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Association of mortality and early tracheostomy in patients with COVID-19: a retrospective analysis
(2022)
Flinspach, Armin Niklas ; Booke, Hendrik ; Zacharowski, Kai ; Balaban, Ümniye ; Herrmann, Eva ; Adam, Elisabeth
COVID-19 adds to the complexity of optimal timing for tracheostomy. Over the course of this pandemic, and expanded knowledge of the disease, many centers have changed their operating procedures and performed an early tracheostomy. We studied the data on early and delayed tracheostomy regarding patient outcome such as mortality. We performed a retrospective analysis of all tracheostomies at our institution in patients diagnosed with COVID-19 from March 2020 to June 2021. Time from intubation to tracheostomy and mortality of early (≤ 10 days) vs. late (> 10 days) tracheostomy were the primary objectives of this study. We used mixed cox-regression models to calculate the effect of distinct variables on events. We studied 117 tracheostomies. Intubation to tracheostomy shortened significantly (Spearman’s correlation coefficient; rho = − 0.44, p ≤ 0.001) during the course of this pandemic. Early tracheostomy was associated with a significant increase in mortality in uni- and multivariate analysis (Hazard ratio 1.83, 95% CI 1.07–3.17, p = 0.029). The timing of tracheostomy in COVID-19 patients has a potentially critical impact on mortality. The timing of tracheostomy has changed during this pandemic tending to be performed earlier. Future prospective research is necessary to substantiate these results.
Aim: To evaluate the influence of the width of keratinized tissue (KT) on the prevalence of peri-implant diseases, and soft- and hard-tissue stability.
Materials and methods: Clinical studies reporting on the prevalence of peri-implant diseases (primary outcome), plaque index (PI), modified plaque index (mPI), bleeding index (mBI), bleeding on probing (BOP), probing pocket depths (PD), mucosal recession (MR), and marginal bone loss (MBL) and/or patient-reported outcomes (PROMs; secondary outcomes) were searched. The weighted mean differences (WMD) were estimated for the assessed clinical and radiographic parameters by employing a random-effect model that considered different KT widths (i.e., <2 and ≥2 mm).
Results: Twenty-two articles describing 21 studies (15 cross-sectional, five longitudinal comparative studies, and one case series with pre–post design) with an overall high to low risk of bias were included. Peri-implant mucositis and peri-implantitis affected 20.8% to 42% and at 10.5% to 44% of the implants with reduced or absent KT (i.e., <2 mm or 0 mm). The corresponding values at the implant sites with KT width of ≥2 mm or >0 mm were 20.5% to 53% and 5.1% to 8%, respectively. Significant differences between implants with KT < 2 mm and those with KT ≥ 2 mm were revealed for WMD for BOP, mPI, PI, MBL, and MR all favoring implants with KT ≥ 2 mm.
Conclusion: Reduced KT width is associated with an increased prevalence of peri-implantitis, plaque accumulation, soft-tissue inflammation, mucosal recession, marginal bone loss, and greater patient discomfort.
Schaller-Paule, Martin A. ; Förch, Christian ; Bohmann, Ferdinand ; Lapa, Sriramya ; Misselwitz, Björn ; Kohlhase, Konstantin ; Rosenow, Felix ; Strzelczyk, Adam ; Willems, Laurent
Objective: To assess predictive factors for poststroke pneumonia (PSP) in patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) of the anterior circulation, with special regard to the impact of intravenous thrombolysis (IVT) and endovascular treatment (EVT) on the risk of PSP. As a secondary goal, the validity of the A2DS2, PNEUMONIA, and ISAN scores in LVO will be determined.
Methods: Analysis was based on consecutive data for the years 2017 to 2019 from the prospective inpatient stroke registry covering the entire federal state of Hesse, Germany, using the Kruskal-Wallis test and binary logistic regression.
Results: Data from 4,281 patients with LVO were included in the analysis (54.8% female, median age = 78 years, range = 18–102), of whom 66.4% (n = 2,843) received recanalization therapy (RCT). In total, 19.4% (n = 832) of all LVO patients developed PSP. Development of PSP was associated with an increase in overall in-hospital mortality of 32.1% compared with LVO patients without PSP (16.4%; p < 0.001). Incidence of PSP was increased in 2132 patients with either EVT (n = 928; 25.9% PSP incidence) or combined EVT plus IVT (n = 1,204; 24.1%), compared with 2,149 patients with IVT alone (n = 711; 15.2%) or conservative treatment only (n = 1,438; 13.5%; p < 0.001). Multivariate analysis identified EVT (OR 1.5) and combined EVT plus IVT (OR 1.5) as significant independent risk factors for PSP. Furthermore, male sex (OR 1.9), age ≥ 65 years (OR 1.7), dysphagia (OR 3.2) as well as impaired consciousness at arrival (OR 1.7) and the comorbidities diabetes (OR 1.4) and atrial fibrillation (OR 1.3) were significantly associated risk factors (each p < 0.001). Minor stroke (NIHSS ≤ 4) was associated with a significant lower risk of PSP (OR 0.5). Performance of risk stratification scores varied between A2DS2 (96.1% sensitivity, 20.7% specificity), PNEUMONIA (78.2% sensitivity and 45.1% specificity) and ISAN score (98.0% sensitivity, 20.0% specificity).
Conclusion: Nearly one in five stroke patients with LVO develops PSP during acute care. This risk of PSP is further increased if an EVT is performed. Other predictive factors are consistent with those previously described for all AIS patients. Available risk stratification scores proved to be sensitive tools in LVO patients but lack specificity.
A novel approach to measure brain-to-brain spatial and temporal alignment during positive empathy
(2022)
Toppi, Jlenia ; Siniatchkin, Michael ; Vogel, Pascal ; Freitag, Christine M. ; Astolfi, Laura ; Ciaramidaro, Angela
Empathy is defined as the ability to vicariously experience others’ suffering (vicarious pain) or feeling their joy (vicarious reward). While most neuroimaging studies have focused on vicarious pain and describe similar neural responses during the observed and the personal negative affective involvement, only initial evidence has been reported for the neural responses to others’ rewards and positive empathy. Here, we propose a novel approach, based on the simultaneous recording of multi-subject EEG signals and exploiting the wavelet coherence decomposition to measure the temporal alignment between ERPs in a dyad of interacting subjects. We used the Third-Party Punishment (TPP) paradigm to elicit the personal and vicarious experiences. During a positive experience, we observed the simultaneous presence in both agents of the Late Positive Potential (LPP), an ERP component related to emotion processing, as well as the existence of an inter-subject ERPs synchronization in the related time window. Moreover, the amplitude of the LPP synchronization was modulated by the presence of a human-agent. Finally, the localized brain circuits subtending the ERP-synchronization correspond to key-regions of personal and vicarious reward. Our findings suggest that the temporal and spatial ERPs alignment might be a novel and direct proxy measure of empathy.
Pati, Sarthak ; Baid, Ujjwal ; Edwards, Brandon ; Sheller, Micah ; Wang, Shih-Han ; Reina, G. Anthony ; Foley, Patrick ; Gruzdev, Alexey ; Karkada, Deepthi ; Davatzikos, Christos ; Sako, Chiharu ; Ghodasara, Satyam ; Bilello, Michel ; Mohan, Suyash ; Vollmuth, Philipp ; Brugnara, Gianluca ; Jayachandran Preetha, Chandrakanth ; Sahm, Felix ; Maier-Hein, Klaus ; Zenk, Maximilian ; Bendszus, Martin ; Wick, Wolfgang ; Calabrese, Evan ; Rudie, Jeffrey ; Villanueva-Meyer, Javier ; Cha, Soonmee ; Ingalhalikar, Madhura ; Jadhav, Manali ; Pandey, Umang ; Saini, Jitender ; Garrett, John ; Larson, Matthew ; Jeraj, Robert ; Currie, Stuart ; Frood, Russell ; Fatania, Kavi ; Huang, Raymond Y. ; Chang, Ken ; Balaña, Carmen ; Capellades, Jaume ; Puig, Josep ; Trenkler, Johannes ; Pichler, Josef ; Necker, Georg ; Haunschmidt, Andreas ; Meckel, Stephan ; Shukla, Gaurav ; Liem, Spencer ; Alexander, Gregory S. ; Lombardo, Joseph ; Palmer, Joshua D. ; Flanders, Adam E. ; Dicker, Adam P. ; Sair, Haris I. ; Jones, Craig K. ; Venkataraman, Archana ; Jiang, Meirui ; So, Tiffany Y. ; Chen, Cheng ; Heng, Pheng Ann ; Dou, Qi ; Kozubek, Michal ; Lux, Filip ; Michálek, Jan ; Matula, Petr ; Keřkovský, Miloš ; Kopřivová, Tereza ; Dostál, Marek ; Vybíhal, Václav ; Vogelbaum, Michael A. ; Mitchell, J. Ross ; Farinhas, Joaquim ; Maldjian, Joseph A. ; Bangalore Yogananda, Chandan Ganesh ; Pinho, Marco C. ; Reddy, Divya ; Holcomb, James ; Wagner, Benjamin C. ; Ellingson, Benjamin M. ; Cloughesy, Timothy F. ; Raymond, Catalina ; Oughourlian, Talia ; Hagiwara, Akifumi ; Wang, Chencai ; To, Minh-Son ; Bhardwaj, Sargam ; Chong, Chee ; Agzarian, Marc ; Falcão, Alexandre Xavier ; Martins, Samuel B. ; Teixeira, Bernardo Corrêa de Almeida ; Sprenger, Flávia ; Menotti, David ; Lucio, Diego R. ; LaMontagne, Pamela ; Marcus, Daniel ; Wiestler, Benedikt ; Kofler, Florian ; Ezhov, Ivan ; Metz, Marie ; Jain, Rajan ; Lee, Matthew ; Lui, Yvonne W. ; McKinley, Richard ; Slotboom, Johannes ; Radojewski, Piotr ; Meier, Raphael ; Wiest, Roland Gerhard Rudi ; Murcia, Derrick ; Fu, Eric ; Haas, Rourke ; Thompson, John ; Ormond, David Ryan ; Badve, Chaitra ; Sloan, Andrew E. ; Vadmal, Vachan ; Waite, Kristin ; Colen, Rivka R. ; Pei, Linmin ; Ak, Murat ; Srinivasan, Ashok ; Bapuraj, Jayapalli Rajiv ; Rao, Arvind ; Wang, Nicholas ; Yoshiaki, Ota ; Moritani, Toshio ; Turk, Sevcan ; Lee, Joonsang ; Prabhudesai, Snehal ; Morón, Fanny ; Mandel, Jacob ; Kamnitsas, Konstantinos ; Glocker, Ben ; Dixon, Luke V. M. ; Williams, Matthew ; Zampakis, Peter ; Panagiotopoulos, Vasileios ; Tsiganos, Panagiotis ; Alexiou, Sotiris ; Haliassos, Ilias ; Zacharaki, Evangelia I. ; Moustakas, Konstantinos ; Kalogeropoulou, Christina ; Kardamakis, Dimitrios M. ; Choi, Yoon Seong ; Lee, Seung-Koo ; Chang, Jong Hee ; Ahn, Sung Soo ; Luo, Bing ; Poisson, Laila ; Wen, Ning ; Tiwari, Pallavi ; Verma, Ruchika ; Bareja, Rohan ; Yadav, Ipsa ; Chen, Jonathan ; Kumar, Neeraj ; Smits, Marion ; Voort, Sebastian R. van der ; Alafandi, Ahmed ; Incekara, Fatih ; Wijnenga, Maarten M. J. ; Kapsas, Georgios ; Gahrmann, Renske ; Schouten, Joost W. ; Dubbink, Hendrikus J. ; Vincent, Arnaud J. P. E. ; Van den Bent, Martin J. ; French, Pim J. ; Klein, Stefan ; Yuan, Yading ; Sharma, Sonam ; Tseng, Tzu-Chi ; Adabi, Saba ; Niclou, Simone P. ; Keunen, Olivier ; Hau, Ann-Christin ; Vallières, Martin ; Fortin, David ; Lepage, Martin ; Landman, Bennett ; Ramadass, Karthik ; Xu, Kaiwen ; Chotai, Silky ; Chambless, Lola B. ; Mistry, Akshitkumar ; Thompson, Reid C. ; Gusev, Yuriy ; Bhuvaneshwar, Krithika ; Sayah, Anousheh ; Bencheqroun, Camelia ; Belouali, Anas ; Madhavan, Subha ; Booth, Thomas C. ; Chelliah, Alysha ; Modat, Marc ; Shuaib, Haris ; Dragos, Carmen ; Abayazeed, Aly ; Kolodziej, Kenneth ; Hill, Michael ; Abbassy, Ahmed ; Gamal, Shady ; Mekhaimar, Mahmoud ; Qayati, Mohamed ; Reyes, Mauricio ; Park, Ji Eun ; Yun, Jihye ; Kim, Ho Sung ; Mahajan, Abhishek ; Muzi, Mark ; Benson, Sean ; Beets-Tan, Regina G. H. ; Teuwen, Jonas ; Herrera-Trujillo, Alejandro ; Trujillo, Maria ; Escobar, William ; Abello, Ana Lorena ; Bernal, Jose ; Gómez, Jhon ; Choi, Joseph ; Baek, Stephen ; Kim, Yusung ; Ismael, Heba ; Allen, Bryan ; Buatti, John M. ; Kotrotsou, Aikaterini ; Li, Hongwei ; Weiss, Tobias ; Weller, Michael ; Bink, Andrea ; Pouymayou, Bertrand ; Shaykh, Hassan F. ; Saltz, Joel ; Prasanna, Prateek ; Shrestha, Sampurna ; Mani, Kartik M. ; Payne, David ; Kurc, Tahsin ; Pelaez, Enrique ; Franco-Maldonado, Heydy ; Loayza, Francis ; Quevedo Sacoto, Andrés Sebastián ; Guevara, Pamela ; Torche, Esteban ; Mendoza, Cristobal ; Vera, Franco ; Ríos, Elvis ; López, Eduardo ; Velastin, Sergio Alejandro ; Ogbole, Godwin ; Soneye, Mayowa ; Oyekunle, Dotun ; Odafe-Oyibotha, Olubunmi ; Osobu, Babatunde ; Shu’aibu, Mustapha ; Dorcas, Adeleye ; Dako, Farouk ; Simpson, Amber L. ; Hamghalam, Mohammad ; Peoples, Jacob J. ; Hu, Ricky ; Tran, Anh ; Cutler, Danielle ; Moraes, Fabio Y. ; Boss, Michael A. ; Gimpel, James ; Kattil Veettil, Deepak ; Schmidt, Kendall ; Bialecki, Brian ; Marella, Sailaja ; Price, Cynthia ; Cimino, Lisa ; Apgar, Charles ; Shah, Prashant ; Menze, Bjoern Holger ; Barnholtz-Sloan, Jill S. ; Martin, Jason ; Bakas, Spyridon
Schaller-Paule, Martin A. ; Yalachkov, Yavor Vasilev ; Steinmetz, Helmuth ; Friedauer, Lucie ; Hattingen, Elke ; Miesbach, Wolfgang ; Weber, Frank ; Kirchmayr, Konstantin ; Schäfer, Jan Hendrik ; Förch, Christian
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Nanoplastics affect the inflammatory cytokine release by primary human monocytes and dendritic cells
(2022)
Weber, Annkatrin ; Schwiebs, Anja ; Solhaug, Helene ; Stenvik, Jørgen ; Nilsen, Asbjørn M. ; Wagner, Martin ; Relja, Borna ; Radeke, Heinfried H.
So far, the human health impacts of nano- and microplastics are poorly understood. Thus, we investigated whether nanoplastics exposure induces inflammatory processes in primary human monocytes and monocyte-derived dendritic cells. We exposed these cells in vitro to nanoplastics of different shapes (irregular vs. spherical), sizes (50–310 nm and polydisperse mixtures) and polymer types (polystyrene; polymethyl methacrylate; polyvinyl chloride, PVC) using concentrations of 30–300 particles cell−1. Our results show that irregular PVC particles induce the strongest cytokine release of these nanoplastics. Irregular polystyrene triggered a significantly higher pro-inflammatory response compared to spherical nanoplastics. The contribution of chemicals leaching from the particles was minor. The effects were concentration-dependent but varied markedly between cell donors. We conclude that nanoplastics exposure can provoke human immune cells to secrete cytokines as key initiators of inflammation. This response is specific to certain polymers (PVC) and particle shapes (fragments). Accordingly, nanoplastics cannot be considered one homogenous entity when assessing their health implications and the use of spherical polystyrene nanoplastics may underestimate their inflammatory effects.
Madrid-Gambin, Francisco ; Gomez-Gomez, Alex ; Busquets-Garcia, Arnau ; Haro, Noemí ; Marco, Santiago ; Mason, Natasha L. ; Reckweg, Johannes T. ; Mallaroni, Pablo ; Kloft, Lilian ; Oorsouw, Kim van ; Tönnes, Stefan W. ; Torre, Rafael de la ; Ramaekers, Johannes Gerardus ; Pozo, Oscar Jeśus
There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids.
Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output.
Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis.
In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
Yoval-Sánchez, Belem ; Ansari, Fariha ; James, Joel ; Niatsetskaya, Zoya ; Sosunov, Sergey ; Filipenko, Peter ; Tikhonova, Irina G. ; Ten, Vadim ; Wittig, Ilka ; Rafikov, Ruslan ; Galkin, Alexander
Pathologies associated with tissue ischemia/reperfusion (I/R) in highly metabolizing organs such as the brain and heart are leading causes of death and disability in humans. Molecular mechanisms underlying mitochondrial dysfunction during acute injury in I/R are tissue-specific, but their details are not completely understood. A metabolic shift and accumulation of substrates of reverse electron transfer (RET) such as succinate are observed in tissue ischemia, making mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase) the most vulnerable enzyme to the following reperfusion. It has been shown that brain complex I is predisposed to losing its flavin mononucleotide (FMN) cofactor when maintained in the reduced state in conditions of RET both in vitro and in vivo. Here we investigated the process of redox-dependent dissociation of FMN from mitochondrial complex I in brain and heart mitochondria. In contrast to the brain enzyme, cardiac complex I does not lose FMN when reduced in RET conditions. We proposed that the different kinetics of FMN loss during RET is due to the presence of brain-specific long 50 kDa isoform of the NDUFV3 subunit of complex I, which is absent in the heart where only the canonical 10 kDa short isoform is found. Our simulation studies suggest that the long NDUFV3 isoform can reach toward the FMN binding pocket and affect the nucleotide affinity to the apoenzyme. For the first time, we demonstrated a potential functional role of tissue-specific isoforms of complex I, providing the distinct molecular mechanism of I/R-induced mitochondrial impairment in cardiac and cerebral tissues. By combining functional studies of intact complex I and molecular structure simulations, we defined the critical difference between the brain and heart enzyme and suggested insights into the redox-dependent inactivation mechanisms of complex I during I/R injury in both tissues.
Patients with coronavirus disease 19 (COVID-19) commonly show abnormalities of liver tests (LTs) of undetermined cause. Considering drugs as tentative culprits, the current systematic review searched for published COVID-19 cases with suspected drug-induced liver injury (DILI) and established diagnosis using the diagnostic algorithm of RUCAM (Roussel Uclaf Causality Assessment Method). Data worldwide on DILI cases assessed by RUCAM in COVID-19 patients were sparse. A total of 6/200 reports with initially suspected 996 DILI cases in COVID-19 patients and using all RUCAM-based DILI cases allowed for a clear description of clinical features of RUCAM-based DILI cases among COVID-19 patients: (1) The updated RUCAM published in 2016 was equally often used as the original RUCAM of 1993, with both identifying DILI and other liver diseases as confounders; (2) RUCAM also worked well in patients treated with up to 18 drugs and provided for most DILI cases a probable or highly probable causality level for drugs; (3) DILI was preferentially caused by antiviral drugs given empirically due to their known therapeutic efficacy in other virus infections; (4) hepatocellular injury was more often reported than cholestatic or mixed injury; (5) maximum LT values were found for alanine aminotransferase (ALT) 1.541 U/L and aspartate aminotransferase (AST) 1.076 U/L; (6) the ALT/AST ratio was variable and ranged from 0.4 to 1.4; (7) the mean or median age of the COVID-19 patients with DILI ranged from 54.3 to 56 years; (8) the ratio of males to females was 1.8–3.4:1; (9) outcome was favorable for most patients, likely due to careful selection of the drugs and quick cessation of drug treatment with emerging DILI, but it was fatal in 19 patients; (10) countries reporting RUCAM-based DILI cases in COVID-19 patients included China, India, Japan, Montenegro, and Spain; (11) robust estimation of the percentage contribution of RUCAM-based DILI for the increased LTs in COVID-19 patients is outside of the current scope. In conclusion, RUCAM-based DILI with its clinical characteristics in COVID-19 patients and its classification as a confounding variable is now well defined, requiring a new correct description of COVID-19 features by removing DILI characteristics as confounders.