Kennedy's disease.

A 57-year-old man developed worsening early morning headaches, muscle cramps and falls over 12 months. He had widespread fasciculation and was diagnosed with motor neurone disease, and treated with nocturnal hypoventilation. Based on this diagnosis, he made significant personal and financial decisions including retiring and selling his house. He subsequently developed a lump in his right breast and was found to have gynaecomastia. This triggered genetic testing for Kennedy's disease leading to the correct diagnosis. This case highlights an unusual presentation of a rare disease leading to misdiagnosis and major repercussions for the patient. Recent genetic analysis from the 100 000 genome project suggests Kennedy's disease may be four times more prevalent in the population than previously thought, highlighting the need to consider genetic testing, especially if there is a suggestion of multisystem disease.

Could an integrated model of health and social care after critical illness reduce socioeconomic disparities in outcomes? A Bayesian analysis.

Background: There is limited evidence to understand what impact, if any, recovery services might have for patients across the socioeconomic spectrum after critical illness. We analysed data from a multicentre critical care recovery programme to understand the impact of this programme across the socioeconomic spectrum. Methods: The setting for this pre-planned secondary analysis was a critical care rehabilitation programme-Intensive Care Syndrome: Promoting Independence and Return to Employment. Data were collected from five hospital sites running this programme. We utilised a Bayesian approach to analysis and explore any possible effect of the InS:PIRE intervention on Health-Related Quality of Life (HRQoL) across the socioeconomic gradient. A Bayesian quantile, non-linear mixed effects regression model, using a compound symmetry covariance structure, accounting for multiple timepoints was utilised. The Scottish Index of Multiple Deprivation (SIMD) was used to measure socioeconomic status and HRQoL was measured using the EQ-5D-5L. Results: In the initial baseline cohort of 182 patients, 55% of patients were male, the median age was 58 yr (inter-quartile range: 50-66 yr) and 129 (79%) patients had two or more comorbidities at ICU admission. Using the neutral prior, there was an overall probability of intervention benefit of 100% (ß=0.71, 95% credible interval: 0.34-1.09) over 12 months to those in the SIMD≤3 cohort, and an 98.6% (ß=-1.38, 95% credible interval: -2.62 to -0.16) probability of greater benefit (i.e. a steeper increase in improvement) at 12 months in the SIMD≤3 vs SIMD≥4 cohort in the EQ-visual analogue scale. Conclusions: Using multicentre data, this re-analysis suggests, but does not prove, that an integrated health and social care intervention is likely to improve outcomes across the socioeconomic gradient after critical illness, with a potentially greater benefit for those from deprived communities. Future research designed to prospectively analyse how critical care recovery programmes could potentially improve outcomes across the socioeconomic gradient is warranted.

The relationship between pain, anxiety and depression in patients with post-intensive care syndrome.

PURPOSE: Survivors of critical illness frequently experience long-term symptoms including physical symptoms such as pain and emotional symptoms such as anxiety and depression. These symptoms frequently co-exist, however, at present there is limited understanding of these relationships. The aim of this study was to quantify the relationship between pain, anxiety and depression across the recovery trajectory. METHODS: This study is a secondary analysis of data from a multi-centre, prospective, cohort study which followed-up patients recovering from critical illness. Data was available at multiple time points and for 3 distinct cohorts. Structural equation modelling was used to investigate the relationship between outcome measures of pain, anxiety and depression. RESULTS: Data from 414 patients was analysed. Pain was significantly associated with both anxiety and depression in all cohorts and at all time points sampled. Path coefficients for the covariances between pain and depression ranged between 0.39 and 0.72 (p < 0.01). Path coefficients for the covariances between pain and anxiety ranged between 0.39 and 0.65 (p < 0.01). CONCLUSIONS: Pain, anxiety and depression are highly correlated in survivors of critical illness. Pharmacological treatments for pain management may be ineffective alone and further research is required to assess interventions targeting these symptoms in combination.

Evaluating pain in survivors of critical illness: the correlation between the EQ-5D-5L and the Brief Pain Inventory.

INTRODUCTION: Pain is a common and debilitating symptom in survivors of critical illness. The 'Core Outcome Set for Survivors of Acute Respiratory Failure' proposes that the pain and discomfort question of the EuroQol 5 Dimension 5 Level (EQ-5D-5L) could be used to assess pain in this group, however, it was recognised that further research is required to evaluate how this single question compares to other more detailed pain tools. This study aims to evaluate the relationship between the pain and discomfort question of the EQ-5D-5L and the Brief Pain Inventory (BPI) in survivors of critical illness. METHODS: This study retrospectively analysed paired EQ-5D-5L and BPI data extracted from a prospective, multicentre study evaluating the impact of a critical care recovery programme. 172 patients who received a complex recovery intervention and 108 patients who did not receive this intervention were included. Data were available for the intervention cohort at multiple time points, namely, baseline, 3 months and 12 months. While, data were available for the usual care cohort at a single time point (12 months). We assessed the correlation between the pain and discomfort question of the EQ-5D-5L and two separate components of the BPI: severity of pain and pain interference. RESULTS: Correlation coefficients comparing the pain and discomfort question of the EQ-5D-5L and the BPI pain severity score ranged between 0.73 (95% CI 0.63 to 0.80) and 0.80 (95% CI 0.72 to 0.86). Correlation coefficients comparing the pain and discomfort question of the EQ-5D-5L and the BPI pain interference score ranged between 0.71 (95% CI 0.62 to 0.79) and 0.83 (95% CI 0.76 to 0.88) across the various time points. CONCLUSIONS: The pain and discomfort question of the EQ-5D-5L correlates moderately well with a more detailed pain tool and may help to streamline assessments in survivorship studies. More in-depth tools may be of use where pain is the primary study outcome or a patient-reported concern.

Evaluation of a health and social care programme to improve outcomes following critical illness: a multicentre study.

RATIONALE: At present, clinicians aiming to support patients through the challenges after critical care have limited evidence to base interventions. OBJECTIVES: Evaluate a multicentre integrated health and social care intervention for critical care survivors. A process evaluation assessed factors influencing the programme implementation. METHODS: This study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme. We compared patients who attended this programme with a usual care cohort from the same time period across nine hospital sites in Scotland. The primary outcome was health-related quality of life (HRQoL) measured via the EuroQol 5-dimension 5-level instrument, at 12 months post hospital discharge. Secondary outcome measures included self-efficacy, depression, anxiety and pain. RESULTS: 137 patients who received the InS:PIRE intervention completed outcome measures at 12 months. In the usual care cohort, 115 patients completed the measures. The two cohorts had similar baseline demographics. After adjustment, there was a significant absolute increase in HRQoL in the intervention cohort in relation to the usual care cohort (0.12, 95% CI 0.04 to 0.20, p=0.01). Patients in the InS:PIRE cohort also reported self-efficacy scores that were 7.7% higher (2.32 points higher, 95% CI 0.32 to 4.31, p=0.02), fewer symptoms of depression (OR 0.38, 95% CI 0.19 to 0.76, p=0.01) and similar symptoms of anxiety (OR 0.58, 95% CI 0.30 to 1.13, p=0.11). There was no significant difference in overall pain experience. Key facilitators for implementation were: integration with inpatient care, organisational engagement, flexibility to service inclusion; key barriers were: funding, staff availability and venue availability. CONCLUSIONS: This multicentre evaluation of a health and social care programme designed for survivors of critical illness appears to show benefit at 12 months following hospital discharge.

A multicentre evaluation exploring the impact of an integrated health and social care intervention for the caregivers of ICU survivors.

BACKGROUND: Caregivers and family members of Intensive Care Unit (ICU) survivors can face emotional problems following patient discharge from hospital. We aimed to evaluate the impact of a multi-centre integrated health and social care intervention, on caregiver and family member outcomes. METHODS: This study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme across 9 sites in Scotland. InS:PIRE is an integrated health and social care intervention. We compared caregivers who attended this programme with a contemporary control group of ICU caregivers (usual care cohort), who did not attend. RESULTS: The primary outcome was anxiety measured via the Hospital Anxiety and Depression Scale at 12 months post-hospital discharge. Secondary outcome measures included depression, carer strain and clinical insomnia. A total of 170 caregivers had data available at 12 months for inclusion in this study; 81 caregivers attended the InS:PIRE intervention and completed outcome measures at 12 months post-hospital discharge. In the usual care cohort of caregivers, 89 completed measures. The two cohorts had similar baseline demographics. After adjustment, those caregivers who attended InS:PIRE demonstrated a significant improvement in symptoms of anxiety (OR: 0.42, 95% CI: 0.20-0.89, p = 0.02), carer strain (OR: 0.39; 95% CI: 0.16-0.98 p = 0.04) and clinical insomnia (OR: 0.40; 95% CI: 0.17-0.77 p < 0.001). There was no significant difference in symptoms of depression at 12 months. CONCLUSIONS: This multicentre evaluation has shown that caregivers who attended an integrated health and social care intervention reported improved emotional health and less symptoms of insomnia, 12 months after the delivery of the intervention.

Long-term outcomes following severe COVID-19 infection: a propensity matched cohort study.

BACKGROUND: There are limited data describing the long-term outcomes of severe COVID-19. We aimed to evaluate the long-term psychosocial and physical consequences of severe COVID-19 for patients. METHODS: We conducted a multicentre observational cohort study; between 3 and 7 months posthospital discharge, patients who had been admitted to critical care due to severe COVID-19 were invited to an established recovery service. Standardised questionnaires concerning emotional, physical and social recovery, including information on employment, were completed by patients. Using propensity score matching, we explored outcomes between patients admitted to critical care with and without COVID-19, using data from the same recovery programme. RESULTS: Between July 2020 and December 2020, 93 patients who had been admitted to critical with COVID-19 participated. Emotional dysfunction was common: 46.2% of patients had symptoms of anxiety and 34.4% symptoms of depression. At follow-up 53.7% of previously employed patients had returned to employment; there was a significant difference in return to employment across the socio-economic gradient, with lower numbers of patients from the most deprived areas returning to employment (p=0.03). 91 (97.8%) COVID-19 patients were matched with 91 non-COVID-19 patients. There were no significant differences in any measured outcomes between the two cohorts. INTERPRETATION: Emotional and social problems are common in survivors of severe COVID-19 infection. Coordinated rehabilitation is required to ensure patients make an optimal recovery.

Post-intensive care syndrome following cardiothoracic critical care: Feasibility of a complex intervention.

OBJECTIVES: To describe the long-term outcomes of cardiac intensive care unit patients and their primary caregivers, and to explore the feasibility of implementing a complex intervention, designed to support problems associated with post-intensive care syndrome and post-intensive care syndrome-family, in the year following discharge from the cardiac intensive care unit. DESIGN: A complex multidisciplinary rehabilitation programme, delivered as a quality improvement initiative, in a single centre in the West of Scotland. Outcomes were measured using surveys of health related quality of life, self efficacy, anxiety, depression, pain, caregiver strain, and insomnia. PARTICIPANTS: Patients and their caregivers were invited to participate 12 weeks after hospital discharge. Twenty-seven patients and 23 caregivers attended the programme. RESULTS: Over 90% of patients had problems in at least one quality of life domain at baseline, 41% of patients had symptoms of anxiety and 22% had symptoms of depression. During the baseline visit, caregiver strain was present in 20% of caregivers, 57% had symptoms of anxiety, and 35% had symptoms of depression. Improvements in outcomes were seen in both patients and caregivers at 1-year follow-up. The programme was implemented, and iterative learning obtained about the content and the operationalization of the service, in order to understand feasibility. CONCLUSION: This small-scale quality improvement project has demonstrated that this complex multidisciplinary rehabilitation programme is feasible and has positive implications for patients following discharge from the cardiac intensive care unit, and their caregivers.

Automated and unbiased discrimination of ALS from control tissue at single cell resolution.

Histopathological analysis of tissue sections is invaluable in neurodegeneration research. However, cell-to-cell variation in both the presence and severity of a given phenotype is a key limitation of this approach, reducing the signal to noise ratio and leaving unresolved the potential of single-cell scoring for a given disease attribute. Here, we tested different machine learning methods to analyse high-content microscopy measurements of hundreds of motor neurons (MNs) from amyotrophic lateral sclerosis (ALS) post-mortem tissue sections. Furthermore, we automated the identification of phenotypically distinct MN subpopulations in VCP- and SOD1-mutant transgenic mice, revealing common morphological cellular phenotypes. Additionally we established scoring metrics to rank cells and tissue samples for both disease probability and severity. By adapting this paradigm to human post-mortem tissue, we validated our core finding that morphological descriptors robustly discriminate ALS from control healthy tissue at single cell resolution. Determining disease presence, severity and unbiased phenotypes at single cell resolution might prove transformational in our understanding of ALS and neurodegeneration more broadly.

Impact of a pharmacist intervention at an intensive care rehabilitation clinic.

OBJECTIVE: While disruptions in medications are common among patients who survive critical illness, there is limited information about specific medication-related problems among survivors of critical care. This study sought to determine the prevalence of specific medication-related problems detected in patients, seen after critical care discharge. DESIGN: Consecutive patients attending an intensive care unit (ICU) follow-up programme were included in this single-centre service evaluation. SETTING: Tertiary care regional centre in Scotland (UK). PARTICIPANTS: 47 patients reviewed after critical care discharge at an ICU follow-up programme. INTERVENTIONS: Pharmacists conducted a full medication review, including: medicines reconciliation, assessing the appropriateness of each prescribed medication, identification of any medication-related problems and checking adherence. MEASUREMENTS: Medication-related problems in patients following critical care discharge. Interventions and medication-related problems were systematically graded and risk factors were identified using an adapted version of the National Patient Safety Agency Risk Matrix. MAIN RESULTS: 69 medication-related problems were identified in 38 (81%) of the 47 patients. The most common documented problem was drug omission (29%). 64% of the medication-related problems identified were classified as either moderate or major. The number of pain medications prescribed at discharge from intensive care was predictive of medication-related problems (OR 2.02, 95% CI 1.14 to 4.26, p=0.03). CONCLUSIONS: Medication problems are common following critical care. Better communication of medication changes both to patients and their ongoing care providers may be beneficial following a critical care admission. In the absence of highly effective communication, a pharmacy intervention may contribute substantially to an intensive care rehabilitation or recovery programme.

Exploring Patients' Goals Within the Intensive Care Unit Rehabilitation Setting.

BACKGROUND: The number of patients surviving critical care is increasing. Quality of life after critical care is known to be poor for some patients. The evidence base for effective rehabilitation interventions in the period following a stay in an intensive care unit is limited. OBJECTIVES: To understand what rehabilitation goals are important to patients after critical care discharge. METHODS: This prospective study, which was undertaken during an intensive care unit recovery program, explored the recovery goals of 43 patients. Framework analysis was used to extract prevalent themes and identify the important components of recovery from the patients' perspective. RESULTS: Participants described diverse goals for their post-intensive care unit recovery. Most goals were about health-related quality of life, including physical goals and rehabilitation. Although health was central to many of the participants' individual recovery aims, themes of family and social engagement and adopting appropriate goal trajectories also emerged within patient goals. Individual strategies for reaching these goals varied, and patients had different aspirations about what they could achieve. CONCLUSIONS: Patients' aspirations for their intensive care unit recovery are diverse. Design of postdischarge care can be informed by this greater understanding of the heterogeneous starting points and goal trajectories of survivors of critical illness.

Chronic pain in intensive care unit survivors: incidence, characteristics and side-effects up to one-year post-discharge.

BACKGROUND: Intensive care unit survivors experience significant physical and psychological problems, including chronic pain following discharge. The aim of this study was to observe the incidence, anatomical sites, intensity, and interference of chronic pain in intensive care unit survivors over a 1-year period. In addition, potential predictors of chronic pain were analysed. METHODS: Data were collected during an intensive care unit follow-up programme as part of a quality improvement initiative. Data from the Brief Pain Inventory and from musculoskeletal assessment were examined, alongside demographic data from the patient. Data were collected from patients at baseline and at a 1-year follow-up appointment. RESULTS: Data from 47 intensive care unit survivors were included in this study. In 66% (n = 31) of the patients a "new" chronic pain that did not exist before their stay in the intensive care, was reported. Pain intensity in this patient group was "moderate"' and did not improve significantly over the 1-year period. Although pain interference with life decreased over the study period, it was still the most common cause of reduced enjoyment of life and reduced employment at 1-year follow-up. CONCLUSION: Chronic pain is associated with morbidity in intensive care unit survivors. Pain interference, but not pain intensity, improved significantly in the first year after discharge. Further multi-centre research is required to elucidate the chronic pain experience.

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.

Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS.

Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.

Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE). Early evaluation of a complex intervention.

BACKGROUND: Many patients suffer significant physical, social and psychological problems in the months and years following critical care discharge. At present, there is minimal evidence of any effective interventions to support this patient group following hospital discharge. The aim of this project was to understand the impact of a complex intervention for ICU survivors. METHODS: Quality improvement project conducted between September 2014 and June 2016, enrolling 49 selected patients from one ICU in Scotland. To evaluate the impact of this programme outcomes were compared to an existing cohort of patients from the same ICU from 2008-2009. Patients attended a five week peer supported rehabilitation programme. This multidisciplinary programme included pharmacy, physiotherapy, nursing, medical, and psychology input. The primary outcome in this evaluation was the EQ-5D, a validated measure of health-related quality of life. The minimally clinically important difference (MCID) in the EQ-5D is 0.08. We also measured change in self-efficacy over the programme duration. Based on previous research, this study utilised a 2.4 (6%) point change in self-efficacy scores as a MCID. RESULTS: 40 patients (82%) completed follow-up surveys at 12 months. After regression adjustment for those factors known to impact recovery from critical care, there was a 0.07-0.16 point improvement in quality of life for those patients who took part in the intervention compared to historical controls from the same institution, depending on specific regression strategy used. Self-efficacy scores increased by 2.5 points (6.25%) over the duration of the five week programme (p = 0.003), and was sustained at one year post intervention. In the year following ICU, 15 InS:PIRE patients returned to employment or volunteering roles (88%) compared with 11 (46%) in the historical control group (p = 0.15). CONCLUSIONS AND RELEVANCE: This historical control study suggests that a complex intervention may improve quality of life and self-efficacy in survivors of ICU. A larger, multi-centre study is needed to investigate this intervention further.

Peripheral neuropathy in complex inherited diseases: an approach to diagnosis.

Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy, for example, spasticity, the type of neuropathy and the other neurological and non-neurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories: (1) ataxia, (2) spasticity and (3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy, for example, cardiomyopathy and neuropathy. We also include a separate category of complex inherited relapsing neuropathy syndromes, some of which may mimic Guillain-Barré syndrome, as many will have a metabolic aetiology and be potentially treatable.

The translational potential of human induced pluripotent stem cells for clinical neurology : The translational potential of hiPSCs in neurology.

The induced pluripotent state represents a decade-old Nobel prize-winning discovery. Human-induced pluripotent stem cells (hiPSCs) are generated by the nuclear reprogramming of any somatic cell using a variety of established but evolving methods. This approach offers medical science unparalleled experimental opportunity to model an individual patient's disease "in a dish." HiPSCs permit developmentally rationalized directed differentiation into any cell type, which express donor cell mutation(s) at pathophysiological levels and thus hold considerable potential for disease modeling, drug discovery, and potentially cell-based therapies. This review will focus on the translational potential of hiPSCs in clinical neurology and the importance of integrating this approach with complementary model systems to increase the translational yield of preclinical testing for the benefit of patients. This strategy is particularly important given the expected increase in prevalence of neurodegenerative disease, which poses a major burden to global health over the coming decades.