Clinical Research and Public Health
Abstract
BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING. This work is the result of NIH funding.
Authors
Narges Alipanah-Lechner, Lucile Neyton, Pratik Sinha, Carolyn Leroux, Kim Bardillon, Sidney A. Carrillo, Suzanna Chak, Olivia Chao, Taarini Hariharan, Carolyn Hendrickson, Kirsten Kangelaris, Charles R. Langelier, Deanna Lee, Chelsea Lin, Kathleen Liu, Liam Magee, Angelika Ringor, Aartik Sarma, Emma Schmiege, Natasha Spottiswoode, Kathryn Sullivan, Melanie F. Weingart, Andrew Willmore, Hanjing Zhuo, Angela J. Rogers, Kathleen A. Stringer, Michael A. Matthay, Carolyn S. Calfee
Abstract
BACKGROUND. Axonal degeneration is believed to be an early hallmark of Alzheimer’s disease (AD). This study investigated the temporal trajectory of axonal loss and its association with cognitive and functional decline using diffusion MRI-derived Axonal Density Index (dMRI-ADI). METHODS. Longitudinal dMRI, CSF and PET data from the ADNI were analyzed, including 117 cognitively normal (CN) and 88 impaired (CI) subjects, consisting of 74 mild cognitive impairment (MCI) and 14 AD individuals. Linear mixed-effects models examined group differences as well as associations between baseline and longitudinal changes in ADI, CSF or PET biomarkers and clinical outcomes. Results derived from larger CSF (n=527) and PET (tau-PET: n=870; amyloid-PET: n=1581) data were also presented. RESULTS. Compared to CN, the CI group exhibited significantly lower baseline ADI values and steeper longitudinal decline (p<10–⁶). Lower baseline ADI predicted faster cognitive and functional decline in the CI group (MMSE: p=0.03; CDR-SB: p<10–⁴), and longitudinal decreases in ADI were associated with worsening clinical outcomes (MMSE: p=0.001; CDR-SB: p<10–¹²). Compared to CSF and PET biomarkers, ADI demonstrated superior sensitivity in tracking disease progression and matched these biomarkers in predicting future cognitive and functional decline. Furthermore, decreases in ADI were significantly associated with declines in clinical outcomes; an association observed only with amyloid-PET, but not CSF biomarkers. CONCLUSION. Axonal degeneration is an early and clinically meaningful feature of AD. ADI is a promising noninvasive biomarker for early detection, prognosis, and disease monitoring. TRIAL REGISTRATION. ClinicalTrials.gov NCT00106899. FUNDING. This work was supported by the National Institute on Aging IRP.
Authors
Zhaoyuan Gong, John P. Laporte, Alexander Y. Guo, Murat Bilgel, Jonghyun Bae, Noam Y. Fox, Angelique de Rouen, Nathan Zhang, Aaliya Taranath, Rafael de Cabo, Josephine M. Egan, Luigi Ferrucci, Mustapha Bouhrara
Abstract
BACKGROUND. Cardiac allograft vasculopathy (CAV) is consistently accompanied by immune infiltrates surrounding affected coronary arteries, including antibody-producing plasma cells (PC). The antigenic drivers of these intragraft PC responses remain poorly defined. METHODS. We characterized graft-infiltrating PC by single-cell RNA sequencing and immunoglobulin gene profiling. Using immunoglobulin sequences we generated 37 recombinant monoclonal antibodies (mAb) from dominant intragraft PC clones and 24 control mAb from peripheral blood PC. Antigen reactivity was screened against chemical adducts, including bilirubin, a heme-degradation by-product. Histologic and tissue analyses assessed bilirubin deposition as well as expression of heme-catabolic enzymes, and the presence of Fe2+ in heart explants with CAV. RESULTS. A majority of graft-derived mAb (21/37; ~57%) but none of the mAb derived from blood PC reacted to bilirubin. Bilirubin deposition was detected within lymphocytic aggregates in CAV grafts. In coronary arteries with CAV lesions, bilirubin accumulated in the cytoplasm and nuclei of smooth muscle cells in the tunica media, a pattern not observed in healthy heart tissue. Lastly, we detected the expression of heme-oxygenase-1 and biliverdin reductases in graft-infiltrating macrophages along with the presence of Fe2+ ion in the media of arteries with hyperplasia. CONCLUSION. These findings suggest that local heme catabolism and resultant bilirubin accumulation create a prominent target for intragraft antibody responses in CAV. Bilirubin-specific antibodies and heme-catabolic pathways may contribute to CAV pathogenesis and represent potential mechanistic and therapeutic avenues for further investigation. FUNDING. National Institute of Health.
Authors
Sarah B. See, Talita Aguiar, Max Dietzel, Mattea Ausmeier, Hang T.T. Nguyen, Shunya Mashiko, Laura Donadeu, Hector Cordero, Poulomi Roy, Lorea Roson, Charles C. Marboe, Matthias J. Szabolcs, Maryjane Farr, Jose González-Costello, Aleix Olivella, Yoshifumi Naka, Koji Takeda, Rodica Vasilescu, Kevin J. Clerkin, Gilles Benichou, Joren C. Madsen, R. Glenn King, Oriol Bestard, Evan P. Kransdorf, Emmanuel Zorn
Abstract
BACKGROUND. Checkpoint inhibitor-associated autoimmune diabetes (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM. AIM. To identify biomarkers for prediction of CIADM. METHODS. From our prospective biobank, 14 CIADM patients who had metastatic melanoma treated with anti-PD-1 ± anti-CTLA4 were identified. Controls were selected from the same biobank, matched 2:1. Pre-treatment, on-ICI and post-CIADM serum and peripheral blood mononuclear cells (PBMCs) were analysed. Serum was analysed for T1D autoantibodies, C-peptide, glucose and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry. RESUTLS. Before treatment, CIADM patients had smaller pancreatic volume (27% reduction, p=0.044) and higher anti-GAD antibody titres (median 2.9 versus 0, p=0.01). They had significantly higher baseline proportions of Th17 helper cells (p=0.03), higher CD4+ central memory cells (p=0.04) and lower naïve CD4+ cells (p=0.01). With ICI treatment, greater declines in pancreatic volume were seen in CIADM patients (p<0.0001). Activated CD4+ subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAE) but not controls without IRAE. Using only pre-treatment results, pancreatic volume, anti-GAD antibody titre and baseline immune flow profile were highly predictive of CIADM development, with an area under the curve (AUC) of >0.96. CONCLUSIONS. People who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumours. FUNDING. JEG is supported by NHMRC Investigator grant 2033228. AMM by NHMRC Investigator grant 2009476 and GVL by NHMRC Investigator grant 2007839.
Authors
Linda Wu, John M. Wentworth, Christopher Liddle, Nicole Fewings, Matteo Carlino, David A. Brown, Roderick Clifton-Bligh, Georgina V. Long, Richard A. Scolyer, Nicholas Norris, Sarah C. Sasson, Venessa H.M. Tsang, Alexander M. Menzies, Jenny E. Gunton
Abstract
BACKGROUND. Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, is preceded by an early period unrelated to motor symptoms, including altered sleep, with increased wakefulness and decreased deep NREM. Whether these alterations in sleep macroarchitecture are associated with, or even precede abnormalities in sleep-related EEG features remains unknown. METHODS. Here, we characterised sleep microarchitecture using polysomnography in patients with ALS (n=33) and controls (n=32), and in asymptomatic carriers of SOD1 or C9ORF72 mutations (n=57) and non-carrier controls (n=30). Patients and controls with factors that could confound sleep structure, including respiratory insufficiency, were prospectively excluded. Results were complemented in three ALS mouse models (Sod1G86R , Fus∆NLS/+ and TDP-43Q331K ). RESULTS. We observed a brain-wide reduction in the density of sleep spindles, slow oscillations and K-complexes in both early-stage ALS patients and presymptomatic gene carriers. These defects in sleep spindles and slow oscillations correlate with cognitive performance in both cohorts, particularly with scores on memory, verbal fluency and language function. Alterations in sleep microarchitecture were replicated in three mouse models and decreases in sleep spindles were rescued following intracerebroventricular supplementation of MCH or by the oral administration of a dual orexin receptor antagonist. CONCLUSION. Sleep microarchitecture is associated with cognitive deficits and is causally linked to aberrant MCH and orexin signalling in ALS. FUNDING. This work was funded by Agence Nationale de la Recherche (ANR-24-CE37-4064, ANR-10-IDEX-0002, ANR-20-SFRI-0012), Fondation Thierry Latran, Association Francaise de Recherche sur la sclérose latérale amyotrophique, Association Française contre les Myopathies (#28944), TargetALS and JPND.
Authors
Christina Lang, Simon J. Guillot, Dorothee Lule, Luisa T. Balz, Antje Knehr, Patrick Weydt, Johannes Dorst, Katharina Kandler, Hans-Peter Müller, Jan Kassubek, Laura Wassermann, Sandrine Da Cruz, Francesco Roselli, Albert C. Ludolph, Matei Bolborea, Luc Dupuis
Abstract
BACKGROUND Inter- and intraindividual fluctuations in pain intensity pose a major challenge to treatment efficacy, with a majority of people perceiving their pain relief as inadequate. Recent preclinical studies have identified circadian rhythmicity as a potential contributor to these fluctuations and a therapeutic target.METHODS We therefore sought to determine the impact of circadian rhythms in people with chronic low back pain (CLBP) through a detailed characterization, including questionnaires to evaluate biopsychosocial characteristics, ecological momentary assessment (7 day e-diaries at 8:00/14:00/20:00) to observe pain fluctuations, and intraday blood transcriptomics (at 8:00/20:00) to identify genes/pathways of interest.RESULTS While most individuals displayed constant or variable/mixed pain phenotypes, a distinct subset had daily fluctuations of increasing pain scores (>30% change in intensity over 12 hours in ≥4/7 days). This population had no opioid users, better biopsychosocial profiles, and differentially expressed transcripts relative to other pain phenotypes. The circadian-governed neutrophil degranulation pathway was particularly enriched among arrhythmic individuals; the link between neutrophil degranulation and opioid use was further confirmed in a separate CLBP cohort.CONCLUSION Our findings identified pain rhythmicity and the circadian expression of neutrophil degranulation pathways as indicators of CLBP outcomes, which may help provide a personalized approach to phenotyping biopsychosocial characteristics and medication use. This highlights the need to better understand the impact of circadian rhythmicity across chronic pain conditions.FUNDING This work was funded by grants from the Canadian Institutes of Health Research (CIHR; grant PJT-190170, to NG and MGP) and the CIHR-Strategy for Patient-Oriented Research Chronic Pain Network (grant SCA-145102, to NG, QD, LD, MGP, and MC). DT was funded by a MS Canada endMS Doctoral Research Award, AMZ by an Ontario Graduate Scholarship, HGMG by a CIHR Doctoral Research Award, MGP by a Junior 2 Research Scholarship from the Fonds de recherche du Québec – Santé, and LD by a Canadian Excellence Research Chairs and Pfizer Canada Professorship in Pain Research.
Authors
Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou
Abstract
BACKGROUND. Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease caused by deletions or mutations of the survival motor neuron 1 gene. Despite the availability of genetically-based treatments for SMA, functional impairments and weakness persist in treated symptomatic individuals. This study addresses whether additional treatment after gene transfer therapy could provide further clinical benefits. METHODS. Interim Day 302 findings are described from the phase 4 open-label RESPOND trial evaluating nusinersen in participants aged ≤ 36 months who had suboptimal clinical status following onasemnogene abeparvovec (OA) treatment, as determined by the investigator. RESULTS. Thirty-seven participants included in the interim analysis were symptomatic at the time of OA administration. Most (92%) had two survival motor neuron 2 gene copies. Age at first nusinersen dose (median [range]) was 9.1 (3–33) months for participants with two SMN2 copies and 34.2 (31–36) months for those with three SMN2 copies, while time from OA dose to first nusinersen dose (median [range]) was 6.3 (3–31) and 13.3 (10–22) months, respectively. Participants had elevated neurofilament light chain (NfL) levels and low compound muscle action potential (CMAP) amplitudes at baseline, suggesting active neurodegeneration and severe denervation at study entry. Improvements from baseline were observed across a range of outcomes at Day 302, including motor function outcomes (HINE-2 and CHOP-INTEND total score), achievement of independent sitting, NfL levels, CMAP, and investigator- and caregiver-reported outcomes. Mean NfL levels decreased rapidly from baseline to Day 183 and remained low at Day 302. Mean ulnar and peroneal CMAP amplitudes increased. No safety concerns were identified. CONCLUSION. Improvements in clinical and biomarker outcomes support the benefit of nusinersen treatment in infants and children with suboptimal clinical status following OA. TRIAL REGISTRATION. ClinicalTrials.gov ID, NCT04488133; EudraCT number, 2020-003492-18. FUNDING. This study was sponsored by Biogen (Cambridge, MA, USA).
Authors
Crystal M. Proud, Richard S. Finkel, Julie A. Parsons, Riccardo Masson, John F. Brandsema, Nancy L. Kuntz, Richard Foster, Wenjing Li, Ross Littauer, Jihee Sohn, Stephanie Fradette, Bora Youn, Angela D. Paradis
Abstract
Background. Statin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond low-density lipoprotein cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin responsive and other inflammatory and metabolic pathways to MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE). Methods. Cox proportional hazards models were used to assess the relationship between MACE and proteomic measurements at study entry and year 2 adjusting for time-updated statin use and baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine learning (ML) model to predict MACE using baseline proteins values with significant associations. Results. In 765 individuals (age: 50.8±5.9 years, 82% males) among 7 proteins changing with statin vs. placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (aHR: 2.31 per 2-fold higher levels; 95%CI: 1.11-4.80; p=0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins not changing in response to statin therapy, 26 were associated with MACE at FDR<0.05. These proteins represented predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomic ML model achieved a 10-fold cross-validated c-index of 0.74±0.11 to predict MACE, improving on models using traditional risk prediction scores only (c-index: 0.61±0.18). Conclusions. ANGPTL3, as well as key inflammatory pathways may contribute to residual risk of MACE among PWH, beyond LDL-C. Trial registration. ClinicalTrials.gov: NCT02344290. Funding. NIH, Kowa, Gilead Sciences, ViiV.
Authors
Márton Kolossváry, Irini Sereti, Markella V. Zanni, Carl J. Fichtenbaum, Judith A Aberg, Gerald S. Bloomfield, Carlos D. Malvestutto, Judith S. Currier, Sarah M. Chu, Marissa R. Diggs, Alex B. Lu, Christopher deFilippi, Borek Foldyna, Sara McCallum, Craig A. Sponseller, Michael T. Lu, Pamela S. Douglas, Heather J. Ribaudo, Steven K. Grinspoon
Abstract
Background. Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which debilitating symptoms persist for at least three months. Elucidating biologic underpinnings of LC could identify therapeutic opportunities. Methods. We utilized machine learning methods on biologic analytes provided over 12-months after hospital discharge from >500 COVID-19 patients in the IMPACC cohort to identify a multi-omics “recovery factor”, trained on patient-reported physical function survey scores. Immune profiling data included PBMC transcriptomics, serum O-link and plasma proteomics, plasma metabolomics, and blood CyTOF protein levels. Recovery factor scores were tested for association with LC, disease severity, clinical parameters, and immune subset frequencies. Enrichment analyses identified biologic pathways associated with recovery factor scores. Results. LC participants had lower recovery factor scores compared to recovered participants. Recovery factor scores predicted LC as early as hospital admission, irrespective of acute COVID-19 severity. Biologic characterization revealed increased inflammatory mediators, elevated signatures of heme metabolism, and decreased androgenic steroids as predictive and ongoing biomarkers of LC. Lower recovery factor scores were associated with reduced lymphocyte and increased myeloid cell frequencies. The observed signatures are consistent with persistent inflammation driving anemia and stress erythropoiesis as major biologic underpinnings of LC. Conclusion. The multi-omics recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets. Trial Registration. ClinicalTrials.gov NCT04378777. Funding. This study was funded by NIH, NIAID and NSF.
Authors
Gisela Gabernet, Jessica Maciuch, Jeremy P. Gygi, John F. Moore, Annmarie Hoch, Caitlin Syphurs, Tianyi Chu, Naresh Doni Jayavelu, David B. Corry, Farrah Kheradmand, Lindsey R. Baden, Rafick-Pierre Sekaly, Grace A. McComsey, Elias K. Haddad, Charles B. Cairns, Nadine Rouphael, Ana Fernandez-Sesma, Viviana Simon, Jordan P. Metcalf, Nelson I. Agudelo Higuita, Catherine L. Hough, William B. Messer, Mark M. Davis, Kari C. Nadeau, Bali Pulendran, Monica Kraft, Chris Bime, Elaine F. Reed, Joanna Schaenman, David J. Erle, Carolyn S. Calfee, Mark A. Atkinson, Scott C. Brakenridge, Esther Melamed, Albert C. Shaw, David A. Hafler, Alison D. Augustine, Patrice M. Becker, Al Ozonoff, Steven E. Bosinger, Walter Eckalbar, Holden T. Maecker, Seunghee Kim-Schulze, Hanno Steen, Florian Krammer, Kerstin Westendorf, IMPACC Network, Bjoern Peters, Slim Fourati, Matthew C. Altman, Ofer Levy, Kinga K. Smolen, Ruth R. Montgomery, Joann Diray-Arce, Steven H. Kleinstein, Leying Guan, Lauren I.R. Ehrlich
Abstract
BACKGROUND. In human lupus nephritis (LuN), tubulointerstitial inflammation (TII) is prognostically more important than glomerular inflammation. However, a comprehensive understanding of both TII complexity and heterogeneity is lacking. METHODS. Herein, we used high-dimensional confocal microscopy, spatial transcriptomics and specialized computer vision techniques to quantify immune cell populations and localize these within normal and diseased renal cortex structures. With these tools, we compared LuN to renal allograft rejection (RAR) and normal kidney on 54 de-identified biopsies. RESULTS. In both LuN and RAR, the 33 characterized immune cell populations formed discrete subgroups whose constituents co-varied in prevalence across biopsies. In both diseases, these co-variant immune cell subgroups organized into the same unique niches. Therefore, inflammation could be resolved into trajectories representing the relative prevalence and density of cardinal immune cell members of each co-variant subgroup. Indeed, in any one biopsy, the inflammatory state could be characterized by quantifying constituent immune cell trajectories. Remarkably, LuN heterogeneity could be captured by quantifying a few myeloid immune cell trajectories while RAR was more complex with additional T cell trajectories. CONCLUSIONS. Our studies identify rules governing renal inflammation and thus provide an approach for resolving LuN into discrete mechanistic categories. FUNDING. NIH (U19 AI 082724 [MRC], R01 AI148705 [MRC and ASC]), Chan Zuckerberg Biohub (MRC) and Lupus Research Alliance (MRC)
Authors
Gabriel Casella, Madeleine S. Torcasso, Junting Ai, Thao P. Cao, Satoshi Hara, Michael S. Andrade, Deepjyoti Ghosh, Daming Shao, Anthony Chang, Kichul Ko, Anita S. Chong, Maryellen L. Giger, Marcus R. Clark
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