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Abstract Background Taping is a common treatment modality used by many rehabilitation providers. Several types of tapes and taping methods are used in the treatment of musculoskeletal dysfunction and pain. Purpose To summarize and map the evidence related to taping methods used for various joints and conditions of the musculoskeletal system, and to provide clinicians and researchers with a user-friendly reference with organized evidence tables. Data sources The PEDro, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register for Controlled Trials, PubMed, and PROSPERO databases were searched from inception through October 31, 2019. Study selection Eligible studies were selected by two independent reviewers and included either systematic reviews (SRs) or randomized controlled trials (RCTs) and included a musculoskeletal complaint using a clinical outcome measure. Data extraction Data was extracted by two investigators independently. Risk of bias and quality were assessed using A MeaSurement Tool to Assess systematic Reviews (AMSTAR) for SRs or the Physiotherapy Evidence Database (PEDro) scale for RCTs. The protocol was registered with PROSPERO (CRD42019122857). Data synthesis Twenty-five musculoskeletal conditions were summarized from forty-one SRs and 127 RCTs. There were 6 SRs and 49 RCTs for spinal conditions. Kinesio tape was the most common type of tape considered. Four evidence tables representing the synthesized SRs and RCTs were produced and organized by body region per condition. Limitations Inclusion of only English language studies. Also, the heterogeneous nature of the included studies prevented a meta-analysis. Conclusions There is mixed quality evidence of effectiveness for the different types of taping methods for different body regions and conditions. All of the SRs and RCTs found during our search of the taping literature have been organized into a series of appendices. A synthesis of the results have been placed in evidence tables that may serve as a useful guide to clinicians and researchers.

Background and Purpose: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes., Methods: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R 2 used to assess the goodness of fit of the model., Results: In total, 2647 ALS patients were included, with mean disease-onset age being 62.2 ± 12.1 years. A linear relationship between log incidence and log age was established across ALS phenotypes, with variable slope estimates: bulbar 5.1 (95% confidence interval [CI] 4.6-5.6); cervical 2.7 (95% CI 2.3-3.0); lumbar 3.5 (95% CI 3.2-3.9); flail arm 4.7 (95% CI 3.9-5.5); flail leg 3.6 (95% CI 2.6-4.5); primary lateral sclerosis 2.7 (95% CI 1.8-3.7). Slope estimates were significantly higher in the bulbar compared to the cervical, lumbar and primary lateral sclerosis phenotypes. McFadden's R 2 values were >0.4 for all phenotypes indicating excellent model fit., Discussion: A multistep process has been established across all ALS phenotypes with variable slope estimates, suggesting that the number of steps to develop disease is different across clinical presentations. Identification of mechanisms underlying slope estimate variability could exert pathophysiological significance., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Donor-derived cell-free DNA (dd-cfDNA) has been widely studied as biomarker for non-invasive allograft rejection monitoring. Earlier rejection detection enables more prompt diagnosis and intervention, ultimately improving patient treatment and outcomes. This multi-centre study aims to verify analytical performance of a next-generation sequencing-based dd-cfDNA assay at end-user environments. Three independent laboratories received the same experimental design and 16 blinded samples to perform cfDNA extraction and the dd-cfDNA assay workflow. dd-cfDNA results were compared between sites and against manufacturer validation to evaluate concordance, reproducibility, repeatability and verify analytical performance. A total of 247 sample libraries were generated across 18 runs, with completion time of <24 h. A 96.0% first pass rate highlighted minimal failures. Overall observed versus expected dd-cfDNA results demonstrated good concordance and a strong positive correlation with linear least squares regression r 2  = 0.9989, and high repeatability and reproducibility within and between sites, respectively (p > 0.05). Manufacturer validation established limit of blank 0.18%, limit of detection 0.23% and limit of quantification 0.23%, and results from independent sites verified those limits. Parallel analyses illustrated no significant difference (p = 0.951) between dd-cfDNA results with or without recipient genotype. The dd-cfDNA assay evaluated here has been verified as a reliable method for efficient, reproducible dd-cfDNA quantification in plasma from solid organ transplant recipients without requiring genotyping. Implementation of onsite dd-cfDNA testing at clinical laboratories could facilitate earlier detection of allograft injury, bearing great potential for patient care., (© 2024 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Background: Motor neurone disease is a rare but debilitating illness with incomplete evidence regarding patients' symptom burden. Palliative care and generalist clinicians are often in-experienced in caring for these patients and assessing their needs., Aim: To identify the symptom prevalence and severity experienced by patients with motor neurone disease. Secondary objectives were to examine differences in symptom burden and clusters according to phenotype, functional status, palliative care provision and those in their last months of life., Design: A point prevalence study assessing patient-reported symptoms using a modified IPOS-Neuro assessment tool, incorporating 41 symptom items., Setting/participants: Patients with motor neurone disease attending the State-wide Progressive Neurological Disease Service or inpatient unit at Calvary Health Care Bethlehem, Melbourne Australia, from March to December 2021., Results: A total of 102 patients participated, the majority diagnosed with lumber-onset (30.4%), bulbar-onset (28.4%) and cervical-onset (25.5%) phenotypes. Patients experienced a median of 17 symptoms (range 2-32) with a median of 3 symptoms rated as severe/overwhelming (range 0-13). Motor and functional symptoms predominated, with differences in symptom clusters present according to phenotype. Patients had a higher number of severe/overwhelming symptoms if they were accessing palliative care services ( p  = 0.005), in their last 6 months of life ( p  = 0.003) and experiencing moderate or severe functional impairment ( p  < 0.001)., Conclusions: Patients with motor neurone disease report high symptom burden. A validated motor neurone disease-specific symptom assessment tool is needed to accurately assess patients, including important variations in symptom clusters according to phenotype. Further research must focus on evidence-based treatment guidelines for symptoms experienced commonly and severely., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Motor neurone disease/amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no known cure, where death is usually secondary to progressive respiratory failure. Assisting people with ALS through their disease journey is complex and supported by clinics that provide comprehensive multidisciplinary care (MDC). This review aims to apply both a respiratory and a complexity lens to the key roles and areas of practice within the MDC model in ALS. Models of noninvasive ventilation care, and considerations in the provision of palliative therapy, respiratory support, and speech and language therapy are discussed. The impact on people living with ALS of both inequitable funding models and the complexity of clinical care decisions are illustrated using case vignettes. Considerations of the impact of emerging antisense and gene modifying therapies on MDC challenges are also highlighted. The review seeks to illustrate how MDC members contribute to collective decision-making in ALS, how the sum of the parts is greater than any individual care component or health professional, and that the MDC per se adds value to the person living with ALS. Through this approach we hope to support clinicians to navigate the space between what are minimum, guideline-driven, standards of care and what excellent, person-centred ALS care that fully embraces complexity could be., Educational Aims: To highlight the complexities surrounding respiratory care in ALS.To alert clinicians to the risk that complexity of ALS care may modify the effectiveness of any specific, evidence-based therapy for ALS.To describe the importance of person-centred care and shared decision-making in optimising care in ALS., Competing Interests: Conflict of interest: D.J. Berlowitz received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. D.J. Berlowitz has previously received competitive grant funding from Motor Neurone Disease Research Australia and the Medical Research Future Fund for unconnected work. S. Mathers received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. S. Mathers has previously received competitive grant funding from Motor Neurone Disease Research Australia, Fight MND and NHMRC for unconnected work. K. Hutchinson received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. A. Hogden received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. K.A. Carey received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. M. Graco received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. M. Graco has previously received competitive grant funding from Motor Neurone Disease Research Australia (MND Research Post-Doctoral Fellowship). B-M. Whelan received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. B-M. Whelan has previously received competitive grant funding from Motor Neurone Disease Research Australia for unconnected work (project grant funding). S. Charania received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. S. Charania has previously received a competitive scholarship from The Prince Charles Hospital for unconnected work (PhD funding in the area of Motor Neurone Disease). F. Steyn received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. F. Steyn has previously received competitive grant funding for unconnected work (project grant funding). This includes industry-funding for preclinical testing of compounds for the treatment of ALS. P. Allcroft received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. A. Crook received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. A. Crook has previously received competitive grant funding from Motor Neurone Disease Research Australia and the University of Technology Sydney for unconnected work (project funding and funding towards conference attendance). N.L. Sheers received no financial support for this work and reports no financial or personal conflicts of interest connected or unconnected with this work. N.L. Sheers has previously received competitive grant funding from Motor Neurone Disease Research Australia for unconnected work (project grant funding and funding towards conference attendance)., (Copyright ©ERS 2023.)

Background: Neuropalliative care is a newly-defined subspeciality bringing specific aspects of fields of neurology and palliative care together to better meet the complex care needs of people with progressive neurological diseases. Examining these needs would help provide guidance about developing relevant models of care and identify gaps in research knowledge., Aim: To identify current models and approaches to neuropalliative care for people with progressive neurological diseases and the priorities for future research work., Design: A scoping literature review following the methods described by the Joanna Briggs Institute., Data Sources: An electronic search of the literature was undertaken from six sources including MEDLINE (Ovid), EMCARE, PsycINFO and CINAHL covering the years January 2011 to September 2021., Results: Twenty-eight studies were found examining neuropalliative care from the perspectives of 4795 PND patients, 774 informal carers and 138 health professionals. All studies held themes of integrative care, with most studies employing outpatient models of multidisciplinary care. Topics discussed included: overcoming local system-issues, providing education for professionals, patients and carers, early referral and capturing outcome measures for quality-assurance and future research work., Conclusions: Most models of neuropalliative care described in the international literature are predominantly outpatient, multidisciplinary and integrative. Clinicians typically utilise existing neurology and palliative care infrastructure to provide care. More high-quality research and outcome tools are needed to guide the design of evidence-based palliative care for people with progressive neurological diseases.

Importance: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown., Objective: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought., Design, Setting, and Participants: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients' homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022., Interventions: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control., Main Outcomes and Measures: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control., Results: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI., Conclusions and Relevance: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis., Trial Registration: ClinicalTrials.gov Identifier: NCT03834857.

Introduction/aims: Rate of disease progression (ΔFS), measured as change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and body mass index (BMI), are predictors of survival in amyotrophic lateral sclerosis (ALS). Our aim in this study was to assess the utility of these clinical biomarkers along with neurophysiological measures, such as the split hand index (SI), in monitoring disease progression., Methods: Clinical trial data were collected from 107 patients recruited into the Tecfidera in ALS trial. The prognostic utility of clinical and neurophysiological measures, including ΔFS, BMI, SI, and neurophysiological index (NPI), were assessed cross-sectionally and longitudinally (40 weeks). The outcome measures of disease severity and progression included: (i) ALSFRS-R score; (ii) Medical Research Council (MRC) score; and (iii) forced vital capacity and sniff nasal inspiratory pressure., Results: Fast-progressor ALS patients (ΔFS ≥1.1) exhibited significantly lower ALSFRS-R and total MRC scores at baseline. A baseline ΔFS score ≥1.1 was associated with a greater reduction in ALSFRS-R (P = .002) and MRC (P = .002) scores over 40 weeks. Baseline BMI <25 was also associated with faster reduction of ALSFRS-R and MRC scores. SI and NPI were associated with disease severity at baseline, but not with subsequent rate of disease progression., Discussion: Implementation of the assessed clinical and neurophysiological biomarkers may assist in patient management and stratification into clinical trials., (© 2022 Wiley Periodicals LLC.)

Background: Communication and cognitive impairments are known barriers to shared decision-making. Most people diagnosed with motor neurone disease (MND) will develop a motor speech impairment over the disease course. Some will develop cognitive, linguistic or behavioural disturbance. Despite this, the impact of communication and cognitive impairment on personal healthcare decision-making in MND is not well known., Aims: This exploratory, longitudinal study aimed to capture the perspectives of people living with MND (plwMND) and family members on managing their healthcare with, or in anticipation of, a communication impairment., Methods & Procedures: Semi-structured interviews and functional assessments were conducted with plwMND and family members over one to three time points between December 2017 and January 2020. Participants were recruited from a specialist MND clinic using a maximum variation sampling approach. Interview transcripts were analysed using trajectory data analysis: a matrix-based approach for thematic analysis of longitudinal data. The study was underpinned by interpretive descriptive methodology., Outcomes & Results: A total of 19 plwMND with a range of MND phenotypes and 15 family members were recruited. Disease progression and participant withdrawal resulted in attrition, however 12 plwMND and seven family members participated at all three time points. Consistent cognitive screening was not feasible, which limited the opportunity to explore the impact of cognitive change. An overarching theme 'Communicating takes effort' was identified and illustrates the efforts required to compensate for, or circumnavigate, impairments to maintain involvement in healthcare. Assistance from family and accommodation from healthcare professionals (HCPs) was needed for ongoing engagement. Where plwMND were dependent on alternative communication devices, this assistance was essential and primarily carried out by family members. Despite these efforts, the quality, quantity and accuracy of communication were sometimes compromised. Participants equated good communication with receiving good healthcare, and some expressed anxiety in the anticipation of being unable to express their needs to healthcare workers., Conclusion & Implications: Communication impairment has a direct impact on healthcare involvement. This study demonstrates the effort required by plwMND and their carers to maintain or maximize ongoing involvement. This effort may not always be visible to HCPs. This information may prompt clinicians to consider the best ways to conduct clinical consultations to accommodate patients' abilities. Compromised communication experiences can be moderated by accommodations and support from HCPs and appropriate adjustments in the health system. Asking patients about their communication preferences and needs, allowing extra time and conducting multidisciplinary sessions are examples of such support., What This Paper Adds: What is already known on this subject? Communication and cognitive impairments are known contributors to negative health outcomes and barriers to shared decision-making generally. The existing literature in decision-making in MND does not address the specific impact of these impairments on personal healthcare involvement for plwMND and their carers. What this paper adds to existing knowledge? This paper reports the findings of a research project that interviewed 19 plwMND and 15 carers on one to three occasions over a 26-month period to obtain their perspectives of the impact of communication on healthcare involvement. Whilst a priori the intention was to look at both communicative and cognitive decline, only the former was achieved. The effort and often 'invisible' activity undertaken to manage or maintain involvement in healthcare is identified. Communication impairment requires support and accommodation, otherwise healthcare involvement can be compromised. Results show participants may associate effective communication with good healthcare. What are the potential or actual clinical implications of the work? Clinicians may wish to use these insights from plwMND and their carers to guide adjustments to their professional practice to maximize healthcare involvement for their patients. Tailored education for different healthcare groups is needed to improve understanding of MND-related communication impairments and supportive strategies so that involvement in healthcare is not compromised., (© 2022 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Objective: Emerging evidences suggest that the trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS., Methods: We measured degeneration in limb-onset ALS patients (n = 14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n = 12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. In order to investigate whether network spread on the brain connectome derived from healthy individuals were significant findings, we compared our findings against network spread simulated on random networks., Results: The cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Network spread simulated on the random networks showed that the findings using healthy brain connectomes are significantly different from null models., Interpretation: Our findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS., Competing Interests: The authors have declared that no competing interests exist.

An innovative approach to patient management, evidence-based policy development, and clinical drug trials is required to provide personalized care and to improve the likelihood of finding an effective treatment for Motor Neurone Disease (MND). The MiNDAus Partnership builds on and extends existing national collaborations in a targeted approach to improve the standard and coordination of care for people living with MND in Australia, and to enhance the prospects of discovering a cure or treatment. Relationships have been developed between leading clinical and research groups as well as patient-centered organizations, care providers, and philanthropy with a shared vision. MiNDAus has established a corporate structure and meets at least biannually to decide on how best to progress research, drug development, and patient management. The key themes are; (i) empowering patients and their family carers to engage in self-management and ensure personalized service provision, treatment, and policy development, (ii) integration of data collection so as to better inform policy development, (iii) unifying patients and carers with advocacy groups, funding bodies, clinicians and academic institutions so as to inform policy development and research, (iv) coordination of research efforts and development of standardized national infrastructure for conducting innovative clinical MND trials that can be harmonized within Australia and with international trials consortia. Such a collaborative approach is required across stakeholders in order to develop innovative management guidelines, underpinned by necessary and evidence-based policy change recommendations, which, will ensure the best patient care until a cure is discovered.

The growing body of information-seeking and decision-making literature in motor neurone disease (MND) has not yet explored the impact of health literacy. Health literacy relates to the skills people have to access, understand, and use health information and is influenced by motivation to engage with healthcare. We aimed to better understand how people affected by MND engage in healthcare by examining longitudinal interview data using the construct of health literacy. Semi-structured interviews were conducted with 19 persons living with MND and 15 carers recruited from a specialist MND clinic using maximum variation sampling. Transcripts were deductively coded using a framework of health literacy behaviours. The analysis used a matrix-based approach for thematic analysis of longitudinal data. People living with MND and carers sought nuanced information dependent on their priorities and attitudes. Information uptake was influenced by perceived relevancy and changed over time. Time allowed opportunity to reflect on and understand the significance of information provided. The findings indicate that persons living with MND and carers benefit when information and consultations are adapted to meet their communication needs. The results highlight the potential benefits of gaining an early understanding of and accommodating the communication needs, personal preferences, and emotional readiness for information for persons living with MND and their carers.

Purpose: Healthcare decision making in motor neurone disease (MND) focuses on symptom management and quality of life. Decision making may be affected by personal approach to receiving information, decision making style, and disease symptoms. This study explored decision making from the perspectives of people living with motor neurone disease (plwMND). The issues impacting engagement and involvement in healthcare decisions were investigated., Methods: Semi-structured interviews were conducted with 19 plwMND and 15 carers. Interview data was inductively analysed to identify and describe patterns and themes., Results: Data analysis identified six overarching themes: Dimensions of decision making; Window of opportunity for choice; Intrinsic influences on decision making; Extrinsic influences impacting decision making; Planning in uncertainty; and, Communication is core. Many participants did not identify a process of "decision-making" except if considering early gastrostomy placement. Information provision requires a balance between ensuring patients are informed but not overwhelmed. Communication impairment impacts involvement. Healthcare professionals' communication style influences engagement in decision making., Conclusion: PlwMND perceive a lack of clinical decisions to make because disease symptoms and clinical phenotypes dictate necessary interventions. PlwMND describe communication impairment as a barrier to involvement in decision making and extra support is required to ensure they maintain engagement.IMPLICATIONS FOR REHABILITATIONPeople living with MND (plwMND) perceive they have few clinical decisions to make and viewed this process as "accepting a recommendation", rather than "making a decision" although early gastrostomy placement is the exception with considerable deliberation evident.Specialist multidisciplinary clinic advice is especially helpful for plwMND without dysphagia (swallowing problems) when considering early gastrostomy placement.Communication impairment may be a barrier to involvement in healthcare decisions and extra support to remain engaged is required.Some plwMND choose not to involve others in their decisions, and patients/families with medical or scientific backgrounds are more likely to collaborate with each other outside the context of clinic appointments.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R 2 ) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R 2 ) of 0.027 (P value = 4.6 × 10 -8 ), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Children aged 3-4 years ( n = 876) were recruited from deprived areas in England, and a significant minority of the sample were second language learners. Oral language ability was assessed using child administered standardized measures, and parents reported on children's language. We adapted the Language Use Inventory [LUI; (1)] to capture carer's reports of the children's structural language in the language of instruction and their home language (where appropriate). The final measure included six subscales from the original: use of simple words, requests for help, gaining attention, talking about activities/actions, interactions with others, and building sentences. Children's language abilities and non-verbal abilities were below norms on all standardized tests administered except non-word repetition. Factor analysis indicated that all the six scales of the adapted parent completed measure loaded on one language factor. The revised total scale score correlated significantly ( p < 0.0005) with child assessed language measures, specifically expressive vocabulary and grammar. Different patterns across gender, language status and parental education were examined. Sensitivity and specificity of the scale to identify children with the greatest delays were evaluated. These preliminary data indicated that parent-reported information on children's language skills at 3 years of age has the potential to provide a reliable indicator to inform pedagogy and practice at the start of nursery school. Study limitations are examined and avenues for future development explored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dockrell, Forrest, Law, Mathers and Charlton.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this., Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO)., Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10 -6 ), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10 -3 , adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression., Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings., (© 2021. The Author(s).)

Polysemy, or the property of words having multiple meanings, is a prevalent feature of vocabulary. In this study we validated a new measure of polysemy knowledge for children with English as an additional language (EAL) and a first language (EL1) and examined the relationship between polysemy knowledge and age, language status, and reading comprehension. Participants were 112 British children aged 5 to 6 (n = 61) or 8 to 9 years (n = 51), 37% of whom had EAL (n = 41). Participants completed the new measure of knowledge of polysemes, along with other measures of language, literacy and cognitive ability. The new measure was reliable and valid with EAL and EL1 children. Age and language status predicted children's polyseme knowledge. Polyseme knowledge uniquely contributed to reading comprehension after controlling for age, language status, non-verbal intelligence, time reading in English, and breadth of vocabulary. This research underscores the importance of polysemy for children's linguistic development.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons., (© 2021. The Author(s).)

Background: Bulbar involvement is a recognised feature of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS), both as a presenting complaint and as a consequence of advancing disease. Hoarseness and dysphonia have been associated with vocal cord abductor weakness. This is usually bilateral and has also been reported as the presenting clinical feature in a handful of patients with superoxide dismutase 1 (SOD1) gene mutations. Presentation with an isolated, unilateral vocal cord adductor weakness, however, is atypical and rare., Case: In this report, we detail the case of a 38-year-old woman with dysphonia and a family history of an SOD1 mutation. Neurological features remained confined to the territory of the left vagus nerve for the next 12 months, before a more rapid rate of disease dissemination and progression., Conclusions: This case highlights the importance of recognition of vocal cord palsy as an early manifestation of MND/ALS and the critical need for monitoring to recognise potential disease progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS., Methods: Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life., Results: A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (-1.12 [-3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [-0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups., Interpretation: Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as "responders", experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease., (Published by Elsevier B.V.)

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease., Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights., Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

Background: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation., Methods: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks., Results: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants., Conclusion: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis., Competing Interests: Competing interests: TJO reports stock options from Synchron, during the conduct of the study; in addition, TJO has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. PEY reports stock options from Synchron, during the conduct of the study; in addition, PEY has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. GSR reports stock options from Synchron, during the conduct of the study; in addition, GSR has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. SMR reports stock options from Synchron, during the conduct of the study; in addition, SMR has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending. RPS reports stock options from Synchron, during the conduct of the study. VH reports personal fees from Synchron, during the conduct of the study. LRH reports that The Massachusetts General Hospital (MGH) Translational Research Center (TRC) has clinical research support agreements with Synchron, Paradromics and Neuralink, for which LRH provides consultative input. TD reports personal fees from Synchron, during the conduct of the study. JM reports stock options from Synchron, during the conduct of the study. NLO reports stock options from Synchron, during the conduct of the study; in addition, NLO has a patent sensing or stimulating activity of tissue issued, and a patent sensing or stimulating activity of tissue pending., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10 -9 ), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Dysregulation of iron in the cerebral motor areas has been hypothesized to occur in individuals with amyotrophic lateral sclerosis (ALS). There is still limited knowledge regarding iron dysregulation in the progression of ALS pathology. Our objectives were to use magnetic resonance based quantitative susceptibility mapping (QSM) to investigate the association between iron dysregulation in the motor cortex and clinical manifestations in patients with limb-onset ALS, and to examine changes in the iron concentration in the motor cortex in these patients over a 6-month period., Methods: Iron concentration was investigated using magnetic resonance based QSM in the primary motor cortex and the pre-motor area in 13 limb-onset ALS patients (including five lumbar onset, six cervical onset and two flail arm patients), and 11 age- and sex-matched control subjects. Nine ALS patients underwent follow-up scans at 6 months., Results: Significantly increased QSM values were observed in the left posterior primary motor area (P=0.02, Cohen's d =0.9) and right anterior primary motor area (P=0.02, Cohen's d =0.92) in the group of limb-onset ALS patients compared to that of control subjects. Increased QSM was observed in the primary motor and pre-motor area at baseline in patients with lumbar onset ALS patients, but not cervical limb-onset ALS patients, compared to control subjects. No significant change in QSM was observed at the 6-month follow-up scans in the ALS patients., Conclusions: The findings suggest that iron dysregulation can be detected in the motor cortex in limb-onset ALS, which does not appreciably change over a further 6 months. Individuals with lumbar onset ALS appear to be more susceptible to motor cortex iron dysregulation compared to the individuals with cervical onset ALS. Importantly, this study highlights the potential use of QSM as a quantitative radiological indicator in early disease diagnosis in limb-onset ALS and its subtypes. Our serial scans results suggest a longer period than 6 months is needed to detect significant quantitative changes in the motor cortex., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-187). The authors have no conflicts of interest to declare., (2020 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case-control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case-control status in the Netherlands sample (area under the curve, AUC = 0.65, CI 95%  = [0.62-0.68], p  = 8.3 × 10 -22 ). The maximum AUC achieved was 0.69 (CI 95%  = [0.66-0.71], p  = 4.3 × 10 -34 ) when cell-type proportion was included in the predictor., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder of the human motor system. Neuroinflammation appears to be an important modulator of disease progression in ALS. Specifically, reduction of regulatory T cell (Treg) levels, along with an increase in pro-inflammatory effector T cells, macrophage activation and upregulation of co-stimulatory pathways have all been associated with a rapid disease course in ALS. Autologous infusion of expanded Tregs into sporadic ALS patients, resulted in greater suppressive function, slowing of disease progression and stabilization of respiratory function. Tecfidera (dimethyl fumarate) increases the ratio of anti-inflammatory (Treg) to proinflammatory T-cells in patients with relapsing remitting multiple sclerosis and rebalances the regulatory: inflammatory axis towards a neuroprotective phenotype. Consequently, the aim of this study was to assess the efficacy, safety, and tolerability of Tecfidera in sporadic ALS., Methods: The study is an investigator led Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial assessing the efficacy and safety of Tecfidera in patients with sporadic ALS. The study duration is 40 weeks, with a 36-week study period and end of study visit occurring at 40 weeks or at early termination/withdrawal from study. The TEALS study has been registered with the Australian and New Zealand Clinical Trials registry (ANZCTR) under the trials registration number ACTRN12618000534280 and has been approved by the Human Research Ethics Committee and Research Governance Office at the lead site (Westmead Hospital) with the ethics number HREC/17/WMEAD/353. The participating sites have obtained site specific ethics and governance approvals from the local institution., Results: The primary endpoint is slowing of disease progression as reflected by the differences in the ALS Functional Rating Score-Revised (ALSFRS-R) score at Week 36. The secondary endpoints will include effects in survival, lower motor neuron function, respiratory function, quality of life and safety., Conclusion: This Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial will provide evidence of efficacy and safety of Tecfidera in sporadic ALS.

Rationale: Motor neurone disease (MND) is a neurodegenerative disease presenting with progressive weakness of voluntary muscles. For any condition, person-centred health care relies on the sharing of information and a mutual understanding of the person's needs and preferences. Decision making in MND becomes more complex as there is no cure and a high prevalence of co-morbid communication and/or cognitive difficulties., Objective: To identify the reported impact of communication and/or cognitive impairment on patient and carer involvement in health care decision making in MND., Methods: A review and synthesis of studies addressing issues of communication impairment and/or cognitive impairment in relation to decision making focussed on MND was conducted. Articles were excluded if they were reviews, case studies, conference papers, or commentaries. To be included studies needed to address issues of communication impairment or cognitive impairment specifically in relation to decision making. Relevant data were extracted verbatim and subjected to content analysis to support the narrative summary., Results: Seventy-six articles were identified, and 35 articles screened. Six articles met inclusion criteria each describing examples of decision making in MND. There was limited data related to communication and/or cognitive impairment, and the impact these impairments may have on decision making despite recognition that many people with MND may lose verbal communication or develop subtle cognitive impairments. The literature is primarily from the perspective of others., Conclusion: This review highlights that the current body of literature exploring decision making within the MND population presents us with extremely limited insights into the impact of communication and/or cognitive impairments on health care decision making. Extant literature focuses on interventions (namely, ventilation and gastrostomy), the broad process of decision making, or cognitive assessment of decision-making ability. Whilst most studies acknowledge that deficits in communication or cognition impact the decision-making process, this issue is not the focus of any study., (© 2019 John Wiley & Sons, Ltd.)

Background: A developing body of evidence has provided valuable insight into the experiences of caregivers of people with motor neuron disease; however, understandings of how best to support caregivers remain limited., Aim: This study sought to understand concepts related to the motor neuron disease caregiver experience which could inform the development of supportive interventions., Design: A qualitative thematic analysis of a one-off semistructured interview with caregivers was undertaken., Setting/participants: Caregivers of people with motor neuron disease were recruited from a progressive neurological diseases clinic in Melbourne, Australia., Results: 15 caregivers participated. Three key themes were identified: (1) The Thief: the experience of loss and grief across varied facets of life; (2) The Labyrinth: finding ways to address ever changing challenges as the disease progressed; (3) Defying fate: being resilient and hopeful as caregivers tried to make the most of the time remaining., Conclusions: Caregivers are in need of more guidance and support to cope with experiences of loss and to adapt to changeable care giving duties associated with disease progression. Therapeutic interventions which target these experiences of loss and change are worth investigation., Trial Registration Number: ACTRN12615000120572, pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background : Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods : Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75 ECD levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings : 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75 ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation : Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.

Background: Informal caregivers of people with motor neurone disease (MND) take on an extensive role. Caregivers are at increased risk of experiencing psychological distress and burden, yet, there is a lack of intervention programmes to support them., Aim: The aim of this study was to investigate the feasibility and acceptability of a therapeutic group intervention promoting self-care, problem-solving and mindfulness to informal caregivers of people with MND., Design: Pilot study that utilised a one-arm pre- and post-design. Acceptability of the intervention was assessed 2 weeks post intervention with a questionnaire designed specifically for this study. Feasibility was assessed with consent, adherence and reasons for non-participation, refusal and attrition. Participants completed baseline and follow-up (6-week post intervention) questionnaires for psychological morbidity, burden, problem-solving, mindfulness and preparedness. Settings/participants: Caregivers of people with a diagnosis of MND within the past 12 months who were 18 years or older; who could speak, read and write in English and who were attending a progressive neurological diseases clinic were eligible., Results: A total of 13 caregivers participated in one of three group intervention sessions which were focused on self-care, problem-solving and mindfulness. The intervention appeared to be feasible and acceptable. All participants stated that they would recommend the intervention to others. The group format appeared to be highly valued. There was no significant change in measures between pre-intervention and 6 weeks post intervention., Conclusion: This pilot serves as an initial step for examining interventions for MND caregivers, with the hope of identifying effective, efficient and sustainable strategies to best support this group.

Objectives: Behavioural and psychological symptoms of dementia (BPSD) cause significant distress to both aged care residents and staff. Despite the high prevalence of BPSD in progressive neurological diseases (PNDs) such as multiple sclerosis, Huntington's disease, and Parkinson's disease, the utility of a structured clinical protocol for reducing BPSD has not been systematically evaluated in PND populations., Method: Staff ( n = 51) and individuals with a diagnosis of PND ( n = 13) were recruited into the study, which aimed to evaluate the efficacy of a PND-specific structured clinical protocol for reducing the impact of BPSD in residential aged care (RAC) and specialist disability accommodation (SDA) facilities. Staff were trained in the clinical protocol through face-to-face workshops, which were followed by 9 weeks of intensive clinical supervision to a subset of staff ("behaviour champions"). Staff and resident outcome measures were administered preintervention and immediately following the intervention. The primary outcome was frequency and severity of BPSD, measured using the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). The secondary outcome was staff coping assessed using the Strain in Dementia Care Scale (SDCS)., Results: In SDA, significant reductions in staff ratings of job-related stress were observed alongside a statistically significant decrease in BPSD from T1 to T2. In RAC, there was no significant time effect for BPSD or staff coping; however, a medium effect size was observed for staff job stress., Conclusions: Staff training and clinical support in the use of a structured clinical protocol for managing BPSD were linked to reductions in staff job stress, which may in turn increase staff capacity to identify indicators of resident distress and respond accordingly. Site variation in outcomes may relate to organisational and workforce-level barriers that may be unique to the RAC context and should be systematically addressed in future RCT studies of larger PND samples.

Objective: The experience of caregiving in the context of motor neurone disease (MND) is extremely challenging. Over the past 15 years, quantitative and qualitative studies have delineated the psychosocial aspects of this experience, exploring its impact on caregivers' quality of life, rates of depression, distress, anxiety, and burden. Our paper aimed to provide an overview of the lived experience of MND caregivers, identifying the variables that can influence MND caregiver functioning that are relevant to the development of an intervention., Method: A narrative review was conducted, synthesizing the findings of literature retrieved from 2000 to early 2016., Results: A total of 37 articles were included in the review. The articles varied considerably in terms of methodology and quality. The main influential aspects reported and identified were factors pertaining to the patient, factors intrinsic to the caregiver, relationship factors, and social support factors., Significance of Results: There is evidence to support the fact that caregivers have poorer outcomes when they care for patients with a more severe clinical profile, poorer emotional health or neurobehavioral concerns, or when the caregivers themselves struggle with adaptive problem-solving and coping skills. The availability and use of social support are also likely to be important for caregiver psychosocial outcomes. Further investigation is required to clarify the influence of changes in the relationship with the patient. Significant factors affecting the caregiver experience are considered in relation to their amenability to psychosocial intervention. Recommendations are made regarding the optimal features of future psychosocial intervention research.

Introduction: Pregnancy and the first few years of a child's life are important windows of opportunity in which to equalise life chances. A Better Start (ABS) is an area-based intervention being delivered in five areas of socioeconomic disadvantage across England. This protocol describes an evaluation of the impact and cost-effectiveness of ABS., Methods and Analysis: The evaluation of ABS comprises a mixed-methods design including impact, cost-effectiveness and process components. It involves a cohort study in the 5 ABS areas and 15 matched comparison sites (n=2885), beginning in pregnancy in 2017 and ending in 2024 when the child is age 7, with a separate cross-sectional baseline survey in 2016/2017. Process data will include a profiling of the structure and services being provided in the five ABS sites at baseline and yearly thereafter, and data regarding the participating families and the services that they receive. Eligible participants will include pregnant women living within the designated sites, with recruitment beginning at 16 weeks of pregnancy. Data collection will involve interviewer-administered and self-completion surveys at eight time points. Primary outcomes include nutrition, socioemotional development, speech, language and learning. Data analysis will include the use of propensity score techniques to construct matched programme and comparison groups, and a range of statistical techniques to calculate the difference in differences between the intervention and comparison groups. The economic evaluation will involve a within-cohort study economic evaluation to compare individual-level costs and outcomes, and a decision analytic cost-effectiveness model to estimate the expected incremental cost per unit change in primary outcomes for ABS in comparison to usual care., Ethics and Dissemination: Ethical approval to conduct the study has been obtained. The learning and dissemination workstream involves working within and across the sites to generate learning via communities of practice and a range of learning and dissemination events., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)