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OBJECTIVES: Disease flares in the post COVID-19 vaccination period represent a prominent concern, though risk factors are poorly understood. We studied these flares among patients with idiopathic inflammatory myopathies (IIMs) and other autoimmune rheumatic diseases (AIRDs). METHODS: The COVAD-1 and -2 global surveys were circulated in early 2021 and 2022 respectively, and we captured demographics, comorbidities, AIRDs details, COVID-19 infection history, and vaccination details.Flares of IIMs were defined as a. patient self-reported, b. immunosuppression (IS) denoted, c. clinical sign directed, and d. with >7.9-point MCID worsening of PROMISPF10a score. Risk factors of flares were analyzed using regression models. RESULTS: Of 15165 total respondents, 1278 IIMs (age 63 years, 70.3% female, 80.8% Caucasians), and 3453 AIRDs were included. Flares of IIM were seen in 9.6%, 12.7%, 8.7%, and 19.6% patients by definitions a-d respectively with a median time to flare of 71.5 (10.7-235) days, similar to AIRDs. Patients with active IIMs pre-vaccination (OR:1.2; 95%CI:1.03-1.6, p = 0.025) were prone to flares, while those receiving Rituximab (OR:0.3; 95%CI:0.1-0.7, p = 0.010) and Azathioprine (OR:0.3, 95%CI:0.1-0.8, p = 0.016) were at lower risk. Female gender and comorbidities predisposed to flares requiring changes in immunosuppression. Asthma (OR: 1.62; 95%CI: 1.05-2.50, p = 0.028) and higher pain VAS (OR: 1.19; 95%CI: 1.11-1.27, p < 0.001) were associated with disparity between self-reported and IS-denoted flares. CONCLUSION: A diagnosis of IIMs confers an equal risk of flares in the post COVID-19 vaccination period to AIRDs, with active disease, female gender, and comorbidities conferring a higher risk. Disparity between patient and physician reported outcomes represents a future avenue for exploration.

BackgroundLower heart rate (HR) increases during exercise and slower HR recovery (HRR) after exercise are markers of worse autonomic function that may be associated with risk of acute respiratory events (ARE).MethodsData from 6-min walk testing (6MWT) in COPDGene were used to calculate the chronotropic index (CI) [(HR immediately post 6MWT - resting HR)/((220 - age) - resting HR)] and HRR at 1 min after 6MWT completion. We used zero-inflated negative binomial regression to test associations of CI and HRR with rates of any ARE (requiring steroids and/or antibiotics) and severe ARE (requiring emergency department visit or hospitalization), among all participants and in spirometry subgroups (normal, chronic obstructive pulmonary disease [COPD], and preserved ratio with impaired spirometry).ResultsAmong 4,484 participants, mean follow-up time was 4.1 years, and 1,966 had COPD. Among all participants, CI-6MWT was not associated with rate of any ARE [adjusted incidence rate ratio (aIRR) 0.98 (0.95-1.01)], but higher CI-6MWT was associated with lower rate of severe ARE [0.95 (0.92-0.99)]. Higher HRR was associated with a lower rate of both any ARE [0.97 (0.95-0.99)] and severe ARE [0.95 (0.92-0.98)]. Results were similar in the COPD spirometry subgroup.ConclusionHeart rate measures derived from 6MWT tests may have utility in predicting risk of acute respiratory events and COPD exacerbations.

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease., QC 20230327

Objective: To test whether high-sensitivity cardiac troponin T (hs-cTnT) could act as a diagnostic or prognostic biomarker in ALS, comparing hs-cTnT to neurofilament light (NfL). Methods: We performed a case-control study, including 150 ALS patients, 28 ALS mimics, and 108 healthy controls, and a follow-up study of the ALS patients, during 2014–2020 in Stockholm, Sweden. We compared concentrations of hs-cTnT in plasma and NfL in the cerebrospinal fluid between cases and controls. To evaluate the diagnostic performance, we calculated the area under the curve (AUC). Hazard ratios (HRs) were estimated from Cox models to assess associations between hs-cTnT and NfL at ALS diagnosis and risk of death. The longitudinal analysis measured changes of hs-cTnT and NfL since ALS diagnosis. Results: We noted higher levels of hs-cTnT in ALS patients (median: 16.5 ng/L) than in ALS mimics (11 ng/L) and healthy controls (6 ng/L). Both hs-cTnT and NfL could distinguish ALS patients from ALS mimics, with higher AUC noted for NfL (AUC 0.88; 95%CI 0.79–0.97). Disease progression correlated weakly with hs-cTnT (Pearson’s r = 0.18, p = 0.04) and moderately with NfL (Pearson’s r = 0.41, p < 0.001). Shorter survival was associated with higher levels of NfL at diagnosis (HR 1.08, 95%CI 1.04–1.11), but not hs-cTnT. hs-cTnT increased (12.61 ng/L per year, 95%CI 7.14–18.06) whereas NfL decreased longitudinally since ALS diagnosis. Conclusions: NfL is a stronger diagnostic and prognostic biomarker than hs-cTnT for ALS. However, hs-cTnT might constitute a disease progression biomarker as it increases longitudinally. The underlying causes for this increase need to be investigated., QC 20220316

Rationale: The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. Objectives: To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). Methods: We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. Results: Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80-0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81-1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. Conclusions: A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up. Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken. Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation. Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations.

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up. Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken. Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation. Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations.

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

Background: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. Objective: The objective of this study is to create a severity metric that can reliably summarize a patient’s disease course. Methods: We developed the nARMSS – normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from −5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. Results: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. Conclusion: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible., QC 20211115

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital. Design, setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland. Participant(s): Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 - 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease. Intervention(s): Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed. Major outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs. Result(s): By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52-1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22-0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48-0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit-cost ratio of 31:1. Conclusion(s): A collaborative pharmacist-GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective).Copyright © 2021 AMPCo

Introduction/Aim. Clinical guidelines recommend people with bronchiectasis undertake exercise training and physical activity as part of their disease management. This systematic review aimed to determine the effects of exercise training compared to usual care on exercise tolerance and health-related quality of life (HRQoL) in people with bronchiectasis. Methods. Randomised controlled trials (RCTs) involving structured exercise training programs of >=4 weeks duration which targeted improvements in physical function +/- exercise tolerance were identified from the Cochrane Airways Specialist Register (up to June 2019). Co-interventions such as airway clearance therapy or respiratory muscle training were permitted. Two review authors independently assessed studies for inclusion, data extraction and risk of bias. Outcomes included incremental shuttlewalk test distance (ISWD), 6-minute walk distance (6MWD), St Georgeas Respiratory Questionnaire (SGRQ) total score and Leicester Cough Questionnaire (LCQ) total score, at end intervention. Results. Six RCTs involving 275 participants were included. When applied for people with stable bronchiectasis (n = 5 studies), exercise training was associated with greater improvements in ISWD (standardised mean difference 0.97 [95%CI 0.64 to 1.31]) and SGRQ total score (mean difference [MD]-9.21[-12.65 to-5.77] units), but not LCQ total score (MD 0.01 [95%CI-0.76 to 0.78] units) compared to usual care. No discernible difference between exercise training and usual care was evident in 6MWD (MD 11 m [95%CI-27 to 49 m]) or LCQ total score (MD-0.08 [95% CI-0.94 to 0.78] units) when applied after an acute exacerbation (n = 1 study). Risk of selection, detection and reporting bias was generally low or unclear. Conclusions. Exercise training improves exercise tolerance, diseasespecific and cough-related QOL in people with stable bronchiectasis, but may offer limited value in the period after a recent exacerbation., A. Lee, Monash University, CONFERENCE ABSTRACT

Introduction/Aim. Aortic stiffness is a key determinant of cardiovascular morbidity and mortality. Acute Exacerbations of COPD (AECOPD) are accompanied by a spike in systemic stiffness. We investigated an important constituent of systemic stiffness, aortic strain (AS), in a prospective observational cohort study of patients admitted to our tertiary centre with doctor-diagnosed AECOPD. The primary hypothesis was that AS would be increased at exacerbation in comparison to recovery, and the secondary hypothesis was that AS would be associated with clinical and biochemical parameters. Methods. 67 individuals underwent dynamic ECG-gated 256-multidetector CT both during hospitalisation for AECOPD and following discharge and clinical recovery. Ascending aortic cross-sectional area was measured at 10% ECG R-R intervals at the ascending aorta midpoint (mid-way between aortic valve and brachiocephalic trunk). AS was calculated as (maximum area a- minimum area)/minimum area. Paired ttests and Pearson correlations were used for analysis. Results. AS was lower at recovery compared to AECOPD (10.2 +/- 6.4 vs 8.3 +/- 4.2, mean +/- SD, P = 0.01) and it was negatively correlated with age (r = -0.434, P < 0.001). AI was not associated with FEV1, diffusing capacity, emphysema index, left ventricular ejection fraction, coronary artery calcium score, troponin, b-type natriuretic peptide, length of stay, baseline modified Medical Research Council dyspnoea score, Charlson Comorbidity Index or COPD Assessment Test. Conclusion. AS is higher during AECOPD than at recovery. However, it was not associated with other measures of disease and comorbidities beyond that of older age. Our findings suggest that complex mechanisms govern vascular stiffness in COPD; processes that are amplified during AECOPD.

Introduction/Aim. Nasal high flow (NHF) may improve symptoms of dyspnoea in both stable and acutely exacerbating chronic obstructive lung disease (COPD). This may reduced symptoms are readmission rate. Method(s): This was a feasibility study prospectively recruiting subjects admitted to hospital for acute uncomplicated exacerbations of COPD.Consenting subjects were commenced on NHF and discharged when clinically stable determined by the clinical team who were not part of the study. NHF was maintained for minimum of 6 hours per day in the home setting for 30 days under supervision of HITH. Outcome measures were compared to matched retrospective controls Conclusion. The addition of NHF to the discharge plan supported by HITH was not associated with reduced LOS but was associated with low 30 day readmission rate.

Introduction/Aim. An increased ratio of pulmonary artery (PA) to aortic diameter (PA:A) on computed tomography (CT) correlates with increased pulmonary artery pressure [1]. PA:A > 1 identifies pulmonary hypertension and in COPD is associated with increased risk of hospitalised exacerbations [2]. Conventional CT has been used in previous studies investigating PA:A, however only samples a single asnapshota at a random point in the cardiac cycle. We hypothesised that ECG-gated, dynamic 256-multidetector CT (256-MDCT) would demonstrate variability in PA:A throughout the cardiac cycle, not identifiable with conventional CT [3]. We further hypothesised that PA:A would be higher at exacerbation versus recovery. Methods. Paired dynamic 256-MDCT were performed both during acute exacerbation and following exacerbation recovery. PA:A was based on the maximal PA and aortic diameter at 10% R-R intervals. The primary outcome was to assess the number of cases where the PA:A ratio crossed 1 at any point in the cardiac cycle. The secondary outcome was the change in PA:A ratio from acute scan to recovery scan. Results. Pairs of CT scans were compared in 63 cases admitted to our hospital with a COPD exacerbation. PA:A was variable throughout the cardiac cycle (highest in systole and lowest in diastole). In 12/63 (19.0%) of acute scans and 14/63 (22.2%) of recovery scans, PA:A crossed the threshold of 1. Figure 1 illustrates the variability in PA:A in the overall population during the cardiac cycle at acute exacerbation and at recovery. There was a reduction in mean PA:A ratio between the acute and recovery scans of 0.0159 (P < 0.0001). Maximal PA diameter was increased in the acute scan cohort by a mean of 0.22 mm in comparison to recovery (P = 0.0031). Conclusion. In patients with COPD, PA:A varies throughout the cardiac cycle and the timing of scan acquisition impacts this measurement. Dynamic CT allows better characterisation of PA:A assessment compared to conventional CT. PA:A inc

Introduction/Aim. Clinical guidelines recommend people with bronchiectasis undertake exercise training and physical activity as part of their disease management. This systematic review aimed to determine the effects of exercise training compared to usual care on exercise tolerance and health-related quality of life (HRQoL) in people with bronchiectasis. Methods. Randomised controlled trials (RCTs) involving structured exercise training programs of >=4 weeks duration which targeted improvements in physical function +/- exercise tolerance were identified from the Cochrane Airways Specialist Register (up to June 2019). Co-interventions such as airway clearance therapy or respiratory muscle training were permitted. Two review authors independently assessed studies for inclusion, data extraction and risk of bias. Outcomes included incremental shuttlewalk test distance (ISWD), 6-minute walk distance (6MWD), St Georgeas Respiratory Questionnaire (SGRQ) total score and Leicester Cough Questionnaire (LCQ) total score, at end intervention. Results. Six RCTs involving 275 participants were included. When applied for people with stable bronchiectasis (n = 5 studies), exercise training was associated with greater improvements in ISWD (standardised mean difference 0.97 [95%CI 0.64 to 1.31]) and SGRQ total score (mean difference [MD]-9.21[-12.65 to-5.77] units), but not LCQ total score (MD 0.01 [95%CI-0.76 to 0.78] units) compared to usual care. No discernible difference between exercise training and usual care was evident in 6MWD (MD 11 m [95%CI-27 to 49 m]) or LCQ total score (MD-0.08 [95% CI-0.94 to 0.78] units) when applied after an acute exacerbation (n = 1 study). Risk of selection, detection and reporting bias was generally low or unclear. Conclusions. Exercise training improves exercise tolerance, diseasespecific and cough-related QOL in people with stable bronchiectasis, but may offer limited value in the period after a recent exacerbation.

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Introduction/Aim. Despite the widespread usage of oxygen, inappropriate administration may lead to adverse events. TSANZ guidelines provide guidance on oxygen prescription and administration, specifically identifying patients with COPD as a group at risk of adverse events. The aim of this study was to assess the adherence to TSANZ oxygen prescription and oxygen saturation aims in admitted patients with COPD. Methods. We conducted a retrospective chart review of patients admitted to Monash Health between the 1/1/2018 and 30/6/2018. Patients were identified from a coding search of relevant categories. Records were reviewed for oxygen prescription and administration with regards to TSANZ guidance. Adverse events possibly due to oxygen toxicity were recorded. Results. 557 episodes were reviewed. Mean (+/-SD) age was 74.1 (+/-11.4), 281 (50.4%) were male, 101 (18.1%) used home oxygen and 85 (15.1%) lived in residential care. Most patients were admitted for an exacerbation of airways disease: 180 (32.3%) non-infective and 170 (30.5%) infective. 521 patients presented through the emergency department with only 78 (14.9%) having a correctly documented oxygen prescription. 469 patients required admission to hospital, with only 166 (35.3%) having a documented oxygen prescription which was TSANZ adherent. Complications possibly related to inappropriate oxygen administration occurred in 48 patients (8.6%). Conclusion. Rates of documentation of an appropriate oxygen prescription adherent to guidelines were low both in the emergency department and during ward admission. However complications due to over oxygenation were infrequent. This study supports the implementation of measures to improve clinician prescribing of oxygen.

Background and objectives: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). Material(s) and Method(s): The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. Result(s): Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. Conclusion(s): This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.Copyright © 2020 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion

Introduction: Acute exacerbations of COPD (AECOPD) are accompanied by escalations in cardiac risk superimposed upon elevated baseline risk. Appropriate treatment for coronary artery disease (CAD) and heart failure with reduced ejection fraction (HFrEF) could improve outcomes. However, securing these diagnoses during AECOPD is difficult, so their true prevalence remains unknown, as does the magnitude of this treatment opportunity. We aimed to determine the prevalence of severe CAD and severe HFrEF during hospitalised AECOPD using dynamic computed tomography (CT). Method(s): A cross-sectional study of 148 patients with hospitalised AECOPD was conducted. Dynamic CT was used to identify severe CAD (Agatston score 400) and HFrEF (left ventricular ejection fraction 40% and/or right ventricular ejection fraction 35%). Result(s): Severe CAD was detected in 51 of 148 patients (35%), left ventricular systolic dysfunction was identified in 12 cases (8%) and right ventricular systolic dysfunction was present in 18 (12%). Clinical history and examination did not identify severe CAD in approximately one-third of cases and missed HFrEF in two-thirds of cases. Elevated troponin and brain natriuretic peptide did not differentiate subjects with severe CAD from nonsevere CAD, nor distinguish HFrEF from normal ejection fraction. Undertreatment was common. Of those with severe CAD, only 39% were prescribed an antiplatelet agent, and 53% received a statin. Of individuals with HFrEF, 50% or less received angiotensin blockers, beta blockers or antimineralocorticoids. Conclusion(s): Dynamic CT detects clinically covert CAD and HFrEF during AECOPD, identifying opportunities to improve outcomes via well-established cardiac treatments.Copyright © ERS 2021. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

Background and objectives: Hypernatremia can be community or hospital-acquired, and there may be specific factors unique to the hospital environment, such as intravenous fluid treatment, which contribute to hypernatremia. The aim of this study was to determine the factors associated with the progression from moderate to severe hospital-acquired hypernatremia among patients admitted under general medicine. Material(s) and Method(s): In this retrospective, single-center cohort study (2012 to 2017), we used ICD-10 coding and medical records to identify adult patients who developed moderate hypernatremia and followed them for progression to severe hypernatremia. We profiled the serum biochemistry and the volume and composition of prescribed intravenous fluids. We applied logistic regression to determine the factors associated with the progression to severe hypernatremia, using the patients with moderate hypernatremia as reference. Result(s): Of the 180 medical inpatients (median age of 81 years) with moderate hospital-acquired hypernatremia, 9.4% progressed to severe hypernatremia. Normal saline comprised 76% of intravenous fluid volume administered prior to onset of moderate hypernatremia. After the onset, 38% of fluid volume prescribed remained normal saline. The factors independently associated with progression to severe hypernatremia included chronic kidney disease stage (odds ratio 2.38, 95% CI: 1.26-4.50, P = 0.008) and serum creatinine increase (per 10 micromol/L, OR 1.29, 95% CI: 1.07-1.57, P = 0.009). Conclusion(s): Patients with chronic kidney disease and acute kidney injury may have an increased risk of severe hospital-acquired hypernatremia.

Rationale: Swallow may be compromised in COPD leading to aspiration and adverse respiratory consequences. However, prevalence and consequences of detectable aspiration in stable COPD are not known. Objective(s): We tested the hypothesis that a significant number of patients with stable COPD will have detectable aspiration during swallow (prandial aspiration) and that they would experience more frequent severe acute exacerbations of COPD (AECOPD) over the subsequent 12 months. Method(s): Patients (n=151) with verified and stable COPD of all severities were recruited at a tertiary care hospital. Videofluoroscopy was conducted to evaluate aspiration using Rosenbek's scale for penetration-aspiration during 100-mL cup drinking. AECOPD was documented as moderate (antibiotics and/or corticosteroid treatment) or severe (emergency department admission or hospitalisation) over the ensuing 12 months. Measurements and Main Results: Aspiration was observed in 30 out of 151 patients (19.9%, 18 males, 12 females; mean age 72.4 years). Patients with aspiration had more overall AECOPD events (3.03 versus 2 per patient; p=0.022) and severe AECOPD episodes (0.87 versus 0.39; p=0.032). Severe AECOPD occurred in more patients with aspiration (50% of patients versus 18.2%; OR 4.5, CI 1.9-10.5; p=0.001) and with silent aspiration (36.7% versus 18.2%; OR 2.6, CI 1.1-6.2; p=0.045). Aspiration was related to a shorter exacerbation-free period during the 12-month follow-up period (p=0.038). Conclusion(s): Prandial aspiration is detectable in a subset of patients with COPD and was predictive of subsequent severe AECOPD. Studies to examine if the association is causal are essential to direct strategies aimed at prevention of aspiration and AECOPD.Copyright © ERS 2021.

Introduction/Aim. A major cause of mortality and morbidity in COPD are acute exacerbations (AECOPD), most frequently triggered by infections, such as influenza A virus (IAV). However, the identity of key factors of the immune system which contribute to AECOPD remain ill-defined. Innate immune responses to pathogens depend on the activation of inflammasomes, which facilitate the maturation and release of proinflammatory cytokines such as IL-1beta. Recently, clinical studies and human in vitro data have demonstrated excessive activation of inflammasomes in AECOPD. The aim of this study was to investigate a novel functional link between inflammasome activation and IAV infection in the pathogenesis of AECOPD. Methods. We employed a murine COPD model with acute IAV infection. Specifically, 6-week-old mice were exposed to cigarette smoke (CS) for 8 weeks. After 8 weeks, mice were infected with IAV and culled 5 days post infection. We also used COPD patient serum during stable disease, with their own corresponding IAV-induced acute exacerbation. Results. We discovered excessive productions of genes and proteins encoding AIM2 which forms a cytoplasmic DNA-sensing inflammasome, and IL-1beta in a murine COPD model with acute IAV infection. Nevertheless, the first-line therapy for AECOPD is glucocorticosteroids, which is limited in its efficacy. In that respect, Pirfenidone (PFD) is clinically used anti-inflammatory therapeutic. Importantly, our compelling data supported that PFD can alleviate the mRNA expressions of Aim2, and Il1beta in COPD model following acute IAV infection. We also discovered an elevated IL-1beta protein levels in serum of AECOPD patients compared to their stable status. Conclusion. Collectively, we define for the first time that hyperactivation of AIM2/IL-1beta axis plays a role in AECOPD. Finally, our data inform the future clinical utility (repurposing) of PFD to target inflammasomes in AECOPD and this would represent an enormous change in the therapeu

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenstrom macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients withWM who were either treatmentna ive (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per InternationalWorkshop onWaldenstromMacroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n 5 50) or 320 mg once daily (n 5 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0months for patientswith R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with singleagent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2020 by The American Society of Hematology.

Background: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. Objective(s): To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. Search Method(s): We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Selection Criteria: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. Data Collection and Analysis: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to

Introduction/Aim. Aortic stiffness is a key determinant of cardiovascular morbidity and mortality. Acute Exacerbations of COPD (AECOPD) are accompanied by a spike in systemic stiffness. We investigated an important constituent of systemic stiffness, aortic strain (AS), in a prospective observational cohort study of patients admitted to our tertiary centre with doctor-diagnosed AECOPD. The primary hypothesis was that AS would be increased at exacerbation in comparison to recovery, and the secondary hypothesis was that AS would be associated with clinical and biochemical parameters. Methods. 67 individuals underwent dynamic ECG-gated 256-multidetector CT both during hospitalisation for AECOPD and following discharge and clinical recovery. Ascending aortic cross-sectional area was measured at 10% ECG R-R intervals at the ascending aorta midpoint (mid-way between aortic valve and brachiocephalic trunk). AS was calculated as (maximum area a- minimum area)/minimum area. Paired ttests and Pearson correlations were used for analysis. Results. AS was lower at recovery compared to AECOPD (10.2 +/- 6.4 vs 8.3 +/- 4.2, mean +/- SD, P = 0.01) and it was negatively correlated with age (r = -0.434, P < 0.001). AI was not associated with FEV1, diffusing capacity, emphysema index, left ventricular ejection fraction, coronary artery calcium score, troponin, b-type natriuretic peptide, length of stay, baseline modified Medical Research Council dyspnoea score, Charlson Comorbidity Index or COPD Assessment Test. Conclusion. AS is higher during AECOPD than at recovery. However, it was not associated with other measures of disease and comorbidities beyond that of older age. Our findings suggest that complex mechanisms govern vascular stiffness in COPD; processes that are amplified during AECOPD.

Introduction/Aim. An increased ratio of pulmonary artery (PA) to aortic diameter (PA:A) on computed tomography (CT) correlates with increased pulmonary artery pressure [1]. PA:A > 1 identifies pulmonary hypertension and in COPD is associated with increased risk of hospitalised exacerbations [2]. Conventional CT has been used in previous studies investigating PA:A, however only samples a single asnapshota at a random point in the cardiac cycle. We hypothesised that ECG-gated, dynamic 256-multidetector CT (256-MDCT) would demonstrate variability in PA:A throughout the cardiac cycle, not identifiable with conventional CT [3]. We further hypothesised that PA:A would be higher at exacerbation versus recovery. Methods. Paired dynamic 256-MDCT were performed both during acute exacerbation and following exacerbation recovery. PA:A was based on the maximal PA and aortic diameter at 10% R-R intervals. The primary outcome was to assess the number of cases where the PA:A ratio crossed 1 at any point in the cardiac cycle. The secondary outcome was the change in PA:A ratio from acute scan to recovery scan. Results. Pairs of CT scans were compared in 63 cases admitted to our hospital with a COPD exacerbation. PA:A was variable throughout the cardiac cycle (highest in systole and lowest in diastole). In 12/63 (19.0%) of acute scans and 14/63 (22.2%) of recovery scans, PA:A crossed the threshold of 1. Figure 1 illustrates the variability in PA:A in the overall population during the cardiac cycle at acute exacerbation and at recovery. There was a reduction in mean PA:A ratio between the acute and recovery scans of 0.0159 (P < 0.0001). Maximal PA diameter was increased in the acute scan cohort by a mean of 0.22 mm in comparison to recovery (P = 0.0031). Conclusion. In patients with COPD, PA:A varies throughout the cardiac cycle and the timing of scan acquisition impacts this measurement. Dynamic CT allows better characterisation of PA:A assessment compared to conventional CT. PA:A inc

Introduction/Aim. Clinical guidelines recommend people with bronchiectasis undertake exercise training and physical activity as part of their disease management. This systematic review aimed to determine the effects of exercise training compared to usual care on exercise tolerance and health-related quality of life (HRQoL) in people with bronchiectasis. Methods. Randomised controlled trials (RCTs) involving structured exercise training programs of >=4 weeks duration which targeted improvements in physical function +/- exercise tolerance were identified from the Cochrane Airways Specialist Register (up to June 2019). Co-interventions such as airway clearance therapy or respiratory muscle training were permitted. Two review authors independently assessed studies for inclusion, data extraction and risk of bias. Outcomes included incremental shuttlewalk test distance (ISWD), 6-minute walk distance (6MWD), St Georgeas Respiratory Questionnaire (SGRQ) total score and Leicester Cough Questionnaire (LCQ) total score, at end intervention. Results. Six RCTs involving 275 participants were included. When applied for people with stable bronchiectasis (n = 5 studies), exercise training was associated with greater improvements in ISWD (standardised mean difference 0.97 [95%CI 0.64 to 1.31]) and SGRQ total score (mean difference [MD]-9.21[-12.65 to-5.77] units), but not LCQ total score (MD 0.01 [95%CI-0.76 to 0.78] units) compared to usual care. No discernible difference between exercise training and usual care was evident in 6MWD (MD 11 m [95%CI-27 to 49 m]) or LCQ total score (MD-0.08 [95% CI-0.94 to 0.78] units) when applied after an acute exacerbation (n = 1 study). Risk of selection, detection and reporting bias was generally low or unclear. Conclusions. Exercise training improves exercise tolerance, diseasespecific and cough-related QOL in people with stable bronchiectasis, but may offer limited value in the period after a recent exacerbation.

Introduction/Aim. Nasal high flow (NHF) may improve symptoms of dyspnoea in both stable and acutely exacerbating chronic obstructive lung disease (COPD). This may reduced symptoms are readmission rate. Method(s): This was a feasibility study prospectively recruiting subjects admitted to hospital for acute uncomplicated exacerbations of COPD.Consenting subjects were commenced on NHF and discharged when clinically stable determined by the clinical team who were not part of the study. NHF was maintained for minimum of 6 hours per day in the home setting for 30 days under supervision of HITH. Outcome measures were compared to matched retrospective controls Conclusion. The addition of NHF to the discharge plan supported by HITH was not associated with reduced LOS but was associated with low 30 day readmission rate.

Background and objectives: Use of convalescent plasma for coronavirus disease 2019 (COVID-19) treatment has gained interest worldwide. However, there is lack of evidence on its dosing, safety and effectiveness. Until data from clinical studies are available to provide solid evidence for worldwide applicable guidelines, there is a need to provide guidance to the transfusion community and researchers on this emergent therapeutic option. This paper aims to identify existing key gaps in current knowledge in the clinical application of COVID-19 convalescent plasma (CCP). Material(s) and Method(s): The International Society of Blood Transfusion (ISBT) initiated a multidisciplinary working group with worldwide representation from all six continents with the aim of reviewing existing practices on CCP use from donor, product and patient perspectives. A subgroup of clinical transfusion professionals was formed to draft a document for CCP clinical application to identify the gaps in knowledge in existing literature. Result(s): Gaps in knowledge were identified in the following main domains: study design, patient eligibility, CCP dose, frequency and timing of CCP administration, parameters to assess response to CCP treatment and long-term outcome, adverse events and CCP application in less-resourced countries as well as in paediatrics and neonates. Conclusion(s): This paper outlines a framework of gaps in the knowledge of clinical deployment of CPP that were identified as being most relevant. Studies to address the identified gaps are required to provide better evidence on the effectiveness and safety of CCP use.Copyright © 2020 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion

Introduction: Acute exacerbations of COPD (AECOPD) are accompanied by escalations in cardiac risk superimposed upon elevated baseline risk. Appropriate treatment for coronary artery disease (CAD) and heart failure with reduced ejection fraction (HFrEF) could improve outcomes. However, securing these diagnoses during AECOPD is difficult, so their true prevalence remains unknown, as does the magnitude of this treatment opportunity. We aimed to determine the prevalence of severe CAD and severe HFrEF during hospitalised AECOPD using dynamic computed tomography (CT). Method(s): A cross-sectional study of 148 patients with hospitalised AECOPD was conducted. Dynamic CT was used to identify severe CAD (Agatston score 400) and HFrEF (left ventricular ejection fraction 40% and/or right ventricular ejection fraction 35%). Result(s): Severe CAD was detected in 51 of 148 patients (35%), left ventricular systolic dysfunction was identified in 12 cases (8%) and right ventricular systolic dysfunction was present in 18 (12%). Clinical history and examination did not identify severe CAD in approximately one-third of cases and missed HFrEF in two-thirds of cases. Elevated troponin and brain natriuretic peptide did not differentiate subjects with severe CAD from nonsevere CAD, nor distinguish HFrEF from normal ejection fraction. Undertreatment was common. Of those with severe CAD, only 39% were prescribed an antiplatelet agent, and 53% received a statin. Of individuals with HFrEF, 50% or less received angiotensin blockers, beta blockers or antimineralocorticoids. Conclusion(s): Dynamic CT detects clinically covert CAD and HFrEF during AECOPD, identifying opportunities to improve outcomes via well-established cardiac treatments.Copyright © ERS 2021. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

Introduction/Aim. Despite the widespread usage of oxygen, inappropriate administration may lead to adverse events. TSANZ guidelines provide guidance on oxygen prescription and administration, specifically identifying patients with COPD as a group at risk of adverse events. The aim of this study was to assess the adherence to TSANZ oxygen prescription and oxygen saturation aims in admitted patients with COPD. Methods. We conducted a retrospective chart review of patients admitted to Monash Health between the 1/1/2018 and 30/6/2018. Patients were identified from a coding search of relevant categories. Records were reviewed for oxygen prescription and administration with regards to TSANZ guidance. Adverse events possibly due to oxygen toxicity were recorded. Results. 557 episodes were reviewed. Mean (+/-SD) age was 74.1 (+/-11.4), 281 (50.4%) were male, 101 (18.1%) used home oxygen and 85 (15.1%) lived in residential care. Most patients were admitted for an exacerbation of airways disease: 180 (32.3%) non-infective and 170 (30.5%) infective. 521 patients presented through the emergency department with only 78 (14.9%) having a correctly documented oxygen prescription. 469 patients required admission to hospital, with only 166 (35.3%) having a documented oxygen prescription which was TSANZ adherent. Complications possibly related to inappropriate oxygen administration occurred in 48 patients (8.6%). Conclusion. Rates of documentation of an appropriate oxygen prescription adherent to guidelines were low both in the emergency department and during ward admission. However complications due to over oxygenation were infrequent. This study supports the implementation of measures to improve clinician prescribing of oxygen.

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital. Design, setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland. Participant(s): Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 - 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease. Intervention(s): Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed. Major outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs. Result(s): By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52-1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22-0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48-0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit-cost ratio of 31:1. Conclusion(s): A collaborative pharmacist-GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective).Copyright © 2021 AMPCo

Background and objectives: Hypernatremia can be community or hospital-acquired, and there may be specific factors unique to the hospital environment, such as intravenous fluid treatment, which contribute to hypernatremia. The aim of this study was to determine the factors associated with the progression from moderate to severe hospital-acquired hypernatremia among patients admitted under general medicine. Material(s) and Method(s): In this retrospective, single-center cohort study (2012 to 2017), we used ICD-10 coding and medical records to identify adult patients who developed moderate hypernatremia and followed them for progression to severe hypernatremia. We profiled the serum biochemistry and the volume and composition of prescribed intravenous fluids. We applied logistic regression to determine the factors associated with the progression to severe hypernatremia, using the patients with moderate hypernatremia as reference. Result(s): Of the 180 medical inpatients (median age of 81 years) with moderate hospital-acquired hypernatremia, 9.4% progressed to severe hypernatremia. Normal saline comprised 76% of intravenous fluid volume administered prior to onset of moderate hypernatremia. After the onset, 38% of fluid volume prescribed remained normal saline. The factors independently associated with progression to severe hypernatremia included chronic kidney disease stage (odds ratio 2.38, 95% CI: 1.26-4.50, P = 0.008) and serum creatinine increase (per 10 micromol/L, OR 1.29, 95% CI: 1.07-1.57, P = 0.009). Conclusion(s): Patients with chronic kidney disease and acute kidney injury may have an increased risk of severe hospital-acquired hypernatremia.

Introduction/Aim. A major cause of mortality and morbidity in COPD are acute exacerbations (AECOPD), most frequently triggered by infections, such as influenza A virus (IAV). However, the identity of key factors of the immune system which contribute to AECOPD remain ill-defined. Innate immune responses to pathogens depend on the activation of inflammasomes, which facilitate the maturation and release of proinflammatory cytokines such as IL-1beta. Recently, clinical studies and human in vitro data have demonstrated excessive activation of inflammasomes in AECOPD. The aim of this study was to investigate a novel functional link between inflammasome activation and IAV infection in the pathogenesis of AECOPD. Methods. We employed a murine COPD model with acute IAV infection. Specifically, 6-week-old mice were exposed to cigarette smoke (CS) for 8 weeks. After 8 weeks, mice were infected with IAV and culled 5 days post infection. We also used COPD patient serum during stable disease, with their own corresponding IAV-induced acute exacerbation. Results. We discovered excessive productions of genes and proteins encoding AIM2 which forms a cytoplasmic DNA-sensing inflammasome, and IL-1beta in a murine COPD model with acute IAV infection. Nevertheless, the first-line therapy for AECOPD is glucocorticosteroids, which is limited in its efficacy. In that respect, Pirfenidone (PFD) is clinically used anti-inflammatory therapeutic. Importantly, our compelling data supported that PFD can alleviate the mRNA expressions of Aim2, and Il1beta in COPD model following acute IAV infection. We also discovered an elevated IL-1beta protein levels in serum of AECOPD patients compared to their stable status. Conclusion. Collectively, we define for the first time that hyperactivation of AIM2/IL-1beta axis plays a role in AECOPD. Finally, our data inform the future clinical utility (repurposing) of PFD to target inflammasomes in AECOPD and this would represent an enormous change in the therapeu

Rationale: Swallow may be compromised in COPD leading to aspiration and adverse respiratory consequences. However, prevalence and consequences of detectable aspiration in stable COPD are not known. Objective(s): We tested the hypothesis that a significant number of patients with stable COPD will have detectable aspiration during swallow (prandial aspiration) and that they would experience more frequent severe acute exacerbations of COPD (AECOPD) over the subsequent 12 months. Method(s): Patients (n=151) with verified and stable COPD of all severities were recruited at a tertiary care hospital. Videofluoroscopy was conducted to evaluate aspiration using Rosenbek's scale for penetration-aspiration during 100-mL cup drinking. AECOPD was documented as moderate (antibiotics and/or corticosteroid treatment) or severe (emergency department admission or hospitalisation) over the ensuing 12 months. Measurements and Main Results: Aspiration was observed in 30 out of 151 patients (19.9%, 18 males, 12 females; mean age 72.4 years). Patients with aspiration had more overall AECOPD events (3.03 versus 2 per patient; p=0.022) and severe AECOPD episodes (0.87 versus 0.39; p=0.032). Severe AECOPD occurred in more patients with aspiration (50% of patients versus 18.2%; OR 4.5, CI 1.9-10.5; p=0.001) and with silent aspiration (36.7% versus 18.2%; OR 2.6, CI 1.1-6.2; p=0.045). Aspiration was related to a shorter exacerbation-free period during the 12-month follow-up period (p=0.038). Conclusion(s): Prandial aspiration is detectable in a subset of patients with COPD and was predictive of subsequent severe AECOPD. Studies to examine if the association is causal are essential to direct strategies aimed at prevention of aspiration and AECOPD.Copyright © ERS 2021.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenstrom macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients withWM who were either treatmentna ive (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per InternationalWorkshop onWaldenstromMacroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n 5 50) or 320 mg once daily (n 5 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0months for patientswith R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with singleagent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2020 by The American Society of Hematology.

Brain microbleeds are increased in chronic kidney disease (CKD) and their presence increases risk of cognitive decline and stroke. We examined the interaction between CKD and brain microhemorrhages (the neuropathological substrate of microbleeds) in mouse and cell culture models and studied progression of microbleed burden on serial brain imaging from humans. Mouse studies: Two CKD models were investigated: adenine-induced tubulointerstitial nephritis and surgical 5/6 nephrectomy. Cell culture studies: bEnd.3 mouse brain endothelial cells were grown to confluence, and monolayer integrity was measured after exposure to 5-15% human uremic serum or increasing concentrations of urea. Human studies: Progression of brain microbleeds was evaluated on serial MRI from control, pre-dialysis CKD, and dialysis patients. Microhemorrhages were increased 2-2.5-fold in mice with CKD independent of higher blood pressure in the 5/6 nephrectomy model. IgG staining was increased in CKD animals, consistent with increased blood-brain barrier permeability. Incubation of bEnd.3 cells with uremic serum or elevated urea produced a dose-dependent drop in trans-endothelial electrical resistance. Elevated urea induced actin cytoskeleton derangements and decreased claudin-5 expression. In human subjects, prevalence of microbleeds was 50% in both CKD cohorts compared with 10% in age-matched controls. More patients in the dialysis cohort had increased microbleeds on follow-up MRI after 1.5 years. CKD disrupts the blood-brain barrier and increases brain microhemorrhages in mice and microbleeds in humans. Elevated urea alters the actin cytoskeleton and tight junction proteins in cultured endothelial cells, suggesting that these mechanisms explain (at least in part) the microhemorrhages and microbleeds observed in the animal and human studies.

BackgroundChronic obstructive pulmonary disease (COPD) is the third leading cause of death by disease worldwide and has a 30-day readmission rate of 22.6%. In 2015, COPD was added to the Medicare Hospital Readmission Reductions Program.ObjectiveThe objective of this paper was to survey the current medical technologies for remote patient monitoring (RPM) tools that forecast COPD exacerbations in order to reduce COPD readmissions.MethodsWe searched literature and digital health news to find commercially available RPM devices focused on predicting COPD exacerbations. These technologies were reviewed and compared according to four criteria: forecasting ability, cost, ease of use, and appearance. A rating system was developed to facilitate the evaluation process.ResultsAs of June 2019, a list of handheld and hands-free devices was compiled. We compared features and found substantial variations. Devices that ranked higher on all criteria tended to have a high or unlisted price. Commonly mass-marketed devices like the pulse oximeter and spirometer surprisingly fulfilled the least criteria.ConclusionsThe COPD RPM technologies with most technological promise and compatibility with daily living appear to have high or unlisted prices. Consumers and providers need better access to product information to make informed decisions.

Background & Aims: The protease plasmin is an important wound healing factor, but it is not clear how it affects gastrointestinal infection-mediated damage, such as that resulting from Clostridioides difficile. We investigated the role of plasmin in C difficile-associated disease. This bacterium produces a spore form that is required for infection, so we also investigated the effects of plasmin on spores. Method(s): C57BL/6J mice expressing the precursor to plasmin, the zymogen human plasminogen (hPLG), or infused with hPLG were infected with C difficile, and disease progression was monitored. Gut tissues were collected, and cytokine production and tissue damage were analyzed by using proteomic and cytokine arrays. Antibodies that inhibit either hPLG activation or plasmin activity were developed and structurally characterized, and their effects were tested in mice. Spores were isolated from infected patients or mice and visualized using super-resolution microscopy; the functional consequences of hPLG binding to spores were determined. Result(s): hPLG localized to the toxin-damaged gut, resulting in immune dysregulation with an increased abundance of cytokines (such as interleukin [IL] 1A, IL1B, IL3, IL10, IL12B, MCP1, MP1A, MP1B, GCSF, GMCSF, KC, TIMP-1), tissue degradation, and reduced survival. Administration of antibodies that inhibit plasminogen activation reduced disease severity in mice. C difficile spores bound specifically to hPLG and active plasmin degraded their surface, facilitating rapid germination. Conclusion(s): We found that hPLG is recruited to the damaged gut, exacerbating C difficile disease in mice. hPLG binds to C difficile spores, and, upon activation to plasmin, remodels the spore surface, facilitating rapid spore germination. Inhibitors of plasminogen activation might be developed for treatment of C difficile or other infection-mediated gastrointestinal diseases.Copyright © 2020

Crohn's disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from 'reactive' management driven by disease complications to 'proactive' care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.Copyright © 2020 Borg-Bartolo SP et al.

Objectives: Objective: To undertake a pilot, feasibility RCT of umbilical cord blood derived cell therapy for treatment of adult patients infected with SARS-CoV-2 virus related moderate-to-severe pneumonia to prevent progression to severe ARDS. Hypothesis: Expanded cord blood derived cell therapy will be feasible, well tolerated and show potential efficacy in the treatment of acute COVID-19 related moderate to severe pneumonia in adult patients because of their powerful anti-inflammatory and immunomodulatory properties. Trial design: Pilot, parallel design randomised controlled trial. Participant(s): The trial will recruit 24 hospitalised patients with confirmed SARS-CoV-2 infection and pneumonia from July to December 2020 at Monash Medical Centre in Melbourne, Australia. Intervention and comparator: Intervention: Intravenous injection of expanded umbilical cord blood cells at a dose of 5 million cells/kg (maximum dose - 500 million cells). Cell infusion will occur over 30-60 minutes through a peripheral intravenous cannula. Standard supportive care will continue as needed. Comparator: Standard supportive care. Main outcomes: Safety and tolerability of cell administration within first 24 hours of administration; clinical improvement on a seven-category clinical improvement ordinal scale. Randomisation: Randomisation will be done using computer generated allocation to intervention/ control groups in a 1:1 ratio (in blocks of 6) using sealed opaque envelopes. Blinding (masking): This will be an unblinded study, given that it is the first study using expanded cord blood cells in COVID-19 patients. There will be no placebo infusion. Numbers to be randomised (sample size): Twelve participants in each group. Total n=24. Trial Status: CBC-19 protocol v2, dated 23rd April 2020. Recruitment has not started yet. Estimated recruitment timeline is between 1st July - 31st December 2020. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12620000478910, reg

Background: Frailty during acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with increased risk of readmission. Despite this, not all patients readmit, and the factors associated with readmission are not clear. Aim(s): To identify the clinical features of patients with AECOPD and frailty who experience readmissions. Method(s): Prospective cohort study of 74 patients recruited during AECOPD at a tertiary hospital in Melbourne, Australia. Frailty was defined according to Fried phenotype (slowness, weakness, exhaustion, weight loss, physical activity) evaluated early during admission. Characteristics of this group, measured during AECOPD and as change (DELTA) up to 1-month review, were compared between those who were vs were not censored due to 90-day respiratoryrelated readmission or death. Result(s): Frailty was detected in 34 (46%) of all patients with AECOPD and associated with a 4.5-fold risk of readmission c.f. non-frail patients (p=0.008). Key findings between those who were (n=15 [44%]) or were not (n=19 [56%]) censored are presented in the table. Discussion(s): Frailty is a highly prevalent, clinically important trait to detect during AECOPD. Follow-up evaluation of frail patients after discharge may be indicated to better detect those at high risk of readmission.

Background: Dupilumab (DPL), a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), add-on DPL 200 or 300 mg every 2 weeks (q2w) vs matched placebo (PBO) reduced severe asthma exacerbations and improved pre-bronchodilator (BD) FEV1 in patients (pts) with uncontrolled, moderate-to-severe asthma. Treatment effects were greater with elevated levels of type 2 biomarkers at baseline (BL). Aim(s): To assess DPL efficacy in pts with moderate asthma defined as asthma pts with BL pre-BD FEV 60-80% predicted (60-90% in adolescents), on medium-dose ICS and >=1 controller, without a minimum requirement for BL blood eosinophil count or FeNO. Method(s): Negative binomial models were used to analyze annualized severe asthma exacerbation rates during the 52-week treatment period and mixed-effects models with repeated measures were used to analyze change from BL in pre-BD FEV1 at Week 12. Result(s): 517/1,902 pts (27%) had pre-BD FEV 60-80% predicted and were on medium-dose ICS at BL. In these pts, DPL 200/300mg q2w reduced annualized severe exacerbation rates by 44%/51% respectively vs PBO (P=0.06/P=0.01). DPL 200/300mg q2w vs PBO also improved FEV at Week 12 with a LS mean difference of 0.11L/0.09L, respectively (P=0.01/P=0.05). Overall, the most frequent adverse event in DPL 200/300mg vs PBO groups was injection-site reaction (15%/18% vs 5%/10%). Conclusion(s): Dupilumab meaningfully reduced severe exacerbations and improved FEV1 in moderate asthma pts with pre-BD FEV 60-80% predicted and on medium-dose ICS, and was generally well tolerated.

Background: There is no histological classification to predict disease flare in children with IgA nephropathy (IgAN). As macrophage (MQ) accumulation correlates with histological injury, we investigated new histological criteria to predict disease flare in pediatric IgAN. Method(s): A total of 73 children with biopsy proven IgAN underwent 2 years of steroid treatment followed by a protocol biopsy and then steroid tapering. The non-flare group successfully discontinued steroid treatment (N=61, 20.1+/-9.2 years at biopsy); the flare group exhibited increased proteinuria during the taper or cessation of treatment (N=12, 11.6+/-2.3 years at biopsy, p<0.05). Histological findings were evaluated using Oxford classification. Macrophage number and phenotype was assessed by immunofluorescence. Result(s): At first (diagnostic) biopsy, urine findings were comparable between the two groups, but the flare group had a higher serum IgA level (279+/-83 vs 214+/-87 mg/dL; P<0.05). Biopsies revealed no difference in mesangial proliferation (M), endocapillary proliferation (E), glomerulosclerosis (S), tubulointerstitial fibrosis (T), and crescent formation (C); however, the flare group had more total MQ (CD68+ cells) (p<0.05) and M1 MQ (CD68+CD86+ cells) (p<0.05). In addition, M1 MQ correlated with glomerular M, E, S, C lesions (all P<0.01). At second (protocol) biopsy, the flare group had more severe S (p<0.01) and T (p<0.05) lesions, and more glomerular and interstitial M2 MQ (CD68+CD163+ cells) (both p<0.01 vs non-flare group). In addition, M2 MQ correlated with S and T lesions (both p<0.001). ROC analyses revealed glomerular MQ number >2.2 cells at first biopsy could predict disease flare by sensitivity of 83%. Conclusion(s): MQ accumulation is a potential marker to predict disease flare in pediatric IgAN. The number of glomerular M1 MQ in active lesions at the first biopsy was related to flare occurrence, while glomerular and interstitial accumulation of M2 MQ in chronic lesions

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4+ TRM cells with a TH17 signature (termed TRM17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal TRM17 cells were induced by pathogens infecting the kidney, such as Staphylococcus aureus, Candida albicans, and uropathogenic Escherichia coli, and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney TRM17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced TRM17 cells have a previously unrecognized function in aggravating autoimmune disease.Copyright © 2020 American Association for the Advancement of Science. All rights reserved.