Quantifying the Economic Impact of Delayed Multiple-Inhaler Triple Therapy Initiation in Patients with COPD: A Retrospective Cohort Study of Linked Electronic Medical Record and Hospital Administrative Data in England.

PURPOSE: To assess if early multiple-inhaler triple therapy (MITT) initiation in patients with chronic obstructive pulmonary disease (COPD) reduces subsequent healthcare resource utilization (HCRU), direct medical costs, and acute exacerbations of COPD (AECOPDs). PATIENTS AND METHODS: This retrospective, longitudinal cohort study used electronic health records and linked hospital administrative data in England. COPD patients with an AECOPD between July 2012 and May 2016 (index), and who subsequently started MITT within 180 days were eligible. Patients with an AECOPD 6 months prior to index were excluded. HCRU, direct healthcare costs, and AECOPDs were assessed in the following 24-month period for early (≤30 days) and delayed (31-180 days) MITT initiators. RESULTS: A total of 934 patients were included in the analysis and categorized as early (n=367, 39%) or delayed (n=567, 61%) MITT initiators. Mean patient age was 68.5 years and 53.2% were male. A significantly higher proportion of delayed MITT initiators required ≥1 outpatient appointment (all-cause) compared with early MITT initiators (87% vs 79%; p=0.0016). A significantly higher proportion of delayed MITT initiators required ≥1 COPD­related inpatient stay versus early MITT initiators (47% vs 40%; p=0.0262). Over the 24-month follow-up, mean all-cause and COPD-related total healthcare costs were significantly higher in delayed MITT initiators compared with early MITT initiators (all­cause: £11,348 vs £8126; p=0.0011; COPD-related: £7307 vs £4535; p=0.0009). CONCLUSION: Delayed initiation of multiple-inhaler triple therapy was associated with higher all-cause and COPD-related costs, suggesting that earlier initiation of triple therapy in COPD patients may help reduce the economic burden on the healthcare system.

Long-Acting Bronchodilator Use in Chronic Obstructive Pulmonary Disease in Primary Care in New Zealand: A Retrospective Study of Treatment Patterns and Evolution Using the HealthStat Database.

PURPOSE: Long-acting bronchodilator (LABD) use is the mainstay of pharmacologic treatment for chronic obstructive pulmonary disease (COPD). Few studies describe evolving patterns of LABD use in the setting of changing inhaler availability and updated clinical guidelines. METHODS: A retrospective cohort study in New Zealand using the HealthStat general practice database (01/2014 to 04/2018). Eligible patients (aged ≥40 years) had COPD and ≥1 LABD prescription (long-acting muscarinic antagonist [LAMA] and/or long-acting ß2-agonist [LABA]) during the index period (05/2015 to 04/2016). Demographics and clinical characteristics of all LABD users (overall/by treatment) were described at baseline. Patients starting LABD treatment during the index period, termed "new" users, were also described, as was their treatment evolution over 24 months of follow-up. Yearly LABD initiation rates were assessed from 2015 to 2017, covering changes to Pharmaceutical Management Agency criteria and clinical guidelines. RESULTS: Across 2140 eligible patients, the most common index treatments were inhaled corticosteroid (ICS)/LABA (59.0%) and open triple therapy (LAMA+LABA+ICS; 26.7%). ICS/LABA therapy was highest in younger patients, with open triple therapy highest in older patients. Prior yearly exacerbation rates were lowest in those receiving monotherapy (LABA: 0.9/year; LAMA: 1.1/year) versus dual therapy (all 1.4/year) and open triple therapy (2.2/year). Of 312 new LABD users, ICS/LABA was the most common index treatment (69.6%), followed by LAMA monotherapy (16.0%). Continuous use with index treatment was 31.1% at 12 months and 13.5% at 24 months; mean time to treatment change was 175.5 and 244.1 days, respectively. Among patients modifying treatment at 24 months, 23.0% augmented, 7.0% switched, 45.6% re-started, and 24.4% discontinued/stepped down. Among patients initiating LABD each year from 2015 to 2017, LAMA prescription increased (17% to 46%) while ICS prescription remained stable (approximately 20%). CONCLUSION: Predominant use of ICS/LABA (05/2015 to 04/2016) reflects available LABDs and previous restrictions on LAMA use in New Zealand.

Splenic Capture and In Vivo Intracellular Biodegradation of Biological-Grade Graphene Oxide Sheets.

Carbon nanomaterials, including 2D graphene-based materials, have shown promising applicability to drug delivery, tissue engineering, diagnostics, and various other biomedical areas. However, to exploit the benefits of these materials in some of the areas mentioned, it is necessary to understand their possible toxicological implications and long-term fate in vivo. We previously demonstrated that following intravenous administration, 2D graphene oxide (GO) nanosheets were largely excreted via the kidneys; however, a small but significant portion of the material was sequestered in the spleen. Herein, we interrogate the potential consequences of this accumulation and the fate of the spleen-residing GO over a period of nine months. We show that our thoroughly characterized GO materials are not associated with any detectable pathological consequences in the spleen. Using confocal Raman mapping of tissue sections, we determine the sub-organ biodistribution of GO at various time points after administration. The cells largely responsible for taking up the material are confirmed using immunohistochemistry coupled with Raman spectroscopy, and transmission electron microscopy (TEM). This combination of techniques identified cells of the splenic marginal zone as the main site of GO bioaccumulation. In addition, through analyses using both bright-field TEM coupled with electron diffraction and Raman spectroscopy, we reveal direct evidence of in vivo intracellular biodegradation of GO sheets with ultrastructural precision. This work offers critical information about biological processing and degradation of thin GO sheets by normal mammalian tissue, indicating that further development and exploitation of GO in biomedicine would be possible.

Non-viral, Tumor-free Induction of Transient Cell Reprogramming in Mouse Skeletal Muscle to Enhance Tissue Regeneration.

Overexpression of Oct3/4, Klf4, Sox2, and c-Myc (OKSM) transcription factors can de-differentiate adult cells in vivo. While sustained OKSM expression triggers tumorigenesis through uncontrolled proliferation of toti- and pluripotent cells, transient reprogramming induces pluripotency-like features and proliferation only temporarily, without teratomas. We sought to transiently reprogram cells within mouse skeletal muscle with a localized injection of plasmid DNA encoding OKSM (pOKSM), and we hypothesized that the generation of proliferative intermediates would enhance tissue regeneration after injury. Intramuscular pOKSM administration rapidly upregulated pluripotency (Nanog, Ecat1, and Rex1) and early myogenesis genes (Pax3) in the healthy gastrocnemius of various strains. Mononucleated cells expressing such markers appeared in clusters among myofibers, proliferated only transiently, and did not lead to dysplasia or tumorigenesis for at least 120 days. Nanog was also upregulated in the gastrocnemius when pOKSM was administered 7 days after surgically sectioning its medial head. Enhanced tissue regeneration after reprogramming was manifested by the accelerated appearance of centronucleated myofibers and reduced fibrosis. These results suggest that transient in vivo reprogramming could develop into a novel strategy toward the acceleration of tissue regeneration after injury, based on the induction of transiently proliferative, pluripotent-like cells in situ. Further research to achieve clinically meaningful functional regeneration is warranted.