Citations

BACKGROUND: Computed tomography (CT) attenuation correction scans are an intrinsic part of positron emission tomography (PET) myocardial perfusion imaging using PET/CT, but anatomic information is rarely derived from these ultralow-dose CT scans. We aimed to assess the association between deep learning-derived cardiac chamber volumes (right atrial, right ventricular, left ventricular, and left atrial) and mass (left ventricular) from these scans with myocardial flow reserve and heart failure hospitalization. METHODS: We included 18 079 patients with cardiac PET/CT from 6 sites. A deep learning model estimated cardiac chamber volumes and left ventricular mass from CT attenuation correction imaging. Associations between deep learning-derived CT mass and volumes with heart failure hospitalization and reduced myocardial flow reserve were assessed in a multivariable analysis. RESULTS: During a median follow-up of 4.3 years, 1721 (9.5%) patients experienced heart failure hospitalization. Patients with 3 or 4 abnormal chamber volumes were 7× more likely to be hospitalized for heart failure compared with patients with normal volumes. In adjusted analyses, left atrial volume (hazard ratio [HR], 1.25 [95% CI, 1.19–1.30]), right atrial volume (HR, 1.29 [95% CI, 1.23–1.35]), right ventricular volume (HR, 1.25 [95% CI, 1.20–1.31]), left ventricular volume (HR, 1.27 [95% CI, 1.23–1.35]), and left ventricular mass (HR, 1.25 [95% CI, 1.18–1.32]) were independently associated with heart failure hospitalization. In multivariable analyses, left atrial volume (odds ratio, 1.14 [95% CI, 1.0–1.19]) and ventricular mass (odds ratio, 1.12 [95% CI, 1.6–1.17]) were independent predictors of reduced myocardial flow reserve. CONCLUSIONS: Deep learning–derived chamber volumes and left ventricular mass from CT attenuation correction were predictive of heart failure hospitalization and reduced myocardial flow reserve in patients undergoing cardiac PET perfusion imaging. This anatomic data can be routinely reported along with other PET/CT parameters to improve risk prediction.

Abstract Rationale Extracellular matrix (ECM) accumulation results from an imbalance between ECM deposition and degradation, due to persistently increased ECM synthesis or reduced resorption. Fibroblasts, as key regulators of ECM homeostasis in both health and disease, are essential targets to rebalance ECM turnover. Recent findings indicate that fibroblasts are regulated by immune cells, which can influence ECM deposition. Specifically, myeloperoxidase (MPO), an enzyme produced by neutrophils, has been shown to enhance fibroblast-driven ECM accumulation in various diseases. In patients with radiographic Interstitial Lung Disease (ILD), elevated MPO levels have been correlated with reduced lung capacity (Cantin et al., 1987), while recent studies report increased MPO levels in the bronchoalveolar lavage fluid of ILD patients (Ngo et al., EJROR 2024). Additionally, MPO and related immune dysregulation proteins are found in fibrotic alveoli in Idiopathic Pulmonary Fibrosis (IPF) (Herrera et al., JCI Insight 2022). These findings suggest an association between MPO and lung fibrosis, yet it remains uncertain whether MPO directly influences ECM accumulation in fibrotic progression. Methods Patient tissue and serum samples were collected with consent, and MPO levels were quantified using ELISA and immunofluorescence techniques. Biochemical assays were performed using MPO isolated from human leukocytes, recombinant cathepsin K, and hydrogen peroxide to investigate whether MPO influences cathepsin K activity. Precision cut lung slices (PCLS) were prepared from untreated C57BL/6 mice and treated with transforming growth factor-beta (TGFβ) and/or MPO for four days, with cathepsin K activity assessed using fluorescence assays. Additionally, MPO-knockout and wild-type mice received intratracheal bleomycin, and after 14 days, cathepsin K activity was quantified via in vivo imaging. Collagen content, as an indicator of fibrosis, was measured by quantifying hydroxyproline in harvested lung tissue. Results/Discussion/Conclusion Increased MPO levels were observed in immunofluorescent-stained samples (57%; 4/7) and serum samples (30%; 3/10) from IPF patients. Biochemical assays demonstrated that physiological levels of MPO (0.2 µg/ml) combined with H2O2 reduced recombinant cathepsin K activity by 85%. In PCLS treated with MPO, cathepsin K activity decreased by 50% with or without TGFβ. After bleomycin treatment, wild-type mice showed reduced cathepsin K activity, while MPO-knockout mice maintained activity levels. Both survival and weight loss were similar between wild-type and MPO-knockout mice; however, collagen content was significantly higher in wild-type mice, whereas MPO-knockout mice were protected from bleomycin-induced collagen accumulation. These findings suggest that MPO contributes to ECM accumulation in lung fibrosis, potentially through inhibition of collagenolytic enzymes such as cathepsin K.

Abstract Rationale: The US prison population carries a high burden of chronic disease and disability, with older adults constituting the fastest growing subpopulation. When medical needs exceed a prison's healthcare service capabilities, incarcerated patients are transported to clinics and hospitals in surrounding communities. The influence of prison policies on off-site medical care of incarcerated patients is poorly understood. This study aims to identify and classify correctional policies regulating the care of incarcerated patients in community hospitals. Methods: Between 6/2024-10/2024 we searched the Internet for policies from states’ Departments of Corrections (DOC) pertaining to healthcare of incarcerated patients. We compiled, reconciled and organized those policies according to date, jurisdiction and relevance to hospital care. We then developed a preliminary thematic coding scheme and, using mixed inductive and deductive content analysis, two coders independently applied our codebook to each policy. Any coding discrepancies were resolved by consensus, and when necessary, with adjudication by a third team member. Results: Forty-eight state DOCs and the District of Columbia (totaling 49 “states”) have publicly available policies pertaining to healthcare. Among these, 20/49 (41%) have policies pertaining to the protection of bodily privacy during healthcare encounters. Separately, 31 (63%) have policies regarding the confidentiality of incarcerated patients’ medical encounters and records. Thirty-four (69%) maintain policies regarding incarcerated individuals’ right to select and consent to treatment. Thirty-three (67%) include language about the right to refuse treatment. Twenty-six states (53%) direct that incarcerated individuals be informed of their right to access healthcare either in writing (22/49; 45%), verbally (20/49; 41%), or through posted signage (5/49; 10%). Twenty-one states (43%) address shackling during off-site medical care, but only 15 (31%) address responding to requests from off-site clinicians to minimize or remove patients’ restraints. Just 4/49 states (8%) use person-centered language (avoiding terms like “offender” and “inmate”). Policy excerpts addressing key domains are depicted in the Table. Conclusions: Correctional policies regarding the care of incarcerated patients in community hospitals vary significantly in scope and content across states. While incarcerated people have a Constitutionally protected right to accept or refuse healthcare, including making their own treatment decisions, many state policies do not explicitly mandate how these disclosures must be communicated to patients or their healthcare providers. These silences, when combined with security measures like shackling and the ubiquitous presence of officers, countermand person-centered care and undermine the ability of hospital healthcare professionals to uphold the rights and dignity of incarcerated patients.

Abstract Chronic obstructive pulmonary disease (COPD) and pulmonary emphysema were the third-leading cause of death globally in 2019. Besides alpha-1 antitrypsin deficiency, emphysema lacks disease-modifying medications due to its heterogeneity and there remains a need to further investigate emphysema subtypes to advance its diagnosis and treatment. Recent unsupervised machine learning of the texture and anatomical location of emphysema on computed tomography (CT) images of the lung defined six quantitative CT emphysema subtypes uniquely associated with specific gene variants, environmental exposures, symptoms, physiology and clinical events. We aim to identify associations of plasma proteins with each CT emphysema subtype cross-sectionally in a multi-ethnic general population sample. MESA is a prospective cohort study that recruited 6,814 participants from six communities who self-identified as White, Black, Hispanic, or Asian race/ethnicity, ages 45-84 years old and free of clinical cardiovascular disease in 2000-02. The MESA Lung Study performed CT scans among 3,137 participants in 2010-12, which were labeled with previously described (PMID: 37268414) CT emphysema subtypes. Proteomics was assessed using SomaScan version 4.1 assay (7,596 plasma proteins). Linear regression models were adjusted for age, height, weight, sex, race, educational attainment, smoking status, pack years, urine cotinine level, body-mass index (BMI), estimated glomerular filtration rate (eGFR), CT scanner manufacturer and other CT emphysema subtypes. Results were adjusted to reflect a False Discovery Rate (FDR) p-value of less than 5% using the Benjamini-Hochberg method. Among 2,343 participants with both CT and proteomic data (mean age 69.5 years, 52.3% women, 23.7% with COPD), we identified statistically significant associations of proteins with the vanishing lung subtype (42 proteins; top hit Natural cytotoxicity triggering receptor 3 ligand 1, q = 2.9[asterisk]10-9), restrictive combined pulmonary fibrosis/emphysema (CPFE) subtype (11 proteins; top hit Integrin alpha-2/b1, q=1.0[asterisk]10-5), the combined bronchitis-apical emphysema subtype (9 proteins; top hit Desmoglein-2, q=8.8[asterisk]10-13), and the diffuse emphysema subtype (4 proteins; top hit Pulmonary surfactant-associated protein D, q=5.7[asterisk]10-3). No significant proteins were associated with the obstructive CPFE or senile subtypes after FDR correction. Most proteins were uniquely associated with one CT emphysema subtype, while a few proteins were associated with more than one subtype. This study identified specific proteins for different CT emphysema subtypes, many of which have been related less specifically to emphysema, including pulmonary surfactant production, anti-inflammatory pathways, and mitochondrial deregulation, amongst others. Validation of these proteomic associations can provide insight into further pathway assessment, clinical biomarker discovery, and targeted prevention of emphysema in the general population.

Abstract Rationale: Application of single cell RNAseq (scRNAseq) in idiopathic pulmonary fibrosis (IPF) and multiple murine models has revealed two unique disease associated fibroblast subsets, the Cthrc1+ fibrotic population, and a population expressing inflammatory markers whose function is unclear. We, and others, have demonstrated that inflammatory fibroblasts are derived from homeostatic fibroblasts and can differentiate to Cthrc1+ fibroblasts. There is also data in mice suggesting that TGFβ inhibition prevents the emergence of Cthrc1+ fibrotic fibroblasts without impacting the inflammatory fibroblast population. Using our inducible genetic murine model of PF, reductionist organoid systems, and scRNAseq from IPF we present evidence and mechanism for inflammatory fibroblasts as a potential regenerative population in the alveolar niche. Methods: Tamoxifen administration to SftpcI73T conditional allelic knock-in mice, induces expression of mutant protein and promotes an inflammatory cascade followed by fibrogenesis. ScRNA-seq and population RNA-seq of bleomycin and SftpcI73T murine models were compared with publicly available data sets from IPF to identify population specific surface marker expression and potential epithelial ligand-receptor pairs. Flow cytometry approaches developed to isolate fibroblast populations were applied for in-vitro organoid modeling and validation of signaling pathways. In-vivo murine intervention in TGFβ signaling was further applied to confirm functional biology of inflammatory fibroblasts. Results: Informatic analysis of human and mouse inflammatory fibroblasts identifies expression of multiple BMP antagonists that have previously been associated with epithelial proliferation. Furthermore, human inflammatory fibroblasts also express key epithelial growth factors including FGF2 and FGF7. Murine organoid modeling confirms that inflammatory fibroblasts support alveolar organoid formation through the inhibition of BMP signaling. As was previously demonstrated in bleomycin, the inhibition of TGFβ signaling in SftpcI73T does not alter the inflammatory fibroblast population, rather this population is sustained, and alveolar epithelial proliferation increases. Additionally, we did not find any evidence for increase inflammation in the mouse lung due to inflammatory fibroblasts preservation. Finally, human data suggests that two populations of inflammatory fibroblasts are present in the lung with only one subset found to express the BMP antagonists and growth factors required to promote alveolar epithelial proliferation. Conclusions: Our data identifies that inflammatory fibroblasts in the alveolar niche inhibit BMP signaling and allow for epithelial expansion. We also determine differences between murine and human inflammatory fibroblasts suggesting that human inflammatory fibroblasts have a greater potential to drive epithelial expansion. These data shed light on the functional role of inflammatory fibroblasts, further refining our understanding of fibroblast heterogeneity in IPF.

Abstract RATIONALE: Vascular dysfunction contributes to pathological tissue remodeling in aging-associated disease such as Idiopathic Pulmonary Fibrosis (IPF). IPF is an incurable lung disease characterized by progressive accumulation of scar-forming fibroblasts and several vascular alterations, including endothelial transcriptional changes leading to a pro-fibrotic endothelial secretory phenotype. To date, the mechanisms governing these transcriptional changes remain largely unexplored. To fill this gap, we sought to investigate whether microRNAs (miRNAs), small non-coding RNA that function as key gene expression regulators, modulate the transcriptional changes of the endothelium associated with progressive pulmonary fibrosis. METHODS AND RESULTS: miRNA expression profiling of lung ECs (LECs) sorted from aged mice with persistent lung fibrosis revealed upregulation of miR-205-5p. Further analysis demonstrated that endothelial miR-205-5p was strongly upregulated in an additional mouse model of progressive lung fibrosis induced by repetitive bleomycin dose as well as in human LECs purified from IPF lungs. RNA-seq analysis of normal human LECs overexpressing miR-205-5p revealed reduction of genes associated to endothelial identity (e.g. PECAM1, ERG, NOS3), and an increase of genes encoding for soluble pro-inflammatory and pro-fibrotic molecules, including TGFBI, TGFB2, TGFB3, CXCL10, CCL5, IL1B and FAS compared to normal LECs transfected with a control mimic. Consistently, conditioned medium from miR-205-5p overxpressing LECs exerted a pro-fibrotic activity on quiescent human lung fibroblasts, as demonstrated by upregulation of a panel of profibrotic transcripts (e.g. COL1A1, CTHRC1, FN1 and TNC) and elevated Collagen I deposition compared to human lung fibroblasts exposed to conditioned medium generated by human LECs transfected with a control mimic. CONCLUSION: Altogether, our findings suggest that lung endothelail miR-205-5p induces loss of endothelial cell identity and drives the secretion of pro-fibrotic molecules that promote the transition of quiescent fibroblasts into scar-forming fibroblast through paracrine signal. Our data set the stage for further investigations into the role of miR-205-5p and associated pathways in lung vascular injury responses, with the long term goal of targeting endothelial dysfunction for slowing the progression of pulmonary fibrosis.

Abstract Rationale: Asthma in the elderly (AIE) presents a unique challenge characterized by hyperreactive and thickened, fibrotic airways (remodeling) that is not adequately addressed by current therapies. Thus, understanding mechanisms that drive AIE become important. Here, airway smooth muscle (ASM) cells play important roles in normal airway physiology and asthma pathophysiology. Recent discoveries have highlighted the significance of mechanosensitive Piezo (Pz) in health and disease. The lung generates mechanical forces of normal breathing and other maneuvers that are transmitted to bronchial airways via tethering parenchyma. While Pz channels are highly expressed in the lung, their specific role in ASM function remains largely unexplored. In this study, we used human ASM cells to test the hypothesis that increased airway stiffness associated with normal aging blunts Pz expression and mechanosensitive functionality, whereas asthmatic triggers (e.g. inflammation) enhance Pz expression and downstream signaling. Methods: Primary human ASM cells isolated from lungs of young (<45y) vs. aged (>65y) non-asthmatic vs. asthmatic individuals were obtained post-surgery (Mayo Clinic IRB approved). Cells were exposed to mechanical stretch (mimicking breathing) and mediators relevant to asthma (TNFα, IL-13) or fibrosis (TGFβ) to determine expression of Pz1/2 across the age spectrum. Separately, intracellular Ca2+ and contractility responses, proliferation and extracellular matrix (ECM) deposition across age/asthma groups were assessed in response to mechanical stretch and Pz1/2 modulation (inhibitors/activators, genetic approaches). Manipulation of Pz1/2 expression or function in ASM accompanied by mechanical stretch was used to assess impact on canonical Wnt/β-catenin signaling. Results: We observed increased Pz1/2 expression with age and asthma as well as with inflammation and mitogenic stimuli. Functionally, Pz1 agonist, Yoda1 induced increase in intracellular Ca2+, ASM proliferation and ECM deposition with greater effects observed in aging asthmatic ASM. Towards linking mechanosensation (via Pz) to remodeling via Wnt signaling, we find that Wnt3a is upregulated by Yoda1 but suppressed by Pz1 shRNA. Yoda1 stimulates TGFβ-induced Wnt3a and β-catenin, an effect further enhanced under mechanical stretch. Conclusions: By elucidating the role of Pz channels in ASM, we aimed to identify novel therapeutic targets for airway diseases. Understanding how mechanical forces and inflammatory stimuli influence Pz-mediated signaling pathways will lead to the development of innovative strategies to prevent or reverse airway remodeling in elderly asthmatic patients. Acknowledgement: Supported by 24POST1241979 (NAB) and NIH grants R01-HL142061 (CMP and YSP), R01- HL088029 (YSP).

Listing and transplanting patients with acute liver failure (ALF) is challenging, requiring rapid assessment of the likelihood of recovery. The availability of a large number of ALF liver explants, along with their clinical data, afforded an opportunity to retrospectively evaluate liver transplantation (LT) decision-making. We hypothesized that, with the benefit of hindsight, a small number of patients might have recovered without LT. Three hundred liver explants from ALF patients of varying etiologies who had undergone LT over 22 years in the Acute Liver Failure Study Group registry were reviewed for histopathological features and degree of necrosis by a committee of 8 hepatopathologists. A second committee of 8 experienced transplant hepatologists independently reviewed clinical data on these same 300 patients and retrospectively scored the likelihood that each patient required transplantation. Only 3 (1%) of those reviewed by the Clinical Committee were considered to “Definitely” not require liver grafting, while an additional 10 (3.3%) were deemed to “Possibly” not require transplantation (Not Likely Group, N=13). There was no difference in the degree of necrosis in explants in these groups, when compared to the remaining Likely Group, N=287 (95.6%), except in acetaminophen (APAP)-associated ALF, where the degree of necrosis was more uniformly graded as severe, correlating with the need for transplantation. Virtually every patient undergoing LT for ALF retrospectively appeared to need their transplant, based on expert clinical consensus review. Overall, there was poor correlation between clinical severity and apparent degree of necrosis seen in the 300 liver explants, except perhaps for APAP subjects.

Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems’ requirements that could enhance and accelerate the integration of these platforms.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.