N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an  Major depressive disorder (MDD), characterized by increased negative affect (depressed mood) and reduced positive affect (anhedonia), is the most prevalent psychiatric disorder in the modern world . So far,N-methyl-D-aspartate receptor (NMDAR) antagonist, has demonstrated a rapid and sustained antidepressant-like effect with a single administration of sub-anesthetic dose in treatment-resistant (refers to an inadequate response of patient to at least two different antidepressants administered at adequate doses and duration) depressed patients. Although bearing such merits, the clinical application of ketamine as an antidepressant has been restricted due to its abuse potential and dissociation properties. A full understanding about the exact mechanisms of the antidepressant-like action of ketamine will provide invaluable insights on the neurobiology of depression, and foster the development of rapid-acting antidepressants without side effects -ketamine and (R)-ketamine. After administration, ketamine has been reported to exert anesthetic, analgesic, anti-inflammatory, and antidepressant effects. The anesthetic and analgesic properties of ketamine are generally attributed to direct inhibition of NMDARs, whereas the exact mechanism of its antidepressant-like action remains a hot issue under debate -ketamine or (R)-ketamine is firstly demethylated to (S)-norketamine or (R)-norketamine. (S)-norketamine is subsequently metabolized to -hydroxynorketamine (HNK) or (S)-dehydronorketamine (DHNK). Accordingly, (R)-norketamine is subsequently metabolized to - HNK or (R)- DHNK. (S)-ketamine and (R)-ketamine can also be metabolized into -hydroxyketamine (HK) and -HK, which are further transformed to -HNK and -HNK respectively -ketamine shows a greater potency and longer-lasting antidepressant-like effect than (S)-ketamine (esketamine) (S)-ketamine, but not (R)-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion and prepulse inhibition deficits  . In behadeficits . Early pdeficits . Interesdeficits   is associated with introspection. The salience network (SAL) processes salient information from external sources, and the central executive network (CEN) participates in working memory and attention. Studies have demonstrated an increase in the activity of the DMN and a decrease in SAL and the CEN in depressed patient. These alterations may increase the time patient spend in rumination or introspection, and impair their ability to deploy attentions to tasks that require responses to external stimuli .In healthy subjects, ketamine decreases functional connectivity of the DMN to the mPFC , thus maThese studies suggest that ketamine might exert its antidepressant-like effects by normalizing the PFC network activity and connectivity. Meanwhile, cortical electrophysiological measurement via non-invasive approaches may serve as a biomarker to evaluate the effectiveness of the antidepressant-like action of ketamine. However, more invasive methodologies on animal models are necessary to delineate the mechanism of ketamine’s antidepressant-like action at molecular level.via modulation of activity and plasticity in these neural circuitries. We will briefly discuss recent discoveries corroborating this hypothesis in the following paragraph.With the advancement of optogenetic and chemogenetic techniques, accumulating evidences indicate that several brain regions functionally connected with the PFC are highly involved with mood disorders including anxiety and depression. Ketamine may exert antidepressant-like effects Drd1-expressing pyramidal cells in the mPFC mimicked rapid and sustained antidepressant-like effects of ketamine in behavioral responses. On the contrary, local infusion of D1R antagonist, optogenetic inhibition and chemogenetic inhibition of Drd1-expressing pyramidal neurons in the mPFC abolished the antidepressant-like actions of systemic ketamine. Stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant-like effects of somatic stimulation in the mPFC  is necessary for the behavioral effects of ketamine, the authors suggested against a direct cell-autonomous regulation of VTA dopaminergic neurons by ketamine. Further experiments revealed that ketamine increased population activity in D1R-expressing pyramidal neurons in the mPFC . These nthe mPFC .To summarize, these studies suggest that several brain regions, including VTA, NAc, BLA, CeA, vHipp, DRN, LHb, PAG, and LS, are directed targeted by PFC afferents and are implicated in depressive-like behaviors, and these regions may employ adaptive changes by antidepressant dose of ketamine. Although it is generally acknowledged that ketamine increases the network activity and induces glutamate surge (will be discussed later) in the mPFC, optogenetic and chemogenetic activation of the downstream targets of the PFC leads to different behavioral outcomes (anxiolytic vs. anxiogenic) depending on the particular circuit investigated. How a unanimous excitation in the PFC, generated by systemic ketamine administration, is translated into distinct activity profiles in different brain regions receiving reciprocal projection from the PFC? Since the total behavioral outcome of ketamine administration is antidepressive-like, does is mean the activation of anxiolytic regions can dominate and successfully antagonize the activation of anxiogenic regions under the influence of ketamine? Or other mechanisms are also involved in remodeling the activity of brain network by ketamine? Answering these questions at neural circuit level will deepen our understanding about the etiology of depression.N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist  neurons in the mPFC abolishes the antidepressant-like effects of ketamine in behavioral animal models . Subanes2+ blockade and exposure of binding site for ketamine at NMDAR channel pore selectively  determine many important characteristics of the NMDARs, including channel open probability, single-channel conductance, pharmacological sensitivities, and deactivation rate. Channel blockade by extracellular Mgsubunits . ExpressStudies have indicated that GluN2A subunits are expressed preferentially at synaptic sites, whereas GluN2B subunits are expressed preferentially at extrasynaptic sites . Recentl2+ is much weaker for receptors containing GluN2C and GluN2D subunits  belongs to a small family of secreted proteins such as nerve growth factor, neurotrophin 3 and neurotrophin 4. BDNF-mediated signaling pathway is acknowledged as a key regulator of neural circuit development and activity-dependent processes, which include neuronal differentiation and growth, synapse formation and plasticity, and higher cognitive functions .BDNF gene specifically knockdown in the forebrain , which compromises BDNF processing and induces deficits in activity-dependent secretion of BDNF, failed to response to ketamine’s antidepressant-like action , and subsequent elevated intracellular cyclic adenosine monophosphate (cAMP) level. Increased cAMP level promotes phosphorylation of cAMP response element-binding protein (CREB), and subsequently upregulates BDNF expression in glia.The effect of augmentation of BDNF/TrkB signaling by ketamine may not be limited in neuron cells. For instance, in C6 glioma cells, ketamine translocates Gαtrations . KetaminIt has been hypothesized that spontaneous and evoked glutamatergic transmission are functionally segregated . At restEukaryotic elongation factor 2 kinase (eEF2K), also known as calmodulin-dependent protein kinase III, belongs to the atypical alpha-kinase family. The activity of eEF2K is regulated by intracellular concentration of calcium and calmodulin. The primary downstream substrate of eEF2K is eEF2, and eEF2 pathway plays an important role in regulation of protein synthesis, synaptic plasticity and memory consolidation . RestingA recent study also indicated that maintenance of basal level NMDAR function may be a key permissive factor required for the antidepressant-like effect of ketamine. Activation of NMDAR at rest (due to spontaneous/asynchronized vesicle release) and by glutamate surge  may lead to distinct responses in postsynaptic cells. Reelin is a glycoprotein of the extracellular matrix, and is involved with cell migration, synaptogenesis and neural network activity modulation . TransgeWith a ubiquitously expression pattern in eukaryotic cell types, mechanistic target of rapamycin (mTOR) is a large (259 kDa), highly conserved, serine/threonine kinase which belongs to the phosphoinositide 3-kinase-related kinase family . mTOR siIt has been documented that the antidepressant-like action of ketamine require activation of the mTORC1 signaling pathway . Ketaminvia an mTOR-dependent mechanism . Blockade of NMDARs by ketamine may augment the mTOR signaling pathway by stabilizing Rheb and subsequently activating mTOR signaling pathway (mTORC1 participates in cap-dependent initiation of mRNA translation via its downstream target 4E-BPs . Followi pathway .Accumulating evidences have demonstrated an interaction between BDNF/TrkB and mTOR pathways in regulating synaptic plasticity. Activation of phosphatidylinositol 3 kinase (PI3K) by BDNF/TrkB induces translocation of Akt (protein kinase B) to plasma membrane . AlternaGlycogen synthase kinase-3 (GSK3) is a master switch serine-threonine kinase implicated in major depressive disorder . GSK3 isInhibition of GSK3 by subanesthetic dose of ketamine is necessary for the rapid antidepressant-like action of ketamine. Knock-in mice carrying a constitutively active GSK3 are completely resistant to ketamine’s antidepressant-like action as measured by animal model of learned helplessness. Furthermore, acute administration of a high dose of lithium, a GSK3 inhibitor, produces antidepressant-like effect comparable to that of ketamine . The inhIn depressed patients, decreased volume of hippocampus and the prefrontal cortex (PFC)  are documented. Atrophy of principle neurons in these regions is reversible with successful treatment or discontinuation of stress exposure . This phKetamine administration increased the levels of the postsynaptic proteins PSD95 and GluR1, as well as the presynaptic protein synapsin I in the PFC of rats . These eRecently, studies have provided some clues regarding the time course of neural structural remodeling triggered by ketamine. Within 2 h of administration, ketamine rapidly enhances the potential of activity-dependent synaptogenesis in the mPFC, and this effect precedes changes in spine density . Within Collectively, these evidences raise a possible scenario in which, initially after administration, ketamine enhances glutamate-evoked synaptic plasticity, which may lead to a transient and labile spinogenesis process. Subsequently, ketamine increases spine density by stabilizing newly generated spinogenesis and preventing stress-induced spine elimination simultaneously, thus exerting prolonged antidepressant-like effects.α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are one type of the principle ionotropic transmembrane receptors responsible for fast synaptic neurotransmission at glutamatergic excitatory terminals . StudiesGluA2 gene, and ketamine-induced AMPAR-dependent synaptic potentiation of Schaffer collateral-CA1 synapses in hippocampal slices is abolished in GluA2 knockout animals -HNK, are the major HNK metabolites found in human plasma and in rodent plasma and brain -HNK do not -HNK metabolites, particularly the -HNK stereoisomer, were found effective in inducing antidepressant-like behavioral and cellular responses in mice -HNK only partially impaired NMDAR-miniature excitatory postsynaptic currents (mEPSCs) -HNK to displace NMDAR antagonist MK-801 is low. Since ketamine is a well-documented NMDAR blocker, this phenomenon leads to the hypothesis that -HNK may exert antidepressant-like effect via mechanisms independent of NMDAR inhibition  , and thehibition .R,6R)-HNK has been found to produce robust synaptic potentiation of excitatory synaptic transmission in hippocampal slices -HNK selectively enhances excitatory synaptic transmission in the CA1 region of hippocampus through a concentration-dependent increase in glutamate release probability. -HNK also increases synchronized high-frequency gamma oscillations, an in vivo marker of AMPAR-dependent neuronal excitation -HNK was not mediated by NMDAR inhibition -HNK induced presynaptic potentiation persists in the presence of tetrodotoxin (TTX) -HNK induced presynaptic potentiation.At concentrations associated with antidepressant-like effect, (2l slices . Using pcitation . Importahibition . This cohibition . Interesin (TTX) , indicatR,6R)-HNK reversed the diminished glutamate transmission and surface GluA1 expression -HNK increased the frequency and amplitude of mEPSCs in the vlPAG -HNK impaired LTP and depressed AMPAR-mediated responses in the NAc, whereas NMDAR-mediated transmission in dopaminergic neurons in VTA remained unchanged -HNK caused a rapid and persistent potentiation of AMPAR-mediated fEPSPs in Schaffer collateral terminals in CA1 of hippocampal slices in rats -HNK attenuated AMPAR-mediated large-amplitude bursts in CA3 of hippocampal slices . A single systemic injection of -HNK-induced AMPAR activation may lead to subsequent activation of plasticity- or synaptogenesis-relevant signaling cascades, such as BDNF/TrkB, eEF2, and mTORC1 pathways. These intracellular signaling pathways may also be recruited by ketamine, suggesting a partially overlapping mechanism of antidepressant-like action between ketamine and its metabolite -HNK.At postsynaptic neurons, -HNK into the mPFC induces a rapid and long-lasting antidepressant-like effects in behavioral tests in mice. The antidepressant-like action of -HNK is blocked in transgenic mice carrying knockin of the BDNF Val66Met allele which compromises the processing and activity-dependent release of mature BDNF. The antidepressant-like action of -HNK is also abolished by anti-BDNF neutralizing antibody, or pharmacological inhibition of the components in the BDNF/TrkB signaling pathway such as L-type voltage-dependent Ca2+ channels (VDCCs), TrkB, and mTORC1 -HNK enhances BDNF/TrkB signaling by directly binding to TrkB -HNK. In contrast to ketamine, the lack of robust NMDAR inhibition by -HNK may underlie its lower adverse effect and abuse potential. This mechanism might be exploited for the development of novel antidepressants without side effects.Collectively, these results indicate the modulation of AMPAR-mediated glutamate transmission as a possible mechanism mediating the antidepressant-like effects of  as a key consolidating factor for the prolonged antidepressant-like effect of ketamine. Mice carrying a MeCP2 mutation abolished the persistant antidepressant-like action of ketamine, leaving its rapid antidepressant-like action intact . MeCP2 i2R,6R)-HNK, when combined with other potential antidepressants, may exert synergistic effects by converging on certain pivotal intracellular processes. For instance, Glu2/3 receptor antagonists have been reported to increase glutamate release at excitatory terminals, mimicking the reported action of -HNK -HNK . AMPAR a,6R)-HNK . These signaling . In anotignaling . On the Structural analysis has negated a direct binding between ketamine and AMPARs at antidepressant relevant concentration . The exaIn this review, we mainly discussed investigations conducted in the PFC and hippocampus. However, other brain regions, such as VTA, NAc, PAG, thalamus, LHb, amygdala, have also been acknowledged to be implicated in depression. These regions have been reported to be reciprocally connected with the PFC. The heterogeneous connectivity within and among different nuclei may lead to their distinct responses to ketamine, thus adding another layer of complexity regarding the influence of ketamine. This possibility may be explored by combining pharmacological approach with optogenetic and chemogenetic tools at neural circuit level.Here, we briefly mention several hypothesized mechanisms not covered in this review, these may function synergistically with the aforementioned mechanisms in mediating the antidepressant-like action of ketamine. Strict scrutinizes of these mechanisms may deepen our understanding about the etiology and pathophysiology of depression, and help translating mechanistic insights into clinical applications. Readers are encouraged to refer to some excellent reviews  for a moBesides depression, ketamine induced synaptic plasticity and structural remodeling might be potentially beneficial for the treatment of other psychiatric disorders or neurological diseases, featured by altered connectivity and network function in the central nervous system. These diseases may include schizophrenia, bipolar disorder, anxiety, post-traumatic stress disorder (PTSD), neurodevelopmental disorder, cognitive decline and Alzheimer’s diseases.The discovery of ketamine as a potential antidepressant with a rapid onset and sustained antidepressant-like actions revolutionized the concept about pharmacological interventions on depression. A full revealing of the underlying mechanisms of ketamine’s antidepressant-like actions precisely at molecular, cellular and neural circuit level, will not only deepen our understanding on the neurobiology of major depression, but may also expedite identification of potential therapeutic targets for the development of novel rapid-onset antidepressant drugs with favorable safety profile, sustained effects, and lacking undesired side effects.


Remdesivir (RDV) is an intravenous antiviral with activity against SARS-CoV-2 for treatment of hospitalized COVID-19 patients with moderate-to-severe disease. Biomarkers associated with clinical outcomes have been identified for COVID-19, but few evaluated in context of antiviral treatment. Here, we assessed baseline  biomarkers and the impact of RDV treatment on longitudinal biomarker readouts.Recently, RDV was evaluated in high-risk, non-hospitalized patients with confirmed SARS-CoV-2 infection and was highly effective at preventing disease progression. The randomized, double-blind, placebo-controlled Phase 3 study included 562 participants who received at least 1 dose of study drug, of which 312 consented for longitudinal biomarker assessments at baseline, day 3, and day 14. We assessed sixteen baseline biomarkers and the impact of RDV treatment on longitudinal biomarker readouts.Six well-known, inflammation-associated biomarkers are elevated at baseline in participants meeting the primary endpoint of hospitalization or death by day 28. Moreover, in comparison to placebo, biomarkers in RDV-treated participants show accelerated improvement, including reduction of soluble angiopoietin-2, D-dimer, and neutrophil-to-lymphocyte ratio, as well as an increase in lymphocyte counts.Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection. These findings have implications for better understanding the activity of antiviral treatments in COVID-19. Certain cells and proteins in the blood can act as markers of COVID-19 severity. However, little is known about the impact of antiviral treatments on these markers. Here, we measured protein and cell markers in patient samples before treatment and those taken during the course of COVID-19 in high-risk non-hospitalized patients treated with or without the antiviral remdesivir (RDV). Several markers were improved with RDV treatment, including those associated with normal responses from the immune system and factors involved in blood clotting. These findings further our understanding of the activity of antivirals in COVID-19 and inform future studies to understand how patients with an increased risk of COVID-19 disease progression respond to these treatments. Pan et al. determine the impact of the antiviral remdesivir (RDV) on biomarkers associated with clinical outcomes, within a randomized, double-blind, placebo-controlled phase 3 study (PINETREE). They demonstrate that RDV-treated patients have an accelerated reduction in soluble angiopoietin-2, D-dimer and neutrophil-to-lymphocyte ratios. In an analysis of more than 1.3 million laboratory-confirmed SARS-CoV-2 infections that were reported in the United States between January and May 2020, 14% of patients required hospitalization, 2% were admitted to the intensive care unit, and 5% died2. The probability of severe COVID-19 is higher in those with pre-existing medical conditions and people ≥60 years old. Men have also been shown to be at higher risk than women for severe outcomes and death, independent of age3.Coronavirus 2019 disease (COVID-19) was first identified in December 2019 and rapidly progressed into a global pandemic that continues to be a major public health concern worldwide. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus belonging to the Coronaviridae family4. Hematologic biomarkers that correlate with COVID-19 severity have also been identified; for example, lymphopenia has been consistently associated with worse clinical outcomes5.Laboratory biomarkers have been identified during the COVID-19 pandemic to inform risk of disease progression and provide information about disease pathogenesis. Early studies described vascular pathology underlying organ damage in severely ill patients, which is associated with higher levels of inflammatory factors, complement activation, and pro-inflammatory mediators in circulation7. RDV has demonstrated clinical benefit in COVID-19 patients hospitalized with moderate-to-severe disease9. A recent phase 3 clinical trial in non-hospitalized patients with COVID-19 who were at high risk of severe disease further demonstrated that a 3-day course of RDV resulted in an 87% lower risk of hospitalization or death compared to placebo (PINETREE study)10. In this study, we investigate biomarkers associated with clinical outcomes for COVID-19 and the impact of RDV treatment on longitudinal biomarker readouts. Overall, the findings suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection.Remdesivir (RDV) is a nucleotide prodrug that binds to the viral RNA-dependent RNA polymerase and inhibits SARS-CoV-2 viral replication through premature termination of RNA transcription10. The trial was approved by the institutional review board or ethics committee at each site and was conducted in compliance with the Declaration of Helsinki Good Clinical Practice guidelines and local regulations. The names of the IRBs who approved the study are available in Supplementary Data NCT04501952).The PINETREE study was a randomized, double-blind, placebo-controlled Phase 3 clinical trial conducted at sixty-four outpatient centers and skilled nursing facilities12. Analysis of biomarker data was prespecified and conducted at study completion.Serum and plasma samples were obtained at baseline, day 3 (on-treatment) and day 14 (post-treatment) in 312 participants of the PINETREE study that consented for optional evaluation of COVID-19 biomarkers. Biomarker analyses included the following: soluble Angiopoietin 2 (sAng2), interleukin (IL)-6, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin (PCT), activated partial thromboplastin time (aPTT), International Normalized Ratio (INR), prothrombin time (PT), D-Dimer, fibrinogen, eosinophil counts, lymphocyte counts, monocyte counts, and neutrophils counts. All biomarkers were measured at Covance Laboratory Services (Labcorp) using standard laboratory assays and Labcorp provided normal ranges for ferritin, LDH, CRP, aPTT, PT, fibrinogen, eosinophil counts, lymphocyte counts, monocyte counts, and neutrophils countsTo determine if there were significant changes in biomarker values between baseline day 1) and post-treatment time points (day 3 or 14) we used a linear mixed effects model (LMM) including age and sex as fixed effect covariates , day 3, and day 14 Fig. . Among tn = 2, Placebo: n = 4), biomarker values at baseline were evaluated using a Wilcoxon rank-sum test comparing patients who met the primary endpoint to those who did not. Six well-established biomarkers associated with inflammation were significantly elevated (FDR < 0.05) in patients who met the primary endpoint  in those who met the primary endpoint, while eosinophil counts were nominally decreased  timepoints Fig. . Since oint Fig. . Fibrino15. In line with these previous findings, CRP was measured above the normal range at baseline, however, there was no significant difference in any biomarkers between treatment arms at baseline , and prothrombin time   in RDV- vs. placebo-treated patients  have been associated with more severe COVID-1916. This may result in concurrent improvement of inflammation, coagulation, and hematologic biomarkers associated with progression to more severe COVID-19. Our analysis demonstrated that RDV treatment may lead to more rapid normalization of several biomarkers  associated with COVID-19 severity by day 14, including sAng2, ferritin, LDH, D-dimer, INR, PT, and lymphocyte count. The most prominent differences between RDV- and placebo-treated patients were observed in D-dimer, which was markedly elevated at day 14 in placebo-treated patients in contrast to reversion to baseline in RDV-treated patients, and lymphocyte count, which was elevated in RDV- versus placebo-treated patients at day 3. Previous studies have shown that progression of COVID-19 severity to intensive care unit admission may be predicted by lymphopenia and/or elevated D-dimer levels upon hospital admission17.With direct inhibition of the SARS-CoV-2 polymerase, RDV treatment should reduce viral load and therefore also the corresponding inflammatory response to infection20. Continued analysis of these biomarkers, as well as additional biomarkers of COVID-19 progression, in the same high-risk outpatient population will be needed to confirm these observations in larger cohorts of patients. Future studies may help further our understanding of the predictive value of these biomarkers, which could prove invaluable in identifying outpatients at increased risk of disease progression who may benefit most from early treatment. Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection.Our analysis is limited by the number of patients with biomarker data reaching the primary endpoint. The reduced numbers and the fact that there were only six patients who had a hospitalization or death by day 28 led us to perform a simple rank-based statistical analysis instead of a prognostic modeling approach. Analysis of baseline samples suggests that sAng2, CRP, ferritin, IL−6, LDH, and procalcitonin (PCT) were elevated in study participants with worse outcomes independent of treatment assignment, which is consistent with previously reported associations of baseline inflammatory biomarkers and COVID-19 severityDescription of Additional Supplementary FilesSupplementary InformationSupplementary Data 1Peer Review FileReporting Summary


The Coronavirus Disease 2019 (COVID-19) showed worse prognosis and higher mortality in individuals with obesity. Dyslipidemia is a major link between obesity and COVID-19 severity. Statins as the most common lipid regulating drugs have shown favorable effects in various pathophysiological states. Importantly, accumulating observational studies have suggested that statin use is associated with reduced risk of progressing to severe illness and in-hospital death in COVID-19 patients. Possible explanations underlie these protective impacts include their abilities of reducing cholesterol, suppressing viral entry and replication, anti-inflammation and immunomodulatory effects, as well as anti-thrombosis and anti-oxidative properties. Despite these benefits, statin therapies have side effects that should be considered, such as elevated creatinine kinase, liver enzyme and serum glucose levels, which are already elevated in severe COVID-19. Concerns are also raised whether statins interfere with the efficacy of COVID-19 vaccines. Randomized controlled trials are being conducted worldwide to confirm the values of statin use for COVID-19 treatment. Generally, the results suggest no necessity to discontinue statin use, and no evidence suggesting interference between statins and COVID-19 vaccines. However, concomitant administration of statins and COVID-19 antiviral drug Paxlovid may increase statin exposure and the risk of adverse effects, because most statins are metabolized mainly through CYP3A4 which is potently inhibited by ritonavir, a major component of Paxlovid. Therefore, more clinical/preclinical studies are still warranted to understand the benefits, harms and mechanisms of statin use in the context of COVID-19. Obese individuals are more vulnerable to the SARS-CoV-2 caused Coronavirus Disease 2019 (COVID-19) . Obese pPrevalence of dyslipidemia was 18–39.7% as a comorbid condition in hospitalized COVID-19 patients –15. A poStatins are the most commonly used lipid-regulating drugs, 145.8 million people used statins in 2018 –23. StruObservational studies have suggested protective effects of statins in COVID-19 patients. Statin use was associated with a 55% decreased risk for IMV , 22–30% Different SARS-CoV-2 variants cause resurges of infections –60. VaccHere, we provide a comprehensive update of the values, possible mechanisms, and noteworthy cautions regarding statin use in COVID-19. This review was conducted by consulting resources from peer-reviewed articles and/or official websites like WHO. Common search terms included “COVID-19 OR SARS-CoV-2” AND “statin OR lipid lowering”, etc.As effective drugs for reducing cholesterol, statins can prevent cardiovascular events which are key risk factors for COVID-19 infection and poor prognosis –69. CholSARS-CoV-2 infection initiates from cell entry by attaching to its receptor ACE2 , 71. Thevia passive transport to reach higher intracellular concentrations  and activates two main downstream pathways, MyD88- and TRIF-dependent pathways, both leading to NF-κB activation , oxidized low-density lipoprotein (oxLDL) and its receptor CD36  which improves production of platelet nitric oxide (NO), a potent inhibitor of platelet activation and aggregation  is associated with high neutrophil to lymphocyte ratio in critically ill COVID-19 . In monoStatins exerts anti-oxidative effect by attenuating NF-κB activation, reducing circulating oxLDL and their uptake by macrophages, inhibiting oxidant enzymes such as NADPH oxidase and myeloperoxidase, and upregulating the activity of antioxidant enzymes like catalase and paraoxonase , 150. AdCurrently, among clinical trials regarding statin use and COVID-19, two have published results, while the others remain uncompleted or have not posted results . In INSPAlthough statins are generally well-tolerated, for COVID-19 patients especially those with obese or chronic statin use, cautions are required for potential risks of statins-associated muscle symptoms, liver injury, new-onset diabetes, renal injury, and neurological and neurocognitive disorders, which may also result from severe COVID-19 , 156 Fi.Statin-associated muscular symptoms (SAMS) are principal cause of poor patient compliance that contribute to adverse outcomes , 158. SAStatins-associated hepatotoxicity may add to COVID-19 related liver injury that potentially caused by psychological stress, systemic inflammation, etc., especially among obese individuals at higher risk of liver dysfunction –163. It COVID-19 may induce or accelerate type 2 diabetes mellitus (T2DM) development as one of its acute and suspected long-term complications , while sClinicians should also be cautious when treating statin users with COVID-19 who show renal or neurological symptoms and relevant laboratory abnormalities. Renal dysfunction can be caused by SARS-CoV-2 infection and is associated with COVID-19 poor prognosis –169; wheCaution is also necessary for drug interaction during COVID-19 management. Most statins are predominantly metabolized by CYP450 enzymes, mainly through CYP3A4 . TherefoThe impact of statins on vaccine efficacy remain controversy. Take influenza vaccine for example, a clinical trial suggested immunosuppressive effect of chronic statin medication may weaken the immune response to vaccine , whereasSARS-CoV-2 variants may have substantial immune evasiveness that weakens vaccine protection due to spike protein mutations –60. SmalProper type of statin. Compared to hydrophilic statins, lipophilic statins enter cells via passive transport to reach higher intracellular concentrations, and have a larger distribution volume, thus may be more protective in respect of anti-viral ability. Intensity of statin therapy. Hypolipidemia is harmful. Decreased LDL-C is observed in some COVID-19 patients and associated with COVID-19 severity , the China Postdoctoral Science Foundation (2021M700050), the Natural Science Foundation of Hubei Province (2021CFA004 and 2021CFB250), and the Postdoctoral Innovation Research Program of Hubei Province.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Multiple randomized controlled trials (RCTs) evaluating the Transitional Care Model (TCM)- an advanced practice registered nurse-led (APRN), team-based, care management strategy- have shown improved outcomes for older adults transitioning from hospital to home. In the current RCT, enrollment of older adults hospitalized with heart failure, chronic obstructive pulmonary disease, or pneumonia began in February 2020, just as the COVID-19 pandemic developed across the U.S. The COVID-19 pandemic dramatically impacted healthcare delivery across diverse local contexts. This parallel convergent mixed methods study aimed to explore the implementation of the TCM intervention as intended during Year 2 of the RCT (February 2021 to January 2022). This mixed-methods analysis presents the challenges and strategies to a key TCM component, “hospital-to-home,” which focuses on delivering in-person visits to patients, as identified through a qualitative descriptive analysis of 63 clinical team and leadership meetings combined with implementation fidelity data collected simultaneously on 188 TCM participants. In Year 2 of the trial, COVID-19-specific challenges continued, including COVID-19 exposure, policy changes, patients declining services, and limited safety equipment. Some challenges to the hospital-to-home TCM component occurred regardless of COVID-19, including patient , nurse provider , and system  barriers. Collectively, these challenges resulted in lower fidelity to APRNs visit patterns during TCM delivery. Strategies to address these challenges were identified. The findings provide critical insight into how to target quality improvement strategies to improve the delivery of services, such as the TCM, from hospital to home settings.


Target modulation of the AhR for inflammatory gastrointestinal (GI) conditions holds great promise but also the potential for safety liabilities both within and beyond the GI tract. The ubiquitous expression of the AhR across mammalian tissues coupled with its role in diverse signaling pathways makes development of a “clean” AhR therapeutically challenging. Ligand promiscuity and diversity in context-specific AhR activation further complicates targeting the AhR for drug development due to limitations surrounding clinical translatability. Despite these concerns, several approaches to target the AhR have been explored such as small molecules, microbials, PROTACs, and oligonucleotide-based approaches. These various chemical modalities are not without safety liabilities and require unique de-risking strategies to parse out toxicities. Collectively, these programs can benefit from in silico and in vitro methodologies that investigate specific AhR pathway activation and have the potential to implement thresholding parameters to categorize AhR ligands as “high” or “low” risk for sustained AhR activation. Exploration into transcriptomic signatures for AhR safety assessment, incorporation of physiologically-relevant in vitro model systems, and investigation into chronic activation of the AhR by structurally diverse ligands will help address gaps in our understanding regarding AhR-dependent toxicities. Here, we review the role of the AhR within the GI tract, novel therapeutic modality approaches to target the AhR, key AhR-dependent safety liabilities, and relevant strategies that can be implemented to address drug safety concerns. Together, this review discusses the emerging therapeutic landscape of modalities targeting the AhR for inflammatory GI indications and offers a safety roadmap for AhR drug development. Dysfunctional response of the immune system to environmental or dietary triggers can result in chronic inflammatory disorders of the gastrointestinal (GI) tract. For prevalent inflammatory GI diseases, such as inflammatory bowel disease (IBD) (including Crohn’s disease (CD) and ulcerative colitis (UC)), alterations in microbiota, exogenous or endogenous factors, and/or pathogenic infection within the gut microbiome influences immune function and potentiation of inflammation. Deficiency in mucosal immunity across epithelial, immune, and mucosal layers promotes intestinal permeability, or a “leaky gut”, which exacerbates inflammatory phenotypes and further decreases barrier defense. Identification of molecular targets and/or pathways that can restore barrier function and alleviate overt inflammatory signaling can aid in restoring tissue homeostasis within the gut microenvironment.p-dioxin (TCDD))-dependent toxicities [−/−) studies revealed a beneficial role for the AhR in regulation of innate and adaptive immunity within the gut [−/− mice demonstrated diminished protection from immune-mediated barrier damage and/or permeability  [CREAhRfl/fl) supported ligand- and AhR-dependent regulation of crypt intestinal stem cell differentiation, IEC regeneration, inhibition of pro-inflammatory signaling, and preservation of barrier integrity, while addition of Citrobacter rodentium to IEC-specific AhR−/− resulted in dysregulation of intestinal stem cell proliferation, differentiation, and subsequent increased tumor burden relative to wild-type mice [The aryl hydrocarbon receptor (AhR) is a ligand-activated basic helix-loop-helix (bHLH)-Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (PAS)-containing transcription factor that acts as a xenosensor for detection of diverse metabolic, environmental, and dietary stimuli to regulate ligand-, cell-, and tissue-specific physiological, and/or toxicological effects. While initial interest in the AhR and AhR-dependent signaling focused on understanding distinct AhR-dependent molecular mechanisms driving a spectrum of dioxin-like compound (DLC)  ,5,6, alty tract) ,10 relatype mice . Exogenoype mice . Notablyype mice , and synype mice . TogetheThe specific AhR ligand used, cell type, or tissue involved, and spectrum of cytokines/chemokines modulated can influence AhR-dependent promotion or suppression of inflammation. This further confounds whether a given therapeutic modulator will induce AhR-dependent toxicological or physiological gene batteries and downstream effects. Therapeutic modulation of the AhR faces complex challenges that need to be addressed including (i) broad expression patterns across mammalian organ systems, (ii) development and regulation of immune cell populations that both confer and oppose tissue- and organ-specific autoimmunity, and (iii) limited understanding of the distinct underlying mechanisms of AhR-dependent beneficial or toxicological gene expression. AhR ligand-dependent and ligand-independent signal transduction pathways can have varied dimerization partners ,16 , and oligonucleotides have been explored to selectively target the promiscuous AhR and/or AhR signaling. In addition to developing a better understanding of the mechanism(s) of action for these new therapeutic modalities, thorough examination of modality-specific and AhR-dependent safety liabilities are necessary. Here, we highlight the role of the AhR in gut immunity, explore the current therapeutic landscape of new modality approaches targeting the AhR, and discuss safety liabilities and de-risking strategies that need to be considered before researchers can pharmacologically modulate the AhR with confidence for inflammatory GI diseases and disorders. Within the GI tract, AhR ligands can originate from several sources , activate the AhR, and mediate downstream modulation of local inflammation through induction of diverse gene batteries within multiple intestinal cell types. h17) cells, which play a key role in balancing physiological functions and pathophysiological pathways by secreting Th17 cytokines involved in autoimmune tissue inflammation and diseases following secretion of cytokines. Ligand-dependent activation of AhR can promote the differentiation of the immunosuppressive regulatory T cells (FoxP3+) [+Tr1) [h22 cells to regulate highly proliferative tissues involved in reproduction and health of IEC. AhR signaling controls differentiation of distinct T cell populations and functional activities of antigen-presenting cells by driving tolerogenic CD103 dendritic cells to maintain immune homeostasis within the gut. Overall, the AhR is highly expressed across epithelial and immune cells within the gut and is responsible for regulation of diverse inflammatory pathways.IECs comprise the mucosal barrier and regulate critical physiological functions such as nutrient absorption, metabolism, secretion, permeability, and mucosal healing necessary to regenerate the intestinal epithelial barrier following injury. Following AhR activation, IECs maintain tight junctions necessary to limit leaky barriers and mucosal atrophy. Among intestinal immune cells, the AhR plays an important role in maintenance, generation, and differentiation of innate and adaptive immune subtypes. Intraepithelial lymphocytes (IELs) are responsible for gut mucosal barrier integrity and maintenance of these T cells depends on AhR activation. AhR-dependent regulation of anti-inflammatory signaling has been shown in IELs to confer protection from pathogenic insult and injury within the gut . AhR con(FoxP3+) , as well) [+Tr1) , which d) [+Tr1) , experim) [+Tr1) , or spon) [+Tr1) . AhR actHigh expression of the AhR within intestinal epithelial and immune cells coupled with its role as a prominent transcription factor involved in adaptive and innate immune signaling makes the AhR a desirable immuno-modulatory target for promotion of mucosal healing and maintenance of barrier integrity for patients. Utilizing Cortellis Drug Discovery Intelligence  to conduThe AhR is widely acknowledged to be a promiscuous xenosensor for structurally diverse small molecules and physicochemical properties influence AhR binding affinity and level of activation  Figure A. This sMultiple AhR agonists have been tested in inflammatory bowel disease clinical trials that were originally derived from traditional medicines. Structurally, each of these agents resemble indole-derived metabolites or contain polyaromatic groups. Indole and indirubin are potent AhR agonists found in traditional medicine known as Inidigo naturalais (IN) or qing-dai ,26. IN iDifficulties relating to low activity, poor pharmacokinetic profile, post-translational modifications, and off-target effects have limited small molecule AhR therapeutic efficacy ,31,32. WSeveral AhR ligands derived from the diet and/or gut microbiota metabolism have been identified to play a role in gut homeostasis and inflammation. Studies evaluating phytochemicals and plant extracts ), microbial-derived short chain fatty acids  , and TrpGut dysbiosis and reduction in host- and microbial-derived AhR ligands can drive altered microbiota surveillance and immunoregulatory responses culminating in impaired mucosal immunity and increased severity in patients with IBD; however, several gut microbiota-derived metabolites have been identified to confer a protective role in gut immunity and offer potential therapeutic promise. Perhaps the most widely studied commensal microbiota-dependent metabolites are derived from the essential amino acid tryptophan, and collectively, Trp metabolites have been shown to play an AhR-dependent protective role in gut immunity. Fewer endogenous Trp metabolites are produced by intestinal microbiota under pathogenic conditions relative to those produced within homeostatic microenvironments. In fact, fecal microbiota analysis confirmed reduced AhR ligand production and AhR activation within stool from celiac patients compared to normal patients , and a nIn contrast to dietary- and gut microbe-derived AhR ligands that mediate intestinal homeostasis, oxazalone has been shown to induce AhR-dependent colitis following downregulation of anti-inflammatory factors  in mouse models . FurtherLactobacillus reuteri can metabolize Trp to indole-3-aldehyde and can drive AhR-mediated transcription of Il-22 leading to balanced mucosal response [−/− mice, GUT-108 colonization helped correct dysbiosis via modulation of AhR pathway genes [Treatment with AhR activators is an attractive therapeutic strategy in GI inflammatory conditions. Fecal microbiota transplantation (FMT) is one therapeutic approach that relies on large amounts of intestinal microbiota transferred from prescreened healthy donors to the GI tract of recipients to help correct a dysbiosis condition. FMT alleviates DSS-induced colitis in mice through increasing the secretion of anti-inflammatory cytokines by activating AhR signaling . Alternaresponse . Live biay genes . Furtheray genes .For microbial, probiotic, and LBP safety assessment, correct strain identification is critical to determine the AhR activation potential. Additional safety components that have been assessed in a de-risking strategy include screening for genetic factors that predispose patients to increased disease severity  polymorphism ,69,70), Two decades ago, Ray Deshaies, Crews, and colleagues  demonstrA possibility of AhR-PROTAC was originally hypothesized by Kim, Swanson, and colleagues ,83. TheyAhR ubiquitin complex made-up of CUL4B, damaged-DNA-binding protein 1 (DDB1), ARNT and transducin-b-like 3 (TBL3) together with RBX1 (ROC1). Ligand-dependent activation of AhR was required to act as a substrate-specific adaptor component of the CUL4BAhR complex to promote ER-α and androgen receptor (AR) degradation via 26S proteosome. Since degradation of a substrate is an event-driven phenomenon, a ligand bound AhR:E3 ligase complex may continue to recruit new substrates until the AhR agonist is metabolized or can no longer maintain an active AhR:ligase complex , small-interfering RNAs (siRNA), microRNA (miRNA), and aptamers. At the time of this review, there are 10 approved therapies across the United States, Europe, and Japan and their target tissues include the central nervous system, muscle, liver, eye, and immune cells . This clRecent efforts have focused on the therapeutic development of ASOs and siRNA which can alter expression of target genes involved in the progression and disease development of IBD . PrimaryMiR-124 has been implicated in induction of intestinal inflammation through the inhibition of the AhR; therefore, initiating key events in the pathogenesis of Crohn’s disease [miR-429 expression in a colitis mouse model. This resulted in an upregulation of Occludin expression, a key transmembrane protein, consequently mitigating intestinal epithelial barrier defects in an AhR-dependent manner [h17 cells and downregulation of Il-10-producing T cells [miR-590-5p, miR-19b, and miR-876-5p) have been identified that promote intestinal homeostasis and modulation of these precursors offers a novel approach to reduce intestinal inflammation [miR-7267-3P) that alter microbial metabolism of AhR ligands  and drive downstream Il-22 production and amelioration of colitis [Identification of molecular targets can be difficult due to the number of genes involved in the gut inflammation response. One immunological target that has yet to be evaluated as an efficacious treatment option is the AhR. Based on the role of AhR in intestinal homeostasis, it is plausible that the AhR or AhR signaling pathway may be a potential target for GI disease treatment. Further, expanding ASO target molecules to include the AhR would take advantage of the ability of ASO to achieve selectivity and to regulate transcriptionally instead of through ligand activation. MiRNA offer an alternative therapeutic target in IBD due to their involvement in epithelial barrier disruption and dysregulation of the immune system. Target modulation of miRNA precursors also represents a novel approach for various inflammatory GI conditions . MiR-124 disease  , heat shock protein 90 (HSP90), and HBV X-associated protein-2 (XAP-2))  in the cEarly de-risking strategies should focus on delineating whether a therapeutic compound activates the AhR through the canonical pathway as a first step in hazard identification . MeasureCYP1A1 induction can identify a novel AhR agonist [CYP1A1/1A2 induction levels, metabolite profile, along with assessment of cell proliferation biomarkers, can also aid to de-risk potential carcinogenicity liabilities and develop improved SAR within the early discovery toxicology space [Many small molecules and candidate endogenous ligands contain indole structures that have demonstrated strong species specificity for the human AhR relative to murine AhRs ,155,156. agonist , and eva agonist . Ultimat agonist . Prioritgy space . UtiliziSustained AhR activation by DLCs and subsequent AhR-dependent gene expression is associated with diverse organ- and tissue-specific toxicities; however, continuous AhR activation by nongenotoxic compounds and/or transient/oscillatory activators, such as Trp metabolites, can also result in activation of AhR-dependent gene expression batteries that will potentiate target organ toxicities. Steps have been taken to establish thresholds for AhR-dependent toxicity based on known physicochemical properties and structure ), which has aided in assessing AhR activation associated with dioxin-like toxicity as an approach for risk assessment; however, this system fails to predict interspecies sensitivities and is not applicable to structurally diverse ligands . WhetherCyp1a1 and Cyp1a2) within 4-day rodent studies. Thresholds for carcinogen and non-carcinogen AhR activation were selected based on weighted average of Log10Cyp1a1 and Cyp1a2 induction at different time points. This approach enabled categorization of compounds as high or low concern for AhR-dependent carcinogenicity and demonstrated low concern compounds lacked sustained AhR activation with continued dosing [Cyp1a1, Cyp1a2, NAD(P)H quinone oxidoreductase (Nqo1), and epoxide hydrolase (Ephx)) and implementation of threshold gene expression values within rat studies to assess levels of AhR activation for hazard identification within a GlaxoSmithKline S1P1 program. In fact, Glaab et al. [Despite these concerns, efforts to better understand AhR-dependent mechanisms underlying toxicological responses and individual susceptibility have progressed using various omics approaches . Toxicogenomic profiling offers a high-throughput methodology to extract mode of action (MOA) information from complex RNA expression datasets, which can enable transcriptomic signatures of ligand- and AhR-dependent toxicity. To date, most transcriptomic biomarker research within the field of toxicology has focused on liver carcinogenesis; however, many of these efforts incorporate AhR activation as a key biomarker for drug-induced carcinogenicity and a combination of AhR activation with additional transcriptomic signatures can aid in development of quantitative effect thresholds associated with AhR-dependent GI toxicological events ,165. Ided dosing . Taylor d dosing  reportedb et al.  reportedb et al. ,171, andb et al. ,174,175 b et al.  within ib et al. , which sIn this light, identification of compounds as transient or sustained AhR activators through transcriptomic approaches can serve as a strategy to flag potential AhR-dependent toxicity liabilities . AdvanceSeveral intestinal in vitro platforms have been developed that can serve as predictive early screens for AhR target modulation within drug discovery programs. Classically, human immortalized colon cell lines  have served as high-throughput models for evaluating GI toxicity and drug absorption, distribution, metabolism, and clearance. Inherent limitations regarding lack of cell–cell communication and cell–environment interaction have resulted in poor translatability of the monoculture cell line models; although, addition of extracellular matrix, three-dimensional culture conditions, and intestinal epithelial or immune cell subtypes has improved predictivity. New methodologies that incorporate diverse IEC subtypes  in 3D microenvironments  have demonstrated superior clinical translatability over cell lines and in vivo-like predictivity for GI toxicity ,183. In Utilization of advanced GI in vitro model systems that harbor microenvironment cellular and environmental crosstalk cues can provide a more physiologically-relevant system for assessment of AhR-dependent GI toxicity liabilities for hazard identification. GI inflammatory conditions can be triggered by microbial, pathogenic, or chemical stimuli and result in a sustained inflammatory response characterized by increased secretion of pro-inflammatory milieu and disruption of intestinal homeostasis. A number of cytokines/chemokines regulated directly  or by crosstalk through the AhR including, IL-6, IL-4, IL-17, IL-23, IFNγ, CCL20, CXCL5, IL-1β, IL-33, IL-10, and IL-27 could be evaluated as secreted predictive biomarkers of AhR-dependent immunomodulation in vitro and in vivo. Use of in vitro or ex vivo models to study host–microbiome interactions with normal and/or diseased-patient strains have shown promise in addressing microbiome signaling influences on intestinal pathogenesis as well . IncorpoTo address on- and off-target safety liabilities pertaining to AhR modulation, a thorough review of potential target safety risks needs to be carried out A. The AhCyp1a1 can be utilized as a pharmacodynamic biomarker for AhR activation across target tissues to assess biodistribution and understand potential AhR-dependent safety liabilities with candidate molecules [Performing a short 3–14 day) repeat-dose exploratory in vivo study can aid in understanding toxicity liabilities early through the collection of AhR target organs of toxicity for histological analysis, clinical pathology , evaluation of biomarkers of toxicity, and/or immunophenotyping, and clinical observations .  day repePharmacokinetic information  within in vitro and in vivo studies can provide relevant information pertaining to potential drug interactions and direct chemical SAR changes for improved target organ biodistribution  and clearance within normal and diseased  preclinical models. Chen and colleagues  utilizedProminent target organs for AhR-dependent toxicity liabilities reported within preclinical animal models and observed within human populations  warrant thorough and early evaluation within an AhR agonist program. Ad-hoc in vitro assays designed to address organ- and/or mechanism-specific safety concerns and subacute repeat-dose in vivo exploratory toxicity studies can provide critical information regarding potential off-target and modality-specific risks. For example, evidence of ligand- and AhR-dependent inhibition of ER-α or AR responses as well as developmental and reproductive toxicity concerns  warrant CYP1A1/1A2), physicochemical properties, and pharmacokinetic parameters  will need to be front-loaded within an AhR agonist program to prioritize clean compounds. Utlimately, de-risking strategies for AhR programs will differ depending on the disease indication, modality, treatment duration, and patient population; however, addressing key AhR-dependent safety liabilities early has the potential to enable development of therapeutics targeting the AhR.Despite high dose levels within preclinical species and long-term treatment durations, examination of approved drugs that activate the AhR across a wide variety of therapeutic areas revealed no overt toxicities synonymous with sustained dioxin-like AhR activation, and in fact, some of the compounds demonstrated anti-carcinogenic activity B,C 200,,202. DatThe stigma surrounding AhR target modulation originates from exhaustive research focused on mechanisms of dioxin-dependent AhR activation and downstream toxicity. The notion of the AhR as the “dioxin receptor” is further fueled by epidemiological studies that evaluated dioxin-exposed populations and reported increases in rates of morbidities and mortalities. The new age role of the AhR as an immunomodulatory agent has ignited novel research into beneficial roles of the AhR across various diseases, including inflammatory GI indications. The AhR has been shown to play a protective role within the gut by mediating immune homeostasis and maintaining barrier integrity, and several therapeutic modality approaches have been developed to target the AhR pathway to combat inflammatory bowel disease. Despite this advancement, AhR drug development is still limited by safety concerns; however, a safety-by-design approach to systematically identify and de-risk potential liabilities can empower AhR drug development programs. Novel chemical modalities targeting the AhR will also require a unique set of de-risking strategies to dial out toxicities. Thus, design, development, and implementation of robust in silico and in vitro tiered screening approaches as well as in vivo toxicity studies for AhR target modulation will not only enhance our understanding in the mechanism of action but will also build confidence in de-risking safety liabilities for inflammatory GI indications.


Since an outbreak started in China in 2019, coronavirus disease 2019 (COVID-19) has rapidly become a worldwide epidemic with high contagiousness and caused mass mortalities of infected cases around the world. Currently, available treatments for COVID-19, including supportive care, respiratory support and antiviral therapy, have shown limited efficacy. Thus, more effective therapeutic modalities are highly warranted. Drug repurposing, as an efficient strategy to explore a potential broader scope of the application of approved drugs beyond their original indications, accelerates the process of discovering safe and effective agents for a given disease. Since the outbreak of COVID-19 pandemic, drug repurposing strategy has been widely used to discover potential antiviral agents, and some of these drugs have advanced into clinical trials. Antitumor drugs compromise a vast variety of compounds and exhibit extensive mechanism of action, showing promising properties in drug repurposing. In this review, we revisit the potential value of antitumor drugs in the treatment of COVID-19 and systematically discuss their possible underlying mechanisms of the antiviral actions. The unexpected pandemic of coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has swept the globe and inevitably causes serious global health crisis. Currently, the clinical treatment for COVID-19 is primarily supportive care. Several investigational drugs which have shown promising antiviral activities or immunomodulatory effects are under evaluation in clinical trials for COVID-19, and some have progressed to clinical use. Remdesivir is a broad-spectrum adenosine analogue antiviral drug which interferes with viral replication via inhibition of RNA-dependent RNA polymerase (RdRp)  and replication in vitro   . CurrentRapamycin (sirolimus) and rapamycin derivatives are specific allosteric inhibitors of mTOR complex 1 (mTORC1). Rapamycin has been approved for use in organ transplantation and lymphangioleiomyomatosis, while its two analogs, temsirolimus and everolimus, have also been approved for clinical use in multiple cancers. In addition to the antitumor action, they are demonstrated to have potential antiviral activities. The SARS-CoV-2 interactome reveals the interaction between N protein and la-related protein 1 (LARP1) in RNA biology . LARP1 kMpro is indispensable for coronavirus replication, as it is responsible for the cleavage of polyproteins to generate nsps . PreviouDuring SARS-CoV-2 infection, delayed early innate immune response and subsequently exuberant inflammatory response result in viral escape and tissue damage. Thus, strategies to boost the innate immunity and dampen aggressive inflammatory response are likely to effectively clear the virus and avoid tissue damage. Numerous studies have attempted to dissect immunopathological changes of COVID-19 patients which may provide critical resources to identify potential targets for drug discovery. The type I and type III interferons (IFNs) are vital components of innate immunity. Accumulating evidence has demonstrated that delayed and impaired type I and type III IFN responses are common immunological events in patients with severe COVID-19, which are induced by SARS-CoV-2 via its viral proteins as an immune evasion strategy to buy time for viral replication –87. Thus+ T cells against tumor-derived DNA [The innate immune system acts as the frontline defense against invading pathogens, and also plays a critical role in the prevention of tumorigenesis. In mammalian cells, cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, and its downstream signaling effector stimulator of interferon genes (STING), form a major DNA sensing mechanism. The activation of cGAS-STING pathway triggers the production and secretion of type I IFNs which subsequently orchestrate innate immune response . In immuived DNA , 91. Alsived DNA . Thus, S50 and low toxicity, and intranasal administration of 10 μg diABZI protected the mice from SARS-CoV-2 infection via the activation of IFN response [STING signaling has also been found to play a role in RNA virus infection –95. Receresponse . In addiresponse . These oIL-6 is a member of the IL-6 cytokine family and functions in the regulation of immunity, tissue homeostasis and metabolism. Dysregulation of IL-6 and key downstream signaling pathways are common events in cancer and portend an adverse outcome. IL-6 helps to create an inflammatory and immunosuppressive tumor microenvironment that promotes tumor angiogenesis and outgrowth –105. ThuAs a critical mediator of the inflammatory response, IL-6 levels are obviously elevated among COVID-19 patients with complicated disease and are closely associated with adverse clinical outcomes . A recen, etc. As major downstream effectors of cytokine signaling, JAKs can be therapeutic targets of cytokine-dependent inflammatory and neoplastic disorders. Actually, mutations in the JAK family have been observed in hematological malignancies and solid tumors [Several cytokines involved in COVID-19 including IL-6 mainly act by Janus kinase-Signal transducer and activator of transcription (JAK-STAT) signaling, one important pathway with a pivotal role in various biological processes including hematopoiesis, immune development, inflammation control, adipogenesisd tumors –115. CurRecent studies suggest that JAK is involved in exaggerated inflammatory responses triggered by SARS-CoV-2 infection. First, JAK is an important downstream signaling molecule that mediates the proinflammatory effect of IL-6 and other cytokines. Second, IFN signaling activated upon SARS-CoV-2 infection leads to excessive activation of complement system in a JAK/STAT-dependent manner, and ruxolitinib, a JAK1 inhibitor, normalizes the local production of active complement component from infected cells to prevent tissue damage . RemarkaTumor necrosis factor alpha (TNF-α) is another important inflammatory cytokine that shows increased production in patient with moderate to severe COVID-19. Evidently, TNF-α can trigger robust cell death by activating apoptotic signaling pathway, and blocking TNF-α with neutralizing antibodies in a murine infection model can significantly reduce SARS-CoV-2 induced mortality . Thalidoactive neutrophils that promote immune response and expanding immunosuppressive immature neutrophils [Corticosteroids are known to have anti-inflammatory and anti-allergic effects, and are widely prescribed for the treatment of inflammatory diseases and cancer. Notably, corticosteroids were used to fight against SARS in 2003. However, the administration of corticosteroids in treating infectious diseases has always been the subject of debate. On the one hand, studies reported that the proper use of corticosteroid in critical SARS patients resulted in lower mortality . Howevertrophils . A largetrophils . Thus, tPulmonary angiogenesis is one of the distinctive angiocentric features of COVID-19 and shows a strong association with disease severity . The upr−1 body weight dosing markedly improved morbidity outcomes of infected mice without affecting viral clearance kinetics [Topoisomerase 1 (TOP1) is one of the key enzymes involved in the regulation of DNA topology, which binds to duplex DNA and introduces a transient single-strand nick, allowing the rotation of the intact DNA strand around the break, thus resolving topological constraints that impede DNA replication. Once DNA is relaxed, TOP1 religates the nicks. But this religation process can be inhibited by TOP1 inhibitors which trap TOP1 and result in DNA single-strand breaks, eventually leading to cell death . Therefokinetics . These r−1 dosing improved oxygenation and decreased inflammatory cytokines of patients, implicating a pro-inflammatory role of BTK in COVID-19 [Bruton’s tyrosine kinase (BTK) is known as a key constituent of B cell receptor signaling which is critical for the proliferation and survival of both normal B cells and malignant B cells. Thus, BTK is an attractive target for developing therapies to fight against B cell malignancies. To date, BTK inhibitors including ibrutinib, acalabrutinib and zanubrutinib, have been successively approved for patients with lymphoid malignancies, and more inhibitors are under development or investigation in clinical trials , 133. ReCOVID-19 . In addiCOVID-19 . AcalabrDespite many advantages, repurposing existing drugs to treat COVID-19 encounters multiple challenges. Firstly, repurposed candidates with established therapeutic efficacy against SARS-CoV-2 in screening models may show limited effects in clinical trials. Currently, drug repurposing screens for COVID-19 are majorly based on transformed cell lines, and the screened drugs are subsequently validated in primary human cell models or animal models. However, these screening models, whether cell models or animal models, fail to entirely recapitulate the physiological conditions of human SARS-CoV-2 infection, which constrains the accurate assessment of the efficacy of drugs to some extent. Thus, the screened repurposed drugs, although exhibiting high efficacy in cell lines and animal models, may fail to achieve the expected treatment response in patients with COVID-19. To overcome the limitations of cell lines, various organoid culture systems which can simulate the process of SARS-CoV-2 infecting different human organs have been, or are being, developed and used to test potential therapies for COVID-19 –142. In −1 body weight dose level when administered intranasally, much lower than its treatment dose 1.5 mg kg−1 body weight in mouse model of colon cancer. Thus, nasal administration is a viable strategy for reducing the required dose of repurposed drugs. Besides, developing organ-targeted drug delivery system is another promising approach allowing for lower drug dosing and reduced off-target effects. Indeed, some novel lung-targeted lipid nanoparticle (LNP) delivery systems have been reported to deliver small interfering RNA (siRNA) and mRNA to the lungs successfully [Secondly, some repurposed drugs tend to have higher therapeutic dosages in COVID-19 treatment than their original indications, which may raise the safety concerns and lead to increased risk of side effects. In this scenario, topical administration is an alternative strategy which enables high local drug concentrations in diseased organ. For example, STING agonist diABZI can achieve therapeutic effect in a transgenic mice model of SARS-CoV-2 infection at the 0.5 mg kgessfully , 144. TaThirdly, drug resistance often develops with the emergence of SARS-CoV-2 new variants. Mechanistically, these potential drugs exert antiviral effects either by directly targeting viral components, or by indirectly targeting host cell signaling pathways that viruses are dependent on for entry or replication. Direct-acting antiviral agents (DAA) have little side-effects compared with host-targeting antivirals (HTA) which have broad effects on various body tissues or cells. However, due to the high variability of the RNA viruses including SARS-CoV-2, drug resistance often develops during the administration of DAA. In this regard, targeting host cell pathways and conserved viral components can reduce the occurrence of drug resistance. HTA, like FASN inhibitor TVB-2640 and STING agonist diABZI, have been shown to have antiviral activities against SARS-CoV-2 variants , 97. ForFinally, targeting host factors is a risky therapeutic strategy. Targeting host metabolic pathways is accompanied by a potential risk for normal cell cytotoxicity that can cause antiviral-related side effects. As mentioned above, topical administration and targeted drug delivery can minimize these off-target effects. Targeting hyperactivated host inflammatory pathways not only limits excessive inflammatory responses and attenuates tissue damage, but also compromises antiviral immunity, which may lead to viral spread within host and increases the risk of secondary infections in patients with COVID-19. Thus, accurately estimating the appropriate timing of initiating anti-inflammatory treatments is very critical to achieve desired therapeutic outcomes. The identification of specific biomarkers of hyperinflammatory condition can also help physicians to recognize the disease course and initiate anti-inflammatory therapy timely. Furthermore, more multicenter randomized clinical trials are warranted to provide accurate information about the rational therapeutic timing and therapeutic efficacy of these agents before clinically used for COVID-19.The COVID-19 pandemic remains a serious public health concern globally and more effective therapies are still urgently needed, especially for those with severe COVID-19. Drug repurposing, as an efficient and time-saving strategy, promises more available agents for COVID-19. Some anticancer drugs, for example, have been repurposed to treat COVID-19, based on common pathophysiological features including dysregulated immune responses and aberrant metabolic pathways which usually act as initiators and/or contributors during the occurrence and progression of both COVID-19 and cancer. Besides, high-throughput screening (HTS) technologies greatly expedite the discovery of anticancer agents that show antiviral properties, improving the success rate of drug repurposing.It is worth noting that drug repurposing is not completely risk-free, and many challenges remain to be addressed. Apart from intellectual property issues, ineffective drug screens caused by imprecise screening models, unrealistic effective dosing, drug resistance of new variants and the obscure effects of immunomodulatory agents are four main challenges as mentioned above. Every challenge lies opportunities and prospects. Optimizing screening strategies and developing organ-targeted drug delivery systems are able to increase the success rate of repurposing drugs for the treatment of COVID-19. Besides, it is necessary to reasonably assess risk–benefit for each individual patient when immunomodulatory agents are under consideration. As for drug resistance of new variants, a combined therapy can be initiated for those suitable patients.In recent years, proteomic studies and interactome analysis have identified many novel therapeutic targets and drug candidates for SARS-CoV-2; however, some of which have not been validated in COVID-19, such as receptor-interacting protein kinase 1 (RIPK1) targeted by ponatinib, an antitumor drug , 76. Thu


This Research Topic focused on new findings regarding the influence of nutrition-based interventions on exercise-induced perturbations in immunity. The immune system reflects the physiological stress that exercisers experience during demanding exercise workloads. Nutrition-based strategies to mitigate exercise-induced immune-related stresses began with the unexpected discovery during the 1990s that carbohydrate ingestion before and during prolonged and intensive exercise was linked to a sizeable decrease in post-exercise inflammation –4. A recn-6 and n-3 polyunsaturated fatty acids (PUFAs) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzyme systems . This study confirmed the oxylipin-lowering effect of acute carbohydrate ingestion during prolonged and intensive exercise. A novel finding was that 2-week blueberry ingestion  increased plasma concentrations of 24 gut-derived phenolic metabolites and decreased post-exercise concentrations of pro-inflammatory ARA-CYP-generated oxylipins. In other words, cyclists exercising vigorously for about 3 h with blueberry gut-derived metabolites in their systems had lower plasma ARA-CYP oxylipins during several hours of recovery. Banana and/or blueberry ingestion did not completely counter post-exercise increases in inflammatory-related oxylipins, but rather attenuated the magnitude of these increases. This study used a multiomics approach to afford a better understanding of the multifaceted interactions between metabolites generated in the gut from blueberry polyphenols and those produced from cell membrane fatty acids.A previous study showed that carbohydrate intake (from bananas or a 6% sugar beverage) had a strong effect in reducing plasma oxylipin concentrations after an intensive 75-km cycling bout . More th systems . The artDoes the nutritional composition of dairy milk based recovery beverages influence post-exercise gastrointestinal and immune status, and subsequent markers of recovery optimisation in response to high intensity interval exercise?”, focused on the effects of flavored dairy-milk recovery beverages of different energy and nutrient densities on gastrointestinal, immune, and metabolic recovery outcomes . In this crossover study, participants completed 2 h of high-intensity interval running followed by consumption of two different chocolate flavored dairy-milk beverages matched for volume but differing in carbohydrate and protein content. No placebo beverage was included in this study. Exercise-induced changes in several types of outcomes including those related to performance, gastrointestinal integrity, and immune function  did not differ between the trials. The authors concluded that ingesting a dairy milk-based supplement beverage with substantially higher vs. lower levels of protein and carbohydrate did not enhance exercise recovery.A study published in 2006 touted chocolate milk as an effective recovery ergogenic aid . This diHealth benefits of probiotics in sport and exercise - non-existent or a matter of heterogeneity? A systematic review,” summarized data from 41 studies . The studies varied so widely in dosing regimens and outcome assessments that the authors were unable to provide conclusive consensus statements. The authors provided a variety of recommendations for future studies including the use of validated questionnaires, improved immune outcomes, and better guidelines for probiotics dosing strategies.Athletic endeavor can be associated with immune dysfunction, an increased risk for acute respiratory infections, and negative gastrointestinal symptoms. Probiotics are a common dietary supplement used to potentially counter these health problems . ProbiotAlmond intake alters the acute plasma dihydroxy-octadecenoic acid (DiHOME) response to eccentric exercise,” examined whether or not 4-weeks almonds intake (57 g/day) compared to cereal bars intake would improve recovery from a 90-min “weekend warrior” eccentric exercise bout . Using a multiomics approach, almond intake was linked to a significant elevation in gut-derived metabolites from almond polyphenols, a post-exercise increase in plasma 12,13-DiHOME, and a decrease in plasma 9,10-DiHOME. 12,13-DiHOME is a lipokine from brown adipose tissue that is elevated in fit and lean individuals and exerts positive effects on metabolic health and energy regulation . In randomized clinical trials, almond consumption has been related to multiple health, metabolic, and disease prevention benefits . The ranDN, GD, VM, and LW wrote this editorial and agree to be accountable for the content of the work. All authors contributed to the article and approved the submitted version.


Patient portal design is rarely centered around patient caregivers—family members, friends and other designated persons who may access these digital tools for the patient’s health needs. This study examines: (a) portal features used by caregivers during their loved-one’s end-of-life; and (b) caregiver perceptions regarding the use of patient portals for caregiving near the end-of-life.Using sequential mixed-methods, we conducted a retrospective cohort analysis of caregiver proxy (N=137) use from 2016-2019 during their loved-ones’  last 12 months of life and interviews with (N=31) 16-former and 15-current caregiver proxies. Caregiver proxy portal use in this population was lower than expected; however, caregivers who used the portal as proxies found value in tools for caregiving near the end-of-life. To leverage the patient portal to better support caregivers, future strategies should target caregiver portal adoption, awareness of beneficial portal tools, and the addition of caregiver specific resources and education.


Staphylococcus aureus (MRSA) that occurred during the COVID-19 pandemic in a gynecology/obstetrics department, despite these intensified contact precautions. Five MRSA originating from clinical samples after surgical intervention led to an outbreak investigation. Firstly, this included environmental sampling of the operation theatre (OT) and, secondly, a point prevalence screening of patients and health care workers (HCW). All detected MRSA were subjected to whole genome sequencing (WGS) and isolate relatedness was determined using core genome multilocus sequence typing (cgMLST). WGS revealed one MRSA cluster with genetically closely related five patient and two HCW isolates differing in a single cgMLST allele at maximum. The outbreak was terminated after implementation of infection control bundle strategies. Although contact precaution measures, which are also part of MRSA prevention bundle strategies, were intensified during the COVID-19 pandemic, this MRSA outbreak could take place. This illustrates the importance of adherence to classical infection prevention strategies.Since March 2020, the COVID-19 pandemic forced hospitals worldwide to intensify their infection control measures to prevent health care-associated transmission of SARS-CoV-2. The correct use of personal protective equipment, especially the application of masks, was quickly identified as priority to reduce transmission with this pathogen. Here, we report a nosocomial cluster of methicillin-resistant  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected in Wuhan City, China, in December 2019. In March 2020, the WHO declared the COVID-19 disease a pandemic. Soon after SARS-CoV-2 spread to Germany and forced the hospitals to increase their infection prevention and control (IPC) measures. These included physical distancing, visitor restrictions and contact precautions, which in particular comprised the use of protective personal equipment (PPE) such as surgical masks. As pregnant women and cancer patients are considered a risk group for severe COVID-19 outcomes, the implementation of SARS-CoV-2 infections IPC measures was a priority for gynecology/obstetrics departments in Germany [S. aureus (MRSA) or vancomycin-resistant enterococci (VRE), one would expect a decrease of hospital-acquired MDRO during the COVID-19 pandemic. In this context, a study from Los Angeles, USA, reported a decline in the MDRO rate per 1000 patients between Q1 and Q2 2020 of 41% for MRSA, 80% for VRE [As contact precautions are part of infection prevention bundle strategies also established in the context of prevention of multi-drug-resistant organisms (MDRO), i.e., methicillin-resistant  for VRE  and in a for VRE ,6 indicaIn recent years, MRSA prevalence in critically ill patients in Germany has decreased, but MRSA is still one of the most common MDRO causing hospital-acquired infections also in obstetrics and gynecology patients ,8. As itNevertheless, here, we present results of an MRSA outbreak we experienced in our department of obstetrics and gynecology in summer 2020.The University Hospital Münster (UHM) is a 1500-bed care center admitting 55,000 patients per year. In accordance with national infection prevention recommendations , all patDuring the COVID-19 pandemic, masks  were worn by employees, visitors and, if possible, for health reasons, also by patients. Hence, a main component of MRSA transmission prevention was established due to the pandemic situation.Nevertheless, in June 2020, we faced an increase of MRSA isolated from clinically relevant samples of patients on a gynecology/obstetric ward during a three-month-timespan  .Detection of MRSA was performed by using selective agar plates . For species identification, we used MALDI-TOF mass spectrometry . Susceptibility testing see also  was perfEnvironmental sampling was performed using sterile packaged polywipes  on contact surfaces and incubating them in Tryptic Soy Broth + lecithin tween (LT)  at 37 °C for 24 h. Ten μL of this broth were streaked onto blood agar and MRSA selective agar and incubated at 37 °C for 24 h. Suspected colonies were subcultured on blood agar and species identification was performed by MALDI-TOF mass spectrometry. Susceptibility testing was performed via agar diffusion and evaluated in accordance with the EUCAST standards for clinical breakpoints (version 11.0).S. aureus isolates were subjected to whole genome sequencing (WGS)-based typing using either the MiSeq platform  or the Sequel II platform . The Nextera XT protocol (Illumina Inc.) was used to prepare genomic DNA for MiSeq sequencing. The resulting 250 bp paired-end reads were then de novo-assembled after quality-trimming using the SKESA algorithm [S. aureus [spa-genotypes as well as the presence of virulence and resistance genes, i.e., lukS, lukF, mecA and mecC, were extracted from the WGS data in silico.For genetic comparison, confirmed lgorithm  using delgorithm , using t. aureus . Clonal All strategies and investigations were performed in accordance with the national recommendations for outbreak investigations of the German legally assigned institute for infection control and prevention (Robert-Koch Institute). Formal consent was therefore not required.S. aureus but lacked methicillin-resistance. In all other probes, only microorganisms of skin flora and the environment were detected , the cluster could be terminated in September 2020. No further MRSA infections nor hospital-acquired colonizations occurred until the day of writing.mecA gene could be detected in absence of mecC and lukS or lukF indicating no PVL existence. Most prevalent spa-type was t032 in all strains of the cluster, whereby t003, t2576 and t5168 were found in one isolate each (All ten MRSA isolates (five originating from patients and HCW each) were subjected to WGS. The analysis resulted in one cluster of seven genetically closely related, i.e., one cgMLST allele distance only, or identical strains, comprising genotypes from all patients and two HCW as well as three singletons with no genetic relation to this cluster. In all isolates, ate each .Transmissions of MRSA in the clinical setting can occur via direct and indirect contact ,13 mostlDespite these intensified measures including wearing of masks that were established from the very beginning of the COVID-19 pandemic, an MRSA outbreak could take place on a gynecology/obstetrics ward in our tertiary care center. This leads to the question if adherence to the infection control bundle strategies for MRSA in the hospital and public health setting during COVID-19 are appropriate. Our study suggests that especially medical staff do not adhere to so-called “basic hygienic measures” despite an increased awareness concerning personal protective equipment (PPE) during the COVID-19 pandemic. Lack of adequate hand hygiene adherence and inadequate use of PPE have been highlighted by recent studies to be causative for multi-drug-resistant organism (MDRO) outbreaks during COVID-19 . Interesspa-typing, this outbreak would have probably been not discovered and contained as the spa-type t032 identified is one of the most prevalent spa-types in our local area. Implementation of routine WGS typing of MRSA and other MDRO, including VRE and gram-negative MDRO should therefore be more widely used.Our outbreak report illustrates the importance of WGS-based typing as part of a routine surveillance strategy for the hospital setting and public health-related questions. WGS is an effective method to detect MRSA transmissions over several weeks and without direct patient-to-patient contact of MRSA colonized or infected patients. With other common typing methods, i.e., During the COVID-19 pandemic period, only outbreaks involving VRE and gram-negative bacteria have been published until today, most of them occurring in intensive care units (ICU) ,16. So fAdherence to basic hygiene measures is essential to prevent the transmission of MRSA in the clinical context. Additionally, basic hygiene measures should not be neglected, despite the contact precautions established during the COVID-19 pandemic. WGS-based approaches can thereby help to early detect and terminate hospital transmissions of MDR bacteria.


Background and Objectives: Endobronchial ultrasound transbronchial lung biopsy with guide sheath (EBUS-GS-TBLB) has been regarded as a reasonable diagnostic method with an acceptable diagnostic yield. In addition, EBUS-GS-TBLB is considered safer and less invasive compared to percutaneous needle biopsy and thoracoscopic surgery. However, we encountered a case of life-threatening procedure-related fatal infection, which was successfully managed. Case presentation: A 61-year-old man with a 30 pack-year smoking history was referred to our clinic with a necrotic lung mass in the right middle lobe on a chest computed tomography scan. EBUS-GS-TBLB was performed for a pathological diagnosis without immediate complications. Eight days after the procedure, the patient visited the hospital with sudden hemoptysis and severe dyspnea with fever. A chest computed tomography revealed a ruptured lung abscess and pneumonia, developed after EBUS-GS-TBLB. Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation were initiated to manage refractory hypoxia. While maintaining ECMO, video-assisted thoracoscopic surgery was performed at the patient’s bedside in the intensive care unit. After surgery, the patient’s vital signs gradually improved, and a chest computed tomography revealed a reduction in the extent of the lung abscess. Results: Although EBUS-GS-TBLB is minimally invasive and relatively safe when used for the diagnosis of peripheral lung lesions, pulmonary physicians should be aware of this rare but critical complication. Conclusions: We suggest that the careful prescription of prophylactic antibiotics before EBUS-GS-TBLB would be wise if the mass featured a necrotic, cavitary, or cystic lesion. Transbronchial lung biopsy using endobronchial ultrasound transbronchial lung biopsy with guide sheath (EBUS-GS-TBLB) has become widely used for the histological diagnosis of peripheral lung lesions; the diagnostic performance is acceptable ,2. GenerA 61-year-old man with a 30 pack-year smoking history and a persistent cough was referred to our clinic with a pulmonary lesion that was suspected to be lung cancer. A chest computed tomography revealed a round mass-like consolidation (5.9 cm in diameter) in the right middle lobe but no mediastinal lymph node enlargement A,B.After the patient had been hospitalized, we used a 4.0 mm-diameter flexible bronchoscope , a radial EBUS probe , and a guide sheath kit  to perform EBUS-GS-TBLB . The patAlthough oxygen was maximally supplied through a reservoir mask, the patient’s hypoxia persisted and his vital signs became unstable; ECMO and MV were initiated. Five days later, despite management with ECMO, MV, increased doses of vasopressor, and continuous renal replacement therapy in the ICU, the patient’s condition worsened, and his entire right lung became hazy B. On dayThree days after surgery, the patient did not require ECMO; he was then weaned from the mechanical ventilator and tracheostomy. The patient was discharged 76 days after admission. He was found to exhibit a mutation in the epidermal growth factor receptor and was thus prescribed gefitinib. When comparing the chest X-rays and chest computed tomography scans obtained on discharge and three months later, a significant improvement was evident A–D.EBUS-GS-TBLB has been regarded as a reasonable diagnostic method with an acceptable diagnostic yield. Compared to percutaneous needle biopsy and thoracoscopic surgery, EBUS-GS-TBLB is safer and less invasive; it is typically performed with the patient under conscious sedation, induced by intravenous midazolam and fentanyl. The overall complication rate is reportedly 1.3–4.5%, and the incidence of infectious complications is reportedly 0.5–4.5% . The devThe British Thoracic Society guidelines for bronchoscopy do not recommend the use of prophylactic antibiotics to prevent endocarditis, fever, or pneumonia before biopsy using bronchoscopy . AdditioWe describe a patient who developed a life-threatening lung infection as a complication of EBUS-GS-TBLB and who struggled to recover despite ECMO, continuous renal replacement therapy, MV, and thoracoscopic surgery in the ICU. Although EBUS-GS-TBLB is minimally invasive and relatively safe when used for the diagnosis of peripheral lung lesions, pulmonary physicians should be aware of this rare but critical complication.