored. AIM: To explore Physiotherapy and Occupational Therapy students' experiences of training in and implementation of Motivational Interviewing. METHODS: Four focus groups including 24 undergraduates (14 OT and 10 PT) were conducted at the completion of the training and a subsequent clinical placement. Transcribed texts were analysed thematically. Data were triangulated with student written post-it notes and open questions in a post training questionnaire. RESULTS: Two overarching themes were developed from the data. Learning different ways to interact and the challenge of transformation illuminates specific aspects of the training which enabled learning as well as areas of contention. Using the spirit of MI, but not every contact counts highlights the facilitators and challenges of implementation on placements. CONCLUSIONS: Motivational interviewing is a useful addition to training neophyte health students. Key skills were adopted and in some cases transferred into practice. The process of learning indicates areas of potential improvement to enhance relevance of practice scenarios. The transfer to practice is more complex illustrating a need to negotiate professional and institutional expectations which should be considered in training.

Multidisciplinary user experience of a newly implemented electronic patient record in Ireland: An exploratory qualitative study.

BACKGROUND: Implementation of an Electronic Patient Record (EPR) in a key milestone in the digital strategy of modern healthcare organisations. The implementation of EPR systems can be viewed as challenging and complex. OBJECTIVE: The aim of the study was to investigate user perspectives and experiences of the implementation of an Electronic Medical Record in a major academic teaching hospital, with simultaneous 'go-live' across the whole hospital taking place. METHODS: Focus groups and individual in-depth interviews were conducted with stakeholders and users (n = 105), approximately nine months post-EPR implementation. The study explored EPR users' perceptions using an extended theoretical framework of the DeLone and McLean Information Systems Success Model (2003), which measured information systems, system quality, information quality, service quality, use/perceived usefulness & user satisfaction and net benefits. RESULTS: Staff engagement and satisfaction was high and the EPR is accepted as the new standard way of completing care. There was agreement that the EPR affords transparency, and greater accountability. There was some concern expressed regarding impact of the EPR on interprofessional and patient/provider interactions and communication. Physicians reported the inputting of social history through free text as an issue of concern and time consuming. The Big Bang approach with mandatory conversion was key to the successful adoption of EPR. There was consensus across professional and administrative respondents that there was no appetite to return to paper-based records. CONCLUSION: The successful roll out of the EPR reflects the digital readiness of healthcare providers and organisations. The potential for unintended consequences on work process requires continual monitoring. A key future benefit of the EPR will be the capacity to reach a broader understanding and analysis of variation in processes and outcomes within healthcare organisations. It is clear that skills in data analytics will be needed to mine data successfully.

Aging Well With a Lifelong Disability: A Scoping Review.

BACKGROUND AND OBJECTIVES: Existing literature highlights notable health and social inequalities for people aging with a lifelong disability and the need for research to better understand how we can support this group to age well. This scoping review mapped existing literature related to "aging well" in people with lifelong disabilities. RESEARCH DESIGN AND METHODS: Five scientific databases and gray literature sources were searched for studies related to "aging well" and "lifelong disability" (defined as a disability that a person had lived with since birth or early childhood). RESULTS: We identified 81 studies that discussed aging well with a lifelong disability, with most (70%) focusing on intellectual disabilities. Two themes captured existing research on aging well with a lifelong disability: (1) framing aging well with a lifelong disability, which included the ways that people with lifelong disability, their supporters, and existing research frame aging well for this group and (2) supporting people to age well with a lifelong disability, which involves the micro-, meso-, and macro-level factors where research suggests interventions to facilitate aging well could be situated. DISCUSSION AND IMPLICATIONS: This synthesis highlights how aging well is currently framed in the literature and where interventions to improve aging well in this group could be situated. Literature highlights the importance of considering multilevel interventions to improve aging well. Evidence gaps include the lack of research conducted with groups other than those with intellectual disabilities and the need for more research examining aging well interventions.

REVEALS-a longitudinal cohort study of multifaceted respiratory assessment in ALS.

OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression. METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model. RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores. CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.

Enhancement of plasmid DNA immunogenicity with linear polyethylenimine.

The utility of plasmid DNA as an immunogen has been limited by its weak immunogenicity. In the present study, we evaluated the ability of a family of linear polyethylenimine (PEI) polymers, complexed to plasmid DNA, to augment DNA expression in vivo and to enhance antigen-specific adaptive immune responses. We showed that four of five structurally different PEIs that we evaluated increased in vivo DNA expression 20- to 400-fold, and enhanced DNA-induced epitope-specific CD8⁺ T-cell responses 10- to 25-fold in BALB/c and C57BL/6J mice respectively, when delivered intravenously. Functional studies of the PEI-DNA-induced CD8⁺ T-cell responses demonstrated that formulation of DNA with PEI was associated with increased numbers of cells secreting type I cytokines. In addition, PEI-DNA complexes improved antigen-specific T(H) 1-helper cell and humoral responses. Most importantly, the PEI-DNA complexes elicited memory cellular responses, capable of rapid expansion and accelerated clearance of a lethal dose of recombinant Listeria monocytogenes. Lastly, we identified physical properties of PEI-DNA complexes that are associated with enhanced DNA-elicited immunogenicity. These findings demonstrate that PEI polymers can play an important role in the development of DNA-based vaccines in the setting of infectious disease prevention and cancer therapy.

Pedometers, the frustrating motivators: a qualitative investigation of users' experiences of the Yamax SW-200 among people with multiple sclerosis.

PURPOSE: Self-monitoring may represent a mechanism to enhance physical activity among people with multiple sclerosis. To optimise activity monitoring as a behavioural tool to increase physical activity, user experience must be understood. This study evaluated user experience of the Yamax SW-200 Digi-walker pedometer in a group of people with MS. METHODS: Semi-structured interviews were conducted with 15 adults who participated in a 12-week pedometer-supported behavioural change intervention, the iStep-MS trial. Interviews were audio-recorded and transcribed verbatim. Data were analysed using the Framework Method. RESULTS: An overarching theme Pedometers, the frustrating motivators captures the complex and often contradictory experience of the pedometer. Sub-themes include: Increasing activity awareness, which describes the pedometer's utility in raising activity consciousness; Numeric motivation provides insight into dual motivating and demotivating experiences of using an objective feedback device; (Un) usability focuses on practical concerns encountered in the day-to-day use of the monitor. CONCLUSION: The Yamax SW-200 Digi-walker raised awareness and enhanced participant motivation to engage in physical activity. Accuracy and usability concerns highlighted warrant consideration in the selection of this pedometer within a population with multiple sclerosis. TRIAL REGISTRATION: Changing physical activity behaviour in people with MS: the iStep-MS trial; ISRCTN15343862; https://doi.org/10.1186/ISRCTN15343862Implications for rehabilitationUse of self-monitoring tools such as pedometers can enhance physical activity awareness.Objective, numeric step count feedback is an effective motivational tool for physical activity.Accuracy and usability concerns may limit the value of the Yamax SW-200 Digiwalker for people with MS.Identification of individualised, reliable, usable and acceptable tools is important to ensure engagement with self-monitoring.

Mapping health services for adults with cerebral palsy in Ireland: a pilot study.

Background: Cerebral palsy (CP) is a common cause of physical disability in childhood. The majority of children with CP survive to adulthood. Once discharged from children's services, adults with CP find it challenging to navigate health services. The aim of this study was to pilot and refine a methodology to map services for adults with CP in Ireland. Methods: We used a multi-informant mapping methodology consisting of: 1. Defining health services; 2. Identifying informants; 3. Designing a survey; 4. Collecting data; 5. Data checking and analysis. We collected data on services from service users and service providers using an online survey. We verified data against information available online and by asking organisations to provide details about the service. Results: Fifteen service users and nine service providers completed the online survey. Data on 265 unique services at 32 organisations were provided. The most commonly provided services were physiotherapy (12%) and occupational therapy (11%). We confirmed the name of 89 services (34%) against online information. We received further details from eight organisations about 27 services. Specifically, we received details about the organisation name for 27 of the 265 services (10%), service name for 25 services (9%), service type for 25 services (9%), a website for 19 services (7%), and data on eligibility criteria and types of supports provided for between 25 or 26 services (9% or 10%). Conclusion: This pilot study highlighted the complexity of mapping services for adults with CP in Ireland. We recommend that an alternative methodology should be used to map services for adults with CP in Ireland.

Unmet Health Needs among Young Adults with Cerebral Palsy in Ireland: A Cross-Sectional Study.

Data describing the unmet health needs of young adults with cerebral palsy (CP) may support the development of appropriate health services. This study aimed to describe unmet health needs among young adults with CP in Ireland and examine if these differed between young adults who were and were not yet discharged from children's services. In this cross-sectional study, young adults with CP aged 16-22 years completed a questionnaire assessing unmet health needs. Logistic regression was used to examine the association between discharge status and unmet health needs. Seventy-five young adults (mean age 18.4 yr; 41% female; 60% in GMFCS levels I-III) were included in the study. Forty (53%) had been discharged from children's services. Unmet health need, as a proportion of those with needs, was highest for speech (0.64), followed by epilepsy (0.50) and equipment, mobility, control of movement and bone or joint problems (0.39 or 0.38). After adjusting for ambulatory status, unmet health needs did not differ according to discharge status. The proportion of young adults with unmet health needs highlights the importance of taking a life-course approach to CP and providing appropriate services to people with CP regardless of age.

Public and Patient Involvement in Doctoral Research During the COVID-19 Pandemic: Reflections on the Process, Challenges, Impact and Experiences From the Perspectives of Adults With Cerebral Palsy and the Doctoral Researcher.

Introduction: Cerebral palsy (CP) is a lifelong condition, where people may experience complications as they age. Including the views of people with CP through Public and Patient Involvement (PPI) ensures that research into the condition is relevant and meaningful in addressing their concerns. However, there is a lack of evidence on incorporating the voices of adults with CP in the doctoral research process. Therefore, this paper aims to provide an overview of how adults with CP were involved in a doctoral research process during the pandemic. Methods: This paper describes the PPI process and its impact at various stages of the doctoral research process and reflects on the experiences from the perspective of the doctoral researcher and adults with CP using the INVOLVE Values and Principles framework. Five adults with CP were consulted throughout the doctoral research programme. The data for this paper is a combination of reflection notes, email exchanges, meeting minutes and informal discussions with the PPI team on their experiences of being involved in the PPI process. The content of this paper is informed by GRIPP 2 checklist. Results: The doctoral researcher and adult reflections highlighted the value of collaboration and the positive impact on research at each stage of the doctoral research process. Although meetings were adapted due to the pandemic, the values of PPI were adhered to throughout the doctoral research. Conclusion: Involving adults with CP positively impacted the doctoral research process. It is recommended to consider individual access needs to ensure meetings and information are accessible for disabled adults. Our reflective findings and recommendations may help other researchers who plan to involve adults with CP in doctoral research.

Interventions for social isolation in older adults who have experienced a fall: a systematic review.

OBJECTIVES: The objective of our systematic review was to identify the effective interventions to prevent or mitigate social isolation and/or loneliness in older adults who experienced a fall. DESIGN: Systematic review. DATA SOURCES: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Ageline were searched (from inception to February 2020). METHODS: Studies were eligible if they described any intervention for social isolation in older adults living in a community setting who experienced a fall, and reported outcomes related to social isolation or loneliness.Two independent reviewers screened citations, abstracted data and appraised risk of bias using the Cochrane risk of bias tool. The results were summarised descriptively. RESULTS: After screening 4069 citations and 55 full-text articles, four studies were included. The four studies varied in study design, including a randomised controlled trial, non-randomised controlled trial, an uncontrolled before-after study and a quasiexperimental study. Interventions varied widely, and included singing in a choir, a patient-centred, interprofessional primary care team-based approach, a multifactorial assessment targeting fall risk, appropriate medication use, loneliness and frailty, and a community-based care model that included comprehensive assessments and multilevel care coordination. Outcome measures varied and included scales for loneliness, social isolation, social interaction, social networks and social satisfaction. Mixed results were found, with three studies reporting no differences in social isolation or loneliness after the intervention. Only the multifactorial assessment intervention demonstrated a small positive effect on loneliness compared with the control group after adjustment (B=-0.18, 95% CI -0.35 to -0.02). CONCLUSIONS: Few studies examined the interventions for social isolation or loneliness in older adults who experienced a fall. More research is warranted in this area. PROSPERO REGISTRATION NUMBER: CRD42020198487.

Global evidence on falls and subsequent social isolation in older adults: a scoping review.

BACKGROUND: Falls are a leading cause of injury-related hospitalizations among adults aged 65 years and older and may result in social isolation. OBJECTIVE: To summarise evidence on falls and subsequent social isolation and/or loneliness in older adults through a scoping review. ELIGIBILITY CRITERIA: Studies were eligible for inclusion if the population had a mean age of 60 years or older, they examined falls and subsequent social isolation, loneliness, fear of falling or risk factors and were primary studies (eg, experimental, quasi-experimental, observational and qualitative). SOURCES OF EVIDENCE: MEDLINE, CINAHL, Embase, Ageline and grey literature from inception until 11 January 2021. CHARTING METHODS: A screening and charting form was developed and pilot-tested. Subsequently, two reviewers screened citations and full-text articles, and charted the evidence. RESULTS: After screening 4993 citations and 304 full-text articles, 39 studies were included in this review. Participants had a history of falling (range: 11% to 100%). Most studies were conducted in Europe (44%) and North America (33%) and were of the cross-sectional study design (66.7%), in the community (79%). Studies utilised 15 different scales. Six studies examined risk factors for social isolation and activity restriction associated with fear of falling. Six studies reported mental health outcomes related to falls and subsequent social isolation. CONCLUSIONS: Consistency in outcome measurement is recommended, as multiple outcomes were used across the included studies. Further research is warranted in this area, given the ageing population and the importance of falls and social isolation to the health of older adults. SCOPING REVIEW REGISTRATION NUMBER: 10.17605/OSF.IO/2R8HM.

Co-designing resources to support the transition from child to adult health services for young people with cerebral palsy: A design thinking approach.

Introduction: Design thinking is a human-centred process that aims to identify the needs of end-users and iteratively develop solutions. Involving end-users in the development and design of solutions may enhance effectiveness by increasing focus on the needs of the target population. This paper describes the process of co-designing resources to support the transition from child-centred to adult-orientated health services using a design thinking approach. Methods: Five co-design workshops were conducted remotely with a young person advisory group and parent advisory group. A design thinking process guided by the Stanford D.School approach was used to understand the transition needs of young people and their parents and iteratively develop solutions to improve end-user experience. Results: Eight resource prototypes were generated: (1) designated transition coordinator, (2) digital stories of transition experience (3) written informational support (4) transition website, (5) transition checklists and worksheets (6) transition app, (7) transition programme or course and (8) educational programme for health professionals. Conclusion: Design thinking is a feasible approach to identify, characterise and prioritise resources collaboratively with end-user partners.

Akt-mediated transactivation of the S1P1 receptor in caveolin-enriched microdomains regulates endothelial barrier enhancement by oxidized phospholipids.

Endothelial cell (EC) barrier dysfunction results in increased vascular permeability, leading to increased mass transport across the vessel wall and leukocyte extravasation, the key mechanisms in pathogenesis of tissue inflammation and edema. We have previously demonstrated that OxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine) significantly enhances vascular endothelial barrier properties in vitro and in vivo and attenuates endothelial hyperpermeability induced by inflammatory and edemagenic agents via Rac and Cdc42 GTPase dependent mechanisms. These findings suggested potential important therapeutic value of barrier-protective oxidized phospholipids. In this study, we examined involvement of signaling complexes associated with caveolin-enriched microdomains (CEMs) in barrier-protective responses of human pulmonary ECs to OxPAPC. Immunoblotting from OxPAPC-treated ECs revealed OxPAPC-mediated rapid recruitment (5 minutes) to CEMs of the sphingosine 1-phosphate receptor (S1P(1)), the serine/threonine kinase Akt, and the Rac1 guanine nucleotide exchange factor Tiam1 and phosphorylation of caveolin-1, indicative of signaling activation in CEMs. Abolishing CEM formation (methyl-beta-cyclodextrin) blocked OxPAPC-mediated Rac1 activation, cytoskeletal reorganization, and EC barrier enhancement. Silencing (small interfering RNA) Akt expression blocked OxPAPC-mediated S1P(1) activation (threonine phosphorylation), whereas silencing S1P(1) receptor expression blocked OxPAPC-mediated Tiam1 recruitment to CEMs, Rac1 activation, and EC barrier enhancement. To confirm our in vitro results in an in vivo murine model of acute lung injury with pulmonary vascular hyperpermeability, we observed that selective lung silencing of caveolin-1 or S1P(1) receptor expression blocked OxPAPC-mediated protection from ventilator-induced lung injury. Taken together, these results suggest Akt-dependent transactivation of S1P(1) within CEMs is important for OxPAPC-mediated cortical actin rearrangement and EC barrier protection.

Polyethylenimine-conjugated gold nanoparticles: Gene transfer potential and low toxicity in the cornea.

This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles (PEI2-GNPs) in the human cornea in vitro and rabbit cornea in vivo. PEI2-GNPs with nitrogen-to-phosphorus ratios of up to 180 exhibited significant transgene delivery in the human cornea without altering the viability or phenotype of these cells. Similarly, PEI2-GNPs applied to corneal tissues collected after 12 hours, 72 hours, or 7 days exhibited appreciable gold uptake throughout the rabbit stroma with gradual clearance of GNPs over time. Transmission electron microscopy detected GNPs in the keratocytes and the extracellular matrix of the rabbit corneas. Additionally, slit-lamp biomicroscopy in live animals even 7 days after topical PEI2-GNP application to the cornea detected no inflammation, redness, or edema in rabbit eyes in vivo, with only moderate cell death and immune reactions. These results suggest that PEI2-GNPs are safe for the cornea and can potentially be useful for corneal gene therapy in vivo. FROM THE CLINICAL EDITOR: This study examined the gene transfer efficiency and toxicity of 2-kDa polyethylenimine conjugated to gold nanoparticles in the human cornea in vitro and rabbit cornea in vivo. The results suggest that PEI2-GNPs are safe for the cornea and can potentially be useful for corneal gene therapy in vivo.