Clinical Research and Public Health
Abstract
BACKGROUND. There is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity. METHODS. We evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after ~20% weight loss in women identified as “Responders” (n=11) or “Non-responders” (n=11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1±7.9 kg/m2). RESULTS. At baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were >50% lower in Responders than Non-Responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-Responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids and C3/C5 acylcarnitines in Non-Responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups. CONCLUSION. The results from our study demonstrate the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when “normal” insulin action is achieved. CLINICAL TRIAL REGISTRATION. NCT00981500, NCT01299519, NCT02207777 FUNDING. This study was supported by National Institutes of Health grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), P30 DK052574 (Washington University Digestive Disease Research Center), and UL1 TR002345 (Washington University Institute of Clinical and Translational Sciences), T32 HL130357 (Obesity and Cardiovascular Disease Postdoctoral Training Program), grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.
Authors
Bettina Mittendorfer, Brandon D. Kayser, Mihoko Yoshino, Jun Yoshino, Jeramie D. Watrous, Mohit Jain, J. Christopher Eagon, Bruce W. Patterson, Samuel Klein
Abstract
BACKGROUND. The Omicron BA.5 subvariant of SARS-CoV-2 markedly escapes neutralizing antibodies induced by vaccination due to mutations in the Spike (S) protein. Solid organ transplant recipients (SOTRs) suffer high COVID-19 morbidity and demonstrate poor Omicron strain recognition after COVID-19 vaccination. T cell responses may provide a crucial second line of defense. Therefore, it is critical to understand which vaccine regimens induce robust, conserved T cell responses. METHODS. We evaluated anti-S IgG titers, subvariant pseudo-neutralization, and S-specific CD4+ and CD8+ T cell responses from SOTRs in a national, prospective observational trial (n=75). Participants were selected if they received 3 doses of mRNA (homologous boosting) or two doses of mRNA followed by Ad26.COV2.S (heterologous boosting). RESULTS. Homologous boosting with three mRNA doses induced the highest anti-S IgG titers. However, antibodies induced by both vaccine regimens demonstrated significantly lower pseudo-neutralization against BA.5 compared to the ancestral strain. In contrast, vaccine-induced S-specific T cells maintained cross-reactivity against BA.5 compared to ancestral recognition. Homologous boosting induced higher frequencies of activated polyfunctional CD4+ T cell responses, with polyfunctional IL-21+ peripheral T follicular helper cells increased in mRNA-1273 compared to BNT¬¬162b2. IL-21+ cells robustly correlated with antibody titers. Heterologous boosting with Ad26.COV2.S did not increase CD8+ responses compared to homologous boosting. CONCLUSIONS. These data demonstrate that boosting with the ancestral strain can induce cross-reactive T cell responses against emerging variants of concern in SOTRs, but alterative vaccine strategies are required to induce robust CD8+ T cell responses. TRIAL REGISTRATION. IRB00248540 FUNDING. U01AI138897, U54CA260492, Emory COVID-19 research repository
Authors
Elizabeth A. Thompson, Wabathi Ngecu, Laila Stoddart, T. Scott Johnston, Amy Chang, Katherine Cascino, Jennifer L. Alejo, Aura T. Abedon, Hady Samaha, Nadine Rouphael, Aaron A.R. Tobian, Dorry L. Segev, William A. Werbel, Andrew H. Karaba, Joel N. Blankson, Andrea L. Cox
Abstract
BACKGROUND Elevated circulating branched chain amino acids (BCAAs), measured at a single time point in middle life, are strongly associated with an increased risk of developing type 2 diabetes mellitus (DM). However, the longitudinal patterns of change in BCAAs through young adulthood and their association with DM in later life are unknown.METHODS We serially measured BCAAs over 28 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective cohort of apparently healthy Black and White young adults at baseline. Trajectories of circulating BCAA concentrations from years 2–30 (for prevalent DM) or years 2–20 (for incident DM) were determined by latent class modeling.RESULTS Among 3,081 apparently healthy young adults, trajectory analysis from years 2–30 revealed 3 distinct BCAA trajectory groups: low-stable (n = 1,427), moderate-stable (n = 1,384), and high-increasing (n = 270) groups. Male sex, higher body mass index, and higher atherogenic lipid fractions were more common in the moderate-stable and high-increasing groups. Higher risk of prevalent DM was associated with the moderate-stable (OR = 2.59, 95% CI: 1.90–3.55) and high-increasing (OR = 6.03, 95% CI: 3.86–9.43) BCAA trajectory groups in adjusted models. A separate trajectory group analysis from years 2–20 for incident DM after year 20 showed that moderate-stable and high-increasing trajectory groups were also significantly associated with higher risk of incident DM, after adjustment for clinical variables and glucose levels.CONCLUSION BCAA levels track over a 28-year span in most young adults, but serial clinical metabolomic measurements identify subpopulations with rising levels associated with high risk of DM in later life.FUNDING This research was supported by the NIH, under grants R01 HL146844 (JTW) and T32 HL069771 (MRC). The CARDIA study is conducted and supported by the NIH National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I and HHSN268201800007I), Northwestern University (HHSN268201800003I), the University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I).
Authors
Konrad T. Sawicki, Hongyan Ning, Norrina B. Allen, Mercedes R. Carnethon, Amisha Wallia, James D. Otvos, Issam Ben-Sahra, Elizabeth M. McNally, Janet K. Snell-Bergeon, John T. Wilkins
Abstract
BACKGROUND. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV. METHOD. Proximity extension assay technology was utilized to measure 1472 plasma proteins. Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for the development of CVD during a 5-year follow-up. RESULTS. PLHIV on ART displayed systemic dysregulation of protein concentrations compared to HCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune- and lipid metabolism-related pathways. Furthermore, we observed that DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD in 5-year follow-up. CONCLUSIONS. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. TRIAL REGISTRATION. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835). FUNDING. The 200HIV and 2000HIV studies are supported by the AIDS-fonds (#P-29001, Netherlands) and a ViiV healthcare grant (A18-1052), respectively; The ViiV healthcare grant was awarded to A.V., M.G.N., L.A.B.J., and Q.d.M; The Spinoza Prize (NWO SPI94-212) and ERC Advanced grant (no. 833247) were awarded to M.G.N; The Indonesia Endowment Fund for Education (LPDP) given by the Ministry of Finance of the Republic of Indonesia was awarded to N.V.
Authors
Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje C.P. Jacobs-Cleophas, Lisa Van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki
Abstract
BACKGROUND. Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using three proteins: L-Ficolin, Hyaluronic Acid (HA), and Stimulation-2 (ST2). METHODS. Between 2017 to 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence at day 35 post-HCT, and overall survival (OS) at day 100 post-HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. RESULTS. Combination of the three biomarkers measured at day 3 post-HCT in the prospective cohort provided 80% (95%CI, 55-100%) sensitivity and 73% (95%CI, 62-83%) specificity for risk of SOS occurrence. Patients with low L-Ficolin were 9 times (95%CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95%CI 1.9-22.0) and 5.5 (95%CI 2.3-13.1) times more likely to develop SOS. These three markers also predicted worse day 100 OS [L-Ficolin: HR, 10.0 (95%CI 2.2-45.1), P=0.0002; HA: HR, 4.1 (95%CI 1.0-16.4), P=0.031; ST2: HR, 3.9 (95%CI 0.9-16.4), P=0.04]. CONCLUSION. L-Ficolin, HA, and ST2 levels measured as early as three days post-HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT03132337. FUNDING. NICHD P50HD090215, R01HD074587, NCI R01CA168814 and NHLBI K24HL156896.
Authors
Yan Han, Alan Bidgoli, Brittany P. DePriest, Alejandra Méndez, Khadijeh Bijangi-Vishehsaraei, Evelio D. Perez-Albuerne, Robert A. Krance, Jamie Renbarger, Jodi L. Skiles, Sung W. Choi, Hao Liu, Sophie Paczesny
Abstract
BACKGROUND. Due to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study to evaluate the impact of local MSC therapy in UP. METHODS. Thirteen refractory UP patients, with endoscopic Mayo score (EMS) 2 or 3, were included. Seven patients received 20-40 x 106 allogeneic MSCs (cohort 1), while six patients received 40-80 x 106 MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and week 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline, week 2 and 6. Furthermore, we evaluated the engraftment of MSCs, presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment. RESULTS. No serious AEs were observed. The clinical Mayo score was significantly improved at week 2 and 6, and the EMS was significantly improved at week 6, compared to baseline. At week 6, donor MSCs were still detectable in rectum biopsies of 4/9 patients and DSAs against both HLA-class I and -class II were found. Mass cytometry showed a reduction of activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy. CONCLUSION. Local administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials. TRIAL REGISTRATION. clinicaltrialsregister.eu, EudraCT: 2017-003524-75, Dutch Trial register: NTR7205. FUNDING. ECCO grant 2020.
Authors
Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea van der Meulen - de Jong
Abstract
BACKGROUND. Longitudinal investigations of murine acute kidney injury (AKI) suggest that injury and inflammation may persist long after the initial insult. However, the evolution of these processes and their prognostic values are unknown in patients with AKI. METHODS. In a prospective cohort of 656 participants hospitalized with AKI, we measured seven urine and two plasma biomarkers of kidney injury, inflammation, and tubular health at multiple timepoints from the diagnosis to 12 months after AKI. We used linear mixed-effect models to estimate biomarker changes over time, and used Cox proportional hazard regressions to determine their associations with a composite outcome of CKD incidence and progression. We compared the gene expression kinetics of biomarkers in murine models of repair and atrophy after ischemic reperfusion injury (IRI). RESULTS. After 4.3 years, 106 and 52 participants developed incident CKD and CKD progression, respectively. Each standard deviation increases in the change of urine KIM-1, MCP-1 and plasma TNFR1 from baseline to 12 months was associated with 2-3-fold increased risk for CKD, while the increase in urine UMOD was associated with 40% reduced risk for CKD. The trajectories of these biological processes were associated with progression to kidney atrophy in mice after IRI. CONCLUSION. Sustained tissue injury and inflammation, and slower restoration of tubular health are associated with higher risk of kidney disease progression. Further investigation into these ongoing biological processes may help understand and prevent the AKI-to-CKD transition. FUNDING. NIH and NIDDK (grants U01DK082223, U01DK082185, U01DK082192, U01DK082183, R01DK098233, R01DK101507, R01DK114014, K23DK100468, R03DK111881, K01DK120783, and R01DK093771).
Authors
Yumeng Wen, Leyuan Xu, Isabel A. Melchinger, Heather Thiessen-Philbrook, Dennis G. Moledina, Steven G. Coca, Chi-yuan Hsu, Alan S. Go, Kathleen D. Liu, Edward D. Siew, T. Alp Ikizler, Vernon M. Chinchilli, James S. Kaufman, Paul L. Kimmel, Jonathan Himmelfarb, Lloyd G. Cantley, Chirag R. Parikh
Abstract
BACKGROUND. After its introduction as standard-of-care for severe COVID-19, dexamethasone has been administered to a large number of patients globally. Detailed knowledge of its impact on the cellular and humoral immune response to SARS-CoV-2 remains scarce. METHODS. We included immunocompetent individuals with 1) mild COVID-19, 2) severe COVID-19 before introduction of dexamethasone treatment, and 3) severe COVID-19 infection treated with dexamethasone from prospective observational cohort studies at Charité-Universitätsmedizin Berlin, Germany. We analyzed SARS-CoV-2 spike-reactive T cells, spike-specific IgG titers as well as serum neutralizing activity against B.1.1.7, B.1.617.2 in samples ranging from two weeks to six months post infection. We also analyzed BA.2 neutralization in sera after booster immunization. RESULTS. Patients with severe COVID-19 and dexamethasone treatment had lower T cell and antibody responses to SARS-CoV-2 compared to patients without dexamethasone treatment in the early phase of disease, which converged in both groups before six months post infection and also post-immunization. Patients with mild COVID-19 had a comparatively lower T cell and antibody response than patients with severe disease, including a lower response to booster-immunization during convalescence. CONCLUSION. Dexamethasone treatment is associated with short-term reduction of T cell and antibody response in severe COVID-19 when compared to the non-treated group, but this difference evens out six months after infection. We confirm higher cellular and humoral immune responses in patients after severe versus mild COVID-19 infection and the concept of improved hybrid immunity upon immunization. TRIAL REGISTRATION.: n/aFunding: Berlin Institute of Health, German Federal Ministry of Education and German Federal Institute for Drugs and Medical Devices
Authors
Charlotte Thibeault, Lara Bardtke, Kanika Vanshylla, Veronica Cristianzano, Kirsten A. Eberhardt, Paula Stubbemann, David Hillus, Pinkus Tober-Lau, Parnika Mukherjee, Friederike Münn, Lena J Lippert, Elisa T. Helbig, Tilman Lingscheid, Fridolin Steinbeis, Mirja Mittermaier, Martin Witzenrath, Thomas Zoller, Florian Klein, Leif E. Sander, Florian Kurth
Abstract
BACKGROUND. Fibrocytes are bone marrow-derived circulating cells that traffic to the injured lungs and contribute to fibrogenesis. The mTOR inhibitor, sirolimus, inhibits fibrocyte CXCR4 expression, reducing fibrocyte traffic and attenuating lung fibrosis in animal models. We sought to test the hypothesis that short-term treatment with sirolimus reduces the concentration of CXCR4+ circulating fibrocytes in patients with idiopathic pulmonary fibrosis (IPF). METHODS. We conducted a short-term randomised double-blind placebo-controlled crossoverpilot trial to assess the safety and tolerability of sirolimus in IPF. Subjects were randomly assigned to sirolimus or placebo for approximately 6 weeks, and after a 4 week washout, assigned to the alternate treatment. Toxicity, lung function, and the concentration of circulating fibrocytes were measured before and after each treatment. RESULTS. In the 28 study subjects, sirolimus resulted in a statistically significant 35% decline in the concentration of total fibrocytes, 34% decline in CXCR4+ fibrocytes, and 42% decline in fibrocytes expressing ɑ-smooth muscle actin, but no significant change in these populations occurred on placebo. Respiratory adverse events occurred more frequently during treatment with placebo than sirolimus; the incidence of adverse events and drug tolerability did not otherwise differ during therapy with drug and placebo. Lung function was unaffected by either treatment with the exception of a small decline in gas transfer during treatment with placebo. CONCLUSIONS. As compared with placebo, short-term treatment with sirolimus resulted inreduction of circulating fibrocyte concentrations in subjects with IPF with an acceptable safety profile. TRIAL REGISTRATION. clinicaltrials.gov identifier number NCT01462006 FUNDING. NIH R01HL098329 and American Heart Association 18TPA34170486
Authors
Diana C. Gomez Manjarres, Dierdre B. Axell-House, Divya C. Patel, John Odackal, Victor Yu, Marie D. Burdick, Borna Mehrad
Abstract
BACKGROUND. Cellular stressors influence the development of clonal hematopoiesis (CH). We hypothesized that aging, environmental, inflammatory, and genotoxic stresses drive the emergence of CH in patients with severe lung disease undergoing lung transplantation. METHODS. We performed a cross-sectional cohort study of 85 patients with severe lung disease undergoing transplantation to characterize CH prevalence. We evaluated somatic variants using duplex error-corrected sequencing and germline variants using whole exome sequencing. We evaluated CH frequency and burden using chi-square and Poisson regression, associations with clinical and demographic variables using logistic regression, and associations with clinical outcomes using chi-square, logistic, and Cox regression. RESULTS. CH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was observed at high frequency in transplant recipients compared to a control group of older adults [28% vs. 0%, aOR 12.9 (1.7-100.3), p=0.0002]. Age [OR 1.13 (1.03-1.25), p=0.014] and smoking history [OR 4.25 (1.02-17.82), p=0.048] were associated with CH in DDR genes. Germline variants causing predisposition to idiopathic pulmonary fibrosis, including telomere biology disorders and surfactant-related lung disease were identified but not associated with CH. DDR CH was associated with increased cytomegalovirus viremia compared to patients with no CH [OR 7.23 (1.95-26.8), p=0.009]] or non-DDR CH [OR 7.64 (1.77-32.89, p=0.012)], decreased lymphopenia (aHR 0.49 (0.27 – 0.90), p=0.021) and mycophenolate discontinuation [aOR 3.8 (1.3-12.9), p=0.031]. CONCLUSION. In patients with severe lung disease requiring lung transplantation, CH due to somatic variants in PPM1D, TP53 or ATM is highly prevalent and associated with post-transplant outcomes including cytomegalovirus activation and mycophenolate intolerance. FUNDING. NIH/NHLBI K01HL155231 (LKT), R25HL105400 (LKT), Foundation for Barnes-Jewish Hospital (LKT), Evans MDS Center at Washington University (KAO, MJW), ASH Scholar Award (KAO), NIH K12CA167540 (KAO), NIH P01AI116501 (AEG, DK), NIH R01HL094601 (AEG), and NIH P01CA101937 (DCL).
Authors
Laneshia K. Tague, Karolyn A. Oetjen, Anirudh Mahadev, Matthew J. Walter, Hephzibah Anthony, Daniel Kreisel, Daniel C. Link, Andrew E. Gelman
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