Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD.

BACKGROUND: Whole lung tissue transcriptomic profiling studies in chronic obstructive pulmonary disease (COPD) have led to the identification of several genes associated with the severity of airflow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentified. METHODS: To determine cell specific transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n = 29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n = 3) and patients with severe COPD (n = 3). The cell type composition and cell specific gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specific cell types contributing to the previously reported transcriptomic signatures. RESULTS: T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more differentially expressed genes in cases vs. controls (log fold change >|0.4| and FDR = 0.05) were: monocytes (n = 1499); macrophages (n = 868) and ciliated epithelial cells (n = 590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES] = 1.28 and = 1.33, FDR = 0.085 and = 0.092 respectively). Among the significantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs. CONCLUSIONS: scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specific manner.

Acute ischemic strokes in patients with developmental disabilities: A cross-sectional analysis.

OBJECTIVE: Patients with developmental disabilities (DD) are frequently excluded from acute ischemic stroke (AIS) randomized control trials. We sought to evaluate the impact of having DD on this patient cohort. METHODS: The National Inpatient Sample was analyzed to explore the impact of AIS and treatment on discharge dispositions in patients with DD. Clinical characteristics, treatments, and outcomes were compared to fully-abled patients with AIS. RESULTS: 1,605,723 patients with AIS were identified from 2010-2019, of whom 4094 (0.30%) had a DD. AIS patients with DD were younger (60.31 vs 70.93 years, p < 0.01), less likely to be Caucasian (66.37%vs 68.09%, p = 0.01), and had higher AIS severity (0.63 vs 0.58, p < 0.01). Tissue plasminogen activator (tPA) was administered in 99,739 (6.2%) fully-abled patients and 196 (4.79%) of patients with DD (p < 0.01). Endovascular thrombectomy (EVT) was performed in 21,066 (1.31%) of fully-abled patients and 35 (0.85%) of patients with DD (p < 0.01). The presence of developmental disabilities were predictive of lower rates of tPA (OR:0.71,CI:0.56-0.87,p < 0.01) and EVT (OR:0.24,CI:0.16-0.36,p < 0.01). In a propensity score-matched cohort of all AIS patients who underwent EVT, there was no difference in functional outcome (p = 0.41), in-hospital mortality (0.10), and LOS (p = 0.79). CONCLUSION: AIS patients with DD were less likely to receive tPA and EVT compared to fully-abled patients. Individuals with DD had higher mortality and worse discharge disposition. There was no significant difference in post-EVT outcomes between fully-abled patients and patients with developmental disabilities. In the absence of prospective clinical trials, population based cross-sectional analyses such as the present study provide valuable clinical insight.

Breast cancer mortality as a function of age.

BACKGROUND: Incidence of breast cancer (BC) in US women continues to increase with age as the strongest risk factor. We aimed to compare clinical, pathological and sociological variables associated to BC diagnosis, as well as the relative mortality rates of BC patients compared to the general US population. METHODS: We performed a retrospective, single-institution study evaluating 52,509 patients diagnosed with unilateral BC at the University of Pittsburgh Medical Center (UPMC) between 1990-2020. Primary outcome was death from any cause with cancer recurrence as a secondary outcome, evaluated for 4 age groups: 20-44, 45-55, 56-69, and 70-90. A dataset of expected mortality for women in the general population over a 10-year period was constructed using the Surveillance, Epidemiology, and End Results (SEER) Program. Observed vs. expected mortality and standardized mortality ratios (SMR) for each age group were calculated. RESULTS: Youngest patients with BC demonstrated the highest SMR at 10-year follow-up from time of diagnosis compared to the general US population (SMR 9.68, 95% CI: 8.99to 10.42), and remained highest compared to other age groups when analysis was limited to Stage 0/1 disease (10-year SMR 3.11, 95% CI: 2.54 to 3.76). SMRs decreased with increasing age at diagnosis with an SMR <1.0 in patients diagnosed with stage 0/1 at ages 70-90 at 5-year follow-up. CONCLUSIONS: Younger BC patients have the highest SMR which declines gradually with age. In the elderly, lower stage 0/1 SMR's are found compared to the general population, suggesting the possibility of an associated protective effect.

An integrated approach to improve clinical trial efficiency: Linking a clinical trial management system into the Research Integrated Network of Systems.

Low-accruing clinical trials delay translation of research breakthroughs into the clinic, expose participants to risk without providing meaningful clinical insight, increase the cost of therapies, and waste limited resources. By tracking patient accrual, Clinical and Translational Science Awards hubs can identify at-risk studies and provide them the support needed to reach recruitment goals and maintain financial solvency. However, tracking accrual has proved challenging because relevant patient- and protocol-level data often reside in siloed systems. To address this fragmentation, in September 2020 the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina, implemented a clinical trial management system (CTMS), with its access to patient-level data, and incorporated it into its Research Integrated Network of Systems (RINS), which links study-level data across disparate systems relevant to clinical research. Within the first year of CTMS implementation, 324 protocols were funneled through CTMS/RINS, with more than 2600 participants enrolled. Integrated data from CTMS/RINS have enabled near-real-time assessment of patient accrual and accelerated reimbursement from industry sponsors. For institutions with bioinformatics or programming capacity, the CTMS/RINS integration provides a powerful model for tracking and improving clinical trial efficiency, compliance, and cost-effectiveness.

Descriptive Analysis of an Interdisciplinary Musculoskeletal Program.

BACKGROUND: Interdisciplinary musculoskeletal programs address comorbidities confounding musculoskeletal conditions and serve as an alternative to the single provider model. OBJECTIVE: Descriptive analysis of an interdisciplinary musculoskeletal program. DESIGN: Retrospective descriptive analysis of patients enrolled in an interdisciplinary musculoskeletal program. Retrospective subanalysis: cohort of patients enrolled in interdisciplinary program with low back pain compared to historical cohort of patients in a single provider clinic. SETTING: Academic interdisciplinary musculoskeletal health program. PATIENTS: Patients referred to program with at least one follow-up visit over a 2-year period. INTERVENTIONS: Interdisciplinary musculoskeletal program involving physiatry, pain anesthesia, nutrition, psychology, rheumatology, sleep medicine, nursing, and physical therapy. MAIN OUTCOME MEASUREMENTS: Patient Specific Functional Scale (PSFS), Oswestry Low Back Disability Index (ODI), number of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, opioid prescriptions; Press Ganey scores. RESULTS: One hundred and seventy-three patients were enrolled and had at least one follow-up visit. Twenty-four percent of patients with any musculoskeletal complaint demonstrated clinically significant improvements in total PSFS. Mean improvement in PSFS was + 0.864 (SD 1.94), which was a statistically significant improvement (P = .0005), but not clinically significant. Magnetic resonance imaging was ordered for 5% of patients, and no computed tomography scans were ordered. Six percent of patients received opioid prescriptions. Press Ganey scores: 96% responded favorably in regard to physician communication quality, 86% of patients responded favorably for access to care, and 78% responded favorably for care coordination. 27.8% of patients with low back pain in the interdisciplinary program achieved a significant decrease in their ODI, compared to 26.6% in the single provider clinic (P = .87). CONCLUSIONS: Interdisciplinary musculoskeletal programs are a promising model to improve the functioning of patients with musculoskeletal pain and decrease downstream utilization. These programs may be more appropriate for patients at higher risk of developing chronic pain.

Analysis of the inflammatory response induced by rhMMP-12 catalytic domain instilled in mouse airways.

Macrophage elastase (MMP-12) is a metalloproteinase able to degrade extracellular matrix components such as elastin. As many MMPs, MMP-12 is involved in acute and chronic lung injury. However, its role in the inflammatory process of the lung parenchyma is not clearly understood. In this study, we have investigated the effects of airway instillation of rhMMP-12 on inflammatory cell recruitment, cytokine release and gelatinase expression in bronchoalveolar lavage fluid (BALF) or in lung homogenate supernatants in mice. Numbers of total and individual cell types were examined in BALF during the first 72 h following rhMMP-12 instillation. A marked recruitment of neutrophils was observed with a maximum increase at 18 h. This cellular recruitment was associated with a very transient increase in IL-6, TNF-alpha MIP-1alpha, MCP-1 and KC levels and gelatinase expression in BALF and in lung homogenate supernatants. From days 4 to 15, performing the same analyses, we observed an important and stable recruitment of macrophages in BALF in absence of the other studied inflammatory markers. These results demonstrate that rhMMP-12 itself is able to induce an early inflammatory response characterized by neutrophil infiltration, cytokine release and gelatinase activation followed by a later response composed mainly of macrophage recruitment.

Lung transplantation for pulmonary vascular disease.

BACKGROUND: Pulmonary hypertension (PHT) is a lethal condition resulting in markedly diminished life expectancy. Continuous prostaglandin I2 infusion has made an important contribution to symptom management, but it is not a panacea. Lung or heart-lung transplantation remains an important treatment option for end-stage PHT patients unresponsive to prostaglandin I2. This study reviews the outcomes after transplantation for PHT in our program. METHODS: A retrospective chart review was performed for 100 consecutive patients with either primary PHT (48%) or secondary PHT (52%) transplants since 1989. Living recipients were contacted to confirm health and functional status. RESULTS: Fifty-five adult and 45 pediatric patients underwent 51 bilateral lung transplants, 39 single lung transplants, and 10 heart-lung transplants. Mean age was 23.7 years (range, 1.2 months to 54.8 years) and mean pre-transplant New York Heart Association class was 3.2. Pre-transplant hemodynamics revealed a mean right atrial pressure of 9.6+/-5.4 mm Hg and mean pulmonary artery pressure of 64+/-14.4 mm Hg. Hospital mortality was 17% with early death predominantly because of graft failure and infection. With an average follow-up of 5.0 years, 1- and 5-year actuarial survival was 75% and 57%, respectively. Mean pulmonary artery pressure on follow-up catheterization was 22+/-6.0 mm Hg, and mean follow-up New York Heart Association class was 1.3 (p < 0.001 for both compared with pre-transplant). Diagnosis and type of transplant did not confer a significant difference in survival between groups. CONCLUSIONS: Whereas lung or heart-lung transplant for PHT is associated with higher early mortality than other pulmonary disease entities, it provides similar long-term outcomes with dramatic improvement in both quality of life and physiologic aspects.

Individual canine airway response variability to a deep inspiration.

In healthy individuals, a DI can reverse (bronchodilation) or prevent (bronchoprotection) induced airway constriction. For individuals with asthma or COPD, these effects may be attenuated or absent. Previous work showed that the size and duration of a DI affected the subsequent response of the airways. Also, increased airway tone lead to increased airway size variability. The present study examined how a DI affected the temporal variability in individual airway baseline size and after methacholine challenge in dogs using High-Resolution Computed Tomography. Dogs were anesthetized and ventilated, and on 4 separate days, HRCT scans were acquired before and after a DI at baseline and during a continuous intravenous infusion of methacholine (Mch) at 3 dose rates (17, 67, and 200 µg/min). The Coefficient of Variation was used as an index of temporal variability in airway size.We found that at baseline and the lowest dose of Mch, variability decreased immediately and 5 minutes after the DI (P < 0.0001). In contrast, with higher doses of Mch, the DI caused a variable response. At a rate of 67 µg/min of Mch, the temporal variability increased after 5 minutes, while at a rate of 200 µg/min of Mch, the temporal variability increased immediately after the DI. Increased airway temporal variability has been shown to be associated with asthma. Although the mechanisms underlying this temporal variability are poorly understood, the beneficial effects of a DI to decrease airway temporal variability was eliminated when airway tone was increased. If this effect is absent in asthmatics, this may suggest a possible mechanism for the loss of bronchoprotective and bronchodilatory effects after a DI in asthma.

Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.

In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.

Cathepsin S deficiency confers protection from neonatal hyperoxia-induced lung injury.

RATIONALE: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that adversely affects long-term pulmonary function as well as neurodevelopmental outcomes of preterm infants. Elastolytic proteases have been implicated in the pathogenesis of BPD. Cathepsin S (cat S) is a cysteine protease with potent elastolytic activity. Increased levels and activity of cat S have been detected in a baboon model of BPD. OBJECTIVES: To investigate whether deficiency of cat S alters the course of hyperoxia-induced neonatal lung injury in mice. METHODS: Newborn wild-type and cat S-deficient mice were exposed to 80% oxygen for 14 days. Histologic and morphometric analysis were performed and bronchoalveolar lavage protein and cells were analyzed. Lung elastin was assessed by real-time polymerase chain reaction, in situ hybridization, desmosine analysis, and Hart's stain. Distribution of myofibroblasts was analyzed by immunofluorescence. Hydroxyproline content of lung tissues was measured. MEASUREMENTS AND MAIN RESULTS: Hyperoxia-exposed cat S-deficient mice were protected from growth restriction and had improved alveolarization, decreased septal wall thickness, lower number of macrophages, and lower protein concentration in bronchoalveolar lavage fluid. alpha-Smooth muscle actin-expressing myofibroblasts accounted for at least some of the increased interstitial cellularity in hyperoxia-exposed mouse lungs and were significantly less in cat S-deficient lungs. Lung hydroxyproline content was increased in hyperoxia-exposed wild-type, but not in cat S-deficient lungs. Desmosine content was significantly reduced in both genotypes with hyperoxia. CONCLUSIONS: Cathepsin S deficiency improves alveolarization, and attenuates macrophage influx and fibroproliferative changes in hyperoxia-induced neonatal mouse lung injury.