eBioMedicine

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ISSN / EISSN : 2352-3964 / 2352-3964
Published by: Elsevier BV (10.1016)
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Published: 20 January 2022
Abstract:
Traumatic brain injury (TBI) is a major cause of morbidity and mortality internationally, with an estimated 69 million individuals estimated to sustain a TBI annually. Dewan MC Rattani A Gupta S Baticulon RE Hung Y-C Punchak M et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018; 130 : 1080-1097 Crossref Scopus (402) Google Scholar There exists heterogeneity in both the initial presentation of TBI, spanning from concussion to severe TBI, as well as recovery following these injuries. There are also inconsistencies in clinical care practices for the evaluation and management of TBI. The initial diagnosis of TBI and prognosis afterward is an important area of study with a need for cost-effective and safe tools to guide decision-making. To help address these critical issues, Whitehouse and colleagues investigated the relationship between baseline computed tomography (CT) imaging findings and concentrations of six serum biomarkers (i.e., GFAP, NFL, NSE, S100B, t-tau, and UCH-L1) obtained within 24 hours following all severities of TBIs. Whitehouse DP Monteiro M Czeiter E Vyvere TV Valerio F Ye Z et al. Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: A CENTER-TBI study. EBioMedicine [Internet]. 2022; 75 ([cited 2022 Jan 5]. Available from:) https://doi.org/10.1016/j.ebiom.2021.103777 https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00571-5/fulltext Summary Full Text Full Text PDF Scopus (0) Google Scholar
Xiaoying Gu, Lixue Huang, Dan Cui, Yeming Wang, Yimin Wang, Jiuyang Xu, Lianhan Shang, Guohui Fan,
Published: 20 January 2022
Abstract:
Summary Background Kidney damage in COVID-19 patients has been of special concern. The association of acute kidney injury (AKI) with post-acute kidney function among COVID-19 survivors was not sufficiently elucidated. Methods An ambidirectional cohort study was conducted with enrollment of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. Study participants were invited to follow-up visits at 6 and 12 months after symptom onset. The primary outcome was percentage of estimated glomerular filtration rate (eGFR) decreased from acute phase (between symptom onset and hospital discharge) to follow-up, and secondary outcome was reduced renal function at follow-up. Findings In total, 1,734 study participants were included in this study. Median follow-up duration was 342.0 days (IQR, 223.0-358.0) after symptom onset. After multivariable adjustment, percentage of eGFR decreased from acute phase to follow-up was 8.30% (95% CI, 5.99-10.61) higher among AKI participants than those without AKI at acute phase. Participants with AKI had an odds ratio (OR) of 4.60 (95% CI, 2.10-10.08) for reduced renal function at follow-up. The percentage of eGFR decreased for participants with AKI stage 1, stage 2, and stage 3 was 6.02% (95% CI, 3.48-8.57), 15.99% (95% CI, 10.77-21.22), and 17.79% (95% CI, 9.14-26.43) higher compared with those without AKI, respectively. Interpretation AKI at acute phase of COVID-19 was closely related to the longitudinal decline and post-acute status of kidney function at nearly one-year after symptom onset. Earlier and more intense follow-up strategies on kidney function management could be beneficial to COVID-19 survivors. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS 2020-I2M-CoV19-005, 2018-I2M-1-003, and 2020-I2M-2-013); National Natural Science Foundation of China (82041011); National Key Research and Development Program of China (2018YFC1200102); Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis (2020ZX09201001).
, Toshiko Tanaka, Richard D. Semba, Giovanna Fantoni, Ruin Moaddel, Julián Candia, Eleanor M. Simonsick, Stefania Bandinelli,
Published: 19 January 2022
Abstract:
Summary Background The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. Methods At baseline, 962 adults (women, 54·4%; age range, 21–98 years) participated in the InCHIANTI, "Aging in the Chianti Area" study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). Findings Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. Interpretation Cellular senescence may contribute to the association between RDW and mortality. Funding This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a ‘targeted project' by the Italian Ministry of Health and in part by the U.S. NIA.
, Nieves Varela, Casimiro Castillejo-López, Céline Coppard, María José Luque, Ying-Yu Wu, Natividad Martín-Morales, Francisco Pérez-Cózar, Gonzalo Gómez-Hernández, Ramesh Kumar, et al.
Published: 19 January 2022
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Summary Background Type I IFN (IFN-I) is a family of cytokines involved in the pathogenesis of autoimmune and autoinflammatory diseases such as psoriasis. SIDT1 is an ER-resident protein expressed in the lymphoid lineage, and involved in anti-viral IFN-I responses in vivo, through an unclear mechanism. Herein we have dissected the role of SIDT1 in the natural IFN-producing cells, the plasmacytoid dendritic cells (pDC). Methods The function of SIDT1 in pDC was determined by silencing its expression in human primary pDC and GEN2.2 cell line. SIDT1 role in vivo was assessed using the imiquimod-induced psoriasis model in the SIDT1-deficient mice (sidt1−/−). Findings Silencing of SIDT1 in GEN2.2 led to a blockade of the IFN-I response after stimulation of TLR7 and TLR9, without affecting the pro-inflammatory responses or upregulation of maturation markers. We found that SIDT1 migrates from the ER to the endosomal and lysosomal compartments together with TLR9 after CpG stimulation, participating in the access of the TLR9-CpG complex to lysosome-related vesicles, and therefore mediating the activation of TBK1 and the nuclear migration of IRF7, but not of NF-κB. sidt1−/− mice showed a significant decrease in severity parameters of the imiquimod-induced acute psoriasis-like model, associated with a decrease in the production of IFN-I and IFN-dependent chemokines. Interpretation Our findings indicate that SIDT1 is at the cross-road between the IFN-I and the proinflammatory pathways and constitutes a promising drug target for psoriasis and other diseases mediated by IFN-I responses. Funding This work was supported by the Consejería de Salud y Familias de la Junta de Andalucía (PIER_S1149 and C2_S0050) and Instituto de Salud Carlos III (PI18/00082 and PI21/01151), partly supported by European FEDER funds, and prior funding to MEAR from the Alliance for Lupus Research and the Swedish Research Council.
, Marcel Gehrung, Cassandra Kosmidou, Xiaodun Li, Izzuddin Diwan, Conor Rafferty, Elnaz Atabakhsh, Florian Markowetz, Rebecca C. Fitzgerald
Published: 17 January 2022
Abstract:
Summary Background Non-endoscopic cell collection devices combined with biomarkers can detect Barrett's intestinal metaplasia and early oesophageal cancer. However, assays performed on multi-cellular samples lose information about the cell source of the biomarker signal. This cross-sectional study examines whether a bespoke artificial intelligence-based computational pathology tool could ascertain the cellular origin of microRNA biomarkers, to inform interpretation of the disease pathology, and confirm biomarker validity. Methods The microRNA expression profiles of 110 targets were assessed with a custom multiplexed panel in a cohort of 117 individuals with reflux that took a Cytosponge test. A computational pathology tool quantified the amount of columnar epithelium present in pathology slides, and results were correlated with microRNA signals. An independent cohort of 139 Cytosponges, each from an individual patient, was used to validate the findings via qPCR. Findings Seventeen microRNAs are upregulated in BE compared to healthy squamous epithelia, of which 13 remain upregulated in dysplasia. A pathway enrichment analysis confirmed association to neoplastic and cell cycle regulation processes. Ten microRNAs positively correlated with columnar epithelium content, with miRNA-192–5p and -194–5p accurately detecting the presence of gastric cells (AUC 0.97 and 0.95). In contrast, miR-196a-5p is confirmed as a specific BE marker. Interpretation Computational pathology tools aid accurate cellular attribution of molecular signals. This innovative design with multiplex microRNA coupled with artificial intelligence has led to discovery of a quality control metric suitable for large scale application of the Cytosponge. Similar approaches could aid optimal interpretation of biomarkers for clinical use. Funding Funded by the NIHR Cambridge Biomedical Research Centre, the Medical Research Council, the Rosetrees and Stoneygate Trusts, and CRUK core grants.
Odile Launay, Cécile Artaud, Marie Lachâtre, Mohand Ait-Ahmed, Jelle Klein, Liem Binh Luong Nguyen, Christine Durier, Bastiaan Jansen, Yvonne Tomberger, Nathalie Jolly, et al.
Published: 15 January 2022
Abstract:
Summary Background V591 (TMV-083) is a live recombinant measles vector-based vaccine candidate expressing a pre-fusion stabilized SARS-CoV-2 spike protein. Methods We performed a randomized, placebo-controlled Phase I trial with an unblinded dose escalation and a double-blind treatment phase at 2 sites in France and Belgium to evaluate the safety and immunogenicity of V591. Ninety healthy SARS-CoV-2 sero-negative adults (18-55 years of age) were randomized into 3 cohorts, each comprising 24 vaccinees and 6 placebo recipients. Participants received two intramuscular injections of a low dose vaccine (1 × 105 median Tissue Culture Infectious Dose [TCID50]), one or two injections of a high dose vaccine (1 × 106 TCID50), or placebo with a 28 day interval. Safety was assessed by solicited and unsolicited adverse events. Immunogenicity was measured by SARS-CoV-2 spike protein-binding antibodies, neutralizing antibodies, spike-specific T cell responses, and anti-measles antibodies. ClinicalTrials.gov, NCT04497298. Findings Between Aug 10 and Oct 13, 2020, 148 volunteers were screened of whom 90 were randomized. V591 showed a good safety profile at both dose levels. No serious adverse events were reported. At least one treatment-related adverse event was reported by 15 (20.8%) participants receiving V591 vs. 6 (33.3%) of participants receiving placebo. Eighty-one percent of participants receiving two injections of V591 developed spike-binding antibodies after the second injection. However, neutralizing antibodies were detectable on day 56 only in 17% of participants receiving the low dose and 61% receiving the high dose (2 injections). Spike-specific T cell responses were not detected. Pre-existing anti-measles immunity had a statistically significant impact on the immune response to V591, which was in contrast to previous results with the measles vector-based chikungunya vaccine. Interpretation While V591 was generally well tolerated, the immunogenicity was not sufficient to support further development.
, Chrysovalantis Voutouri, , Mohammad Reza Nikmaneshi, Ankit B. Patel, Ashish Verma, Melin J. Khandekar, Sayon Dutta, Triantafyllos Stylianopoulos, Rakesh K. Jain, et al.
Published: 13 January 2022
Abstract:
Summary Background Mathematical modelling may aid in understanding the complex interactions between injury and immune response in critical illness. Methods We utilize a system biology model of COVID-19 to analyze the effect of altering baseline patient characteristics on the outcome of immunomodulatory therapies. We create example parameter sets meant to mimic diverse patient types. For each patient type, we define the optimal treatment, identify biologic programs responsible for clinical responses, and predict biomarkers of those programs. Findings Model states representing older and hyperinflamed patients respond better to immunomodulation than those representing obese and diabetic patients. The disparate clinical responses are driven by distinct biologic programs. Optimal treatment initiation time is determined by neutrophil recruitment, systemic cytokine expression, systemic microthrombosis and the renin-angiotensin system (RAS) in older patients, and by RAS, systemic microthrombosis and trans IL6 signalling for hyperinflamed patients. For older and hyperinflamed patients, IL6 modulating therapy is predicted to be optimal when initiated very early (<4th day of infection) and broad immunosuppression therapy (corticosteroids) is predicted to be optimally initiated later in the disease (7th – 9th day of infection). We show that markers of biologic programs identified by the model correspond to clinically identified markers of disease severity. Interpretation We demonstrate that modelling of COVID-19 pathobiology can suggest biomarkers that predict optimal response to a given immunomodulatory treatment. Mathematical modelling thus constitutes a novel adjunct to predictive enrichment and may aid in the reduction of heterogeneity in critical care trials. Funding C.V. received a Marie Skłodowska Curie Actions Individual Fellowship (MSCA-IF-GF-2020-101028945). R.K.J.'s research is supported by R01-CA208205, and U01-CA 224348, R35-CA197743 and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Advanced Medical Research Foundation and Harvard Ludwig Cancer Center. No funder had a role in production or approval of this manuscript.
, Ruth Aguilar, Marta Ribes, Natalia Ortega, , Gemma Salmerón, María José Molina, Marta Vidal, Diana Barrios, , et al.
Published: 11 January 2022
Abstract:
Summary Background Two doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naïve adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness. Methods We measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events. Findings Vaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects (p<0·05). A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with 43% (95% CI, 19-59) and 45% (95% CI, 63-18) lower neutralization, respectively, and 35% (95% CI, 3-57%) and 55% (95% CI, 33-70%) lower antibody levels, respectively. Among fully vaccinated, 6·3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection. Interpretation Our data support administering a single-dose in pre-exposed healthy individuals as primary vaccination. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination and in face of variants that escape immunity such as Omicron. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year. Funding This work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clínic de Barcelona, the Fundació Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.
, Bethany de la Haye, Gabrielle Nord, Kevin Klatt, Kevin Stephenson, Sara Adams, Lucy Bollinger, Neil Hanchard, Erland Arning, Teodoro Bottiglieri, et al.
Published: 11 January 2022
Abstract:
Summary Background Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. Methods Blood was collected from children aged 12–60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. Findings Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L (± SD): 0·549 (± 0·217) P = 0·00045 & 90 (± 40) P< 0·0001, respectively) and kwashiorkor (0·557 (± 0·195) P< 0·0001 & 115 (± 50) P< 0·0001), relative to marasmus (0·698 (± 0·212) & 153 (± 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. Interpretation Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation. Funding The Hickey Family Foundation, the American College of Gastroenterology, the NICHD, and the USDA/ARS.
Arjun Baghela, Olga M. Pena, Amy H. Lee, Beverlie Baquir, Reza Falsafi, Andy An, Susan W. Farmer, Andrew Hurlburt, Alvaro Mondragon-Cardona, Juan Diego Rivera, et al.
Published: 10 January 2022
Abstract:
Summary Background Inter-individual variability during sepsis limits appropriate triage of patients. Identifying, at first clinical presentation, gene expression signatures that predict subsequent severity will allow clinicians to identify the most at-risk groups of patients and enable appropriate antibiotic use. Methods Blood RNA-Seq and clinical data were collected from 348 patients in four emergency rooms (ER) and one intensive-care-unit (ICU), and 44 healthy controls. Gene expression profiles were analyzed using machine learning and data mining to identify clinically relevant gene signatures reflecting disease severity, organ dysfunction, mortality, and specific endotypes/mechanisms. Findings Gene expression signatures were obtained that predicted severity/organ dysfunction and mortality in both ER and ICU patients with accuracy/AUC of 77–80%. Network analysis revealed these signatures formed a coherent biological program, with specific but overlapping mechanisms/pathways. Given the heterogeneity of sepsis, we asked if patients could be assorted into discrete groups with distinct mechanisms (endotypes) and varying severity. Patients with early sepsis could be stratified into five distinct and novel mechanistic endotypes, named Neutrophilic-Suppressive/NPS, Inflammatory/INF, Innate-Host-Defense/IHD, Interferon/IFN, and Adaptive/ADA, each based on ∼200 unique gene expression differences, and distinct pathways/mechanisms (e.g., IL6/STAT3 in NPS). Endotypes had varying overall severity with two severe (NPS/INF) and one relatively benign (ADA) groupings, consistent with reanalysis of previous endotype studies. A 40 gene-classification tool (accuracy=96%) and several gene-pairs (accuracy=89–97%) accurately predicted endotype status in both ER and ICU validation cohorts. Interpretation The severity and endotype signatures indicate that distinct immune signatures precede the onset of severe sepsis and lethality, providing a method to triage early sepsis patients.
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