Clinical Research and Public Health
Abstract
Hematopoietic stem cell transplantation (HCT) is a potentially life-saving therapy but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. We previously showed that bronchoalveolar lavage (BAL) transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality. To test whether peripheral blood might be a suitable surrogate for BAL, we compared 210 paired BAL and blood transcriptomes obtained from 166 pediatric HCT patients at 27 hospitals. BAL and blood RNA abundance showed minimal correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, pathways related to immunity, hypoxia, and epithelial mesenchymal transition were tightly co-expressed and linked to mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups with significantly different rates of hypoxia and clinical outcomes within 1 week of BAL. These findings reveal a compartmentalized injury response, where BAL and blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.
Authors
Emma M. Pearce, Erica Evans, Madeline Y. Mayday, Gustavo Reyes, Miriam R. Simon, Jacob Blum, Hanna Kim, Jessica Mu, Peter J. Shaw, Courtney M. Rowan, Jeffery J. Auletta, Paul L. Martin, Caitlin Hurley, Erin M. Kreml, Muna Qayed, Hisham Abdel-Azim, Amy K. Keating, Geoffrey D.E. Cuvelier, Janet R. Hume, James S. Killinger, Kamar Godder, Rabi Hanna, Christine N. Duncan, Troy C. Quigg, Paul Castillo, Nahal R. Lalefar, Julie C. Fitzgerald, Kris M. Mahadeo, Prakash Satwani, Theodore B. Moore, Benjamin Hanisch, Aly Abdel-Mageed, Dereck B. Davis, Michelle P. Hudspeth, Greg A. Yanik, Michael A. Pulsipher, Christopher C. Dvorak, Joseph L. DeRisi, Matt S. Zinter
Abstract
BACKGROUND. Thymic involution with age leads to reduced T cell output and impaired adaptive immunity. However, the extent to which thymic activity persists later in life and how this contributes to immunological ageing remains unclear. This study aimed to assess the presence and function of thymic tissue in older adults and identify factors influencing residual thymopoiesis. METHODS. Patients aged ≥ 50 undergoing cardiothoracic surgery were recruited. Thymic structures within mediastinal adipose tissue were evaluated using histology, immunofluorescence, flow cytometry, TCR sequencing, and RNA sequencing. Recent thymic emigrants (RTEs) were quantified in peripheral blood and correlated with transcriptomic, epigenetic, and TCR repertoire data. Primary outcomes included thymic tissue identification, RTE frequency, and immune correlates. RESULTS. Functional thymic tissue was identified in mediastinal adipose tissue of older individuals. The frequency of CD31+CD4+ T cells (RTEs) positively correlated with the presence of thymic tissue. Thymic output showed substantial heterogeneity and was influenced by sex and smoking history. Thymic activity was associated with increased TCR repertoire diversity, improved immune protection to infections, and reduced epigenetic ageing. Detailed profiling uncovered functional and phenotypic heterogeneity within naïve CD4+ T cell subsets shaped by thymic activity. CONCLUSION. This study demonstrates that thymic function can persist into later life and is modulated by factors such as sex and smoking. These findings suggest that thymic activity during ageing is heterogenous and influenced by more than chronological age alone, with potential implications for immune competence in older adults.
Authors
Balraj Sandhar, Vishal Vyas, Daniel Harding, Roberta Ragazzini, Paola Bonfanti, Federica M. Marelli-Berg, Christopher G. Bell, Benny M. Chain, M. Paula Longhi
Abstract
BACKGROUND Obesity, a growing health concern, often leads to metabolic disturbances, systemic inflammation, and vascular dysfunction. Emerging evidence suggests that adipose tissue-derived extracellular vesicles (adiposomes) may propagate obesity-related complications. However, their lipid composition and effect on cardiometabolic state remain unclear.METHODS This study examined the lipid composition of adiposomes in 122 participants (75 in obesity group, 47 in lean group) and its connection to cardiometabolic risk. Adiposomes were isolated via ultracentrifugation and characterized using nanoparticle tracking and comprehensive lipidomic analysis by mass spectrometry. Cardiometabolic assessments included anthropometry, body composition, glucose-insulin homeostasis, lipid profiles, inflammatory markers, and vascular function.RESULTS Compared with lean controls, individuals with obesity exhibited elevated adiposome release and shifts in lipid composition, including higher ceramides, free fatty acids, and acylcarnitines, along with reduced levels of phospholipids and sphingomyelins. These alterations strongly correlated with increased BMI, insulin resistance, systemic inflammation, and impaired vascular function. Pathway enrichment analyses highlight dysregulation in glycerophospholipid and sphingolipid metabolism, bile secretion, proinflammatory pathways, and vascular contractility. Machine-learning models utilizing adiposome lipid data accurately classified obesity and predicted cardiometabolic conditions, such as diabetes, hypertension, dyslipidemia, and liver steatosis, achieving accuracy above 85%.CONCLUSION Obesity profoundly remodels the adiposome lipid landscape, linking lipid changes to inflammation, metabolic dysfunction, and vascular impairment. These findings underscore adiposome lipids as biomarkers for obesity and related cardiometabolic disorders, supporting personalized interventions and offering therapeutic value in risk stratification and treatment.FUNDING This project was supported by NIH grants R01HL161386, R00HL140049, P30DK020595 (PI: AMM), R01DK104927, and P30DK020595 as well as by a VA Merit Award (1I01BX003382, PI: BTL).
Authors
Abeer M. Mahmoud, Imaduddin Mirza, Elsayed Metwally, Mohammed H. Morsy, Giorgia Scichilone, Monica C. Asada, Amro Mostafa, Francesco M. Bianco, Mohamed M. Ali, Mario A. Masrur, Chandra Hassan, Brian T. Layden
Abstract
BACKGROUND While urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial.METHODS. We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change.RESULTS. Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30–89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424–1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3–3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels.CONCLUSION. Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD.TRIAL REGISTRATION. ClinicalTrials.gov NCT00555217.FUNDING. NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.
Authors
Christina L. Tamargo, Steven G. Coca, Heather Thiessen Philbrook, David G. Hu, Joachim H. Ix, Michael G. Shlipak, Linda F. Fried, Orlando M. Gutierrez, Sushrut S. Waikar, Sarah J. Schrauben, Jeffrey R. Schelling, Peter Ganz, Paul L. Kimmel, Jason H. Greenberg, Rajat Deo, Ayumi Takakura, Ramachandran S. Vasan, Joseph V. Bonventre, Chirag R. Parikh
Abstract
Background: Traumatic optic neuropathy (TON) is a leading cause of blindness following closed traumatic brain injury, with no effective treatments available. Previous interventional clinical trials were complicated by its low prevalence, variability in neurodegenerative severity, and unavailability of reliable biomarkers. Methods: We analyzed data from 1226 patients enrolled in the prospective National Multi-Center Collaborative Clinical Research Program of China (2017-2024) to establish a clinical profile and identify non-invasive biomarkers for neurodegenerative severity. Subgroup analysis of monocular TON patients revealed potential biomarkers including visual functional parameters, inner retinal thickness, and time post-injury. Results: The ganglion cell complex (GCC) thickness showed a strong correlation with retinal ganglion cell somata (R² = 0.87, p < .0001) and axon density (R² = 0.89, p < .0001) in a clinically relevant large animal model. Computational analysis demonstrated that using GCC thickness as a biomarker could substantially enhance the statistical power of clinical trials (by up to 4.5-fold), as confirmed by real-world data. Conclusion: This study presented the largest epidemiological analysis of TON to date and established GCC thickness as a crucial biomarker for stratifying disease severity and improving the efficiency of clinical trials. Trial registration: Chinese Clinical Trial Registry (ChiCTR-OOC-17013437). Funding: National Key R&D Program of China (Grant No.2022YFA1105500); Key Science and Technology Program of Wenzhou (Grant No.ZY2022021); National Natural Science Foundation of China (Grant No.82471080).
Authors
YiKui Zhang, BoYue Xu, ShiWei Huang, ZhaoHui Shi, Wei Xiong, Ruijun Wang, GuiQin Liu, Linlin Chen, ZhenHua Ge, YongJie Zhang, HongLei Liu, BaoYun Jia, Chunxia Wang, HaiHong Shi, Jun Kang, NingYu An, Shuirui Huang, De-Fu Chen, Shenghai Huang, YuTing Luo, MingYue Liu, ZhuoWei Wang, Zhonghao Yu, Jingwei Zheng, Wentao Yan, Gen Li, Hao Chen, XingGuang Deng, Shihui Wei, YunHai Tu, EnDe Wu, Kang Zhang, Wencan Wu
Abstract
BACKGROUND. Symptoms of early-onset sepsis (EOS) in preterm infants are nonspecific, overlapping with normal postnatal physiological adaptations and noninfectious pathologies. This clinical uncertainty and the lack of reliable EOS diagnostics results in liberal use of antibiotics in the first days to weeks of life, leading to increased risk of antibiotic-related morbidities in infants who do not have an invasive infection. METHODS. To identify potential biomarkers for EOS in newborn infants, we used unlabelled tandem mass spectrometry proteomics to identify differentially abundant proteins in the umbilical cord blood of infants with and without culture-confirmed EOS. Proteins were then confirmed using immunoassay, and logistic regression and random forest models were built including both biomarker concentration and clinical variables to predict EOS. RESULTS. These data identified five proteins that were significantly upregulated in infants with EOS, three of which (serum amyloid A, C-reactive protein, and lipopolysaccharide-binding protein) were confirmed using a quantitative immunoassay. The random forest classifier for EOS was applied to a cohort of infants with culture-negative presumed sepsis (PS). Most PS infants were classified as resembling control infants, having low EOS biomarker concentrations. CONCLUSION. These results suggest that cord blood biomarker screening may be useful for early stratification of EOS risk among neonates, improving targeted, evidence-based use of antibiotics early in life. FUNDING. National Institutes of Health, Gerber Foundation, Friends of Prentice, Thrasher Research Fund, Ann & Robert H. Lurie Children’s Hospital, Stanley Manne Children’s Research Institute of Lurie Children’s.
Authors
Leena B. Mithal, Mark E. Becker, Ted Ling-Hu, Young Ah Goo, Sebastian Otero, Aspen Kremer, Surya Pandey, Nicola Lancki, Yawei Li, Yuan Luo, William Grobman, Denise Scholtens, Karen K. Mestan, Patrick C. Seed, Judd F. Hultquist
Abstract
Mitochondrial DNA (mtDNA) shares characteristics with bacterial DNA and activates immune cells via Toll like receptor (TLR)-9. Extracellular vesicles (EVs) and mtDNA have been found in blood products and can activate immune cells; we sought to characterize their evolution in stored blood products. From a previous study of hemolysis in 13,403 blood donors, a second blood unit was drawn from 651 donors and sampled at days 10, 21, and 42. EV counts and RBC-EVs increased with storage time, and EV levels were higher in males and in RBC units processed in AS-1 compared to AS-3. mtDNA levels were higher in females and RBC units processed in AS-3. EV populations and mtDNA levels were highly correlated within donors for 98 donations obtained 2-12 months apart. Quantitative trait locus analysis revealed several genetic associations, most notably linking mtDNA levels with polymorphisms in ANKLE1, which encodes an erythroid-specific protein that preferentially cleaves mtDNA. These data suggest that donor-intrinsic factors may influence mtDNA and EV levels found in RBC units. This finding lends impetus to determining if genetic or environmental factors control levels of these immune mediators in blood donors.
Authors
Xutao Deng, Clara Di Germanio, Erika G. Marques de Menezes, Pamela Milani, Mars Stone, Heather Tanner, Sonia Coco Bakkour, Daniel M. Chafets, Sarah E. Reese, Nareg H. Roubinian, Steven Kleinman, Tamir Kanias, Michael P. Busch, Eric J. Earley, Grier P. Page, Travis Nemkov, Angelo D’Alessandro, Philip J. Norris
Abstract
Sickle cell disease (SCD) causes severe morbidity and early mortality, yet it varies phenotypically. Both air pollution and SCD affect the cardiorespiratory, inflammatory, and endothelial systems; however, limited evidence exists on the effect of long-term air pollution exposure in SCD. We hypothesized that annual ambient (outdoor) concentrations of fine particulate matter (PM2.5), particles with a diameter of 2.5 μm or less, at a child’s home would be significantly associated with worse clinical, laboratory, and stroke-risk imaging outcomes. Patient data for this retrospective study were obtained from a cohort of children with SCD (from 2010 to 2019). Annual PM2.5 exposure was estimated using remote-sensing air pollution datasets. Statistical analyses employed fixed effects multivariable models, offering a robust approach to isolate the effect of PM2.5 exposure. The final cohort included 1,089 children with SCD. Higher annual PM2.5 concentrations were significantly associated with more annual hospital days, higher likelihood of hospitalization and abnormal stroke-risk screening, and elevated inflammatory markers. Of note, hydroxyurea use mitigated the inflammatory response to PM2.5 but did not mitigate the effect of PM2.5 on clinical outcomes. Importantly, the elevated stroke risk associated with PM2.5 exposure persisted, even among children receiving hydroxyurea therapy, highlighting a critical concern in pediatric SCD management. These results underscore the clinical importance of addressing environmental factors for comprehensive SCD care.
Authors
Paul E. George, Grace Kalmus, Joseph Lipscomb, David H. Howard, Benjamin Kopp, Wilbur A. Lam, Stefanie Ebelt
Abstract
Background. NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function, and thus may reduce viral reservoirs. Methods. To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given three 6 mcg/kg doses of N-803 subcutaneously. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose. Results. We found a non-statistically significant ~0.50 median log reduction in the frequency of viral(v)RNA+ and vDNA+ cells/g in the 6 participants with baseline and post-treatment LNs. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells, and between NKG2A expression on NK cells and the frequency of vRNA+ cells. Conclusions. Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.
Authors
Joshua Rhein, Jeffrey G. Chipman, Gregory J. Beilman, Ross Cromarty, Kevin Escandón, Jodi Anderson, Garritt Wieking, Jarrett Reichel, Rodolfo Batres, Alexander Khoruts, Christopher M. Basting, Peter Hinderlie, Zachary B. Davis, Anne Eaton, Byron P. Vaughn, Elnaz Eilkhani, Jeffrey T. Safrit, Patrick Soon-Shiong, Jason V. Baker, Nichole R. Klatt, Steven G. Deeks, Jeffrey S. Miller, Timothy W. Schacker
Abstract
Community-acquired infectious meningoencephalitis is associated with high rates of mortality and morbidity, compounded by limited access to diagnostic resources. The current study assessed acute central nervous system (CNS) infections in patients with meningoencephalitis enrolled in a hospital-based diagnostic surveillance study in São Paulo, Brazil. Cerebrospinal fluid (CSF) was collected from 600 subjects between March 2018 and November 2019 and initially screened for a broad range of pathogens according to a local diagnostic algorithm. Standard microbiological and molecular diagnostic methods were applied. Metagenomic sequencing was used as a complementary approach to investigating etiology in cases where no pathogen was initially identified. Standard testing identified infectious etiologies in 292 cases (48.6%), with 227 (77.7%) confirmed as viral infections, predominantly caused by enteroviruses (n=144) and herpesviruses (n=40). Non-viral agents were identified in 65 cases (22.3%). Metagenomic sequencing (mNGS) of 279 out of 308 undiagnosed cases revealed several additional potential etiologies, including Parvovirus B19, Toxoplasma gondii, Picobirnavirus, other enterovirus species and Vesivirus, the latter being associated with CNS infection for the first time. These findings underscore the complexity of CNS infections and highlight the potential of metagenomics to improve diagnostic accuracy, inform treatment strategies, and support efforts to address future pandemics.
Authors
Noely Evangelista Ferreira, Michael G. Berg, Antonio C. da Costa, Mary A. Rodgers, Esper G. Kallas, Cassia G. Terrasani Silveira, Mateus Vailant Thomazella, Ana Carolina Soares de Oliveira, Layla Honorato, Heuder G.O. Paião, Renan Barros Domingues, Carlos Senne, Marina F. Côrtes, Tania R. Tozetto-Mendoza, Hélio R. Gomes, Maria Laura Mariano Matos, Geovani de Oliveria Ribeiro, Steven S. Witkin, Gavin A. Cloherty, Maria Cassia Mendes-Correa
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