Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of cardiovascular disease (CVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, many of these studies have included a broad array of CVD events or have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of atherosclerotic cardiovascular disease (ASCVD)hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 30-days and 1 year after-COPD hospitalization relative to the same time period before-COPD hospitalization. Time in the before- and after-COPD hospitalization time periods to a composite ASCVD hospitalization outcome were modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients in the 30-day and 1-year cohorts, (mean age, 73-74 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization for the 30-day cohort was 0.99 (0.93, 1.05; p = 0.67) and for the 1-year cohort was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations 1 year after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased 30-day or 1-year after COPD-hospitalization relative to before-COPD hospitalization. In sub-group analyses, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups with increased risk of ASCVD events 1-year after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Review of the Evidence for Pulmonary Rehabilitation in COPD: Clinical Benefits and Cost-Effectiveness.

COPD is a common and lethal chronic condition, recognized as a leading cause of death worldwide. COPD is associated with significant morbidity and disability, particularly among older adults. The disease course is marked by periods of stability and disease exacerbations defined by worsening respiratory status resulting in a high burden of health care utilization and an increased risk of mortality. Treatment is focused on pharmacologic therapies, but these are not completely effective. Pulmonary rehabilitation (PR) represents a key medical intervention for patients with chronic respiratory diseases, including COPD. PR provides individualized and progressive exercise training, education, and self-management strategies through a comprehensive and multidisciplinary program. PR has been associated with improvement in exercise capacity, health-related quality of life, and dyspnea in patients living with COPD. Moreover, PR has been associated with improvements in hospital readmission and 1-y survival. In addition to the clinical benefits, PR is estimated to be a cost-effective medical intervention. Despite these benefits, participation in PR remains low. We will review the evidence for PR in each of these benefit domains among patients with stable COPD and in those recovering from a COPD exacerbation.

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after COPD Hospitalization among Older Adults.

BACKGROUND: Meta-analyses have suggested the risk of atherosclerotic cardiovascular disease (ASCVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, these studies have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. METHODS: We assessed the risk of ASCVD hospitalizations after COPD hospitalization compared to before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016-2019 in the US. The primary outcome was risk of a ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery by-pass graft surgery, stroke, or transient ischemic attack) in the 1 year after-COPD hospitalization relative to the 1 year before-COPD hospitalization. Time from discharge to a composite ASCVD hospitalization outcome was modeled using an extension of the Cox Proportional-Hazards model, the Anderson-Gill model with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups and risk factors associated with the composite ASCVD hospitalization outcome. RESULTS: Among 920,550 patients (mean age, 73 years) the hazard ratio estimate (HR; 95% CI) for the composite ASCVD hospitalization outcome after-COPD hospitalization vs before-COPD hospitalization was 0.99 (0.97, 1.02; p = 0.53) following adjustment. We observed 3 subgroups that were significantly associated with higher risk for ASCVD hospitalizations after COPD hospitalization: 76+ years old, women, COPD hospitalization severity. Among the 19 characteristics evaluated, 10 were significantly associated with higher risk of CVD events 1 year after COPD hospitalization with hyperlipidemia (2.78; 2.67, 2.90) and history of cardiovascular disease (1.77; 1.72 1.83) associated with the greatest risk. CONCLUSION: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalizations was not significantly increased after COPD-hospitalization relative to before-COPD hospitalization. Although, we identified age 76+ years old, female sex, and COPD hospitalization severity as high risk subgroups and 10 risk factors associated with increased risk of ASCVD events after-COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Timing of Treatment Outcomes and Risk Factors for Failure of BPAP in Patients Hospitalized for COPD Exacerbation.

BACKGROUND: Patients hospitalized for COPD exacerbation have an increased risk of mortality, particularly among those who fail bi-level positive airway pressure (BPAP) for hypercapnic respiratory failure subsequently requiring invasive mechanical ventilation. Therefore, we sought to investigate the treatment course of BPAP and factors associated with BPAP treatment failure. METHODS: We performed a retrospective cohort study using real-world evidence to investigate subjects with COPD who were treated with BPAP during a hospitalization for COPD exacerbation. Treatment outcomes were defined within 7 d from BPAP initiation as either failure, persistent, or success. Failure was defined as death or progression to invasive ventilation. Persistent was defined as receiving BPAP during hospital day 7. Success was defined as liberation from BPAP prior to hospital day 7 and not meeting criteria for failure. Unadjusted multinomial logistic regression models were used to examine the association between BPAP treatment outcomes and 17 recipient characteristics. RESULTS: Among the 427 clinical encounters, 78% were successful, 10% were persistent, and 12% experienced failure. The median time to failure and success was 8 h and 16 h, respectively. Increasing age, body mass index (BMI), bicarbonate level, and creatinine level were significantly associated with either BPAP treatment failure, persistent treatment, or both. CONCLUSIONS: The first 8 h following initiation of BPAP is a critical time period where patients are at high risk for life-threatening decompensation. Careful consideration should be given to increasing age, BMI, bicarbonate level, and creatinine level as these factors were associated with BPAP treatment failure or persistent treatment.

Cost-effectiveness of Pulmonary Rehabilitation Among US Adults With Chronic Obstructive Pulmonary Disease.

Importance: Pulmonary rehabilitation (PR) after exacerbation of chronic obstructive pulmonary disease (COPD) is effective in reducing COPD hospitalizations and mortality while improving health-related quality of life, yet use of PR remains low. Estimates of the cost-effectiveness of PR in this setting could inform policies to improve uptake. Objective: To estimate the cost-effectiveness of participation in PR after hospitalization for COPD. Design, Setting, and Participants: This economic evaluation estimated the cost-effectiveness of participation in PR compared with no PR after COPD hospitalization in the US using a societal perspective analysis. A Markov microsimulation model was developed to estimate the cost-effectiveness in the US health care system with a lifetime horizon, 1-year cycle length, and a discounted rate of 3% per year for both costs and outcomes. Data sources included published literature from October 1, 2001, to April 1, 2021, with the primary source being an analysis of Medicare beneficiaries living with COPD between January 1, 2014, and December 31, 2015. The analysis was designed and conducted from October 1, 2019, to December 15, 2021. A base case microsimulation, univariate analyses, and a probabilistic sensitivity analysis were performed. Interventions: Pulmonary rehabilitation compared with no PR after COPD hospitalization. Main Outcomes and Measures: Net cost in US dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Results: Among the hypothetical cohort with a mean age of 76.9 (age range, 60-92) years and 58.6% women, the base case microsimulation from a societal perspective demonstrated that PR resulted in net cost savings per patient of $5721 (95% prediction interval, $3307-$8388) and improved quality-adjusted life expectancy (QALE) (gain of 0.53 [95% prediction interval, 0.43-0.63] years). The findings of net cost savings and improved QALE with PR did not change in univariate analyses of patient age, the Global Initiative for Obstructive Lung Disease stage, or number of PR sessions. In a probabilistic sensitivity analysis, PR resulted in net cost savings and improved QALE in every one of 1000 samples and was the dominant strategy in 100% of simulations at any willingness-to-pay threshold. In a 1-way sensitivity analysis of total cost, assuming completion of 36 sessions, a single PR session would remain cost saving to $171 per session and had an incremental cost-effectiveness ratio of $884 per session for $50 000/QALY and $1597 per session for $100 000/QALY. Conclusions and Relevance: In this economic evaluation, PR after COPD hospitalization appeared to result in net cost savings along with improvement in QALE. These findings suggest that stakeholders should identify policies to increase access and adherence to PR for patients with COPD.

Green electrospinning for biomaterials and biofabrication.

Green manufacturing has emerged across industries, propelled by a growing awareness of the negative environmental and health impacts associated with traditional practices. In the biomaterials industry, electrospinning is a ubiquitous fabrication method for producing nano- to micro-scale fibrous meshes that resemble native tissues, but this process traditionally utilizes solvents that are environmentally hazardous and pose a significant barrier to industrial scale-up and clinical translation. Applying sustainability principles to biomaterial production, we have developed a 'green electrospinning' process by systematically testing biologically benign solvents (U.S. Food and Drug Administration Q3C Class 3), and have identified acetic acid as a green solvent that exhibits low ecological impact (global warming potential (GWP) = 1.40 CO2eq. kg/L) and supports a stable electrospinning jet under routine fabrication conditions. By tuning electrospinning parameters, such as needle-plate distance and flow rate, we updated the fabrication of widely utilized biomedical polymers (e.g. poly-α-hydroxyesters, collagen), polymer blends, polymer-ceramic composites, and growth factor delivery systems. Resulting 'green' fibers and composites are comparable to traditional meshes in terms of composition, chemistry, architecture, mechanical properties, and biocompatibility. Interestingly, material properties of green synthetic fibers are more biomimetic than those of traditionally electrospun fibers, doubling in ductility (91.86 ± 35.65 vs. 45 ± 15.07%,n= 10,p< 0.05) without compromising yield strength (1.32 ± 0.26 vs. 1.38 ± 0.32 MPa) or ultimate tensile strength (2.49 ± 0.55 vs. 2.36 ± 0.45 MPa). Most importantly, green electrospinning proves advantageous for biofabrication, rendering a greater protection of growth factors during fiber formation (72.30 ± 1.94 vs. 62.87 ± 2.49% alpha helical content,n= 3,p< 0.05) and recapitulating native ECM mechanics in the fabrication of biopolymer-based meshes (16.57 ± 3.92% ductility, 33.38 ± 30.26 MPa elastic modulus, 1.30 ± 0.19 MPa yield strength, and 2.13 ± 0.36 MPa ultimate tensile strength,n= 10). The eco-conscious approach demonstrated here represents a paradigm shift in biofabrication, and will accelerate the translation of scalable biomaterials and biomimetic scaffolds for tissue engineering and regenerative medicine.

Risk factors for mortality in lung transplant recipients aged ≥65 years: A retrospective cohort study of 5,815 patients in the scientific registry of transplant recipients.

BACKGROUND: Lung transplantation is increasingly performed in recipients aged ≥65 years. However, the risk factors for mortality specific to this population have not been well studied. In lung transplant recipients aged ≥65 years, we sought to determine post-transplant survival and clinical factors associated with post-transplant mortality. METHODS: We investigated 5,815 adult lung transplants recipients aged ≥65 years in the Scientific Registry of Transplant Recipients. Mortality was defined as a composite of recipient death or retransplantation. The Kaplan-Meier method was used to estimate the median time to mortality. Univariable and multivariable Cox proportional hazards regression models were used to examine the association between time to mortality and 23 donor, recipient, or center characteristics. RESULTS: Median survival in lung transplant recipients aged ≥65 years was 4.41 years (95% CI: 4.21-4.60 years) and significantly worsened by increasing age strata. In the multivariable model, increasing recipient age strata, creatinine level, bilirubin level, hospitalization at the time of transplantation, single lung transplant operation, steroid use at the time of transplantation, donor diabetes, and cytomegalovirus mismatch were independently associated with increased mortality. CONCLUSIONS: Among the 8 risk factors we identified, 5 factors are readily available, which can be used to optimize post-transplant survival by informing risk during candidate selection of patients aged ≥65 years. Furthermore, bilateral lung transplantation may confer improved survival in comparison with single lung transplantation. Our results support that after careful consideration of risk factors, lung transplantation can provide life-extending benefits in individuals aged ≥65 years.

Time to diagnosis of idiopathic pulmonary fibrosis in the IPF-PRO Registry.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. Patient characteristics associated with diagnostic delays are not well described. METHODS: Subjects who had not been diagnosed with IPF prior to referral and received a new diagnosis of IPF at an enrolling centre for the IPF-PRO (Idiopathic Pulmonary Fibrosis Prospective Outcomes) Registry were characterised as having a longer (>1 year) or shorter (≤1 year) time from symptom onset to diagnosis and from first imaging evidence of fibrosis to diagnosis. Patient characteristics, evaluations and time to death or lung transplant were compared between these cohorts. RESULTS: Among 347 patients with a symptom onset date, 49% were diagnosed with IPF >1 year after symptom onset. These patients were slightly younger and had more cardiac comorbidities than patients diagnosed ≤1 year after symptom onset. Among 454 patients with a date for imaging evidence of fibrosis, 78% were diagnosed with IPF ≤1 year later. A greater proportion of patients with >1 year versus ≤1 year from imaging evidence of fibrosis to diagnosis had cardiac comorbidities and gastro-oesophageal reflux. There was no significant difference in time to death or lung transplant between groups by time to diagnosis. CONCLUSIONS: The time from symptom onset to diagnosis remains over 1 year in approximately half of the patients with IPF, but once imaging evidence is obtained, most of the patients are diagnosed within a year. Cardiac conditions and gastro-oesophageal disorders were more commonly reported in patients with a longer time to diagnosis.

Cardiovascular implications of idiopathic pulmonary fibrosis: A way forward together?

Cardiovascular disease has an increased prevalence among patients with idiopathic pulmonary fibrosis (IPF). Cardiovascular disease and IPF share similar symptoms with overlapping demographics and risk factors for disease development. Common cellular mediators leading to disease development and progression have been identified in both the cardiovascular and pulmonary organ systems. In this context, discovery of new therapeutic targets and medical therapies could be mutually beneficial across cardiopulmonary diseases. Here we present (1) a clinical review of IPF for the cardiovascular clinician and (2) common cellular mechanisms responsible for fibrosis in the heart and lungs and (3) highlight future research considerations and the potential role of novel therapeutic agents which may be mutually beneficial in cardiac and pulmonary fibrosis.

Polymeric mesh and insulin-like growth factor 1 delivery enhance cell homing and graft-cartilage integration.

Cartilage injury, such as full-thickness lesions, predisposes patients to the premature development of osteoarthritis, a degenerative joint disease. While surgical management of cartilage lesions has improved, long-term clinical efficacy has stagnated, owing to the lack of hyaline cartilage regeneration and inadequate graft-host integration. This study tests the hypothesis that integration of cartilage grafts with native cartilage can be improved by enhancing the migration of chondrocytes across the graft-host interface via the release of chemotactic factor from a degradable polymeric mesh. To this end, a polylactide-co-glycolide/poly-ε-caprolactone mesh was designed to localize the delivery of insulin-like growth factor 1 (IGF-1), a well-established chondrocyte attractant. The release of IGF-1 (100 ng/mg) enhanced cell migration from cartilage explants, and the mesh served as critical structural support for cell adhesion, growth, and production of a cartilaginous matrix in vitro, which resulted in increased integration strength compared with mesh-free repair. Further, this neocartilage matrix was structurally contiguous with native and grafted cartilage when tested in an osteochondral explant model in vivo. These results demonstrate that this combined approach of a cell homing factor and supportive matrix will promote cell-mediated integrative cartilage repair and improve clinical outcomes of cartilage grafts in the treatment of osteoarthritis.

Mechanical behaviour of biodegradable AZ31 magnesium alloy after long term in vitro degradation.

Biodegradable magnesium alloys including AZ31 are exciting candidates for temporary implants as they eliminate the requirement for surgical removal, yet have higher mechanical properties than degradable polymers. However, the very long term mechanical properties and degradation of these alloys have not been fully characterized. The tensile, bending and corrosion behaviour of biodegradable AZ31 Mg alloy specimens have been investigated for up to 9months in vitro in phosphate buffered saline (PBS). Small AZ31 Mg specimens showed a significant drop in bend yield strength and modulus after 3months in vitro degradation and an average mass loss of 6.1%. Larger dumbbell specimens showed significant drops in tensile strength from 251.96±3.53MPa to 73.5±20.2MPa and to 6.43±0.9MPa and in modulus from 47.8±5.6GPa to 25.01±3.4GPa and 2.36±0.89GPa after 3 and 9months respectively. These reductions were accompanied by an average mass loss of 18.3% in 9months. Degradation rate for the small and large specimens followed similar profiles with immersion time, with peak degradation rates of 0.1747gm-2h-1 and 0.0881gm-2h-1, and average rates of 0.1038gm-2h-1 and 0.0397gm-2h-1 respectively. SEM fractography and polished specimen cross-sections revealed corrosion pits, cracks and corrosion induced defects. These data indicate the potential of AZ31 Mg for use in implants that require medium term degradation with load bearing mechanical properties.

Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling.

AIMS: Valve interstitial cells are active and aggressive players in aortic valve calcification, but their dynamic mediation of mechanically-induced calcific remodeling is not well understood. The goal of this study was to elucidate the feedback loop between valve interstitial cell and calcification mechanics using a novel three-dimensional culture system that allows investigation of the active interplay between cells, disease, and the mechanical valve environment. METHODS & RESULTS: We designed and characterized a novel bioreactor system for quantifying aortic valve interstitial cell contractility in 3-D hydrogels in control and osteogenic conditions over 14 days. Interstitial cells demonstrated a marked ability to exert contractile force on their environment and to align collagen fibers with the direction of tension. Osteogenic environment disrupted interstitial cell contractility and led to disorganization of the collagen matrix, concurrent with increased αSMA, TGF-ß, Runx2 and calcific nodule formation. Interestingly, RhoA was also increased in osteogenic condition, pointing to an aberrant hyperactivation of valve interstitial cells mechanical activity in disease. This was confirmed by inhibition of RhoA experiments. Inhibition of RhoA concurrent with osteogenic treatment reduced pro-osteogenic signaling and calcific nodule formation. Time-course correlation analysis indicated a significant correlation between interstitial cell remodeling of collagen fibers and calcification events. CONCLUSIONS: Interstitial cell contractility mediates internal stress state and organization of the aortic valve extracellular matrix. Osteogenesis disrupts interstitial cell mechanical phenotype and drives disorganization, nodule formation, and pro-calcific signaling via a RhoA-dependent mechanism.

Stratified scaffold design for engineering composite tissues.

A significant challenge to orthopaedic soft tissue repair is the biological fixation of autologous or allogeneic grafts with bone, whereby the lack of functional integration between such grafts and host bone has limited the clinical success of anterior cruciate ligament (ACL) and other common soft tissue-based reconstructive grafts. The inability of current surgical reconstruction to restore the native fibrocartilaginous insertion between the ACL and the femur or tibia, which minimizes stress concentration and facilitates load transfer between the soft and hard tissues, compromises the long-term clinical functionality of these grafts. To enable integration, a stratified scaffold design that mimics the multiple tissue regions of the ACL interface (ligament-fibrocartilage-bone) represents a promising strategy for composite tissue formation. Moreover, distinct cellular organization and phase-specific matrix heterogeneity achieved through co- or tri-culture within the scaffold system can promote biomimetic multi-tissue regeneration. Here, we describe the methods for fabricating a tri-phasic scaffold intended for ligament-bone integration, as well as the tri-culture of fibroblasts, chondrocytes, and osteoblasts on the stratified scaffold for the formation of structurally contiguous and compositionally distinct regions of ligament, fibrocartilage and bone. The primary advantage of the tri-phasic scaffold is the recapitulation of the multi-tissue organization across the native interface through the layered design. Moreover, in addition to ease of fabrication, each scaffold phase is similar in polymer composition and therefore can be joined together by sintering, enabling the seamless integration of each region and avoiding delamination between scaffold layers.

Engineering complex orthopaedic tissues via strategic biomimicry.

The primary current challenge in regenerative engineering resides in the simultaneous formation of more than one type of tissue, as well as their functional assembly into complex tissues or organ systems. Tissue-tissue synchrony is especially important in the musculoskeletal system, wherein overall organ function is enabled by the seamless integration of bone with soft tissues such as ligament, tendon, or cartilage, as well as the integration of muscle with tendon. Therefore, in lieu of a traditional single-tissue system (e.g., bone, ligament), composite tissue scaffold designs for the regeneration of functional connective tissue units (e.g., bone-ligament-bone) are being actively investigated. Closely related is the effort to re-establish tissue-tissue interfaces, which is essential for joining these tissue building blocks and facilitating host integration. Much of the research at the forefront of the field has centered on bioinspired stratified or gradient scaffold designs which aim to recapitulate the structural and compositional inhomogeneity inherent across distinct tissue regions. As such, given the complexity of these musculoskeletal tissue units, the key question is how to identify the most relevant parameters for recapitulating the native structure-function relationships in the scaffold design. Therefore, the focus of this review, in addition to presenting the state-of-the-art in complex scaffold design, is to explore how strategic biomimicry can be applied in engineering tissue connectivity. The objective of strategic biomimicry is to avoid over-engineering by establishing what needs to be learned from nature and defining the essential matrix characteristics that must be reproduced in scaffold design. Application of this engineering strategy for the regeneration of the most common musculoskeletal tissue units (e.g., bone-ligament-bone, muscle-tendon-bone, cartilage-bone) will be discussed in this review. It is anticipated that these exciting efforts will enable integrative and functional repair of soft tissue injuries, and moreover, lay the foundation for the development of composite tissue systems and ultimately, total limb or joint regeneration.