Comparative Effectiveness of Umeclidinium/Vilanterol versus Indacaterol/Glycopyrronium on Moderate-to-Severe Exacerbations in Patients with Chronic Obstructive Pulmonary Disease in Clinical Practice in England.

Purpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with significant morbidity and mortality and increased economic healthcare burden for patients with COPD. Long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) dual therapy is recommended for patients receiving mono-bronchodilator therapy who experience exacerbations or ongoing breathlessness. This study compared two single-inhaler LAMA/LABA dual therapies, umeclidinium/vilanterol (UMEC/VI) and indacaterol/glycopyrronium (IND/GLY), on moderate-to-severe exacerbation rates in patients with COPD in England. Patients and Methods: This retrospective cohort study used linked primary care electronic health record data (Clinical Practice Research Datalink-Aurum) and secondary care data (Hospital Episode Statistics) to assess outcomes for patients with COPD who had a first prescription for single-inhaler UMEC/VI or IND/GLY (index date) between 1 January 2015 and 30 September 2019 (indexing period). Analyses compared UMEC/VI and IND/GLY on moderate-to-severe, moderate, and severe exacerbations, healthcare resource utilization (HCRU), and direct costs at 6, 12, 18, and 24 months, and time-to-first on-treatment exacerbation up to 24 months post-index date. Following inverse probability of treatment weighting (IPTW), non-inferiority and superiority of UMEC/VI versus IND/GLY were assessed. Results: In total, 12,031 patients were included, of whom 8753 (72.8%) were prescribed UMEC/VI and 3278 (27.2%) IND/GLY. After IPTW, for moderate-to-severe exacerbations, weighted rate ratios were <1 at 6, 12, and 18 months and equal to 1 at 24 months for UMEC/VI; around the null value for moderate exacerbations and <1 at all timepoints for severe exacerbations. UMEC/VI showed lower HCRU incidence rates than IND/GLY for all-cause Accident and Emergency visits and COPD-related inpatient stays and associated all-cause costs at 6 months post-indexing. Time-to-triple therapy was similar for both treatments. Conclusion: UMEC/VI demonstrated non-inferiority to IND/GLY in moderate-to-severe exacerbation reduction at 6, 12 and 18 months. These results support previous findings demonstrating similarity between UMEC/VI and IND/GLY on reduction of moderate-to-severe exacerbations.

Comparison of Rescue Medication Prescriptions in Patients with Chronic Obstructive Pulmonary Disease Receiving Umeclidinium/Vilanterol versus Tiotropium Bromide/Olodaterol in Routine Clinical Practice in England.

Purpose: Routinely collected healthcare data on the comparative effectiveness of the long-acting muscarinic antagonist/long-acting ß2-agonist combination umeclidinium/vilanterol (UMEC/VI) versus tiotropium bromide/olodaterol (TIO/OLO) for chronic obstructive pulmonary disease (COPD) is limited. This study compared rescue medication prescriptions in patients with COPD in England receiving UMEC/VI versus TIO/OLO. Patients and Methods: This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05. Results: In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups. Conclusion: UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.

Comparative Effectiveness of Umeclidinium/Vilanterol versus Inhaled Corticosteroid/Long-Acting ß2-Agonist in Patients with Chronic Obstructive Pulmonary Disease in a Primary Care Setting in England.

Purpose: To compare adherence to once-daily umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA), and twice-daily inhaled corticosteroids (ICS)/LABA single-inhaler dual therapy in patients with chronic obstructive pulmonary disease (COPD) in a primary care cohort in England. Patients and Methods: Active comparator, new-user, retrospective cohort study using CPRD-Aurum primary care data and linked Hospital Episode Statistics secondary care administrative data. Patients without exacerbations in the previous year were indexed on first/earliest prescription date of once-daily UMEC/VI or twice-daily ICS/LABA as initial maintenance therapy between July 2014-September 2019. Primary outcome: medication adherence at 12 months post-index, defined as proportion of days covered (PDC) ≥80%. PDC represented proportion of time over the treatment duration that the patient was theoretically in possession of the medication. Secondary outcomes: adherence at 6, 18, and 24 months post-index, time-to-triple therapy, time-to-first on-treatment COPD exacerbation, COPD-related and all-cause healthcare resource utilization (HCRU), and direct health-care costs. A propensity score was generated and inverse probability of treatment weighting (IPTW) was used to balance potential confounders. Superiority was defined as >0% difference between treatment groups. Results: In total, 6815 eligible patients were included (UMEC/VI:1623; ICS/LABA:5192). At 12 months post-index, weighted odds of a patient being adherent were significantly greater with UMEC/VI versus ICS/LABA (odds ratio [95% CI]: 1.71 [1.09, 2.66]; p=0.0185), demonstrating superiority of UMEC/VI. Patients taking UMEC/VI were statistically significantly more adherent than those taking ICS/LABA at 6, 18, and 24 months post-index (p<0.05). Differences in time-to-triple therapy, time-to-moderate COPD exacerbations, HCRU, and direct medical costs were not statistically significant between treatments after IPTW was applied. Conclusion: At 12 months post-treatment initiation, once-daily UMEC/VI was superior to twice-daily ICS/LABA in medication adherence among patients with COPD without exacerbations in the previous year, newly initiating dual maintenance therapy in England. The finding was consistent at 6, 18, and 24 months.

Reducing voltage-dependent potassium channel Kv3.4 levels ameliorates synapse loss in a mouse model of Alzheimer's disease.

Synapse loss is associated with cognitive decline in Alzheimer's disease, and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human Alzheimer's disease brain tissue, but the mechanisms leading from Aß to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltage-gated potassium channel subtype 3.4 (Kv3.4) may play a role in Aß-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aß synaptotoxicity. Using adeno-associated virus and clustered regularly interspaced short palindromic repeats technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial Alzheimer's disease-associated mutations in amyloid precursor protein and presenilin-1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in Alzheimer's disease brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human Alzheimer's disease and control brain and is associated with synapses in human induced pluripotent stem cell-derived cortical neurons. We also noted morphological changes in induced pluripotent stem cell neurones challenged with human Alzheimer's disease-derived brain homogenate containing Aß but, in this in vitro model, total mRNA levels of Kv3.4 were found to be reduced, perhaps as an early compensatory mechanism for Aß-induced damage. Overall, our results suggest that approaches to reduce Kv3.4 expression and/or function in the Alzheimer's disease brain could be protective against Aß-induced synaptic alterations.

Sequential habituation to space, object and stranger is differentially modulated by glutamatergic, cholinergic and dopaminergic transmission.

Novel object and social interaction tasks allow assessments of rodent cognition and social behavior. Here, we combined these tasks and defined unequivocal locations of interest. Our procedure, termed OF-NO-SI, comprised habituation to the open field (OF), novel object (NO) and social interaction (SI) stages. Habituation was measured within- and between-trials (10 minutes each, two per stage). Ambulation emerged as the appropriate proxy during the OF stage, but NO and SI trials were best quantified via direct exploration measures. We pharmacologically validated the paradigm using 5-month old C57BL/6J male mice, treated intraperitoneally with (1) 0.5 mg/kg scopolamine, (2) 0.05 mg/kg MK-801 and (3) 0.05 mg/kg SCH-23390 to block muscarinic (M1), NMDA, and D1 receptors, respectively, or (4) vehicle (distilled water). Activity and gross exploratory behavior were affected by all compounds cf. vehicle: scopolamine and MK-801 cohorts were hyperactive, while SCH-23390 caused hypo-locomotion throughout. Vehicle treated mice showed reliable habituation to all stages for time in interaction zone, directed exploration and number of visits. Exploration was severely impaired by scopolamine. MK-801 mostly affected within-session exploration but also increased exploration of the conspecific compared to the object. Interestingly, even though within-trial habituation was lacking in the SCH-23390 cohort, between-trial habituation was largely intact, despite reduced locomotion. Our data suggest that the OF-NO-SI task is a convenient and robust paradigm to measure habituation to different experimental settings and stimuli. It allows the dissociation of proxies related to activity and non-associative learning/memory, as revealed by distinct pharmacological treatment effects within- vs. between-trials.

Of mice and motion: Behavioural-EEG phenotyping of Alzheimer's disease mouse models.

BACKGROUND: Rodent electroencephalography (EEG) in preclinical research is frequently conducted in behaving animals. EEG analysis is complicated by a number of confounds, particularly 1. The close relationship between EEG power and movement speed must be controlled for prior to further analysis. 2. The difficulty inherent in identifying EEG epochs associated with a particular behaviour. NEW METHOD: We utilized infra-red event stamping to accurately synchronize EEG recorded superficially above the hippocampus and prefrontal cortex with motion tracking data in a transgenic Alzheimer's disease (AD) mouse model (PLB1APP) and wild-type controls (PLBWT) performing a Y-maze spontaneous alternation task. Video tracking synchronized epochs capturing specific behaviours were automatically identified and extracted prior to auto-regressive spectral analysis. RESULTS: Despite comparable behavioural performance, PLB1APP mice demonstrated region and behavioural context specific deficits in regulation of Gamma power: In contrast to controls, hippocampal Gamma response to speed as well as prefrontal activity associated with correct vs. incorrect alternations was absent in PLB1APP mice. Regulation of hippocampal Gamma power in response to direction of movement did not differ. COMPARISON WITH EXISTING METHODS: This method allows for the first time to detect behaviour-specific differences in EEG response to speed that can be quantified and actively controlled for. Analysis across multiple parameters engaging different brain regions can now be used for detailed EEG profiling of brain-region specific functions. CONCLUSION: Combining infra-red event-stamping and auto-regressive modelling enables rapid, automated and sensitive phenotyping of AD mouse models. Subtle alterations in brain signalling can be detected prior to overt behavioural impairments.

Histological and Behavioral Phenotypes of a Novel Mutated APP Knock-In Mouse.

Gene mutations within amyloid precursor protein (APP or AßPP) and/or presenilin 1 (PS1) genes are determinants of familial Alzheimer's disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP) with mutated human APPSwe/Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1A246E) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-ß (Aß) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels of intracellular Aß in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aß build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aß in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1, including a shift from hippocampal to cortical Aß pathology, alongside reduced deficits in spatial learning.