Clinical Research and Public Health
Abstract
BACKGROUND. Plasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown. METHODS. We studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly-assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography-mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the non-representative sampling design. RESULTS. Plasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (p = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI 0.98–2.27), 1.30 (1.00–1.69), 1.09 (0.82–1.44), 0.88 (0.66–1.16), and 0.71 (0.52–0.97) for 10th, 25th, 50th, 75th and 90th percentiles of baseline chondroitin sulfate. CONCLUSIONS. Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal vs. restrictive intravenous fluid resuscitation strategy. TRIAL. ClinicalTrials.gov NCT03434028.
Authors
Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D'Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
Abstract
BACKGROUND. Chronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear. METHODS. Thirty-two people with AUD (17 women) and 29 controls (17 women) completed one positron emission tomography (PET) brain imaging scan with the radiotracer [11C]UCB-J, which binds to SV2A, a marker of synaptic density. Levels of synaptic density were quantified by estimating binding potential (BPND) across four regions of interest: frontal cortex, striatum, hippocampus, and cerebellum. RESULTS. People with AUD were on average(±SD) 43±13 years old and most met criteria for mild or moderate AUD. Controls were 37±12 years old. People with AUD had on average 11% lower [11C]UCB-J BPND than controls in the frontal cortex (F(1,62)=13.074, p<0.001), striatum (F(1,60)=10.283, p=0.002), hippocampus (F(1,60)=5.964, p=0.018), and trending in the same direction in cerebellum (F(1,50)=3.438, p=0.070). Among people with AUD, lower [11C]UCB-J BPND was significantly related to more drinks per drinking day in the frontal cortex (p=0.022) and striatum (p=0.026). People with AUD performed worse on executive function than controls (p=0.020), but this was not related to [11C]UCB-J BPND. CONCLUSION. Synaptic density deficits are evident, even in people with mild-to-moderate AUD, with greater deficits in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD. TRIAL REGISTRATION. N/A. FUNDING. This work was supported by the National Institute of Health.
Authors
Yasmin Zakiniaeiz, Nakul R. Raval, Will Riordan, Nabeel Nabulsi, Yiyun Huang, Brian Pittman, David Matuskey, Gustavo A. Angarita, Robin Bonomi, Sherry A. McKee, Ansel T. Hillmer, Kelly P. Cosgrove
Abstract
BACKGROUND. Infection is an important complication of implanted devices and prosthetics. Identifying infections sufficiently early to salvage implants and avoid reconstructive failure is a persistent medical challenge. METHODS. Two female cohorts >21 years undergoing breast implant reconstruction were recruited. Seroma fluid (82 breasts, 70 patients) was collected upon implant removal for infectious or non-infectious causes. Post-implantation drain fluid (100 samples, 44 breasts, 32 patients) was collected at routine visits prior to implant removal. A liquid-chromatography/mass spectrometry-based metabolomic approach was used to identify infection correlates. RESULTS. In seroma fluid specimens, infection was associated with a diverse set of small molecules including acetylated polyamines, defensins, glucosyl-sphingosine, and several peptide-like features (all P<0.001, diagnostic areas under the receiver operating curve 0.82-0.93). Notably, a subset of these markers were significantly elevated (p<0.05) in post-implantation drain fluid before recorded infection symptoms and diagnosis. Pseudomonas aeruginosa and its specialized exometabolites in drain specimens were also associated with subsequent P. aeruginosa infections. CONCLUSION. Tissue fluid from infected patients has a distinctive metabolome reflecting human and bacterial physiologic processes that often precede clinical diagnoses. A diagnostic based on these findings has potential to improve patient outcomes through early recognition of infection. TRIAL REGISTRATION. Not applicable. FUNDING. Work was supported by U54CK000609 from the CDC and an unencumbered research gift to TMM from Sientra. Metabolomic approaches were supported by RO1DK125860 and RO1DK111930 to JPH. The contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
Authors
John A. Wildenthal, Margaret A. Olsen, Hung D. Tran, John I. Robinson, Terence M. Myckatyn, David K. Warren, Keith E. Brandt, Marissa M. Tenenbaum, Joani M Christensen, Thomas H. Tung, Justin M. Sacks, Rachel A. Anolik, Katelin B. Nickel, Hideji Fujiwara, Peter J. Mucha, Jeffrey P. Henderson
Abstract
BACKGROUND. Amino acid (AA) concentrations are increased in prediabetes and diabetes. Since AA stimulate glucagon secretion which should then increase hepatic AA catabolism, it has been hypothesized that hepatic resistance (associated with hepatic fat content) to glucagon’s actions on AA metabolism leads to hyperglucagonemia and hyperglycemia. METHODS. To test this hypothesis, we therefore studied lean and obese individuals, the latter group with and without hepatic steatosis as defined by Proton Density Fat Fraction (PDFF) > 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed. [3-3H] glucose and L-[1-13C,15N]-leucine were used to measure glucose turnover and leucine oxidation respectively. During a hyperglycemic clamp, an amino acid mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0 – 120 min; 3.0 ng/kg/min 120 – 240 min). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arterio-venous differences across the liver), of the other AA were the main outcomes measured. RESULTS. The presence of hepatic steatosis did not alter hepatic glucose metabolism and leucine oxidation in response to insulin and rising concentrations of glucagon. Splanchnic balance of a few amino acids, and related metabolites differed amongst the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis. CONCLUSION. The action of glucagon on hepatic amino acid metabolism is unaffected by hepatic steatosis in humans. TRIAL REGISTRATION. This study was registered at Clinical Trials.Gov: NCT05500586. FUNDING. This work was funding by the NIH.
Authors
Hannah E. Christie, Sneha Mohan, Aoife M. Egan, Federica Boscolo, Chiara Dalla Man, Scott M. Thompson, Michael Jundt, Chad J. Fleming, James C. Andrews, Kent R. Bailey, Michael D. Jensen, K. Sree Nair, Adrian Vella
Abstract
BACKGROUND. Among antiretroviral therapy (ART)-suppressed people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the broader effect of sex on the inflammatory proteome, and whether these differences are modified by age, remains unclear. METHODS. 363 plasma inflammatory protein levels (Olink Inflammation Explore) were assessed in ART-suppressed PWH sampled from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The relationship between sex and 363 plasma proteins – including 22 in the interferon-α response pathway – was assessed with linear regression models adjusting for confounders, assessing interactions by age. FINDINGS. Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age impacted the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 (P = 0.024), but higher in women in those > 47 (P = 0.005, p-interaction < 0.001). Among the 131 proteins associated with mortality risk (q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women . Women had decreased mortality than men ≤47 (P < 0.001) but had similar mortality > 47 (P = 0.84). INTERPRETATION. The menopausal transition appears to have a dramatic effect on systemic Type I interferon responses and the broader inflammatory proteome in women with HIV. Among older PWH, women have greater inflammation than men, including the majority of proteins linked with mortality risk.
Authors
Rebecca A. Abelman, Samuel R. Schnittman, Natalia Faraj Murad, Adam Olshen, Gabriele B. Beck-Engeser, Noah Aquino, Gabrielle C. Ambayec, Edward R. Cachay, Joseph J. Eron, Michael Saag, Robin M. Nance, Joseph A. Delaney, Stephanie A. Ruderman, Richard D. Moore, Kenneth H. Mayer, Jeffrey M. Jacobson, Heidi M. Crane, Peter W. Hunt
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
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