Publications by authors named "Alexander Thompson"

288 Publications

Effect of competing mortality risks on predictive performance of the QRISK3 cardiovascular risk prediction tool in older people and those with comorbidity: external validation population cohort study.

Lancet Healthy Longev 2021 Jun;2(6):e352-e361

Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: Primary prevention of cardiovascular disease (CVD) is guided by risk-prediction tools, but these rarely account for the risk of dying from other conditions (ie, competing mortality risk). In England and Wales, the recommended risk-prediction tool is QRISK2, and a new version (QRISK3) has been derived and internally validated. We aimed to externally validate QRISK3 and to assess the effects of competing mortality risk on its predictive performance.

Methods: For this retrospective population cohort study, we used data from the Clinical Practice Research Datalink. We included patients aged 25-84 years with no previous history of CVD or statin treatment who were permanently registered with a primary care practice, had up-to-standard data for at least 1 year, and had linkage to Hospital Episode Statistics discharge and Office of National Statistics mortality data. We compared the QRISK3-predicted 10-year CVD risk with the observed 10-year risk in the whole population and in important subgroups of age and multimorbidity. QRISK3 discrimination and calibration were examined with and without accounting for competing risks.

Findings: Our study population included 1 484 597 women with 42 451 incident CVD events (4·9 cases per 1000 person-years of follow-up, 95% CI 4·89-4·99), and 1 420 176 men with 53 066 incident CVD events (6·7 cases per 1000 person-years, 6·66-6·78), with median follow-up of 5·0 years (IQR 1·9-9·2). Non-CVD death rose markedly with age (0·4% of women and 0·5% of men aged 25-44 years had a non-CVD death 20·1% of women and 19·6% of men aged 75-84 years). QRISK3 discrimination in the whole population was excellent (Harrell's C-statistic 0·865 in women and 0·834 in men) but was poor in older age groups (<0·65 in all subgroups aged 65 years or older). Ignoring competing risks, QRISK3 calibration in the whole population and in younger people was excellent, but there was significant over-prediction in older people. Accounting for competing risks, QRISK3 systematically over-predicted CVD risk, particularly in older people and in those with high multimorbidity.

Interpretation: QRISK3 performed well at the whole population level when ignoring competing mortality risk. The tool performed considerably less well in important subgroups, including older people and people with multimorbidity, and less well again after accounting for competing mortality risk.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S2666-7568(21)00088-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175241PMC
June 2021

Operational research for the safe and effective design of COVID-19 mass vaccination centres.

Vaccine 2021 06 14;39(27):3537-3540. Epub 2021 May 14.

Centre for Healthcare Improvement and Innovation, School of Management, University of Bath, Bath, UK.

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http://dx.doi.org/10.1016/j.vaccine.2021.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120437PMC
June 2021

Quantifying early gastric cancer in Australia: What is the opportunity for gastric endoscopic submucosal dissection?

J Gastroenterol Hepatol 2021 May 22. Epub 2021 May 22.

Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.

Background And Aims: Endoscopic submucosal dissection (ESD) is the recommended treatment for early gastric cancer (EGC). However, there are challenges in attaining expertise in ESD in countries where the incidence of gastric cancer and proportion diagnosed at an early stage of disease are relatively low. This study aims to establish the proportion of gastric cancer meeting histological criteria for EGC, which may be suitable for ESD, in a Western population.

Methods: Gastric cancers reported to the Victorian Cancer Registry between January 2011 and December 2016 were analyzed. EGC was defined as tumor confined to mucosa (T1a) or submucosa (T1b). Histology reports were analyzed using Japanese and European guidelines to identify potential ESD candidates. Criteria for extended ESD were based on grade of differentiation, tumor depth, lymphovascular and perineural invasion, and ulceration.

Results: Twenty percent of 1217 gastric cancers was EGC (237 cases), with detailed histopathology reports suitable for evaluating ESD criteria recorded in 182 cases. Standard and extended ESD criteria were met in 46% (84/182) and 75% (132/182), respectively. Actual treatment of the 237 EGC was endoscopic in 14% (n = 33) and surgery in 86% (n = 204). Endoscopically treated EGCs were more likely to be stage T1a and located in the proximal stomach.

Conclusions: EGCs represented 20% of reported gastric adenocarcinomas with the majority fulfilling criteria for ESD. ESD should be considered in the management algorithm and discussed at tumor board meetings involving interventional endoscopists. To increase utilization of ESD, systems need to be implemented to improve training, accreditation, and access to ESD.
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http://dx.doi.org/10.1111/jgh.15552DOI Listing
May 2021

Antiviral kinetics of tenofovir alafenamide and tenofovir disoproxil fumarate over 24 weeks in women of childbearing potential with chronic HBV.

PLoS One 2021 13;16(5):e0251552. Epub 2021 May 13.

New Zealand Liver Transplant Unit, Auckland Clinical Studies, Auckland, New Zealand.

Background/purpose: Use of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV.

Methods: In a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA <200,000 IU/mL at weeks 12 and 24 were assessed. Multivariate logistic regression was used to identify factors predictive of failure to suppress HBV DNA to the target level.

Results: In 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA <200,000 IU/mL at weeks 12 and 24, respectively. Results for TAF (n = 194) vs TDF (n = 81) treatment were similar at weeks 12 and 24 (94% vs. 90% and 97% vs. 93%), respectively. High baseline HBV DNA level, genotype D infection, and prior interferon (week 24 only) were predictive of failure to achieve the target level. Both treatments were well tolerated with TAF showing less impact on renal and bone parameters.

Conclusions: In WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251552PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118264PMC
May 2021

Provision of interaural time difference information in chronic intracochlear electrical stimulation enhances neural sensitivity to these differences in neonatally deafened cats.

Hear Res 2021 Jul 23;406:108253. Epub 2021 Apr 23.

Bionics Institute, Melbourne, Victoria, Australia; Medical Bionics Department, University of Melbourne, Melbourne, Victoria, Australia.. Electronic address:

Although performance with bilateral cochlear implants is superior to that with a unilateral implant, bilateral implantees have poor performance in sound localisation and in speech discrimination in noise compared to normal hearing subjects. Studies of the neural processing of interaural time differences (ITDs) in the inferior colliculus (IC) of long-term deaf animals, show substantial degradation compared to that in normal hearing animals. It is not known whether this degradation can be ameliorated by chronic cochlear electrical stimulation, but such amelioration is unlikely to be achieved using current clinical speech processors and cochlear implants, which do not provide good ITD cues. We therefore developed a custom sound processor to deliver salient ITDs for chronic bilateral intra-cochlear electrical stimulation in a cat model of neonatal deafness, to determine if long-term exposure to salient ITDs would prevent degradation of ITD processing. We compared the sensitivity to ITDs in cochlear electrical stimuli of neurons in the IC of cats chronically stimulated with our custom ITD-aware sound processor with sensitivity in acutely deafened cats with normal hearing development and in cats chronically stimulated with a clinical stimulator and sound processor. Animals that experienced stimulation with our custom ITD-aware sound processor had significantly higher neural sensitivity to ITDs than those that received stimulation from clinical sound processors. There was no significant difference between animals received no stimulation and those that received stimulation from clinical sound processors, consistent with findings from clinical cochlear implant users. This result suggests that development and use of clinical ITD-aware sound processing strategies from a young age may promote ITD sensitivity in the clinical population.
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http://dx.doi.org/10.1016/j.heares.2021.108253DOI Listing
July 2021

Non-neuronal cells in amyotrophic lateral sclerosis - from pathogenesis to biomarkers.

Nat Rev Neurol 2021 Jun 29;17(6):333-348. Epub 2021 Apr 29.

Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.

The prevailing motor neuron-centric view of amyotrophic lateral sclerosis (ALS) pathogenesis could be an important factor in the failure to identify disease-modifying therapy for this neurodegenerative disorder. Non-neuronal cells have crucial homeostatic functions within the CNS and evidence of involvement of these cells in the pathophysiology of several neurodegenerative disorders, including ALS, is accumulating. Microglia and astrocytes, in crosstalk with peripheral immune cells, can exert both neuroprotective and adverse effects, resulting in a highly nuanced range of neuronal and non-neuronal cell interactions. This Review provides an overview of the diverse roles of non-neuronal cells in relation to the pathogenesis of ALS and the emerging potential of non-neuronal cell biomarkers to advance therapeutic development.
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http://dx.doi.org/10.1038/s41582-021-00487-8DOI Listing
June 2021

Patient-reported outcomes of the Treatment and Prevention Study: A real-world community-based trial of direct-acting antivirals for hepatitis C among people who inject drugs.

J Viral Hepat 2021 Jul 3;28(7):1068-1077. Epub 2021 May 3.

Burnet Institute, Melbourne, Vic., Australia.

The impact of hepatitis C cure with direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) in community settings remains unclear. We aimed to assess changes in PROs over time and whether treatment was associated with sustained improved PROs in a cohort of people who inject drugs. This study is a sub-analysis of the Treatment and Prevention Study, a nurse-led trial where people who inject drugs and their injecting partners were recruited in a community setting, in Melbourne, Australia. Three participant groups were characterized: treatment, untreated and non-viremic (hepatitis C RNA negative at screening). PROs included assessment of health-related quality of life using the Short Form-8 (SF-8) Survey and life satisfaction using Personal Wellbeing Index (PWI). PROs were measured at baseline and every 12 weeks until week 84. Generalized estimating equations were used to measure whether treatment was associated with longitudinal PRO change. A total of 215 participants were included in this analysis. PWI scores were significantly higher at week 12 for both treatment group (p = 0.0309) and non-viremic group (p = 0.0437) compared to baseline. However, treatment was not associated with longitudinal change in PRO scores. In conclusion, we found DAA treatment did not significantly improve PRO scores compared to those not receiving treatment and without hepatitis C. The measures used in this study may not be sensitive enough to capture the hepatitis C specific improvements in quality of life that treatment affords or factors other than treatment may be influencing quality of life scores in this cohort.
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http://dx.doi.org/10.1111/jvh.13516DOI Listing
July 2021

Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS.

Front Neurosci 2021 17;15:642324. Epub 2021 Mar 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Background: Amyotrophic lateral sclerosis is a clinical syndrome with complex biological determinants, but which in most cases is characterized by TDP-43 pathology. The identification in CSF of a protein signature of TDP-43 network dysfunction would have the potential to inform the identification of new biomarkers and therapeutic targets.

Methods: We compared CSF proteomic data from patients with ALS ( = 41), Parkinson's disease ( = 19) and healthy control participants ( = 20). Weighted correlation network analysis was used to identify modules within the CSF protein network and combined with gene ontology enrichment analysis to functionally annotate module proteins. Analysis of module eigenproteins and differential correlation analysis of the CSF protein network was used to compare ALS and Parkinson's disease protein co-correlation with healthy controls. In order to monitor temporal changes in the CSF proteome, we performed longitudinal analysis of the CSF proteome in a subset of ALS patients.

Results: Weighted correlation network analysis identified 10 modules, including those enriched for terms involved in gene expression including nucleic acid binding, RNA metabolism and translation; humoral immune system function, including complement pathways; membrane proteins, axonal outgrowth and adherence; and glutamatergic synapses. Immune system module eigenproteins were increased in ALS, whilst axonal module eigenproteins were decreased in ALS. The 19 altered protein correlations in ALS were enriched for gene expression (OR 3.05, = 0.017) and membrane protein modules (OR 17.48, = 0.011), including intramodular hub proteins previously identified as TDP-43 interactors. Proteins decreasing over longitudinal analysis ALS were enriched in glutamatergic synapse and axonal outgrowth modules. Protein correlation network disruptions in Parkinson's disease showed no module enrichment.

Conclusions: Alterations in the co-correlation network in CSF samples identified a set of pathways known to be associated with TDP-43 dysfunction in the pathogenesis of ALS, with important implications for therapeutic targeting and biomarker development.
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http://dx.doi.org/10.3389/fnins.2021.642324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010303PMC
March 2021

A costing analysis of a state-wide, nurse-led hepatitis C treatment model in prison.

Int J Drug Policy 2021 Mar 18;94:103203. Epub 2021 Mar 18.

Disease Elimination Program, Burnet Institute, Melbourne, Victoria, Australia; School of Population Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Background: Hepatitis C is highly prevalent among prisoners. The simplicity of direct-acting antiviral (DAA) treatment for hepatitis C makes it possible to use novel models of care to increase treatment uptake within prisons. We estimate the average non-drug cost of initiating a prisoner on treatment using real world data from the State-wide Hepatitis Program (SHP) in Victoria, Australia - a coordinated nurse-led model of care.

Methods: Data were considered from prisoners presenting to the SHP (following antibody-positive diagnosis) during the evaluation period, November 2015 to December 2016. All costs associated with the SHP were estimated, including staffing salaries, medical tests, pharmacy costs and overhead costs. DAA costs were excluded as in Australia an unlimited number are available, covered by a federal government risk-sharing agreement with pharmaceutical companies. The average non-drug cost of treatment initiation through the SHP was compared to equivalent costs from primary and hospital-based models of care in the community.

Results: The total non-drug cost accumulated by prisoners in the SHP was AUD$749,470 (uncertainty range: AUD$728,905-794,111). 659/803 were PCR positive, 424/659 had sentences long enough to be eligible for treatment, and 416/424 were initiated on treatment, resulting in an average non-drug cost of AUD$1,802 (95% CI: AUD$1799-1841) per prisoner initiated. A protocol change allowing prisoners with short sentences to start treatment reduced the average non-drug cost to AUD$1263 (95% CI: AUD$1263-1287) per prisoner initiating treatment - 11% and 56% cheaper than estimated equivalent costs in primary (AUD$1654) and hospital-based (AUD$2847) models of care in the community, respectively.

Conclusion: Delivering hepatitis C treatment in prison using a nurse-led model of care is cheaper than delivering treatment in the community. These findings provide an economic rationale for implementing coordinated prison-based hepatitis C treatment programs.
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http://dx.doi.org/10.1016/j.drugpo.2021.103203DOI Listing
March 2021

Response of primary auditory neurons to stimulation with infrared light in vitro.

J Neural Eng 2021 03 16;18(4):046003. Epub 2021 Mar 16.

Faculty of Science, Engineering and Technology, Swinburne University of Technology, John Street, Hawthorn VIC 3122, Australia.

Objective: Infrared light can be used to modulate the activity of neuronal cells through thermally-evoked capacitive currents and thermosensitive ion channel modulation. The infrared power threshold for action potentials has previously been found to be far lower in the in vivo cochlea when compared with other neuronal targets, implicating spiral ganglion neurons (SGNs) as a potential target for infrared auditory prostheses. However, conflicting experimental evidence suggests that this low threshold may arise from an intermediary mechanism other than direct SGN stimulation, potentially involving residual hair cell activity.

Approach: Patch-clamp recordings from cultured SGNs were used to explicitly quantify the capacitive and ion channel currents in an environment devoid of hair cells. Neurons were irradiated by a 1870 nm laser with pulse durations of 0.2-5.0 ms and powers up to 1.5 W. A Hodgkin-Huxley-type model was established by first characterising the voltage dependent currents, and then incorporating laser-evoked currents separated into temperature-dependent and temperature-gradient-dependent components. This model was found to accurately simulate neuronal responses and allowed the results to be extrapolated to stimulation parameter spaces not accessible during this study.

Main Results: The previously-reported low in vivo SGN stimulation threshold was not observed, and only subthreshold depolarisation was achieved, even at high light exposures. Extrapolating these results with our Hodgkin-Huxley-type model predicts an action potential threshold which does not deviate significantly from other neuronal types.

Significance: This suggests that the low-threshold response that is commonly reported in vivo may arise from an alternative mechanism, and calls into question the potential usefulness of the effect for auditory prostheses. The step-wise approach to modelling optically-evoked currents described here may prove useful for analysing a wider range of cell types where capacitive currents and conductance modulation are dominant.
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http://dx.doi.org/10.1088/1741-2552/abe7b8DOI Listing
March 2021

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

Inflamm Bowel Dis 2021 Mar 11. Epub 2021 Mar 11.

Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Australia.

Background: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD.

Methods: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction.

Results: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent.

Conclusions: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.
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http://dx.doi.org/10.1093/ibd/izab021DOI Listing
March 2021

Immunosuppression as a risk factor for COVID-19: a meta-analysis.

Intern Med J 2021 02;51(2):199-205

Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia.

Background: While immunosuppression poses a theoretical increase in the risk of COVID-19, the nature of this relationship is yet to be ascertained.

Aims: To determine whether immunosuppressed patients are at higher risk of COVID-19 to help inform the management of patients receiving immunosuppressant therapies during the pandemic.

Methods: We performed a random-effects meta-analysis of data from studies that reported on the prevalence of immunosuppression among patient cohorts with COVID-19.

Results: Sixty full-text publications were identified. In total, six individual studies were included in the final analysis, contributing a total of 10 049 patients with COVID-19 disease. The prevalence of immunosuppressed patients among the study cohorts with COVID-19 ranged from 0.126% to 1.357%. In the pooled cohort a total of 64/10 049 (0.637%) patients with COVID-19 disease was immunosuppressed. Observed to expected ratios were used to compare the prevalence of immunosuppression in cohorts with confirmed COVID-19 disease to the background prevalence of immunosuppression in the general community. The observed to expected ratio of immunosuppression among patients with COVID-19 illness, relative to the general community, was 0.12 (95% confidence interval: 0.05-0.27).

Conclusions: Compared to the general population, immunosuppressed patients were not at significantly increased risk of COVID-19 infection. This finding provides support for current expert consensus statements, which have recommended the continuation of immunosuppressant therapy in the absence of COVID-19.
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http://dx.doi.org/10.1111/imj.15142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014211PMC
February 2021

A mechanic with confusion and right-sided weakness.

Pract Neurol 2021 Feb 23. Epub 2021 Feb 23.

Department of Neurology, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, UK.

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http://dx.doi.org/10.1136/practneurol-2020-002862DOI Listing
February 2021

Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates.

Aliment Pharmacol Ther 2021 04 19;53(7):810-820. Epub 2021 Feb 19.

Melbourne, Vic., Australia.

Background: Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined.

Aims: To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes.

Methods: Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre-conception, in each trimester, at delivery and post-partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved.

Results: Forty patients were included with measurements on at least two occasions, and two with only mother-baby levels at delivery. The median maternal 6-TGN level dropped in the second trimester compared with post-partum (179.0 vs 323.5 pmol/8 × 10 RBCs, P < 0.001) and the median 6-MMP level increased in the second trimester compared with post-partum (1103.0 vs 329.5 pmol/8 × 10 RBCs, P < 0.01). At delivery, the median 6-TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 10 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved.

Conclusions: 6-TGN levels decrease and 6-MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear.
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http://dx.doi.org/10.1111/apt.16294DOI Listing
April 2021

Producing health information in consultation with health workers and the hepatitis B-affected communities is worthwhile.

Aust J Prim Health 2021 Feb 15. Epub 2021 Feb 15.

Globally, approximately 257 million people are living with chronic hepatitis B. Many people are undiagnosed, have low health literacy and experience barriers to engaging in care. In Australia, there is a lack of culturally and linguistically appropriate resources to support people living with the infection to increase their understanding and build their capacity. This innovative practice paper describes the process of developing a culturally and linguistically appropriate resource using the principles of participatory action research. The hepatitis B story was designed to facilitate discussion between healthcare workers and consumers, and to increase the knowledge and understanding of both. Consultation with consumers and a broad range of health services contributed to the quality of and demand for the resource. A case study tells the story of 'Thuy'. This case study demonstrates the practical application of the resource and describes the positive affect its use had on Thuy and her family. Increasing our understandings of how people experience chronic hepatitis B is crucial to improving health information, testing and engagement in care. Producing health information with consumers is a worthwhile process to increase consumers' health literacy and improve service delivery.
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http://dx.doi.org/10.1071/PY20188DOI Listing
February 2021

Long-term outcomes of perianal fistulizing Crohn's disease in the biologic era.

JGH Open 2021 Feb 20;5(2):235-241. Epub 2020 Dec 20.

Department of Gastroenterology St Vincent's Hospital Melbourne Victoria Australia.

Background And Aim: While the advent of biologic therapy has led to improved outcomes in perianal fistulizing Crohn's disease (pfCD), loss of response is common. Previous studies suggest that patients who achieve radiological healing (with healing of underlying tracts on magnetic resonance imaging [MRI]) have a longer duration of response. The aim of this study was to characterize MRI outcomes of pfCD at a specialist inflammatory bowel disease (IBD) unit and compare the long-term clinical outcomes between patients achieving MRI and clinical healing.

Methods: A retrospective analysis of perianal fistulizing Crohn's patients treated at one specialist IBD unit was performed. Records were reviewed for patient demographics, disease history, clinical assessments, investigation results, and disease flares. Clinical remission was defined as closure of all baseline fistula openings. Radiological healing was defined as the absence of any T2-hyperintense sinuses, tracts, or collections. The primary end-point was rate of MRI healing. The secondary outcome was defined as flare-free period (time between clinical or radiological healing and patients' first signs/symptoms requiring therapy escalation).

Results: A total of 93 patients were included, with a median follow-up of 4.8 years (interquartile range, 2.4-6 years). Of 44 patients, 22 (50%) achieved clinical remission, while 15 of 93 (16%) achieved radiological healing. Of 22 patients, 10 (45%) with clinical remission had a subsequent disease flare (median time of 7 months) compared with 3 of 15 (20%) patients with MRI healing (median time of 3.6 years). Radiological healing was associated with a significantly longer flare-free period ( = 0.01).

Conclusion: Radiological healing occurs less commonly but represents a deeper form of healing, associated with improved long-term clinical outcomes.
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http://dx.doi.org/10.1002/jgh3.12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857282PMC
February 2021

Determinants of long-term function and general well-being in patients with an ileoanal pouch.

JGH Open 2021 Jan 12;5(1):91-98. Epub 2020 Nov 12.

Department of Gastroenterology St Vincent's Hospital Melbourne Victoria Australia.

Background And Aim: Fecal incontinence and/or evacuation difficulty are common after ileoanal pouch surgery. This study aimed to determine whether the development of these symptoms can be predicted so that preventive measures might be instituted.

Methods: A consecutive series of 46 patients with ulcerative colitis (median age at surgery, 41 years; 50% female) and a functioning pouch for a duration ≥12 months was included. Assessment utilized medical record review and questionnaires on pre- and postoperative bowel function, quality of life, and psychological well-being. Pouch function was assessed by the Colorectal Functional Outcome score (0 = no impairment, 100 = worst impairment). Good pouch function was defined as a score ≤24.

Results: Fecal incontinence occurred in 67% preoperatively and 54% postoperatively; evacuation difficulty occurred in 65% and preoperatively and 85% postoperatively. The postoperative median Colorectal Functional Outcome score was 20 (range 2-74), with 44% of patients >24 (poor pouch function). Preoperative nocturnal fecal incontinence (odds ratio [OR] 4.92, 95% confidence interval [CI] 1.2-19.4, = 0.02) and pouchitis (OR 5.41, 95% CI 1.2-23.7, = 0.02) were associated with poor pouch function after multivariable regression analysis. Postoperative satisfaction, psychological well-being, and quality of life were significantly better in those with good pouch function, while poor sleep, impaired work, and sexual dysfunction were independently associated with poor pouch function.

Conclusions: Functional bowel symptoms are common before and after pouch surgery and are associated with the impairment of patient-reported outcomes. Preoperative nocturnal fecal incontinence predicts poor pouch function. Therapeutic focus on continence, bowel evacuation, psychological well-being, and quality of life should begin before surgery.
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http://dx.doi.org/10.1002/jgh3.12452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812478PMC
January 2021

Addressing pregnancy-related concerns in women with inflammatory bowel disease: Insights from the patient's perspective.

JGH Open 2021 Jan 9;5(1):28-33. Epub 2020 Nov 9.

Department of Gastroenterology St Vincent's Hospital Melbourne Victoria Australia.

Background And Aim: Therapeutic options for inflammatory bowel disease (IBD) have expanded, as has the use of IBD medications in women during the reproductive period. However, no qualitative data exist that examine the pregnancy-related concerns of women with IBD in the current era of widespread immunomodulator and biologic use. Hence, we aimed to explore in detail the impact of IBD on pregnancy from the patient's perspective.

Methods: This qualitative study used semistructured interviews to explore participants' experiences regarding IBD and pregnancy until no new themes emerged. Key themes were identified using thematic analysis.

Results: Fifteen women with IBD were interviewed. The majority of participants reported lingering concerns regarding their IBD medications, despite advice from their gastroenterologist that the drugs were considered safe in pregnancy. Participants more often reported medication-related fears, such as potential negative effects on their child's immune system, than concerns regarding the effect of the disease itself on their pregnancy outcomes. A common theme was a perceived lack of knowledge among non-IBD clinicians regarding IBD medications during pregnancy, which augmented pre-existing anxiety.

Conclusions: This study is the first of its kind to provide an in-depth assessment of female patients' perspectives of IBD in relation to conception, pregnancy, and caring for offspring. In particular, this research characterizes the unique fears and persisting anxieties regarding IBD medications in pregnancy. The study has unearthed important insights into the specific concerns and support needs of women with IBD in order to facilitate nonjudgmental counseling designed around patient concerns and beliefs.
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http://dx.doi.org/10.1002/jgh3.12442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812482PMC
January 2021

Australian recommendations for the management of hepatocellular carcinoma: a consensus statement.

Med J Aust 2021 06 13;214(10):475-483. Epub 2020 Dec 13.

University of New South Wales, Sydney, NSW.

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths both globally and in Australia. Surveillance for HCC in at-risk populations allows diagnosis at an early stage, when potentially curable. However, most Australians diagnosed with HCC die of the cancer or of liver disease. In the changing landscape of HCC management, unique challenges may lead to clinical practice variation. As a result, there is a need to identify best practice management of HCC in an Australian context. This consensus statement has been developed for health professionals involved in the care of adult patients with HCC in Australia. It is applicable to specialists, general medical practitioners, nurses, health coordinators and hospital administrators.

Methods And Recommendations: This statement has been developed by specialists in hepatology, radiology, surgery, oncology, palliative care, and primary care, including medical practitioners and nurses. The statement addresses four main areas relevant to HCC management: epidemiology and incidence, diagnosis, treatment, and patient management. A modified Delphi process was used to reach consensus on 31 recommendations. Principal recommendations include the adoption of surveillance strategies, use of multidisciplinary meetings, diagnosis, treatment options and patient management.

Changes In Management As A Result Of This Statement: This consensus statement will simplify HCC patient management and reduce clinical variation. Ultimately, this should result in better outcomes for patients with HCC.
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http://dx.doi.org/10.5694/mja2.50885DOI Listing
June 2021

Non-invasive fibrosis algorithms are clinically useful for excluding cirrhosis in prisoners living with hepatitis C.

PLoS One 2020 18;15(11):e0242101. Epub 2020 Nov 18.

Department of Gastroenterology, St Vincent's Hospital and the University of Melbourne, Melbourne, Australia.

Background And Aims: Prison-based HCV treatment rates remain low due to multiple barriers, including accessing transient elastography for cirrhosis determination. The AST-to-platelet ratio index (APRI) and FIB-4 scores have excellent negative predictive value (NPV) in hospital cohorts to exclude cirrhosis. We investigated their performance in a large cohort of prisoners with HCV infection.

Methods: This was a retrospective cohort study of participants assessed by a prison-based hepatitis program. The sensitivity, specificity, NPV and positive predictive value (PPV) of APRI and FIB-4 for cirrhosis were then analysed, with transient elastography as the reference standard. The utility of age thresholds as a trigger for transient elastography was also explored.

Results: Data from 1007 prisoners were included. The median age was 41, 89% were male, and 12% had cirrhosis. An APRI cut-off of 1.0 and FIB-4 cut-off of 1.45 had NPVs for cirrhosis of 96.1% and 96.6%, respectively, and if used to triage prisoners for transient elastography, could reduce the need for this investigation by 71%. The PPVs of APRI and FIB-4 for cirrhosis at these cut-offs were low. Age ≤35 years alone had a NPV for cirrhosis of 96.5%. In those >35 years, the APRI cut-off of 1.0 alone had a high NPV >95%.

Conclusion: APRI and FIB-4 scores can reliably exclude cirrhosis in prisoners and reduce requirement for transient elastography. This finding will simplify the cascade of care for prisoners living with hepatitis C.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242101PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673506PMC
December 2020

Point-of-Care Tests for Hepatitis B: An Overview.

Cells 2020 10 2;9(10). Epub 2020 Oct 2.

Burnet Institute, Melbourne, VIC 3004, Australia.

Despite the heavy disease burden posed by hepatitis B, around 90% of people living with hepatitis B are not diagnosed globally. Many of the affected populations still have limited or no access to essential blood tests for hepatitis B. Compared to conventional blood tests which heavily rely on centralised laboratory facilities, point-of-care testing for hepatitis B has the potential to broaden testing access in low-resource settings and to engage hard-to-reach populations. Few hepatitis B point-of-care tests have been ratified for clinical use by international and regional regulatory bodies, and countries have been slow to adopt point-of-care testing into hepatitis B programs. This review presents currently available point-of-care tests for hepatitis B and their roles in the care cascade, reviewing evidence for testing performance, utility, acceptability, costs and cost-effectiveness when integrated into hepatitis B diagnosis and monitoring programs. We further discuss challenges and future directions in aspects of technology, implementation, and regulation when adopting point-of-care testing in hepatitis B programs.
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http://dx.doi.org/10.3390/cells9102233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650625PMC
October 2020

Intravenous versus oral antibiotics for eradication of Pseudomonas aeruginosa in cystic fibrosis (TORPEDO-CF): a randomised controlled trial.

Lancet Respir Med 2020 10;8(10):975-986

Liverpool Clinical Trials Centre, University of Liverpool, Liverpool Health Partners, Liverpool, UK.

Background: Chronic pulmonary infection with Pseudomonas aeruginosa is one of the most important causes of mortality and morbidity in cystic fibrosis. If antibiotics are commenced promptly, infection can be eradicated. The aim of the trial was to compare the effectiveness and safety of intravenous ceftazidime and tobramycin versus oral ciprofloxacin in the eradication of P aeruginosa.

Methods: We did a multicentre, parallel group, open-label, randomised controlled trial in 72 cystic fibrosis centres (70 in the UK and two in Italy). Eligible participants were older than 28 days with an isolate of P aeruginosa (either the first ever isolate or a new isolate after at least 1 year free of infection). Participants were excluded if the P aeruginosa was resistant to, or they had a contraindication to, one or more of the trial antibiotics; if they were already receiving P aeruginosa suppressive therapy; if they had received any P aeruginosa eradication therapy within the previous 9 months; or if they were pregnant or breastfeeding. We used web-based randomisation to assign patients to 14 days intravenous ceftazidime and tobramycin or 12 weeks oral ciprofloxacin. Both were combined with 12 weeks inhaled colistimethate sodium. Randomisation lists were generated by a statistician, who had no involvement in the trial, using a computer-generated list. Randomisation was stratified by centre and because of the nature of the interventions, blinding was not possible. Our primary outcome was eradication of P aeruginosa at 3 months and remaining free of infection to 15 months. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who received at least one dose of study drug. TORPEDO-CF was registered on the ISRCTN register, ISRCTN02734162, and EudraCT, 2009-012575-10.

Findings: Between Oct 5, 2010, and Jan 27, 2017, 286 patients were randomly assigned to treatment: 137 to intravenous antibiotics and 149 to oral antibiotics. 55 (44%) of 125 participants in the intravenous group and 68 (52%) of 130 participants in the oral group achieved the primary outcome. Participants randomly assigned to the intravenous group were less likely to achieve the primary outcome, although the difference between groups was not statistically significant (relative risk 0·84, 95% CI 0·65-1·09; p=0·18). 11 serious adverse events occurred in ten (8%) of 126 participants in the intravenous antibiotics group and 17 serious adverse events in 12 (8%) of 146 participants in the oral antibiotics group.

Interpretation: Compared with oral therapy, intravenous antibiotics did not achieve sustained eradication of P aeruginosa in a greater proportion of patients with cystic fibrosis and was more expensive. Although there were fewer hospitalisations in the intravenous group than the oral group during follow-up, this confers no advantage over oral treatment because intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P aeruginosa in cystic fibrosis.

Funding: National Institute for Health Research Health Technology Assessment Programme.
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http://dx.doi.org/10.1016/S2213-2600(20)30331-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606906PMC
October 2020

A global investment framework for the elimination of hepatitis B.

J Hepatol 2021 Mar 22;74(3):535-549. Epub 2020 Sep 22.

Disease Elimination Programme, Burnet Institute, Melbourne, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Infectious Diseases, The Alfred and Monash University, Australia.

Background & Aims: More than 292 million people are living with hepatitis B worldwide and are at risk of death from cirrhosis and liver cancer. The World Health Organization (WHO) has set global targets for the elimination of viral hepatitis as a public health threat by 2030. However, current levels of global investment in viral hepatitis elimination programmes are insufficient to achieve these goals.

Methods: To catalyse political commitment and to encourage domestic and international financing, we used published modelling data and key stakeholder interviews to develop an investment framework to demonstrate the return on investment for viral hepatitis elimination.

Results: The framework utilises a public health approach to identify evidence-based national activities that reduce viral hepatitis-related morbidity and mortality, as well as international activities and critical enablers that allow countries to achieve maximum impact on health outcomes from their investments - in the context of the WHO's 2030 viral elimination targets.

Conclusion: Focusing on hepatitis B, this health policy paper employs the investment framework to estimate the substantial economic benefits of investing in the elimination of hepatitis B and demonstrates how such investments could be cost saving by 2030.

Lay Summary: Hepatitis B infection is a major cause of death from liver disease and liver cancer globally. To reduce deaths from hepatitis B infection, we need more people to be tested and treated for hepatitis B. In this paper, we outline a framework of activities to reduce hepatitis B-related deaths and discuss ways in which governments could pay for them.
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http://dx.doi.org/10.1016/j.jhep.2020.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505744PMC
March 2021

Validation of the TREAT-B score for hepatitis B treatment eligibility in a large Asian cohort: TREAT-B improves with age.

J Hepatol 2020 11 1;73(5):1282-1284. Epub 2020 Sep 1.

Department of Gastroenterology, St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy 3068, Victoria, Australia; Department of Medicine, University of Melbourne, 41 Victoria Pde, Fitzroy 3068, Victoria, Australia.

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http://dx.doi.org/10.1016/j.jhep.2020.06.031DOI Listing
November 2020

Efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir for HCV NS5A-inhibitor experienced patients with difficult to cure characteristics.

Clin Infect Dis 2020 Sep 5. Epub 2020 Sep 5.

Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.

Background: In clinical trials, HCV salvage treatment with Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort.

Methods: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE).

Findings: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n=46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n=82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n=18/18, GT1b n=2/4), 89% in GT3 (n=59/66) and 100% in GT6 (n=3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were four serious AEs including one death and three hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12.

Conclusion: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most however serious AEs can occur in those with advanced liver disease.
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http://dx.doi.org/10.1093/cid/ciaa1318DOI Listing
September 2020

Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML.

J Transl Med 2020 09 3;18(1):339. Epub 2020 Sep 3.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7AE, Northern Ireland, UK.

Background: The cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member.

Methods: Here we use functional genomics (RNA-seq, ChIP-seq and HiChIP) to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss.

Results: The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains that, in turn, led to altered genome compartmentalisation. These changes in genome structure resulted in altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway, resulting in increased sensitivity to MEK inhibition.

Conclusions: The altered genomic architecture driven by the chronic loss of STAG2 results in altered gene expression that may contribute to leukaemogenesis and may be therapeutically targeted.
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http://dx.doi.org/10.1186/s12967-020-02500-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469420PMC
September 2020

The Yin and the Yang of Treatment for Chronic Hepatitis B-When to Start, When to Stop Nucleos(t)ide Analogue Therapy.

Viruses 2020 08 25;12(9). Epub 2020 Aug 25.

Gastroenterology Department, St Vincent's Hospital Melbourne, 41 Victoria Pde, Fitzroy, VIC 3065, Australia.

Over 257 million individuals worldwide are chronically infected with the Hepatitis B Virus (HBV). Nucleos(t)ide analogues (NAs) are the first-line treatment option for most patients. Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are both potent, safe antiviral agents, have a high barrier to resistance, and are now off patent. They effectively suppress HBV replication to reduce the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Treatment is continued long-term in most patients, as NA therapy rarely induces HBsAg loss or functional cure. Two diverging paradigms in the treatment of chronic hepatitis B have recently emerged. First, the public health focussed "treat-all" strategy, advocating for early and lifelong antiviral therapy to minimise the risk of HCC as well as the risk of HBV transmission. In LMICs, this strategy may be cost saving compared to monitoring off treatment. Second, the concept of "stopping" NA therapy in patients with HBeAg-negative disease after long-term viral suppression, a personalised treatment strategy aiming for long-term immune control and even HBsAg loss off treatment. In this manuscript, we will briefly review the current standard of care approach to the management of hepatitis B, before discussing emerging evidence to support both the "treat-all" strategy, as well as the "stop" strategy, and how they may both have a role in the management of patients with chronic hepatitis B.
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http://dx.doi.org/10.3390/v12090934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552074PMC
August 2020

COVID-19 and its impact on endoscopy services: what is the threshold for missed malignant diagnosis?

Gut 2021 07 26;70(7):1414-1415. Epub 2020 Aug 26.

Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia

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http://dx.doi.org/10.1136/gutjnl-2020-322769DOI Listing
July 2021

CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis.

Clin Proteomics 2020 17;17:31. Epub 2020 Aug 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU UK.

Background: Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers.

Methods: CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed.

Results: CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in . Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted  = 0.057) in the ALS group. The sub-group of ALS patients associated with the HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non- cases.

Conclusions: Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.
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http://dx.doi.org/10.1186/s12014-020-09294-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433176PMC
August 2020