Factors associated with self-awareness impairment in an inpatient brain injury rehabilitation cohort.

BACKGROUND: Self-awareness impairment is common following acquired brain injury and can impact rehabilitation outcomes. Knowledge of factors associated with impaired self-awareness may assist with rehabilitation planning. OBJECTIVES: To identify factors associated with self-awareness and determine predictors of self-awareness impairment for adults with traumatic brain injury (TBI) and stroke. DESIGN AND METHODS: A retrospective cohort study of rehabilitation inpatients was conducted by medical record audit. Self-awareness was measured using the Self-awareness of Deficits Interview (SADI). Relationships between SADI scores and demographic and clinical variables were identified with non-parametric statistics. Predictors of SADI scores were identified using ordinal regression analyses for TBI and stroke groups. RESULTS: Participants were 149 adults (18-70 years) with TBI (n = 110) and stroke (n = 39). For TBI, longer post-traumatic amnesia (PTA), lower functional cognition/communication, and behaviors of concern (BoC) were significantly associated with higher SADI scores (i.e. impaired self-awareness). For stroke, lower functional cognition/communication and motor scores were associated with higher SADI scores. Impaired self-awareness was predicted by PTA duration, acute length of stay and presence of BoC for the TBI group, and by functional cognition/communication for the stroke group. CONCLUSION: Different factors were associated with impaired self-awareness for individuals with TBI and stroke during inpatient rehabilitation.

Capacity building for providers of cognitive rehabilitation in Queensland: a needs analysis survey.

Background Cognitive rehabilitation of people with traumatic brain injury is a complex and challenging area of practice. Practitioners working in cognitive rehabilitation require ongoing training to stay abreast of new research and best practice interventions. A needs analysis was conducted to inform the development of a capacity building program for cognitive rehabilitation providers. Methods A cross-sectional online survey of providers of cognitive rehabilitation services in Queensland collected data on demographic information, perceptions of knowledge, skills and confidence in cognitive rehabilitation, previously completed training, desired training opportunities and delivery methods, and barriers and facilitators to engaging in training. Results The 103 respondents included 67 occupational therapists, 17 speech pathologists, 12 psychologists and seven social workers with a broad range of practice experience. Participants perceived a need for further training, with executive function and functional cognition the most desired topics. The number of topics previously trained on was significantly correlated with levels of knowledge, skills and confidence (P Conclusion Cognitive rehabilitation providers in Queensland reported a need for further training, delivered flexibly, with a focus on managing complex cognitive impairments.

Online awareness: a concept analysis and review of assessment approaches for adults with neurological conditions.

PURPOSE: Self-awareness is a multifaceted phenomenon that comprises two main concepts: general awareness and online awareness. The latter is an emerging concept that requires further consensus on its definition. The aim of this paper is to define the key components of online awareness and identify approaches for measuring this concept for adults with neurological conditions. MATERIALS AND METHODS: Concept analysis using Rodgers' evolutionary method was used to systematically review and summarise relevant literature. Papers were included if they provided a definition of online awareness or method for assessing online awareness for an adult neurological population. RESULTS: Fifty-six papers were included in this review, with 21 online awareness assessment approaches identified. Online awareness was described to occur within the context of task performance, with the definition framework comprising four main aspects: 1/appraisal; 2/anticipation and prediction; 3/monitoring; and 4/self-evaluation. Self-regulation is a related concept that is considered to sit outside the conceptual boundaries of online awareness. CONCLUSIONS: The findings of this analysis highlight the complexity of online awareness and its importance in rehabilitation. Psychometrically robust measures of online awareness that are inclusive of the essential elements of this concept are needed to advance practice in this area.

Online awareness or awareness of performance within the context of an activity should be included in the comprehensive assessment of self-awareness for individuals with neurological conditions.Online awareness is a task-specific phenomenon that is activated in the context of task performance, and requires assessment across a range of tasks and environments.When assessing online awareness, careful consideration is required when selecting tasks to ensure they have the right level of challenge to elicit the need to monitor performance.The heterogeneity of existing online awareness assessments highlights the need to interpret outcomes with caution.Future efforts should be directed towards development of an online awareness assessment that includes key attributes of this concept.

The underappreciated diversity of bile acid modifications.

The repertoire of modifications to bile acids and related steroidal lipids by host and microbial metabolism remains incompletely characterized. To address this knowledge gap, we created a reusable resource of tandem mass spectrometry (MS/MS) spectra by filtering 1.2 billion publicly available MS/MS spectra for bile-acid-selective ion patterns. Thousands of modifications are distributed throughout animal and human bodies as well as microbial cultures. We employed this MS/MS library to identify polyamine bile amidates, prevalent in carnivores. They are present in humans, and their levels alter with a diet change from a Mediterranean to a typical American diet. This work highlights the existence of many more bile acid modifications than previously recognized and the value of leveraging public large-scale untargeted metabolomics data to discover metabolites. The availability of a modification-centric bile acid MS/MS library will inform future studies investigating bile acid roles in health and disease.

Canine-Assisted Occupational Therapy for Children within a Student-Led University Clinic: The Influence on Child Engagement from the Perspectives of Student and Parent Participants.

AIMS: Animal-assisted therapy has gained increased attention in occupational therapy. Yet there remains minimal education opportunities available. In addition to supporting student learning, student-led clinics have the potential to provide a valuable, cost-effective health service to the community. This study aimed to explore the potential benefits to the children clients participating in a student-led, canine-assisted occupational therapy pediatric clinic from the perspectives of the students and parents. METHOD: Semi-structured interviews were conducted with nine occupational therapy students, and five parents to describe their experience. Transcripts were analyzed using inductive thematic analysis. RESULTS: Participants emphasized how the presence of the therapy dog supported child engagement within the therapy session. Ways in which participants believed the therapy dog influenced the children's engagement were described within three themes. The first highlighted the importance of the relationship between the children and the therapy dog. The second described how this relationship facilitated a sense of safety within the sessions. The third captured how this sense of safety supported the children's participation within their meaningful occupations. CONCLUSIONS: Parents and students involved in the canine-assisted occupational therapy clinic perceived that canine-assisted therapy was supportive of child engagement in therapy.

Further investigations into performance variance on the Multiple Errands Test.

INTRODUCTION: The Multiple Errands Test (MET) is a complex, performance-based assessment that is useful for characterising the impact of impairments of executive function on everyday activities. However, performance variance amongst those without neurological pathology, and the impact of non-cognitive factors on this, requires further investigation. METHODS: This was a cross-sectional analytic study, conducted with a convenience sample of 40 neurologically intact community-dwelling Australian adults. Participants completed a hospital or shopping centre version of the MET, where their Performance Efficiency, Task Completions and Rule Breaks were recorded. Non-cognitive factors of interest were demographic (age, sex and education), psychological (measured with the Hospital Anxiety and Depression Scale and self-ratings of test anxiety) and assessment-related (assessment site, self-reported site familiarity and observed strategy use). MET performance was analysed using descriptive statistics. A series of standard multiple and binary logistic regression analyses examined the relationships between MET performance and non-cognitive factors. RESULTS: Most participants (n = 35, 87.5%) completed at least 10 of the 12 prescribed tasks and broke an average of four rules (SD = 2.36). They achieved an average performance efficiency rating of 0.75/1 (SD = 0.15), suggesting variability in the extent to which participants made non-essential location stops and/or failed to complete tasks whilst at an essential location. The assessment site and participant site familiarity had a statistically significant (p < 0.05) impact on Performance Efficiency and Task Completion scores, and psychological factors had a statistically significant (p < 0.05) relationship with Rule Breaks. CONCLUSION: Findings suggest that the impact of factors other than cognition should be considered when interpreting MET performance. The assessment site and participant site familiarity may contribute to significant variability in Performance Efficiency scores. Clinicians should also be aware of the potential impact of these assessment-related factors on Task Completions and psychological distress on Rule Breaks.

Development of the Japanese version of the awareness questionnaire for assessment of self-awareness after acquired brain injury: reliability and validity.

BACKGROUND: The evaluation of impaired self-awareness (ISA) after brain injury is not widespread in Japan, and there is a lack of Japanese assessments of self-awareness. OBJECTIVES: To translate the original version of the Awareness Questionnaire (AQ), an instrument for assessing ISA, into Japanese using a validated method and examine its reliability and validity in inpatients with stroke. METHODS: This cross-sectional, prospective study enrolled 130 participants. The double-translation process was used to develop the Japanese version of the AQ. RESULTS: Data were collected from 120 patients. High intra-rater reliability was observed for the patient (Cronbach's α = 0.824) and clinician samples (Cronbach's α = 0.933). High intra- and inter-rater reliability were found for all AQ items [interclass coefficient (ICC) (1, 1) = 0.828, ICC (2, 1) = 0.852, ICC (3, 1) = 0.848]; however, the sub-item analysis revealed only moderate reliability. Validity assessment revealed a low but significant positive correlation (r = 0.209; p < 0.05) between the Japanese version of the AQ and the Japanese version of the Self-Regulation Skills Interview and a low but significant negative correlation (r = 0.197; p < 0.05) between the Japanese version of the AQ and the Mini-Mental State Examination. CONCLUSIONS: The Japanese version of the AQ was developed and applied to stroke patients, but the concept of post-stroke ISA may differ from ISA after traumatic brain injury, highlighting the need for a stroke-specific version of the AQ.

The perspectives of participants with traumatic brain injury on prospective memory rehabilitation incorporating compensatory and metacognitive skills training.

OBJECTIVE: Patient feedback is rarely gathered systematically in cognitive rehabilitation research. This study examined the perceptions and experiences of people with traumatic brain injury (TBI) who participated in a trial of a 6-session educational program for the rehabilitation of prospective memory (PM) impairment. METHODS: A mixed methods design was used with 47 participants with TBI who completed a compensatory strategy training program (COMP) or COMP plus metacognitive strategy training program (COMP-MST) delivered by an occupational therapist. Data were collected via a participant survey, extracts from progress notes, and audiotaped discussions about learnings from the program during the final session. RESULTS: Participants from both programs were highly satisfied and perceived improvements in everyday PM performance post-intervention. Elements that were highly valued include setting individualised client-centred goals, repetitive training of strategy use, establishing habits and routines, and receiving experiential, verbal, and written feedback.Changes including more therapy sessions were recommended. CONCLUSIONS: Both the COMP and COMP-MST programs were perceived as effective by participants with TBI in improving their PM performance in everyday life using compensatory strategies such as assistive technology. PRACTICE IMPLICATIONS: Routine collection of patient feedback on cognitive rehabilitation can provide valuable information to support person-centred implementation of clinical practice guidelines.

Profiling self-awareness in brain injury rehabilitation: A mixed methods study.

ABSTRACTImpaired self-awareness impacts outcomes for individuals with brain injury. Self-awareness is a complex construct, with little known about how its presentation differs across diagnostic groups, or how brain injury-related changes are expressed by individuals in the early phase post-brain injury. This study aims to identify differences and similarities in patterns of self-awareness between patients with different brain injury diagnoses, and provide a clinical account of how individuals with ABI describe changes to themselves arising from brain injury. This is a mixed methods retrospective cohort study involving an audit of medical files that included extraction of data from the Self-Awareness of Deficits Interview. Quantitative and qualitative techniques were used to analyse data from 173 participants. Individuals identified a range of brain injury-related impairments across domains, with greatest difficulty noted with linking impairments to functional implications and setting realistic goals. There were similarities and distinct differences in the expression of changes across diagnostic groups. Two main themes that aligned with self-awareness theory were identified from the data: 1/ Development of self-awareness; and 2/ Dimensions of self-awareness. These interrelated themes demonstrated the multifaceted nature of the clinical presentation of self-awareness, and highlight the need for an individualized approach to cognitive rehabilitation.

Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death.

The nuclear receptor liver receptor homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role in liver cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis and inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen receptor alpha and elevated nuclear factor κB (NF-κB) activity, while LRH-1 overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction of LRH-1's ligand-binding domain and the Rel homology domain of NF-κB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-κB target genes and the proteasomal degradation of pro-apoptotic BCL-2 interacting mediator of cell death prevent mitochondrial apoptosis and ultimately protect mice from TNF-induced liver damage. Collectively, our study emphasizes LRH-1 as a critical, sex-dependent regulator of cell death and inflammation in the healthy and diseased liver.

Efficacy of Early Enhanced Occupational Therapy in an Intensive Care Unit (EFFORT-ICU): A Single-Site Feasibility Trial.

IMPORTANCE: This research trial contributes to the evidence for occupational therapy service delivery in intensive care settings. OBJECTIVE: To explore the feasibility of a trial to evaluate the impact of early enhanced occupational therapy on mechanically ventilated patients in intensive care. DESIGN: Single-site assessor-blinded randomized controlled feasibility trial. SETTING: Level 5 8-bed adult medical-surgical intensive care unit (ICU) at Logan Hospital, Brisbane, Australia. PARTICIPANTS: Participants were 30 mechanically ventilated patients randomly allocated to two groups. OUTCOMES AND MEASURES: We compared standard care with enhanced occupational therapy with outcomes measured at discharge from the ICU, hospital discharge, and 90 days post randomization. The primary outcome measure was the FIM®. Secondary outcomes included the Modified Barthel Index (MBI); Montreal Cognitive Assessment; grip strength, measured using a dynamometer; Hospital Anxiety and Depression Scale; and the 36-Item Short-Form Health Survey (Version 2). The intervention group received daily occupational therapy, including cognitive stimulation, upper limb retraining, and activities of daily living. Data were analyzed using independent groups t tests and effect sizes. RESULTS: Measures and procedures were feasible. A significant difference was found between groups on FIM Motor score at 90 days with a large effect size (p = .05, d = 0.76), and MBI scores for the intervention group approached significance (p = .051) with a large effect size (d = 0.75) at 90 days. Further moderate to large effect sizes were obtained for the intervention group for cognitive status, functional ability, and quality of life. CONCLUSIONS AND RELEVANCE: This trial demonstrated that occupational therapy is feasible and beneficial in the ICU. Criteria to progress to a full-scale randomized controlled trial were met. This study contributes to embedding ongoing consistency of practice and scope of service delivery for occupational therapy in this field. What This Article Adds: Occupational therapists should be considered core team members in the critical care-ICU, with funding to support ongoing service provision and optimization of patient outcomes based on effective and feasible service delivery.

AMP-dependent phosphite dehydrogenase, a phosphorylating enzyme in dissimilatory phosphite oxidation.

Oxidation of phosphite (HPO32-) to phosphate (HPO42-) releases electrons at a very low redox potential (E0'= -690 mV) which renders phosphite an excellent electron donor for microbial energy metabolism. To date, two pure cultures of strictly anaerobic bacteria have been isolated that run their energy metabolism on the basis of phosphite oxidation, the Gram-negative Desulfotignum phosphitoxidans (DSM 13687) and the Gram-positive Phosphitispora fastidiosa (DSM 112739). Here, we describe the key enzyme for dissimilatory phosphite oxidation in these bacteria. The enzyme catalyzed phosphite oxidation in the presence of adenosine monophosphate (AMP) to form adenosine diphosphate (ADP), with concomitant reduction of oxidized nicotinamide adenine dinucleotide (NAD+) to reduced nicotinamide adenine dinucleotide (NADH). The enzyme of P. fastidiosa was heterologously expressed in Escherichia coli. It has a molecular mass of 35.2 kDa and a high affinity for phosphite and NAD+. Its activity was enhanced more than 100-fold by addition of ADP-consuming adenylate kinase (myokinase) to a maximal activity between 30 and 80 mU x mg protein-1. A similar NAD-dependent enzyme oxidizing phosphite to phosphate with concomitant phosphorylation of AMP to ADP is found in D. phosphitoxidans, but this enzyme could not be heterologously expressed. Based on sequence analysis, these phosphite-oxidizing enzymes are related to nucleotide-diphosphate-sugar epimerases and indeed represent AMP-dependent phosphite dehydrogenases (ApdA). A reaction mechanism is proposed for this unusual type of substrate-level phosphorylation reaction.

"Be ready to learn": a qualitative study of the patient perspective of falls and fall prevention following discharge from a spinal injuries unit.

PURPOSE: Falls following a spinal cord injury (SCI) can have physical and psychological consequences, although some risk of falls may be acceptable to enable participation in meaningful activity. The study aimed to explore the patients' perspective of falls and fall prevention after discharge from a inpatient spinal injuries unit. METHODS: An interpretive descriptive approach guided the study. Semi structured interviews were conducted in the 6-12 months post discharge period. Thematic analysis was used to analyze the data and identify themes. RESULTS: Fifteen individuals with SCI, with a mean age of 57 years and varied fall experiences were included. Three themes were identified including: 1. Expectation of falling; 2. Learning from my own experience and the experience of others' and 3. How to prevent falls. Learning from their own experience and the experience of others was highly valued by persons with SCI and influenced expectations of falls. A variety of strategies were used to prevent falls. CONCLUSIONS: Strategies that include learning from others, include activities that are individual and provide skills in self-reflection may aid to make fall prevention meaningful.Implications for RehabilitationPatients want to learn from practical experience and the experience of others with spinal cord injury (SCI).Clinicians need to consider patients' readiness to receive education and could benefit from the inclusion of peers in the delivery of information/education provided.A shift of focus for clinicians providing fall prevention education to skills in risk assessment, self-reflection and ability to formulate fall management plans may be beneficial to patients with SCI.Patients appreciate demonstration of skills. Clinicians are encouraged to learn wheelchair skills when performing functional tasks and demonstrate them to add credibility to their fall prevention education.

Crystal structure of a GCN5-related N-acetyltransferase from Lactobacillus curiae.

Members of the GCN5-related N-acetyltransferase (GNAT) family are found in all domains of life and are involved in processes ranging from protein synthesis and gene expression to detoxification and virulence. Due to the variety of their macromolecular targets, GNATs are a highly diverse family of proteins. Currently, 3D structures of only a small number of GNAT representatives are available and thus the family remains poorly characterized. Here, the crystal structure of the guanidine riboswitch-associated GNAT from Lactobacillus curiae (LcGNAT) that acetylates canavanine, a structural analogue of arginine with antimetabolite properties, is reported. LcGNAT shares the conserved fold of the members of the GNAT superfamily, but does not contain an N-terminal ß0 strand and instead contains a C-terminal ß7 strand. Its P-loop, which coordinates the pyrophosphate moiety of the acetyl-coenzyme A cosubstrate, is degenerated. These features are shared with its closest homologues in the polyamine acetyltransferase subclass. Site-directed mutagenesis revealed a central role of the conserved residue Tyr142 in catalysis, as well as the semi-conserved Tyr97 and Glu92, suggesting that despite its individual substrate specificity LcGNAT performs the classical reaction mechanism of this family.

Titin UN2A Acts as a Stable, Non-Polymorphic Scaffold in its Binding to CARP.

The N2A segment of titin functions as a pivotal hub for signal transduction and interacts with various proteins involved in structural support, chaperone activities, and transcriptional regulation. Notably, the "unique N2A" (UN2A) subdomain has been shown to interact with the stress-regulated cardiac ankyrin repeat protein (CARP), which contributes to the regulation of sarcomeric stiffness. Previously, the UN2A domain's three-dimensional structure was modelled based on its secondary structure content identified by NMR spectroscopy, considering the domain in isolation. In this study, we report experimental long-range distance distributions by electron paramagnetic resonance (EPR) spectroscopy between the three helixes within the UN2A domain linked to the immunoglobulin domain I81 in the presence and absence of CARP. The data confirm the central three-helix bundle fold of UN2A and show that this adopts a compact and stable conformation in absence of CARP. After binding to CARP, no significant conformational change was observed, suggesting that the UN2A domain retains its structure upon binding to CARP thereby, mediating the interaction approximately as a rigid-body.

Clinical utility of a decision-making aid for upper limb neurorehabilitation: applying the Hypertonicity Intervention Planning Model across cultures.

BACKGROUND: The Hypertonicity Intervention Planning Model (HIPM) is a decision-making aid which guides clinical reasoning in individualizing upper limb (UL) neurorehabilitation. AIM: To examine the HIPM's clinical utility across cultures, using therapists' perceptions of its usefulness and challenges when applied in clinical practice. METHODS: Interpretive description methodology guided qualitative data collection and analysis because it produces clinically practical applications. Forty-four occupational therapists working in Australia or Singapore participated. Three group discussions were conducted using a modified nominal group technique. RESULTS: Three themes were: (1) The HIPM guides systematic clinical decision-making for assessment, goal-setting, and intervention; (2) Utility was influenced by systemic or organizational supports and barriers including availability of time, resources, and funding; organizational readiness to change; multidisciplinary and transorganizational collaboration; (3) Therapists' skills and confidence to apply the HIPM, and openness to changing practice, influenced utility. CONCLUSIONS: Therapists strongly support HIPM use for structuring and communicating clinical reasoning in UL neurorehabilitation. However, organizational support is key to optimizing clinical utility. Incorporating decision-making aids into documentation and referral processes may strengthen multidisciplinary and transorganizational teamwork, enhancing clinical use. Different training tiers to suit therapist experience levels, refresher courses, and supplementary resources may improve therapists' skills and confidence, thereby boosting utility.

Molecular insights into titin's A-band.

The thick filament-associated A-band region of titin is a highly repetitive component of the titin chain with important scaffolding properties that support thick filament assembly. It also has a demonstrated link to human disease. Despite its functional significance, it remains a largely uncharacterized part of the titin protein. Here, we have performed an analysis of sequence and structure conservation of A-band titin, with emphasis on poly-FnIII tandem components. Specifically, we have applied multi-dimensional sequence pairwise similarity analysis to FnIII domains and complemented this with the crystallographic elucidation of the 3D-structure of the FnIII-triplet A84-A86 from the fourth long super-repeat in the C-zone (C4). Structural models serve here as templates to map sequence conservation onto super-repeat C4, which we show is a prototypical representative of titin's C-zone. This templating identifies positionally conserved residue clusters in C super-repeats with the potential of mediating interactions to thick-filament components. Conservation localizes to two super-repeat positions: Ig domains in position 1 and FnIII domains in position 7. The analysis also allows conclusions to be drawn on the conserved architecture of titin's A-band, as well as revisiting and expanding the evolutionary model of titin's A-band.

PREdiction and Diagnosis using Imaging and Clinical biomarkers Trial in Traumatic Brain Injury (PREDICT-TBI) study protocol: an observational, prospective, multicentre cohort study for the prediction of outcome in moderate-to-severe TBI.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition with a broad spectrum of injury severity, pathophysiological processes and variable outcomes. For moderate-to-severe TBI survivors, recovery is often protracted and outcomes can range from total dependence to full recovery. Despite advances in medical treatment options, prognosis remains largely unchanged. The objective of this study is to develop a machine learning predictive model for neurological outcomes at 6 months in patients with a moderate-to-severe TBI, incorporating longitudinal clinical, multimodal neuroimaging and blood biomarker predictor variables. METHODS AND ANALYSIS: A prospective, observational, cohort study will enrol 300 patients with moderate-to-severe TBI from seven Australian hospitals over 3 years. Candidate predictors including demographic and general health variables, and longitudinal clinical, neuroimaging (CT and MRI), blood biomarker and patient-reported outcome measures will be collected at multiple time points within the acute phase of injury. The predictor variables will populate novel machine learning models to predict the Glasgow Outcome Scale Extended 6 months after injury. The study will also expand on current prognostic models by including novel blood biomarkers (circulating cell-free DNA), and the results of quantitative neuroimaging such as Quantitative Susceptibility Mapping and Dynamic Contrast Enhanced MRI as predictor variables. ETHICS AND DISSEMINATION: Ethical approval has been obtained by the Royal Brisbane and Women's Hospital Human Research Ethics Committee, Queensland. Participants or their substitute decision-maker/s will receive oral and written information about the study before providing written informed consent. Study findings will be disseminated by peer-review publications and presented at national and international conferences and clinical networks. TRIAL REGISTRATION NUMBER: ACTRN12620001360909.

Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

The Multiple Errands Test: A Guide for Site-Specific Version Development.

Background. The complex and real-world nature of the Multiple Errands Test (MET) makes it a valuable and increasingly popular assessment of cognitive function. However, these same qualities make its local implementation challenging. Purpose. To produce an evidence-based guide for site-specific adaptation of the MET. Method. The CAN-IMPLEMENT© knowledge translation framework informed a structured approach to the creation of a guide to site-specific version development, informed by twenty-two published approaches to MET adaptation. Applicability of the guide was supported by a two-phase revision process, in which a site-specific hospital and community version produced from its recommendations were administered with forty-two neurologically intact participants and stakeholder feedback obtained. Findings. We offer an outline of core components which maintain the integrity of the MET, and adaptable peripheries which may be modified when required by the local setting. Implications. The proposed guide provides a systematic yet flexible guide for site-specific MET development.