Publications by authors named "Robert Henderson"

386 Publications

Cleansing and separation procedures reflect resource concerns.

Behav Brain Sci 2021 02 18;44:e22. Epub 2021 Feb 18.

Department of Psychology, University of Cambridge, CambridgeCB2 3EB, UK.

We propose that procedures of separation have two functions, namely first, to establish the integrity of individual parts, and second, to make previously joint entities discreet and therefore countable. This allows taking stock of available resources, including evaluating the use of individual objects, a process that is especially adaptive under conditions of threat of contagious disease and resource scarcity.
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http://dx.doi.org/10.1017/S0140525X20000631DOI Listing
February 2021

Hemoglobin, Body Mass Index, and Age as Risk Factors for Paclitaxel- and Oxaliplatin-Induced Peripheral Neuropathy.

JAMA Netw Open 2021 Feb 1;4(2):e2036695. Epub 2021 Feb 1.

Prince of Wales Clinical School, UNSW Medicine, University of New South Wales Sydney, Sydney, Australia.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development.

Objective: To identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin.

Design, Setting, And Participants: This cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020.

Exposures: Paclitaxel or oxaliplatin chemotherapy.

Main Outcomes And Measures: CIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development.

Results: The study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (β = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (β = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (β = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (β = -1.08; 95% CI, -1.76 to -0.16; P = .01).

Conclusions And Relevance: The results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.36695DOI Listing
February 2021

Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis.

Oncoimmunology 2021 Jan 25;10(1):1859263. Epub 2021 Jan 25.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, NUI Galway, Galway, Ireland.

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.
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http://dx.doi.org/10.1080/2162402X.2020.1859263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849715PMC
January 2021

Ghrelin as a treatment for amyotrophic lateral sclerosis.

J Neuroendocrinol 2021 Jan 29:e12938. Epub 2021 Jan 29.

Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider-ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin-mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide-ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease-relevant processes observed in ALS. Expanding on the well-known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin-mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin-like growth factor-1 (IGF-1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF-1 are associated with faster disease progression and worse disease outcome in patients with ALS.
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http://dx.doi.org/10.1111/jne.12938DOI Listing
January 2021

Kelvin probe force microscopy to study electrostatic interactions of DNA with lipid-gemini surfactant monolayers for gene delivery.

Soft Matter 2021 Jan 21;17(4):826-833. Epub 2020 Dec 21.

Department of Physics & Astronomy, University of Waterloo, Waterloo, ON, Canada.

In novel gene therapy mechanisms utilising gemini surfactants, electrostatic interactions of the surfactant molecules with the DNA strands is a primary mechanism by which the two components of the delivery vehicle bind. In this work, we show for the first time direct evidence of electrostatic interactions of these compounds visualised with Kelvin probe force microscopy (KPFM) and correlated to their topography from atomic force microscopy (AFM). We construct monolayers of lipids and gemini surfactant to simulate interactions on a cellular level, using lipids commonly found in cell membranes, and allow DNA to bind to the monolayer as it is formed on a Langmuir-Blodgett trough. The difference in topography and electrical surface potential between monolayers with and without DNA is striking. In fact, KPFM reveals a strongly positive relative electrical surface potential in between where we identify a background lipid and the DNA strands, evidenced by the height profiles of the domains. Such identification is not possible without KPFM. We conclude that it is likely we are seeing cationic surfactant molecules surrounding DNA strands within a sea of background lipid.
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http://dx.doi.org/10.1039/d0sm01926gDOI Listing
January 2021

Identifying cell-enriched miRNAs in kidney injury and repair.

JCI Insight 2020 Dec 17;5(24). Epub 2020 Dec 17.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.
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http://dx.doi.org/10.1172/jci.insight.140399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819746PMC
December 2020

Recommended protocol for performing oral fundus fluorescein angiography (FFA) in children.

Eye (Lond) 2020 Dec 15. Epub 2020 Dec 15.

Pharmacy Department, Great Ormond Street Hospital for Children, London, UK.

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http://dx.doi.org/10.1038/s41433-020-01328-6DOI Listing
December 2020

Turning the Mre11/Rad50 DNA repair complex on its head: lessons from SMC protein hinges, dynamic coiled-coil movements and DNA loop-extrusion?

Biochem Soc Trans 2020 Dec;48(6):2359-2376

Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, U.K.

The bacterial SbcC/SbcD DNA repair proteins were identified over a quarter of a century ago. Following the subsequent identification of the homologous Mre11/Rad50 complex in the eukaryotes and archaea, it has become clear that this conserved chromosomal processing machinery is central to DNA repair pathways and the maintenance of genomic stability in all forms of life. A number of experimental studies have explored this intriguing genome surveillance machinery, yielding significant insights and providing conceptual advances towards our understanding of how this complex operates to mediate DNA repair. However, the inherent complexity and dynamic nature of this chromosome-manipulating machinery continue to obfuscate experimental interrogations, and details regarding the precise mechanisms that underpin the critical repair events remain unanswered. This review will summarize our current understanding of the dramatic structural changes that occur in Mre11/Rad50 complex to mediate chromosomal tethering and accomplish the associated DNA processing events. In addition, undetermined mechanistic aspects of the DNA enzymatic pathways driven by this vital yet enigmatic chromosomal surveillance and repair apparatus will be discussed. In particular, novel and putative models of DNA damage recognition will be considered and comparisons will be made between the modes of action of the Rad50 protein and other related ATPases of the overarching SMC superfamily.
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http://dx.doi.org/10.1042/BST20170168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752040PMC
December 2020

Diffuse bear-track retina: profound, bilateral, grouped congenital pigmentation of the retinal pigment epithelium in an infant.

J AAPOS 2020 Oct 22. Epub 2020 Oct 22.

Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, United Kingdom; UCL-GOSH Institute of Child Health, University College London, London, United Kingdom.

Grouped congenital hypertrophy of the retinal pigment epithelium is a conspicuous ocular anomaly wherein highly pigmented, demarcated but flat retinal lesions arise from the retinal pigment epithelium. These lesions ("bear tracks") typically increase in size as they approach the retinal periphery. The discovery of pigmentary lesions in a young infant with a poor red reflex warrants urgent ophthalmological and electrodiagnostic review to exclude serious diagnoses, including an early-onset severe retinal dystrophy. We present the case of a 2-month-old boy with marked bear-tracks over the entirety of each retina, but with normal electrodiagnostic findings, genetics, and visual behavior.
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http://dx.doi.org/10.1016/j.jaapos.2020.08.003DOI Listing
October 2020

New variants and in silico analyses in GRK1 associated Oguchi disease.

Hum Mutat 2021 Feb 30;42(2):164-176. Epub 2020 Nov 30.

Division of Molecular Medicine, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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http://dx.doi.org/10.1002/humu.24140DOI Listing
February 2021

Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis.

Brain Commun 2020 24;2(2):fcaa154. Epub 2020 Sep 24.

Centre for Clinical Research, The University of Queensland, Herston, Brisbane 4029, Australia.

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the superoxide dismutase 1, glycine to alanine substitution at amino acid 93 (SOD1) mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677608PMC
September 2020

Traumatic Retinal Detachment in Patients with Self-Injurious Behavior: An International Multicenter Study.

Ophthalmol Retina 2020 Nov 22. Epub 2020 Nov 22.

Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

Purpose: To describe the clinical characteristics, surgical outcomes, and management recommendations in patients with traumatic rhegmatogenous retinal detachment (RRD) resulting from self-injurious behavior (SIB).

Design: International, multicenter, retrospective, interventional case series.

Participants: Patients with SIB from 23 centers with RRD in at least 1 eye.

Methods: Clinical histories, preoperative assessment, surgical details, postoperative management, behavioral intervention, and follow-up examination findings were reviewed.

Main Outcome Measures: The rate of single-surgery anatomic success (SSAS) was the primary outcome. Other outcomes included new RRD in formerly attached eyes, final retinal reattachment, and final visual acuity.

Results: One hundred seven eyes with RRDs were included from 78 patients. Fifty-four percent of patients had bilateral RRD or phthisis bulbi in the fellow eye at final follow-up. The most common systemic diagnoses were autism spectrum disorder (35.9%) and trisomy 21 (21.8%) and the most common behavior was face hitting (74.4%). The average follow-up time was 3.3 ± 2.8 years, and surgical outcomes for operable eyes were restricted to patients with at least 3 months of follow-up (81 eyes). Primary initial surgeries were vitrectomy alone (33.3%), primary scleral buckle (SB; 26.9%), and vitrectomy with SB (39.7%), and 5 prophylactic SBs were placed. Twenty-three eyes (21.5%) with RRDs were inoperable. The SSAS was 23.1% without tamponade (37.2% if including silicone oil), and final reattachment was attained in 80% (36.3% without silicone oil tamponade). Funnel-configured RRD (P = 0.006) and the presence of grade C proliferative vitreoretinopathy (P = 0.002) correlated with re-detachment. The use of an SB predicted the final attachment rate during the initial surgery (P = 0.005) or at any surgery (P = 0.008. These associations held if restricting to 64 patients with ≥12 months followup. Anatomic reattachment correlated with better visual acuity (P < 0.001).

Conclusions: RRD resulting from SIB poses therapeutic challenges because of limited patient cooperation, bilateral involvement, chronicity, and ongoing trauma in vulnerable and neglected patients. The surgical success rates were some of the lowest in the modern retinal detachment literature. The use of an SB may result in better outcomes, and visual function can be restored in some patients.
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http://dx.doi.org/10.1016/j.oret.2020.11.012DOI Listing
November 2020

Impact of sight and hearing loss in patients with Norrie disease: advantages of Dual Sensory clinics in patient care.

BMJ Paediatr Open 2020 16;4(1):e000781. Epub 2020 Nov 16.

Great Ormond Street Hospital for Children, London, London, UK.

Norrie disease (ND) is a rare, X-linked condition of visual and auditory impairment, often presenting with additional neurological features and developmental delays of varying severity. While all affected patients are born blind, or lose their vision in infancy, progressive sensorineural hearing loss develops in the majority of cases and is typically detected in the second decade of life. A range of additional symptoms of ND, such as seizure disorders, typically appear from a young age, but it is difficult to predict the range of symptoms ND patients will experience. After growing up without vision, hearing loss represents the greatest worry for many patients with ND, as they may lose the ability to participate in previously enjoyed activities or to communicate with others. Dual sensory loss has a physical, psychosocial and financial impact on both patients with ND and their families. Routine monitoring of the condition is required in order to identify, treat and provide support for emerging health problems, leading to a large burden of medical appointments. Many patients need to travel long distances to meet with specialists, representing a further burden on time and finances. Additionally, the rare nature of dual sensory impairment in children means that few clinical environments are designed to meet their needs. Dual Sensory clinics are multidisciplinary environments designed for sensory-impaired children and have been suggested to alleviate the impact of diseases involving sensory loss such as ND. Here, we discuss the diagnosis, monitoring and management of ND and the impact it has on paediatric patients and their caregivers. We describe the potential for dual sensory clinics to reduce disease burden through providing an appropriate clinical environment, access to multiple clinical experts in one visit, and ease of monitoring for patients with ND.
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http://dx.doi.org/10.1136/bmjpo-2020-000781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670942PMC
November 2020

Disorders of sleep and wakefulness in amyotrophic lateral sclerosis (ALS): a systematic review.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Nov 16:1-9. Epub 2020 Nov 16.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.

Disorders of sleep and wakefulness are common among neurodegenerative diseases. While amyotrophic lateral sclerosis (ALS) predominately manifests as motor symptoms, there is emerging evidence that disruptions to sleep and wakefulness also occur. This systematic review aims to report the most common disorders of sleep and wakefulness in ALS. We conducted a qualitative systematic review as per PRISMA guidelines and searched literature assessing the association between disorders of sleep and wakefulness with ALS using the PubMed and Medline database. Overall, 50-63% of patients with ALS have poor sleep quality as reported using the Pittsburgh Sleep Quality Index Questionnaire (PSQI). A higher proportion of ALS patients are categorized as poor sleepers, however there is conflicting evidence as to whether patients with ALS are more likely to exhibit excessive daytime sleepiness. Of the studies that utilized polysomnography, all reported various degrees of impairment to sleep microstructure and architecture among ALS patients. In future, longitudinal clinical studies will be essential for establishing the significance of impaired sleep in ALS. Future studies are also needed to establish whether the self-reported measures of poor sleep and impairment to sleep architecture occurs as a direct consequence of the disease, whether they are an early manifestation of the disease, and/or if they contribute to the neurodegenerative process.
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http://dx.doi.org/10.1080/21678421.2020.1844755DOI Listing
November 2020

Clinical and electrophysiological examination of pinch strength in patients with amyotrophic lateral sclerosis.

Muscle Nerve 2021 01 9;63(1):108-113. Epub 2020 Nov 9.

Department of Neurology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.

Background: The split-hand concept has highlighted the preferential wasting of the thenar side of the hand in amyotrophic lateral sclerosis (ALS). Our objective is to re-explore pinch grip strength to assess whether it has the potential to be a practical biomarker of ALS.

Methods: We measured different pinch grip strengths (thumb, index, and fifth) using a pinch gauge from both hands of 54 ALS patients and correlated this with the Medical Research Council (MRC) score, the upper-limb component of the revised ALS Functional Rating Scale - Revised (ALSFRS-R) score, and compound muscle action potentials (CMAPs) that comprise the split-hand index.

Results: Pinch grip strength using any of the three fingers showed a positive correlation with its corresponding CMAP, MRC grading, and upper-limb ALSFRS-R score. The thumb pinch showed the strongest correlation with the split-hand index and MRC grading.

Conclusions: Pinch grip strength test using a simple gauge deserves further study as a potentially practical biomarker of ALS.
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http://dx.doi.org/10.1002/mus.27111DOI Listing
January 2021

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.

Cell Rep 2020 Oct;33(4):108323

Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK; King's College Hospital, Bessemer Road, London SE5 9RS, UK.

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), 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.
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http://dx.doi.org/10.1016/j.celrep.2020.108323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610013PMC
October 2020

Biclonal lymphoproliferative disorders: another association with NOTCH1-mutated chronic lymphocytic leukaemias.

Ir J Med Sci 2020 Oct 17. Epub 2020 Oct 17.

Department of Cancer Molecular Diagnostics, St. James's Hospital, Dublin, Ireland.

Introduction: Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence.

Methods: We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated.

Results: Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up.

Conclusion: In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.
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http://dx.doi.org/10.1007/s11845-020-02386-1DOI Listing
October 2020

Association of mild cognitive impairment and characteristic of COPD and overall health status in a cohort study.

Expert Rev Respir Med 2021 Jan 18;15(1):153-159. Epub 2020 Nov 18.

Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine , Houston, United States.

: We evaluated risk factors and demographic characteristics of associated with mild cognitive impairment (MCI) in patients with COPD. : 220 individuals with COPD enrolled in a cohort study designed to evaluate anxiety conducted at 16 clinical centers. Cognitive impairment was assessed with the Montreal Cognitive Assessment (MoCA), a cutoff score of <26 defined as MCI. Data were collected including spirometry, 6-minute walk test, symptom burden by COPD Assessment Test and dyspnea by Modified Medical Research Council, anxiety measured by Anxiety Inventory of Respiratory Disease, Generalized Anxiety Disorder-7 and Hospital Anxiety Depression Scale, depression by Patient Health Questionnaire-9 and health status by Patient Reported Outcomes Measurement Information System and sleep quality by the Pittsburg Sleep Quality Index. : The median age was 65 years and 54% of participants were male. 119(54%) of participants had MCI as classified by MoCA. In multivariable logistic regression, higher odds ratios (OR) (95% confidence interval) for MCI (MoCA) <26 were associated with increased years of age, 1.06 (1.02 -1-09, p<0.003); African-American race, 3.68(1.67-8.11, p<0.001); persistent phlegm, 2 (1.12-3.57, p<0.01) and sleep disturbance, 1.04(1.01-1.08, p<0.01). : COPD patients commonly screen positive for MCI. Characteristics associated with MCI included age, African-American race, sleep disturbance and persistent phlegm.
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http://dx.doi.org/10.1080/17476348.2021.1838278DOI Listing
January 2021

Monocytes and neutrophils are associated with clinical features in amyotrophic lateral sclerosis.

Brain Commun 2020 14;2(1):fcaa013. Epub 2020 Feb 14.

School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.

Immunity has emerged as a key player in neurodegenerative diseases such as amyotrophic lateral sclerosis, with recent studies documenting aberrant immune changes in patients and animal models. A challenging aspect of amyotrophic lateral sclerosis research is the heterogeneous nature of the disease. In this study, we investigate the associations between peripheral blood myeloid cell populations and clinical features characteristic of amyotrophic lateral sclerosis. Peripheral blood leukocytes from 23 healthy controls and 48 patients with amyotrophic lateral sclerosis were analysed to measure myeloid cell alterations. The proportion of monocytes (classical, intermediates and non-classical subpopulations) and neutrophils, as well as the expression of select surface markers, were quantitated using flow cytometry. Given the heterogeneous nature of amyotrophic lateral sclerosis, multivariable linear analyses were performed to investigate associations between patients' myeloid profile and clinical features, such as the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, bulbar subscore of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale over disease duration and respiratory function. We demonstrate a shift in monocyte subpopulations in patients with amyotrophic lateral sclerosis, with the ratio of classical to non-classical monocytes increased compared with healthy controls. In line with this, patients with greater disease severity, as determined by a lower Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score, had reduced non-classical monocytes. Interestingly, patients with greater bulbar involvement had a reduction in the proportions of classical, intermediate and non-classical monocyte populations. We also revealed several notable associations between myeloid marker expression and clinical features in amyotrophic lateral sclerosis. CD16 expression on neutrophils was increased in patients with greater disease severity and a faster rate of disease progression, whereas HLA-DR expression on all monocyte populations was elevated in patients with greater respiratory impairment. This study demonstrates that patients with amyotrophic lateral sclerosis with distinct clinical features have differential myeloid cell signatures. Identified cell populations and markers may be candidates for targeted mechanistic studies and immunomodulation therapies in amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530830PMC
February 2020

The spectrum of language impairments in amyotrophic lateral sclerosis.

Cortex 2020 Nov 18;132:349-360. Epub 2020 Sep 18.

Neuropsychology Research Unit, School of Psychology, The University of Queensland, St Lucia, Brisbane, QLD, Australia; Neurology, Royal Brisbane and Women's Hospital, Heston, Brisbane, QLD, Australia; Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, Australia. Electronic address:

Language disorders are increasingly recognised in Amyotrophic lateral sclerosis (ALS), supporting the view of ALS as a multi-system disorder, impacting cognitive and motor function. However, the language impairments are heterogeneous and recent focus has been on determining the language profile across the ALS spectrum with little focus on spontaneous speech. The current study systematically investigated a wide range of language abilities in an unselected ALS sample (N = 22), including spontaneous speech. We analysed the ALS patients' performance as a group, compared to age-, education- and IQ-matched healthy controls (N = 21), and as a case series to identify dementia and specific language profiles. The ALS group was impaired on measures of spontaneous speech, word fluency and action naming. By contrast, object naming, semantic memory (object and actions), sentence comprehension and repetition (word and sentences) were comparable to healthy controls. In line with recent suggestions, our ALS patients' action naming (but not action semantic) deficit does not support the notion that action processing may be selectively impaired in ALS. The case series demonstrated that 14% of patients had probable dementia, 31% showed significant cognitive and/or language impairment and 55% were unimpaired, consistent with the spectrum of cognitive and language impairments reported in the literature. In addition, 36% of ALS patients produced significantly fewer words per minute on a spontaneous speech task than the control group, with this difference remaining when the ALS patients with frontotemporal dementia were excluded from the analysis. This pattern was observed across the ALS spectrum and in both limb and bulbar onset patients. The pattern of performance observed in the present study suggests that spontaneous speech is reduced across the ALS spectrum even in those with intact core language abilities.
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http://dx.doi.org/10.1016/j.cortex.2020.09.003DOI Listing
November 2020

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of In Patients With ALS.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Sep 24:1-13. Epub 2020 Sep 24.

Cytokinetics, Inc, South San Francisco, CA, USA.

Objective: To evaluate safety, dose response, and preliminary efficacy of over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Patients ( = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance ( = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,  = 0.09; muscle strength mega-score,  = 0.31). Post hoc analyses pooling all active -treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
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http://dx.doi.org/10.1080/21678421.2020.1822410DOI Listing
September 2020

Artificial Intelligence Solutions for Analysis of X-ray Images.

Can Assoc Radiol J 2021 Feb 6;72(1):60-72. Epub 2020 Aug 6.

Department of Medical Imaging, Royal University Hospital, 7235University of Saskatchewan, Saskatoon, Canada.

Artificial intelligence (AI) presents a key opportunity for radiologists to improve quality of care and enhance the value of radiology in patient care and population health. The potential opportunity of AI to aid in triage and interpretation of conventional radiographs (X-ray images) is particularly significant, as radiographs are the most common imaging examinations performed in most radiology departments. Substantial progress has been made in the past few years in the development of AI algorithms for analysis of chest and musculoskeletal (MSK) radiographs, with deep learning now the dominant approach for image analysis. Large public and proprietary image data sets have been compiled and have aided the development of AI algorithms for analysis of radiographs, many of which demonstrate accuracy equivalent to radiologists for specific, focused tasks. This article describes (1) the basis for the development of AI solutions for radiograph analysis, (2) current AI solutions to aid in the triage and interpretation of chest radiographs and MSK radiographs, (3) opportunities for AI to aid in noninterpretive tasks related to radiographs, and (4) considerations for radiology practices selecting AI solutions for radiograph analysis and integrating them into existing IT systems. Although comprehensive AI solutions across modalities have yet to be developed, institutions can begin to select and integrate focused solutions which increase efficiency, increase quality and patient safety, and add value for their patients.
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http://dx.doi.org/10.1177/0846537120941671DOI Listing
February 2021

Serial MRI studies over 12 months using manual and atlas-based region of interest in patients with amyotrophic lateral sclerosis.

BMC Med Imaging 2020 08 3;20(1):90. Epub 2020 Aug 3.

The University of Queensland, Centre for Clinical Research, Brisbane, Australia.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of upper and lower motor neurons. There is a need for an imaging biomarker to track disease progression. Previously, magnetic resonance imaging (MRI) has shown loss of grey and white matter in the brain of patients with ALS compared to controls. We performed serial diffusion tractography imaging (DTI) study of patients with ALS looking for changes over time.

Methods: On all subjects (n = 15), we performed three MRI studies at 6 month intervals. DTI changes were assessed with tract-based spatial statistics (TBSS) and region of interest (ROI) studies. Cortic-spinal tract (CST) was selected for our ROI at the upper level; the posterior limb of internal capsule (PLIC), and a lower level in the pons.

Results: There was no significant change in DTI measures over 12 months of observation. Better correlation of manual and atlas-based ROI methods was found in the posterior limb of the internal capsule than the pons.

Conclusion: While previous DTI studies showed significant differences between ALS subjects and controls, within individual subjects there is little evidence of progression over 12 months. This suggests that DTI is not a suitable biomarker to assess disease progression in ALS.
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http://dx.doi.org/10.1186/s12880-020-00489-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397614PMC
August 2020

Subcutaneous administration of benzathine benzylpenicillin G has favourable pharmacokinetic characteristics for the prevention of rheumatic heart disease compared with intramuscular injection: a randomized, crossover, population pharmacokinetic study in healthy adult volunteers.

J Antimicrob Chemother 2020 10;75(10):2951-2959

Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.

Background: Benzathine penicillin G has been used as monthly deep intramuscular (IM) injections since the 1950s for secondary prevention of acute rheumatic fever and rheumatic heart disease (RHD). Injection frequency and pain are major programmatic barriers for adherence, prompting calls for development of better long-acting penicillin preparations to prevent RHD. We hypothesized that subcutaneous (SC) administration of benzathine penicillin G could delay penicillin absorption when compared with IM injections.

Methods: To compare the pharmacokinetic profile and tolerability of benzathine penicillin G according to different routes of administration, 15 healthy males participated in a randomized crossover study to receive benzathine penicillin G by either SC or IM routes, with a 10 week washout period before the second dose by the alternative route. Ultrasound guidance confirmed injection location. Penicillin concentrations and pain scores were measured for 6 weeks following injections.

Results: SC administration was well tolerated with no significant differences in pain scores. Following SC injection, the principal absorption half-life (95% CI) was 20.1 (16.3-29.5) days and 89.6% (87.1%-92.0%) of the drug was directed via this pathway compared with 10.2 (8.6-12.5) days and 71.3% (64.9%-77.4%) following IM administration. Lower peak and higher trough penicillin concentrations resulted following SC injection. Simulations demonstrated that SC infusion of higher doses of benzathine penicillin G could provide therapeutic penicillin concentrations for 3 months.

Conclusions: SC administration of benzathine penicillin G is safe and significantly delays penicillin absorption. High-dose benzathine penicillin G via the SC route would fulfil many product characteristics required for the next generation of longer-acting penicillins for use in RHD.
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http://dx.doi.org/10.1093/jac/dkaa282DOI Listing
October 2020

Biomarkers of Type 2 Airway Inflammation as Predictors of Loss of Asthma Control During Step-Down Therapy for Well-Controlled Disease: The Long-Acting Beta-Agonist Step-Down Study (LASST).

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3474-3481. Epub 2020 Jul 18.

Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking.

Objective: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down.

Methods: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator).

Results: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (<25 parts per billion), those with intermediate (25-50 parts per billion) and high (>50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers.

Conclusions: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.
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http://dx.doi.org/10.1016/j.jaip.2020.06.067DOI Listing
July 2020

Sustainable quality and safety improvement in healthcare: further lessons from the aviation industry.

Br J Anaesth 2020 10 15;125(4):425-429. Epub 2020 Jul 15.

Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand; Department of Anaesthesia, Auckland City Hospital, Auckland, New Zealand.

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http://dx.doi.org/10.1016/j.bja.2020.06.045DOI Listing
October 2020

Progression and survival of patients with motor neuron disease relative to their fecal microbiota.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 9;21(7-8):549-562. Epub 2020 Jul 9.

Wesley Medical Research, The Wesley Hospital, Brisbane, QLD, Australia.

Gut microbiota studies have been well-investigated for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, however, fewer studies have comprehensively examined the gut microbiome in Motor Neuron Disease (MND), with none examining its impact on disease prognosis. Here, we investigate MND prognosis and the fecal microbiota, using 16S rRNA case-control data from 100 individuals with extensive medical histories and metabolic measurements. We contrast the composition and diversity of fecal microbiome signatures from 49 MND and 51 healthy controls by combining current gold-standard 16S microbiome pipelines. Using stringent quality control thresholds, we conducted qualitative assessment approaches including; direct comparison of taxa, PICRUSt2 predicted metagenomics, Shannon and Chao1-index and Firmicutes/Bacteroidetes ratio. We show that the fecal microbiome of patients with MND is not significantly different from that of healthy controls that were matched by age, sex, and BMI, however there are distinct differences in Beta-diversity in some patients with MND. Weight, BMI, and metabolic and clinical features of disease in patients with MND were not related to the composition of their fecal microbiome, however, we observe a greater risk for earlier death in patients with MND with increased richness and diversity of the microbiome, and in those with greater Firmicutes to Bacteroidetes ratio. This was independent of anthropometric, metabolic, or clinical features of disease, and warrants support for further gut microbiota studies in MND. Given the disease heterogeneity in MND, and complexity of the gut microbiota, large studies are necessary to determine the detailed role of the gut microbiota and MND prognosis.
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http://dx.doi.org/10.1080/21678421.2020.1772825DOI Listing
November 2020

Misaligned foveal morphology and sector retinal dysfunction in AKT1-mosaic Proteus syndrome.

Doc Ophthalmol 2021 Feb 2;142(1):119-126. Epub 2020 Jul 2.

Clinical and Academic Department of Ophthalmology, Great Ormond Street Hospital for Children, London, UK.

Purpose: Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome.

Methods: Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics.

Results: Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina.

Conclusion: We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.
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http://dx.doi.org/10.1007/s10633-020-09778-9DOI Listing
February 2021

What do we know about the variability in survival of patients with amyotrophic lateral sclerosis?

Expert Rev Neurother 2020 09 7;20(9):921-941. Epub 2020 Aug 7.

Centre for Clinical Research, The University of Queensland , Brisbane, Australia.

Introduction: ALS is a fatal neurodegenerative disease. However, patients show variability in the length of survival after symptom onset. Understanding the mechanisms of long survival could lead to possible avenues for therapy.

Areas Covered: This review surveys the reported length of survival in ALS, the clinical features that predict survival in individual patients, and possible factors, particularly genetic factors, that could cause short or long survival. The authors also speculate on possible mechanisms.

Expert Opinion: a small number of known factors can explain some variability in ALS survival. However, other disease-modifying factors likely exist. Factors that alter motor neurone vulnerability and immune, metabolic, and muscle function could affect survival by modulating the disease process. Knowing these factors could lead to interventions to change the course of the disease. The authors suggest a broad approach is needed to quantify the proportion of variation survival attributable to genetic and non-genetic factors and to identify and estimate the effect size of specific factors. Studies of this nature could not only identify novel avenues for therapeutic research but also play an important role in clinical trial design and personalized medicine.
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http://dx.doi.org/10.1080/14737175.2020.1785873DOI Listing
September 2020

Levels of clusterin, CD5L, ficolin-3, and gelsolin in ALS patients and controls.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 19;21(7-8):631-634. Epub 2020 Jun 19.

UQ Centre for Clinical Research, The University of Queensland, Brisbane, Australia and.

In amyotrophic lateral sclerosis, there is a need for biomarkers to distinguish patients from controls, to follow disease progression and to provide information about the pathogenesis of disease. In a previous mass spectrometry study that searched for potential proteins of interest, we identified clusterin, CD5L, ficolin-3, and gelsolin as molecules that differed in abundance between ALS patients and controls, with a greater difference in patients with cognitive impairment. Here, we have measured levels of these molecules in plasma from a separate cohort of ALS patients and controls. The plasma was depleted of abundant plasma proteins. We confirmed our previous findings that levels of clusterin are decreased and ficolin-3 are increased in ALS patients compared to controls. In this study, we found that levels of CD5L were increased in patients with ALS and levels correlated with survival. We found that levels of gelsolin were modestly increased in ALS compared to controls whereas in our previous study these were decreased, especially in patients with cognitive impairment who were not included in this study. We suggest that clusterin and ficolin-3 deserve further study as potential ALS biomarkers.
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http://dx.doi.org/10.1080/21678421.2020.1779303DOI Listing
November 2020