The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines.

Sequence variants or mutations in the GBA gene are numerically the most important risk factor for Parkinson disease (PD). The GBA gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase). GBA mutations often reduce GCase activity and lead to the impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most common GBA variants associated with PD, there is limited understanding of its biochemical effects. We have characterized homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause a significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444P GBA mutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines overexpressing GCase with either E326K or L444P protein. Despite no loss of the GCase activity, a significant increase in insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y overexpressing E326K demonstrated a significant increase in the lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to the common loss of function GBA mutations; however, lipid dyshomeostasis and alpha-synuclein pathology are still evident.

Experiences of Living With the Nonmotor Symptoms of Parkinson's Disease: A Photovoice Study.

BACKGROUND: Nonmotor symptoms (NMSs) are frequently experienced by people with Parkinson's disease (PD) and are often perceived as their most bothersome symptoms. However, these remain poorly understood with suboptimal clinical management. These unmet needs are an important determinant of health-related quality of life (QoL) in PD. OBJECTIVE: The aim of this study was to gain insights into the experience of living with the NMS of PD in real-time using participatory action methodology. METHOD: Using the photovoice method, 14 people with PD took photographs to document their experiences of living with the NMS of PD. They composed corresponding written narratives to capture the impact of NMS on their daily activities and QoL. In total, 152 photographs and corresponding narratives were analysed using thematic analysis with an inductive approach. RESULTS: Four interrelated themes were identified. Emotional well-being and sense of self encompassed a process of adjustment to living with PD. Engaging in valued activities, adopting a positive mindset and utilising coping strategies were thought to enhance confidence and self-esteem. Social support and societal awareness highlighted the importance of supportive relationships and socialising to aid participation and avoid isolation. Barriers to social engagement included the unpredictability of NMS and nonvisible NMS being neglected or misunderstood. CONCLUSION: Findings demonstrated the far-reaching impact of nonmotor aspects of PD on emotional, occupational and social dimensions. These needs could be addressed through person-centred and comprehensive approaches to care. PATIENT OR PUBLIC CONTRIBUTION: This study utilised a participatory research approach allowing participants to choose the subjects that mattered to them and how to present their results. Additionally, a group workshop was held with people with PD, their family members and healthcare professionals to guide theme development.

A systematic review of vestibular stimulation in post-stroke visual neglect.

Unilateral visual neglect is a condition that negatively impacts the lives of many stroke survivors. Studies have investigated different forms of vestibular stimulation as a potential therapy, but evidence is yet to be systematically reviewed. We therefore reviewed the effects of vestibular stimulation on outcomes of neglect and activities of daily living (ADL) for people with visual neglect. We searched relevant databases up until September 2022. Eligible articles included any form of vestibular stimulation, study design, or control condition. Included participants were 18 years or older, presenting with neglect following a haemorrhagic or ischaemic stroke. Relevant outcomes were clinically validated measures of neglect and ADL. Cochrane risk of bias tools were used to assess study quality. Meta-analyses and narrative methods were used to synthesize the data. Our search returned 17 relevant studies comprising 180 participants. Meta-analyses showed no difference between galvanic vestibular stimulation and sham conditions on outcomes, whereas caloric vestibular stimulation led to improvement compared to pre-stimulation scores. Narrative syntheses showed mixed results. Clinical and methodological heterogeneity was found both within and between studies. Overall, results were inconsistent regarding the effects of vestibular stimulation as a treatment for neglect. Further trials are warranted but require more careful methodological planning.

Impact and experiences of vestibular disorders and psychological distress: Qualitative findings from patients, family members and healthcare professionals.

INTRODUCTION: People with vestibular disorders frequently experience reduced quality of life and challenges with activities of daily living. Anxiety, depression and cognitive problems often co-present with vestibular disorders and can aggravate symptoms and prolong clinical recovery. We aimed to gain in-depth insights into the impact of vestibular disorders and the contribution of psychological factors by exploring multistakeholder perspectives. METHODS: Semistructured interviews were conducted between October 2021 and March 2022 with 47 participants in the United Kingdom including: 20 patients (age M = 50.45 ± 13.75; 15 females), nine family members (age M = 61.0 ± 14.10; four females), and 18 healthcare professionals. Data were analysed using framework analysis. RESULTS: Vestibular disorders impact diverse aspects of patients' lives including work, household chores, socialising, and relationships with family and friends. Being unable to engage in valued activities or fulfil social roles contributes to feelings of grief and frustration, affecting identity, confidence, and autonomy. Anxiety and low mood contribute to negative thought processes, avoidance, and social withdrawal, which can impede clinical recovery through reduced activity levels, and end engagement with treatment. Coping strategies were thought to help empower patients to self-manage their symptoms and regain a sense of control, but these require oversight from healthcare providers. CONCLUSIONS: Daily activity limitations, social participation restrictions, and psychological distress can interact to impact quality of life, sense of self, and clinical recovery amongst people with vestibular disorders. Information and resources could aid societal awareness of the impact of vestibular disorders and help patients and families feel understood. An individualised and comprehensive approach that concurrently addresses mental, physical, social, and occupational needs is likely to be beneficial. PATIENT OR PUBLIC CONTRIBUTION: Two group meetings were held at the beginning and end of the study with a patient and public involvement network formed of people with vestibular disorders and family members. These individuals commented on the study aims, interview schedule, participant recruitment practices, and interpretation of the themes identified. Two core patient members were involved at all stages of the research. These individuals contributed to the formulation of the interview schedule, development and application of the coding scheme, development and interpretation of themes, and preparation of the final manuscript.

A passive and objective measure of recognition memory in Alzheimer's disease using Fastball memory assessment.

Earlier diagnosis of Alzheimer's disease requires biomarkers sensitive to associated structural and functional changes. While considerable progress has been made in the development of structural biomarkers, functional biomarkers of early cognitive change, unconfounded by effort, practice and level of education, are still needed. We present Fastball, a new EEG method for the passive and objective measurement of recognition memory, that requires no behavioural memory response or comprehension of the task . Younger adults, older adults and Alzheimer's disease patients (n = 20 per group) completed the Fastball task, lasting just under 3 min. Participants passively viewed rapidly presented images and EEG assessed their automatic ability to differentiate between images based on previous exposure, i.e. old/new. Participants were not instructed to attend to previously seen images and provided no behavioural response. Following the Fastball task, participants completed a two-alternative forced choice (2AFC) task to measure their explicit behavioural recognition of previously seen stimuli. Fastball EEG detected significantly impaired recognition memory in Alzheimer's disease compared to healthy older adults (P < 0.001, Cohen's d = 1.52), whereas behavioural recognition was not significantly different between Alzheimer's disease and healthy older adults. Alzheimer's disease patients could be discriminated with high accuracy from healthy older adult controls using the Fastball measure of recognition memory (AUC = 0.86, P < 0.001), whereas discrimination performance was poor using behavioural 2AFC accuracy (AUC = 0.63, P = 0.148). There were no significant effects of healthy ageing, with older and younger adult controls performing equivalently in both the Fastball task and behavioural 2AFC task. Early diagnosis of Alzheimer's disease offers potential for early treatment when quality of life and independence can be retained through disease modification and cognitive enhancement. Fastball provides an alternative way of testing recognition responses that holds promise as a functional marker of disease pathology in stages where behavioural performance deficits are not yet evident. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball provides a new powerful method for the assessment of cognition in dementia and opens a new door in the development of early diagnosis tools.

Priming with biocides: A pathway to antibiotic resistance?

AIMS: To investigate the priming effects of sub-inhibitory concentrations of biocides on antibiotic resistance in bacteria. METHODS AND RESULTS: Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus were exposed to sub-inhibitory concentrations of biocides via a gradient plate method. Minimum inhibitory concentration (MIC) and antibiotic susceptibility were determined, and efflux pump inhibitors (thioridazine and chlorpromazine) were used to investigate antibiotic resistance mechanism(s). Escherichia coli displayed a twofold increase in MIC (32-64 mg l-1 ) to H2 O2 which was stable after 15 passages, but lost after 6 weeks, and P. aeruginosa displayed a twofold increase in MIC (64-128 mg l-1 ) to BZK which was also stable for 15 passages. There were no other tolerances observed to biocides in E. coli, P. aeruginosa or S. aureus; however, stable cross-resistance to antibiotics was observed in the absence of a stable increased tolerance to biocides. Sixfold increases in MIC to cephalothin and fourfold to ceftriaxone and ampicillin were observed in hydrogen peroxide primed E. coli. Chlorhexidine primed S. aureus showed a fourfold increase in MIC to oxacillin, and glutaraldehyde-primed P. aeruginosa showed fourfold (sulphatriad) and eightfold (ciprofloxacin) increases in MIC. Thioridazine increased the susceptibility of E. coli to cephalothin and cefoxitin by fourfold and twofold, respectively, and both thioridazine and chlorpromazine increased the susceptibility S. aureus to oxacillin by eightfold and fourfold, respectively. CONCLUSIONS: These findings demonstrate that sub-inhibitory concentrations of biocides can prime bacteria to become resistant to antibiotics even in the absence of stable biocide tolerance and suggests activation of efflux mechanisms may be a contributory factor. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the effects of low-level exposure of biocides (priming) on antibiotic resistance even in the absence of obvious increased biocidal tolerance.

Stem cell-derived clade F AAVs mediate high-efficiency homologous recombination-based genome editing.

The precise correction of genetic mutations at the nucleotide level is an attractive permanent therapeutic strategy for human disease. However, despite significant progress, challenges to efficient and accurate genome editing persist. Here, we report a genome editing platform based upon a class of hematopoietic stem cell (HSC)-derived clade F adeno-associated virus (AAV), which does not require prior nuclease-mediated DNA breaks and functions exclusively through BRCA2-dependent homologous recombination. Genome editing is guided by complementary homology arms and is highly accurate and seamless, with no evidence of on-target mutations, including insertion/deletions or inclusion of AAV inverted terminal repeats. Efficient genome editing was demonstrated at different loci within the human genome, including a safe harbor locus, AAVS1, and the therapeutically relevant IL2RG gene, and at the murine Rosa26 locus. HSC-derived AAV vector (AAVHSC)-mediated genome editing was robust in primary human cells, including CD34+ cells, adult liver, hepatic endothelial cells, and myocytes. Importantly, high-efficiency gene editing was achieved in vivo upon a single i.v. injection of AAVHSC editing vectors in mice. Thus, clade F AAV-mediated genome editing represents a promising, highly efficient, precise, single-component approach that enables the development of therapeutic in vivo genome editing for the treatment of a multitude of human gene-based diseases.

A rapid, neural measure of implicit recognition memory using fast periodic visual stimulation.

Fast periodic visual stimulation (FPVS) has recently emerged as a powerful new tool in cognitive neuroscience. Capable of measuring a range of cognitive functions in single subjects in just minutes of recording time, it has been adapted to measure visual, semantic and linguistic processing. We present a new adaptation of the FPVS approach to measure recognition memory via old/new contrasts. Twenty one subjects (23 (±6) yrs, 7 males) completed an FPVS-oddball paradigm that assessed their spontaneous ability to differentiate between rapidly presented images on the basis of a pre-FPVS encoding task, i.e. oddball stimuli were only defined by the subject's experimentally induced memory of them. A clear oddball detection response reflecting recognition memory was observed within one minute of EEG recording time, simply through the passive viewing of stimuli, i.e. subjects received no task instructions and provided no behavioural response. Performance on a subsequent behavioural recognition task showed high levels of recognition of the oddball stimuli. As such, the FPVS approach returned an objective, non-verbal measure of recognition memory in just one minute of recording time, free from the confounds of behavioural recognition tasks. This finding reinforces the adaptability of the FPVS approach for the examination of higher-level cognition and provides a new method for the neural measurement of recognition memory.

From formulation to in vivo model: A comprehensive study of a synergistic relationship between vancomycin, carvacrol, and cuminaldehyde against Enterococcus faecium.

Vancomycin-resistant Enterococcus faecium (VRE) has become endemic in healthcare settings, reducing treatment options for enterococcal infections. New antimicrobials for VRE infections are a high priority, but the development of novel antibiotics is time-consuming and expensive. Essential oils (EOs) synergistically enhance the activity of some existing antibiotics, suggesting that EO-antibiotic combinations could resensitise resistant bacteria and maintain the antibiotic repertoire. The mechanism of resensitisation of bacteria to antibiotics by EOs is relatively understudied. Here, the synergistic interactions between carvacrol (1.98 mM) and cuminaldehyde (4.20 mM) were shown to reestablish susceptibility to vancomycin (0.031 mg/L) in VRE, resulting in bactericidal activity (4.73 log10 CFU/ml reduction). Gene expression profiling, coupled with ß-galactosidase leakage and salt tolerance assays, suggested that cell envelope damage contributes to the synergistic bactericidal effect against VRE. The EO-vancomycin combination was also shown to kill clinical isolates of VRE (2.33-5.25 log10 CFU/ml reduction), and stable resistance did not appear to develop even after multiple passages. The in vivo efficacy of the EO-vancomycin combination was tested in a Galleria mellonella larvae assay; however, no antimicrobial action was observed, indicating that further drug development is required for the EO-vancomycin combination to be clinically useful for treatment of VRE infections.

Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence.

Mycobacterium tuberculosis (MTb) is the causative agent of pulmonary tuberculosis (TB). MTb colonizes the human lung, often entering a non-replicating state before progressing to life-threatening active infections. Transcriptional reprogramming is essential for TB pathogenesis. In vitro, Cmr (a member of the CRP/FNR super-family of transcription regulators) bound at a single DNA site to act as a dual regulator of cmr transcription and an activator of the divergent rv1676 gene. Transcriptional profiling and DNA-binding assays suggested that Cmr directly represses dosR expression. The DosR regulon is thought to be involved in establishing latent tuberculosis infections in response to hypoxia and nitric oxide. Accordingly, DNA-binding by Cmr was severely impaired by nitrosation. A cmr mutant was better able to survive a nitrosative stress challenge but was attenuated in a mouse aerosol infection model. The complemented mutant exhibited a ∼2-fold increase in cmr expression, which led to increased sensitivity to nitrosative stress. This, and the inability to restore wild-type behaviour in the infection model, suggests that precise regulation of the cmr locus, which is associated with Region of Difference 150 in hypervirulent Beijing strains of Mtb, is important for TB pathogenesis.

Literacy-Adapted Cognitive Behavioral Therapy Versus Education for Chronic Pain at Low-Income Clinics: A Randomized Controlled Trial.

Background: Chronic pain is common and challenging to treat. Although cognitive behavioral therapy (CBT) is efficacious, its benefit in disadvantaged populations is largely unknown. Objective: To evaluate the efficacy of literacy-adapted and simplified group CBT versus group pain education (EDU) versus usual care. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01967342). Setting: Community health centers serving low-income patients in Alabama. Patients: Adults (aged 19 to 71 years) with mixed chronic pain. Interventions: CBT and EDU delivered in 10 weekly 90-minute group sessions. Measurements: Self-reported, postintervention pain intensity (primary outcome) and physical function and depression (secondary outcomes). Results: 290 participants were enrolled (70.7% of whom were women, 66.9% minority group members, 72.4% at or below the poverty level, and 35.8% reading below the fifth grade level); 241 (83.1%) participated in posttreatment assessments. Linear mixed models included all randomly assigned participants. Members of the CBT and EDU groups had larger decreases in pain intensity scores between baseline and posttreatment than participants receiving usual care (estimated differences in change scores-CBT: -0.80 [95% CI -1.48 to -0.11]; P = 0.022; EDU: -0.57 [CI, -1.04 to -0.10]; P = 0.018). At 6-month follow-up, treatment gains were not maintained in the CBT group but were still present in the EDU group. With regard to physical function, participants in the CBT and EDU interventions had greater posttreatment improvement than those receiving usual care, and this progress was maintained at 6-month follow-up. Changes in depression (secondary outcome) did not differ between either the CBT or EDU group and the usual care group. Limitations: Participants represented a single health care system. Self-selection bias may have been present. Conclusion: Simplified group CBT and EDU interventions delivered at low-income clinics significantly improved pain and physical function compared with usual care. Primary Funding Source: Patient-Centered Outcomes Research Institute.

Engineering Cellular Microenvironments with Photo- and Enzymatically Responsive Hydrogels: Toward Biomimetic 3D Cell Culture Models.

Conventional cell culture techniques using 2D polystyrene or glass have provided great insight into key biochemical mechanisms responsible for cellular events such as cell proliferation, differentiation, and cell-cell interactions. However, the physical and chemical properties of 2D culture in vitro are dramatically different than those found in the native cellular microenvironment in vivo. Cells grown on 2D substrates differ significantly from those grown in vivo, and this explains, in part, why many promising drug candidates discovered through in vitro drug screening assays fail when they are translated to in vivo animal or human models. To overcome this obstacle, 3D cell culture using biomimetic hydrogels has emerged as an alternative strategy to recapitulate native cell growth in vitro. Hydrogels, which are water-swollen polymers, can be synthetic or naturally derived. Many methods have been developed to control the physical and chemical properties of the hydrogels to match those found in specific tissues. Compared to 2D culture, cells cultured in 3D gels with the appropriate physicochemical cues can behave more like they naturally do in vivo. While conventional hydrogels involve modifications to the bulk material to mimic the static aspects of the cellular microenvironment, recent progress has focused on using more dynamic hydrogels, the chemical and physical properties of which can be altered with external stimuli to better mimic the dynamics of the native cellular microenvironment found in vivo. In this Account, we describe our progress in designing stimuli-responsive, optically transparent hydrogels that can be used as biomimetic extracellular matrices (ECMs) to study cell differentiation and migration in the context of modeling the nervous system and cancer. Specifically, we developed photosensitive agarose and hyaluronic acid hydrogels that are activated by single or two-photon irradiation for biomolecule immobilization at specific volumes within the 3D hydrogel. By controlling the spatial location of protein immobilization, we created 3D patterns and protein concentration gradients within these gels. We used the latter to study the effect of VEGF-165 concentration gradients on the interactions between endothelial cells and retinal stem cells. Hyaluronic acid (HA) is particularly compelling as it is naturally found in the ECM of many tissues and the tumor microenvironment. We used Diels-Alder click chemistry and cryogelation to alter the chemical and physical properties of these hydrogels. We also designed HA hydrogels to study the invasion of breast cancer cells. HA gels were chemically cross-linked with matrix metalloproteinase (MMP)-degradable peptides that degrade in the presence of cancer cell-secreted MMPs, thus allowing cells to remodel their local microenvironment and invade into HA/MMP-degradable gels.

Diels-Alder Click-Cross-Linked Hydrogels with Increased Reactivity Enable 3D Cell Encapsulation.

Engineered hydrogels have been extensively used to direct cell function in 3D cell culture models, which are more representative of the native cellular microenvironment than conventional 2D cell culture. Previously, hyaluronan-furan and bis-maleimide polyethylene glycol hydrogels were synthesized via Diels-Alder chemistry at acidic pH, which did not allow encapsulation of viable cells. In order to enable gelation at physiological pH, the reaction kinetics were accelerated by replacing the hyaluronan-furan with the more electron-rich hyaluronan-methylfuran. These new click-cross-linked hydrogels gel faster and at physiological pH, enabling encapsulation of viable cells, as demonstrated with 3D culture of 5 different cancer cell lines. The methylfuran accelerates Diels-Alder cycloaddition yet also increases the retro Diels-Alder reaction. Using computational analysis, we gain insight into the mechanism of the increased Diels-Alder reactivity and uncover that transition state geometry and an unexpected hydrogen-bonding interaction are important contributors to the observed rate enhancement. This cross-linking strategy serves as a platform for bioconjugation and hydrogel synthesis for use in 3D cell culture and tissue engineering.

Learning to live with Parkinson's disease in the family unit: an interpretative phenomenological analysis of well-being.

We investigated family members' lived experience of Parkinson's disease (PD) aiming to investigate opportunities for well-being. A lifeworld-led approach to healthcare was adopted. Interpretative phenomenological analysis was used to explore in-depth interviews with people living with PD and their partners. The analysis generated four themes: It's more than just an illness revealed the existential challenge of diagnosis; Like a bird with a broken wing emphasizing the need to adapt to increasing immobility through embodied agency; Being together with PD exploring the kinship within couples and belonging experienced through support groups; and Carpe diem! illuminated the significance of time and fractured future orientation created by diagnosis. Findings were interpreted using an existential-phenomenological theory of well-being. We highlighted how partners shared the impact of PD in their own ontological challenges. Further research with different types of families and in different situations is required to identify services required to facilitate the process of learning to live with PD. Care and support for the family unit needs to provide emotional support to manage threats to identity and agency alongside problem-solving for bodily changes. Adopting a lifeworld-led healthcare approach would increase opportunities for well-being within the PD illness journey.

Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria.

Mycobacterium smegmatis is a fast-growing, saprophytic, mycobacterial species that contains two cAMP-receptor protein (CRP) homologues designated herein as Crp1 and Crp2. Phylogenetic analysis suggests that Crp1 (Msmeg_0539) is uniquely present in fast-growing environmental mycobacteria, whereas Crp2 (Msmeg_6189) occurs in both fast- and slow-growing species. A crp1 mutant of M. smegmatis was readily obtained, but crp2 could not be deleted, suggesting it was essential for growth. A total of 239 genes were differentially regulated in response to crp1 deletion (loss of function), including genes coding for mycobacterial energy generation, solute transport and catabolism of carbon sources. To assess the role of Crp2 in M. smegmatis, the crp2 gene was overexpressed (gain of function) and transcriptional profiling studies revealed that 58 genes were differentially regulated. Identification of the CRP promoter consensus in M. smegmatis showed that both Crp1 and Crp2 recognized the same consensus sequence (TGTGN8CACA). Comparison of the Crp1- and Crp2-regulated genes revealed distinct but overlapping regulons with 11 genes in common, including those of the succinate dehydrogenase operon (MSMEG_0417-0420, sdh1). Expression of the sdh1 operon was negatively regulated by Crp1 and positively regulated by Crp2. Electrophoretic mobility shift assays with purified Crp1 and Crp2 demonstrated that Crp1 binding to the sdh1 promoter was cAMP-independent whereas Crp2 binding was cAMP-dependent. These data suggest that Crp1 and Crp2 respond to distinct signalling pathways in M. smegmatis to coordinate gene expression in response to carbon and energy supply.

Gene transfer properties and structural modeling of human stem cell-derived AAV.

Adeno-associated virus (AAV) vectors are proving to be remarkably successful for in vivo gene delivery. Based upon reports of abundant AAV in the human marrow, we tested CD34(+) hematopoietic stem cells for the presence of natural AAV. Here, we report for the first time, the presence of novel AAV variants in healthy CD34(+) human peripheral blood stem cells. The majority of healthy peripheral blood stem cell donors were found to harbor AAV in their CD34(+) cells. Every AAV isolated from CD34(+) cells mapped to AAV Clade F. Gene transfer vectors derived from these novel AAVs efficiently underwent entry and postentry processing in human cord blood stem cells and supported stable gene transfer into long-term, in vivo engrafting human HSCs significantly better than other serotypes. AAVHSC-transduced human CD34(+) cells engrafted in vivo and gave rise to differentiated transgene-expressing progeny. Importantly, gene-marked CD34(+) stem cells persisted long term in xenograft recipients, indicating transduction of primitive progenitors. Notably, correlation of structure with function permitted identification of potential capsid components important for HSC transduction. Thus, AAVHSCs represent a new class of genetic vectors for the manipulation of HSC genomes.

Cognition in vestibular disorders: state of the field, challenges, and priorities for the future.

Vestibular disorders are prevalent and debilitating conditions of the inner ear and brain which affect balance, coordination, and the integration of multisensory inputs. A growing body of research has linked vestibular disorders to cognitive problems, most notably attention, visuospatial perception, spatial memory, and executive function. However, the mechanistic bases of these cognitive sequelae remain poorly defined, and there is a gap between our theoretical understanding of vestibular cognitive dysfunction, and how best to identify and manage this within clinical practice. This article takes stock of these shortcomings and provides recommendations and priorities for healthcare professionals who assess and treat vestibular disorders, and for researchers developing cognitive models and rehabilitation interventions. We highlight the importance of multidisciplinary collaboration for developing and evaluating clinically relevant theoretical models of vestibular cognition, to advance research and treatment.

Framework for an interprofessional experience addressing health and disability for health professional students.

BACKGROUND AND PURPOSE: A Health and Disabilities Interprofessional Education (IPE) course was implemented to join three healthcare disciplines together to collaboratively plan, implement, and reflect on professional roles and responsibilities. The goal and purpose of this course was to create an advancement of interprofessional education and practice within health science professions early in their students' programs utilizing innovative teaching methods working directly with individuals with disabilities. EDUCATIONAL ACTIVITY AND SETTING: 72 students were assigned to interprofessional teams of 10-11 people. Through asynchronous and synchronous learning activities, student teams worked together to plan and conduct community-based client interviews. FINDINGS: Quantitative and qualitative evaluation methods were used to explore the impact of interprofessional experiential learning experiences. Qualitative data showed a greater awareness and understanding of the different roles and responsibilities in interprofessional teams as well as a greater appreciation for the value of interacting with persons with disabilities (PWD) during their training. Quantitative data showed a significant change in students' understanding of their roles and responsibilities as a member of an interprofessional team, their confidence with working with PWD in a future healthcare capacity, as well as their understanding of how the social determinants of health may influence the healthcare experience of a PWD. SUMMARY: Interprofessional education and experiential learning opportunities are good ways to facilitate "real" patient care experiences and team roles and responsibilities. This enables healthcare students to practice communication, build relationships, and understand the lived experience of their patients.

Experiential Interprofessional Education Rooted in the Social Determinants of Health and Ecological Model Fosters Interprofessional Socialization.

OBJECTIVE: Experiential interprofessional education (IPE) fostering socialization to interprofessional teams is essential to clinical practice. Inclusion of authentic patient voices cultivates an understanding of social factors that patients face. We qualitatively assessed how experiential IPE framed around social determinants of health (SDH) and socioecological model (SEM) influenced early health profession students' development of interprofessional socialization while working with patients. Secondarily, we explored how students shifted their mindsets for future interactions. METHODS: Fifty-one health profession students participated in the Longitudinal Interprofessional Family-based Experience (LIFE), a virtual, 13-week experiential IPE opportunity during which students interacted with patients living with chronic illnesses through two interviews. Prompts representing aspects of working on an interprofessional team while interacting with a patient framed around social factors affecting healthcare were coded using the constant comparative method of analysis. Themes were derived and tallied for frequencies. RESULTS: Themes from prompt related to working with an interprofessional team included: 1) perspectives, 2) informative, and 3) collaboration. Themes related to patients as a team member included: 1) active listening, 2) patients of similar/dissimilar back¬grounds, 3) person-centered care, and 4) awareness. Themes derived from prompt about future collaborations included: 1) collaboration, 2) awareness, and 3) person-centered care. CONCLUSIONS: This SDH-focused experiential IPE advanced the understanding among early learners of how social factors that patients experience are barriers to how care is delivered and interprofessional teams must collaborate to consider factors to support patients.

Working Memory Impairment in Transient Ischaemic Attack: N-back as a Sensitive Measure for Detection.

BACKGROUND: Transient ischaemic attack (TIA) can lead to lasting changes in brain structure and function resulting in cognitive impairment. Cognitive screening tools may lack sensitivity for detecting cognitive impairments, particularly executive function, which tends to be the earliest affected domain in vascular cognitive impairment. AIM: In this preliminary study, we examine a working memory (WMem) task as a sensitive measure of cognitive impairment in TIA. METHOD: Patients referred to a TIA clinic for transient neurological symptoms completed a general cognitive screening tool (Montreal Cognitive Assessment; MoCA), and a WMem task (2-N-back) in a cross-sectional design. RESULTS: TIA patients (n = 12) showed significantly reduced WMem performance on the N-back compared to patients diagnosed with mimic clinical conditions with overlapping symptoms (n = 16). No group differences were observed on the MoCA. CONCLUSIONS: Assessing WMem may provide a sensitive measure of cognitive impairment after TIA, with implications for cognitive screening in TIA services to triage patients for further neuropsychological support, or for interventions to prevent vascular dementia.