IVUS-guided second-generation DES implantation was associated with a significantly lower long-term risk of cardiac death or MI compared with angiography guidance, regardless of lesion complexity.Long-term follow-up data on differential effects of intravascular ultrasound (IVUS) according to lesion complexity are limited in patients undergoing percutaneous coronary intervention (PCI). The current study compared long-term clinical outcomes between IVUS-guided and angiography-guided PCI in patients with second-generation drug-eluting stents (DES). Between February 2008 and December 2015, 5488 patients undergoing PCI with second-generation DES were recruited from an institutional registry of Samsung Medical Center. The primary outcome was a composite of cardiac death or myocardial infarction (MI) during 46 months of median follow-up (interquartile range: 32–102 months). IVUS-guided PCI was performed in 979 patients (17.8%). IVUS-guided PCI was associated with a significantly lower risk of cardiac death or MI compared with angiography-guided PCI . Results were consistent after propensity score matching analysis with 801 matched pairs. In subgroup analysis, there was no significant interaction between lesion complexity (defined by complex procedures, P Several randomized trials conducted to identify the clinical benefits of IVUS-guided PCI compared with angiography-guided PCI have shown that IVUS guidance is associated with significantly lower risk of adverse events5. Despite clear evidence of the benefits of IVUS-guided PCI, it is not utilized frequently in real-world practice, especially for non-complex lesions8. This might be because previous studies have focused on the effects of IVUS use for complex lesion subsets, such as left main disease, chronic total occlusion, diffuse long lesion, or bifurcation lesion11.Intravascular ultrasound (IVUS) provides tomographic images of coronary artery structure and is a helpful tool for evaluating lesion geometry, reference vessel status, and post-intervention stent optimization during percutaneous coronary intervention (PCI)2. While a large prospective ADAPT-DES  registry showed the benefits of IVUS were more prominent in patients with complex lesions12. Furthermore, some previous studies failed to show the significant clinical benefits of IVUS guidance in non-complex lesions15. However, there is a lack of data regarding the long-term follow-up outcomes of IVUS-guided PCI in patients with non-complex lesion.Recently, the Intravascular Ultrasound Guided Drug Eluting Stents Implantation in All-Comers Coronary Lesion (ULTIMATE) randomized trial demonstrated that IVUS-guided drug-eluting stent (DES) implantation significantly reduced the risk of target vessel failure in all-comer patients with coronary artery disease (CAD)Therefore, we sought to compare the long-term clinical outcomes between IVUS-guided versus angiography-guided PCI with second-generation DES in patients undergoing PCI and to identify whether the benefits of IVUS guidance differed according to lesion complexity.This is a retrospective, single-center, observational study. From February 2008 to December 2015, a total of 5488 consecutive patients treated with PCI with second-generation DES was recruited from an institutional cardiovascular catheterization database of Samsung Medical Center . Patients who treated with balloon angioplasty only, bare-metal stent (BMS), or first-generation DES were excluded. Patients who underwent PCI with optical coherence tomography guidance were also excluded from the current analysis  and P2Y12 inhibitors  before PCI unless they had previously received these antiplatelet medications. Anticoagulation during PCI was performed using low-molecular weight heparin or unfractionated heparin to achieve an activated clotting time of 250 to 300 s. The revascularization treatment strategy, use of glycoprotein IIb/IIIa receptor inhibitors, choice of DES, duration of dual antiplatelet therapy, and any adjunctive pharmacologic treatment after PCI were at the discretion of the operators. IVUS imaging was performed using a commercially available system  after administration of 0.2 mg intracoronary nitroglycerin. The use of IVUS during PCI was left to the operator’s preference. Timing of IVUS use was also based on operator discretion. The IVUS probe was pulled back automatically at a speed of 0.5 mm/s.All interventions were performed according to current practice guidelines18. Peri-procedural MI was excluded as a clinical event in this study. Definite or probable ST was defined according to the definition of the Academic Research Consortium19. Ischemia-driven TLR was defined as a revascularization procedure at a previously treated segment from 5 mm proximal to the stent to 5 mm distal to the stent with ≥ 50% diameter stenosis and at least one of the following: (1) recurrence of angina, (2) positive non-invasive test, or (3) positive invasive physiologic test.The primary outcome of this study was a composite of cardiac death or myocardial infarction (MI) during follow-up. Secondary endpoints were cardiac death; all-cause death; MI; definite or probable stent thrombosis (ST); ischemia-driven target lesion revascularization (TLR); and major adverse cardiac events (MACE), a composite of cardiac death, MI, ST, and ischemia-driven TLR. Cardiac death was defined as death from any cardiac cause including sudden cardiac death, MI, congestive heart failure, and cardiac arrhythmias. MI was defined as an elevation of creatine kinase-myocardial band or troponin level greater than the upper limit of normal with concomitant ischemic symptoms or electrocardiography findings indicative of ischemia20, SYNTAX score 21, and previously used definition for complex PCI. (1) bifurcation lesion with side branch diameter ≥ 2.5 mm, (2) chronic total occlusion with duration ≥ 3 months, (3) unprotected left main CAD, (4) long lesion (implanted stent length ≥ 38 mm), (5) multi-vessel PCI , (6) multiple stent implantation (3 or more stents per patient), (7) in-stent restenosis lesion, or (8) severely calcified lesion (requiring a rotablator system)9.Anatomical lesion complexity was assessed using ACC/AHA lesion classificationDifferences between continuous variables were evaluated using Welch’s t-test, and the data are presented as mean ± standard deviation. Categorical data were analyzed between groups using the Chi-square test and are presented as number and relative frequency (%). The cumulative incidence of clinical events is presented as Kaplan–Meier estimates and compared using log-rank test. The Cox proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI) to compare risk of clinical events between IVUS-guided versus angiography-guided PCI groups. In the multivariable model, we included covariates that were significant in univariate analysis or that were clinically relevant. The adjusted HRs and 95% CIs were evaluated by Cox regression to identify independent predictors of clinical events based on old age (> 65 years), male, hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, current smoker, previous history of PCI, MI, or cerebrovascular accident, reduced left ventricular ejection fraction (< 40%), acute coronary syndrome, multivessel disease, left main disease, lesion locations , complex procedure, and medications .To adjust for concomitant baseline demographics, cardiovascular risk factors, clinical presentation, and lesion severity, we performed propensity score matching analysis. A total of 801 matched pairs was generated. A matched population was obtained by logistic regression and one-to-one nearest neighbor matching based on propensity scores. A full non-parsimonious model was developed with all variables listed in Tables 22.All probability values were two-sided, and p-values < 0.05 were considered statistically significant. Statistical analyses were performed using R Statistical Software Among the total 5488 patients who underwent PCI with current generation DES, 979 17.8%) patients received PCI with IVUS guidance. Patients undergoing PCI with angiography guidance were older and more likely to have general cardiovascular risk factors including hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, and current smoker compared to those with IVUS guidance   among 801 matched pairs . A total of 373 cardiac deaths or MIs occurred during the study period, and the cumulative incidence of the primary composite endpoint was significantly lower in the IVUS-guided PCI group than in the angiography-guided PCI group  , ACC/AHA classification , or SYNTAX score , which was also consistent in matched population  In real-world practice, use of IVUS tended to be more frequent when performing PCI for complex lesions. (2) Compared with angiography-guided PCI, IVUS-guided PCI with second-generation DES was strongly associated with lower risk of cardiac death or MI in patients with CAD. (3) The effects of IVUS guidance during PCI were identified regardless of lesion complexity or clinical complexity.24. In addition, previous randomized trials showed lower adverse cardiac events with IVUS-guided PCI, but did not show the improvement in hard endpoints, such as cardiac death or MI5. In this regard, the current guidelines recommend that IVUS could be considered in selected patients, including those with left main disease or in-stent restenosis17. In line with such guidelines, the current study showed that use of IVUS was more frequent during complex PCI in real-world practice.Although IVUS is well-known as a useful tool for evaluation of lesion characteristics and optimization of PCI procedures, especially in complex lesion subsets, the beneficial effects of IVUS guidance for long-term outcomes in routine clinical practice are controversial. Most previous studies comparing outcomes between IVUS- and angiography-guided PCI have been focused on complex lesion subsets, such as left main disease, bifurcations, chronic total occlusions, or diffuse long lesions25. Recently, Mentias et al. reported the long-term beneficial effect of IVUS-guided PCI in patients by using the Medicare system with extremely large study population26. However, in that study, more than 20 percent of the study population have received PCI with BMS, which is not currently used, and the details of procedural or lesion characteristics are lacking due to the limitation of the study design. Therefore, we sought to compare the long-term clinical outcomes between IVUS- and angiography-guided PCI in patients treated with the second-generation DES by using the large institutional registry, which can contain detailed information about the procedural or lesion characteristics. In agreement with previous results, we found that routine IVUS-guided PCI with second-generation DES was associated with significantly reduced risks of cardiac death or MI during a median 46 months of follow-up compared with angiography-guided PCI in patients, even after strict adjustments for baseline differences using propensity score matching and multivariable Cox regression analysis. In addition, the IVUS-guided PCI group had a larger stent size, longer stent length, higher proportion of post-dilatation, and higher inflation pressures, which are surrogate markers of stent optimization27. These results support the hypothesis that routine use of IVUS is helpful to optimize stent deployment and to reduce long-term stent-related adverse events in patients with CAD who underwent PCI with second-generation DES.After introduction of DES, which is associated with dramatic reductions of stent-related adverse events, two large non-randomized prospective registries and one randomized controlled trial were conducted for evaluating clinical benefits of routine use of IVUS guidance and consistently showed that IVUS-guided PCI was associated with significantly lower risk of 1- or 2-year adverse events compared with angiography-guided PCI in patients28. In this regard, use of IVUS during PCI, which requires extra cost and time, remains debatable when treating non-complex coronary lesion subsets, where minimal clinical benefits are expected from a procedure. A previous study demonstrated that complex IVUS-guided PCI was associated with significantly reduced risk of adverse events up to 10 years 9. However, there are limited data regarding the efficacy and safety of IVUS guidance in patients with non-complex lesions who underwent PCI with DES. Although the ADAPT-DES registry and the ULTIMATE randomized trial consistently showed the beneficial effects of IVUS-guided PCI even in patients with non-complex lesions, there were discrepancies in the interaction between lesion complexity and use of IVUS for clinical outcomes among the two studies, and these studies reported only 1-year outcomes. Surprisingly, recent large Medicare based registry shows the benefits of IVUS guidance was significantly greater in the non-complex PCI than in the complex PCI with significant interaction (p < 0.001)26. On the other hand, there was no significant difference in 1-year MACE between IVUS- and angiography-guided PCI for short-length lesions in one observational study14. Because of these conflicting results, we additionally performed a subgroup analysis to determine whether the long-term benefits of IVUS differs according to type of lesion complexity. Interestingly, use of IVUS was associated with a significantly lower risk of cardiac death or MI in both complex and non-complex procedure groups. Similarly, when we classified lesion complexity using the AHA/ACC lesion classification (Type A/B1 vs. Type B2/C) or the SYNTAX score (≤ 15 vs. > 15), PCI with IVUS guidance showed favorable long-term outcomes regardless of lesion complexity. Taken together, our results suggest that routine use of IVUS might be helpful to reduce future adverse events even when performing PCI with non-complex lesions.Coronary artery lesion complexity is a powerful indicator of poor clinical outcomes in patients undergoing PCI9, routine IVUS-guided PCI did not show a significant difference in rates of ischemia-driven TLR compared with angiography-guided PCI. A possible explanation of this discrepancy is the inclusion of patients with non-complex lesions in the current study. In addition, unlike previous studies, the current study population received PCI with second-generation DES only. Therefore, long-term follow-up data for randomized controlled trials comparing outcomes between IVUS-guided and angiography-guided PCI for patients treated with current generation DES will be needed to confirm our findings.In contrast to a previous studyThe main limitation of this study is that it is a retrospective, single-center, and observational study. Although selection bias affecting the independent variables was balanced by propensity score matching, the use of a matched population has fundamental limitations compared with real randomized clinical trials. In this regard, the current study was a hypothesis-generating study, and the results should be interpreted with caution. Due to limited clinical evidence, the proportion of IVUS-guided PCI in patients with non-complex lesions was relatively small compared to that of IVUS guidance in patients with complex lesions. This low proportion of IVUS usage could have masked the real effects of IVUS guidance, especially in non-complex lesions. Among patients with IVUS guidance, no definitive criteria for IVUS optimization were suggested. Despite IVUS guidance, some patients might not have experienced optimal stent deployment or expansion and might have experienced poor clinical outcomes. Because of the definition and data collection process of endpoints, the significant difference of some endpoints between IVUS- and angiography-guided group could be underestimated. The incidence of ischemia-driven TLR, which could be identified only in few patients with evidence of myocardial ischemia, was relatively lower, compared to other endpoints. If patients were lost to follow-up, mortality data with cause were obtained through a National Death Records. On the other hand, other endpoints could not be investigated in loss of follow-up patients due to the limitations of registry data. These might affect the higher rates of mortality and relatively lower rates of other clinical endpoints.In conclusion, IVUS guidance during PCI with second-generation DES showed significantly lower long-term risks of cardiac death and MI in patients with CAD compared with angiography guidance only. These results suggest that routine use of IVUS would actively be considered to reduce the long-term risk of adverse events after PCI, regardless of lesion complexity.Supplementary Figures.


Mechanistically, cytosolic calcium oscillations include calcium release from internal stores and calcium entry via channels located in the cell membrane. Recently, numerous publications have shown substantial evidence that calcium-permeable channels play an important role in maintaining the integrity of the endothelium barrier function of the vessel wall in ALI. These novel endothelial signaling pathways are future targets for the treatment of lung injury. This short review focuses on the up-to-date research and provide insight into the contribution of calcium influx via ion channels to the disruption of lung microvascular endothelial-barrier function during ALI.The increased permeability of the lung microvascular endothelium is one critical initiation of acute lung injury (ALI). The disruption of vascular-endothelium integrity results in leakiness of the endothelial barrier and accumulation of protein-rich fluid in the alveoli. During ALI, increased endothelial-cell (EC) permeability is always companied by high frequency and amplitude of cytosolic Ca Acute lung injury (ALI) is a significant source of morbidity and mortality in various critically ill patient population, including pneumonia, non-pulmonary sepsis, inhalation of toxicants, severe trauma, shock, or other factors . Pulmona2+ play a key role in maintaining the endothelial-barrier integrity i also results in the leukocyte adhesion receptor P-selectin expression i participates in the activation of ECs. Furthermore, some studies in humans or animal models indicated that elevated circulating calcium levels also affected EC functions i and NO production. This study also suggests that the T-type CaV channel mediating Ca2+ influx may play an important role in the release of VWF (von Willebrand factor) and membrane-surface expression of P-selectin from lung microvascular endothelium, which plays an active part in inflammation [Voltage-gated calcium channels are considered key transducers of membrane potential changes for intracellular Cal events . ECs areal cells ,36. T-tyal cells . There aessation ,38. Voltefradil) ,39. T-ty pathway ,40. Immuammation .V3.1 might contribute to the prevention of lung injury. However, T-type CaV channels in pulmonary microvascular endothelial cells are quite limited and the channel expression was not only limited in lung ECs. Therefore, direct evidence of EC CaV3.1 in ALI needs more studies of experimental lung-injury models based on transgenic animal technology.Furthermore, the channel inhibitors mibefradil and flunarizine  were found to protect mice against LPS-induced lung injury . The tre2+-entry pathway, stimulated by numerous cell surface receptors via the depletion of Ca2+ concentration in the ER. SOC channels are considered the major Ca2+-entry pathways in non-excitable cells. The STIM1  on endoplasmic reticulum (ER) and Orai1 on plasma membrane are the molecular identities responsible for SOC-channel activation. When ER Ca2+ stores are depleted, STIM1 proteins are promoted to aggregate and interact with Orai1 to open the channel, mediating Ca2+ entry [2+ sensors and Orai proteins are structural components of the SOC channel.SOCs are a ubiquitous Ca2+ entry ,44. TherStim1-knockout mice, LPS-induced vascular permeability changes were significantly reduced [2+ entry and nuclear accumulation of NFAT, a family transcription factor that influences gene expression. Similar results were obtained in human cell lines. Using a human septic serum or lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) experimental system, downregulation of STIM1 by RNAi or channel inhibitors significantly inhibited serum or LPS-induced extracellular calcium influx, and then the release of inflammatory cytokines [2+. Their results demonstrated that STIM1 protein played a key role in RhoA activation and the formation of actin stress fibers [In EC-specific  reduced ,46. Moreytokines ,48. Howeytokines . In HUVEs fibers . 2+ entry induced by LPS, and exhibited the potential inhibition of endothelial activation induced by LPS [Pharmacological channel inhibitors also showed potential therapeutic effects in an LPS-induced ALI mouse model. BTP2, a small-molecule SOC-channel blocker, was delivered two hours after systemic LPS administration and resulted in a striking reduction in vascular leakage and pulmonary edema ,46. The d by LPS .2+ located mostly on the plasma membranes of animal tissues [2+ ions, the depletion of Ca2+ stores in the ER, and many others. Additionally, some TRP channels are voltage-sensitive and ligand-gated. TRP channels are ubiquitously present in different tissues of mammalian species. The channels mediate various physical activities, such as the sensation of pain, coldness, warmth or hotness, pressure, taste, and vision. The activation of TRP channels is associated with G-protein-coupled receptors (GPCRs), receptor tyrosine kinases, and phospholipase C. The role of TRP channels and their diverse involvement in critical pathophysiological events has been reviewed elsewhere [The TRP channel is a non-selective cation channel that is predominately permeable for Ca tissues ,53. Theslsewhere ,55,56.2+ influx and signaling. Neither the expression nor functional role(s) of any TRPML, TRPP, and TRPA family members has been studied in the lung endothelium. Considering the activation characteristics of the channel, TRP channels may act as chemosensors during toxicant induced ALI [According to their amino-acid sequence, TRP channels are categorized into six sub-families, including TRP canonical or classical (TRPC), TRP vanilloid (TRPV), TRP melastatin (TRPM), TRP ankyrin (TRPA), TRP polycystin (TRPP), and TRP mucolipin (TRPML) . They aruced ALI . Besidesuced ALI . It is w2+ entry in ECs. TLR4 or EGFR are activated by their ligands. Then, EC TRPC channels are opened by GPCR-operated activation resulting in increased intracellular Ca2+. Ca2+ binds to CaM and in turn activates MLCK. The downstream events include the activation of myosin light chain II, the interaction of actin–myosin and the formation of F-actin stress fibers. Thus, the endothelial inter-endothelial gap is formed and endothelial-barrier failure ensues.The TRPC family has been shown to play an important role in regulating Ca−/− mice showed significant resistance to thrombin-induced hyperpermeability and exhibited 60% less mortality from endotoxin. A mechanistic study indicated that the loss of TRPC1 augments cell-surface VE-cadherin expression and thereby prevents AJ disruption [Evidence indicates that TRPC1/4 activation can disrupt adherence junctions (AJs), resulting in endothelial hyperpermeability . ECs Trpsruption . In HUVEsruption .2+ influx, cellular shape changes and impaired barrier function [2+ entry mediated by TRPC6 in ECs in a TLR4-dependent manner. Furthermore Ca2+ entry mediated by TRPC6, in turn, activates the non-muscle myosin light chain kinase (MYLK), which not only increases lung vascular permeability but also serves as a scaffold to promote the interaction of myeloid differentiation factor 88 (MyD88) and IL-1R-associated kinase 4, which are required for NF-κB activation and lung inflammation [TRPC6 is gated by C-type phospholipase (PLC) pathways and highly expressed in the lung. Lung endothelial cells from TRPC6-deficient mice showed attenuated ischemia-induced Cafunction . Norbertfunction . In anotammation .−/− mice, whereas the response to thapsigargin remained unchanged [TRPV4 is a key channel for increasing endothelial permeability . TRPV4-dnchanged . Notablynchanged , which anchanged , ROS- [7nchanged , chemicanchanged , and evenchanged .Therefore, TRPV4 antagonists are the most studied compounds to reduce EC permeability (review ). In aniClinicaltrials.gov identifier: NCT02119260, accessed on 26 April 2022) [GlaxoSmithKline (GSK) previously reported a series of TRPV4 antagonists quinolines and benzimidazoles, but failed to deliver clinical drug candidates ,81. GSK2il 2022) . Howeveril 2022) . The res2+-permeable channel. Oxidants generated by activated endothelial cells are known to increase vascular endothelial permeability and play a crucial role in several lung diseases. In cultured pulmonary-artery endothelial cells, TRPM2 proved to be involved in mediating oxidant-induced calcium entry and endothelial hyperpermeability [2+ and activated the apoptosis pathway [The TRPM2 channel is an oxidant-sensitive Caeability . In huma pathway . Particu pathway . TRPM2 d pathway .2+. TRPC1 is activated by IP3-dependet Ca2+ release and TRPC6 is activated by DAG. Ca2+ influx activates the CaM/MLCK (myosin light chain kinase)-signaling pathway by binding to CaM, which in turn activates MLCK. Activated MLCK inhibits MLCP, thereby activating MLC II (myosin light chain II), the actin–myosin interaction and the formation of F-actin stress fibers. The resulting tensile force on endothelial cell–cell junctions  causes inter-endothelial gap formation and endothelial-barrier failure.In summary, pro-inflammatory or barrier-disturbing receptors including TLR4 and EGFR are activated by their ligands, which open the EC GPCR-operated activation of TRPC channels, increasing intracellular CaBesides increased intracellular calcium levels, the role of TRP channels in EC dysfunction during ALI are also mediated through the covalent modification of cysteine residues on the ion channel or through lipid messengers, such as diacylglycerol and phosphatidylinositol phosphate.2+ but also to other cations, such as Na+, K+, and Mg2+, therefore being non-selective Ca2+ channels. Studies showed that piezo1 plays an important role in various physical activities, including vascular function, epithelial homeostasis, red-blood-cell-volume regulation, etc. Piezo1 is activated by several mechanical stress forces such as physiological shear stress and cell-wall tension.The Piezo channel is a mechanically activated ion channel involved in sensing forces in various cell types and tissues. In 2010, the Piezo family was discovered and named. During the past 10 years, Piezo1 was found mainly to be expressed in non-excitable cell types in experimental animal models, while Piezo2 is expressed in sensory neurons . Piezo cCalcium influx is mediated by Piezo transduction of mechanical signals into biological signals . RecentlPiezo1-KOmice, in which Piezo1 was conditionally deleted in ECs [2+, which increases calpain activity and the degradation of VE-cadherin. Therefore, Piezo1 probably mediates lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherence-junction (AJ) protein VE-cadherin.Lung-endothelial-barrier dysfunction and edema induced by raising pulmonary microvessel pressure were abolished in ECd in ECs . The defd in ECs . In an id in ECs . The uprPiezo1 and TRPV4 channels have both, independently, been involved in high-venous-pressure- and fluid-shear-stress-induced lung microvascular hyperpermeability in endothelial cells. Sandip M Swain and Rodger A Liddle investigated the mechanism that Piezo1 and TRPV4 channels perform during endothelial dysfunction . HC06704Calcium influx plays a crucial role in the occurrence and development of ALI. An increase in intracellular calcium not only increases the permeability of endothelial cells, but also contributes to neutrophil activation and endothelial cellular inflammation. Therefore, blocking calcium influx into ECs is a potential therapeutic strategy for lung injury. Some calcium-channel modulators were effective in inhibiting lung EC permeability, as well as in lung-injury mouse models. The compounds mentioned in this article are shown in The key role of calcium influx in ALI has been illuminated by the accumulated studies. Increased intracellular calcium promotes the transformation of EC morphology and the expansion of AJs, which leads to the increased permeability of ECs. The calcium-signaling cascade also contributes to the endothelial cellular inflammatory response, such as the increased expression of vascular adhesion molecules. Therefore, targeting calcium influx into cells is an effective strategy for ALI therapy and some calcium-channel blockers significantly reduce the increase in endothelial permeability and inflammation. Evidence obtained from these studies provides a convincing rationale for human therapies that target the EC dysfunction during ALI, especially in the early phase of ALI. However, several important points still need to be addressed before calcium-channel blockers can be used to treat human lung injury. First, these calcium channels such as TRPV4 channels are not only expressed in EC but also other cell types. Channel blockers may have off-target effects, especially on immune cells. Second, most lung-injury models used in evaluating the protection effect of channel blockers are induced by LPS. The channel-antagonist-mediated inhibition of lung EC dysfunction should be tested in the presence of a live bacterial infection, which is more comparable to innate or adaptive immune response to infection. Finally, although modulators for calcium channels are the pots of gold for anti-ALI development, high quality and widely available channel modulators are not many, and modulators should be further generated with properties that make them suitable for in vivo use.


This quality improvement study uses data from the MedSafer trial to evaluate drug-drug interactions between nirmatrelvir-ritonavir and maintenance medications to identify use of potentially inappropriate medications in older adults with polypharmacy. We used data from the MedSafer cluster randomized clinical trial2  to identify DDIs between nirmatrelvir-ritonavir and potentially inappropriate medications (PIMs) in older adults with polypharmacy and to craft deprescribing guidance.The antiviral nirmatrelvir-ritonavir reduces the risk of severe complications in high-risk, symptomatic, unvaccinated adults with COVID-19.2 and participants provided consent to the secondary use of data. Additional details for the present quality improvement study are provided in the eMethods in the SQUIRE reporting guideline.3Ethics board approval was obtained from the study sites of the MedSafer trial,Briefly, the MedSafer trial enrolled hospitalized adults 65 years or older who were taking 5 or more medications. Data pertaining to medications and comorbidities were analyzed according to an expert rule set for identifying PIMs  anticipatory deprescribing for drugs that cannot simply be held or dose-reduced at the time of nirmatrelvir-ritonavir exposure, and/or (2) deprescribing at the approximate time of nirmatrelvir-ritonavir receipt. Recommendations were based on the literature and our expert opinion .6 Data were analyzed from January 20 to February 8, 2022.Herein, we theoretically exposed the trial cohort to treatment with nirmatrelvir-ritonavir to identify DDIs with maintenance medications and, specifically, with PIMs (candidate drugs for deprescribing). We linked these interactions with potential harms, which were classified as other, moderate, or severe . The median (IQR) number of daily at-home medications was 10 (8-14) and PIMs was 2 (1-4).The MedSafer trialOf 5698 patients, 3869 (67.9%) received at least 1 interacting medication prescription . The mosIn a population of older adults with polypharmacy, DDIs with nirmatrelvir-ritonavir were common. Many DDIs involved PIMs, which were candidate drugs for deprescribing. Because of these DDIs, many older adults with polypharmacy could not safely receive nirmatrelvir-ritonavir. Not all DDIs could be mitigated by simply holding or dose-reducing a medication. Some medications required anticipatory deprescribing to prevent adverse drug withdrawal events attributed to sudden stopping  or prolonged half-life .2 Symptomatic COVID-19 and potential treatment with nirmatrelvir-ritonavir should prompt a thorough medication review for DDIs, at which point deprescribing could be considered for PIMs. A study limitation was the theoretical nature of exposure to nirmatrelvir-ritonavir; however, with tens of millions of treatment courses purchased worldwide and with older adults at risk for both severe COVID-19 and polypharmacy, nirmatrelvir-ritonavir will be relatively common.Intercurrent health conditions can be an opportune time to deprescribe PIMs.Overall, anticipatory deprescribing could increase the proportion of older adults who benefit from nirmatrelvir-ritonavir. Furthermore, deprescribing PIMs, rather than simply represcribing after receipt of nirmatrelvir-ritonavir, could be beneficial for older adults with polypharmacy.


The Chimeric antigen receptor (CAR)-T cell therapy has made inroads in treating hematological malignancies. Nonetheless, there are still multiple hurdles in CAR-T cell therapy for solid tumors. Primary CAR-expressing macrophage cells (CAR-Ms) and induced pluripotent stem cells (iPSCs)-derived CAR-expressing macrophage cells (CAR-iMacs) have emerged as attractive alternatives in our quest for an efficient and inexpensive approach for tumor immune cell therapy. In this review, we list the current state of development of human CAR-macrophages and provide an overview of the crucial functions of human CAR-macrophages in the field of tumor immune cell therapy. In recent years, there has been a burgeoning interest in harnessing immune cell therapy for solid cancers. Inspired by the pattern that T-cell antigen receptor (TCR)-formed immunological synapse stimulates immune activation of cytotoxic T cell, chimeric antigen receptor (CAR) has emerged in response to the desire to use engineered cell products for much more effective treatment. CAR is a type of synthetic chimera protein which encompasses an extracellular antigen-recognition domain, a transmembrane domain, and an intracellular domain . The extMacrophages are well established for their unique roles in immunoregulation and capacity to infiltrate solid tumors ,8. TradiTregs) and Myeloid-derived suppressor cells (MDSCs), secreting inhibitory cytokines, inducing hyper-expression of PD-L1, which is the ligand of programmed cell death protein 1 (PD-1) of T cells and altering the metabolic profile of immune cells [Current evidence suggests that tumor-associated macrophages (TAMs) account for the majority of infiltrating immune cells in tumor tissue ,14 and one cells ,15. It hne cells  and recrne cells . Moreovene cells ,18. Overne cells ,21,22,23ne cells . Meanwhine cells . Consequne cells . Apart fne cells . Otherwine cells ,29. In ane cells ,31,32,33Given the critical promoting role of M2 macrophages in the progression of solid tumors, reprogramming M2 macrophages into a pro-inflammatory phenotype in the TME represents a promising therapeutic approach. To achieve this goal, radiotherapy via fractionated cumulative radiation dose regimens , chemothMacrophages are well recognized as effector cells that eliminate cancer cells due to their phagocytic ability, and are therefore drawing attention in the field of immunotherapy of cancers ,47. In tTHP-1, a human leukemia monocytic cell line isolated from a one-year-old male patient, was found to share some canonical morphological and functional properties with primary monocytes and macrophages and the expression of differentiation markers ,49. Meth+ monocytes by treating them with GM-CSF  macrophages instead of CAR-Ms could upregulate the M2 marker CD206 when stimulated with IL4-, IL13-, or SKOV3-conditioned media. Accordingly, UTD macrophages stimulated with IL4 showed an evident increase in basal oxygen consumption rate, indicating the M2 polarization tendency of the wild-type macrophages, while CAR-Ms could withstand remodeling towards the M2 phenotype. Moreover, transcriptome analysis indicated that IL4 or IL13 triggered fewer genes, including MRC1, in CAR-Ms than UTD macrophages .Furthermore, in vitro experiments were conducted to verify the effect of CAR on surrounding macrophages which are likely to exist in an immunosuppressive TME, and found that CAR-Ms induced the activation of macrophage-specific pro-inflammatory pathways, such as interferon signaling and iNOS signaling pathways. Moreover, CAR-Ms-conditioned media could lead to a phenotypic shift in wild-type macrophages towards the pro-inflammatory state (M1). Finally, exposure to CAR-Ms resulted in the expression and localization of the pro-inflammatory markers on the macrophage plasma membrane. Overall, CAR-macrophages strongly affected surrounding immune cells, which accounted for CAR-Ms’ antitumor activity to a certain extent .+ T cells than the CAR-Ms alone or tumor cells alone.Based on the interaction between macrophages and lymphocytes, experiments were performed to assess the stimulation and antigen-presenting capability of CAR-Ms to T cells. The above findings suggested that the combination of CAR-Ms and the tumor-associated antigen NY-ESO1-expressing tumor cells led to more robust activation of anti-NY-ESO-1 CD8null-3/GM/SF (NSGS) mice. The first approach involved intravenous (IV) injection of SKOV3 cells to trigger lung metastases and then dividing mice into different groups that received various treatments via a single IV injection. The other approach was to model intraperitoneal (IP) carcinomatosis using a similar approach to offer distinctive management with a single IP injection. It was concluded that CAR-Ms resulted in significant tumor deterioration, while UTD macrophages did not [Two procedures have been conducted to explore CAR-Ms’ anticancer effects in NOD-scid IL2Rg did not . In addiImportantly, persistence, biodistribution, and even chemotaxis ability of adoptive transplanted immune cells in living bodies have been associated with antitumor efficacy. The authors reported that CAR-Ms could survive at least 62 days in tumor-free NSGS mice. Furthermore, adenovirus-based genetic manipulation did not destroy the expression profile of chemokine receptors, meaning intact migrating and infiltrating ability of CAR-Ms towards relevant chemokines. Interestingly, CAR-Ms accumulated in the liver, regarded as an innate immune organ after IV injection in all experimental mice.Subsequently, given that adenoviral infection can activate the inflammasome ,72, it wMoreover, the dynamic interaction of CAR-Ms with the human tumor microenvironment (TME) in a humanized immune system (HIS) mouse model was next elucidated. HIS mouse models generated through the transplantation of HSCs in NSG mice were treated with CAR-Ms. The single-cell RNA-Seq analysis showed that CAR-Ms and UTD macrophages isolated from HIS mice shared distinct phenotypes within the humanized TME, and CAR-Ms maintained pro-inflammatory features compared to UTD macrophages.Finally, similar to in vitro studies, an experiment in vivo was performed to assess the potential of CAR-Ms to stimulate T cells. As expected, tumor-bearing NSGS mice that received combination therapy of CAR-Ms and donor-derived T cells displayed a favorable prognosis compared to the mice which received treatment of the single type of CAR-Ms or T cells. This finding illustrated that the interplay between adoptive-transplanted CAR-Ms and endogenous T cells should be taken into the evaluation of syngeneic immunocompetent murine tumor models in future studies.Zhang et al. successfully obtained CAR (CD19)-iMacs and CAR (Mesothelin)-iMacs cells using the iPSC-derived CAR-iMacs approach and subsequently examined their antitumor potency by incubating with CD19-expressing K562 leukemia cells or Mesothelin-expressing OVCAR3/ASPC1 ovarian/pancreatic cancer cells, respectively, in vitro . Based oSimilarly, when injected into NSG mice, the CAR-iMacs proliferated in vivo for 3 days; the therapeutic effect persisted for 3–4 weeks and gradually disappeared . FurtherDespite the substantial progress CAR-T cell therapy has achieved in clinical treatment , many chCompared with CAR-T cells, CAR-macrophages bring several unique benefits. T cells exhibit limited ability to reach the tumor environment due to the matrix-forming physical barriers throughout the tumor cells, while macrophages can effortlessly submerge in the cancer environment . AdditioNonetheless, though macrophages have been studied in vivo and in vitro for many years, their genetic modification to improve their application to solid tumor therapy remains challenging. Further studies are required to demonstrate the effectiveness of CAR-macrophages in immunotherapy. Given that macrophages cannot proliferate by themselves in vitro or in vivo, their limited cell number is a significant challenge in CAR-macrophages immunotherapy. Moreover, little is known about the dose of macrophages required in vivo. Exogenous macrophages cross the lung after injection and predominantly linger in the liver , lowerinRemodeling TAMs is an exciting and promising strategy for generating antitumor effects during the immunotherapy of neoplasms. Among the multiple efforts, adoptive transfer of genetically modified macrophages represents a promising therapeutic prospect. Accordingly, macrophages equipped with tumor antigen-specific CARs exhibit significantly improved cytotoxicity against tumor antigen-expressing cells and potentially reprogram the surrounding microenvironment  Figure . Except


Bacterial co-infection has been reported with COVID-19, but risk factors for bacterial co-infection remain unclear due to limited large scale studies. We seek to identify predictive factors associated with risk of co-infection with multidrug-resistant organisms for patients hospitalized at Veterans Affairs (VA) hospitals with COVID-19.This retrospective cohort study included Veterans admitted to VA hospitals from March 1, 2020 through May 31, 2022 with a confirmed positive COVID-19 test within the previous 14 days and up to 2 days after admission. Outcomes of interest were hospital-onset co-infection  and community-onset co-infection . Potential risk factors included both patient-  and facility-level covariates . We compared the covariate distributions for patients with and without HOI and COI. Our analytical approaches included variance inflation factors to detect the presence of multicollinearity among these factors, and Least Absolute Shrinkage and Selection Operator to identify the subset of factors associated with HOI and COI. We conducted a two-stage analysis, first performing feature selection among the individual-level risk factors followed by identification of facility-level risk factors. Optimal models were identified using 10-fold cross validation.C difficile infection rates were more likely to have COI detected ) [Table 2]. Homeless Veterans had higher risk of developing an HOI ), but not a COI.By July 2021, 33,383 patients were admitted to VA with positive COVID-19 test. We found that medications for ventilator induction ), norepinephrine ) and antimicrobial therapies for gram-positive infections ) [Table 1] were associated with the increased risk of HOI and patients in facilities with high Risk factors for HOI and COI in COVID-19 were distinct, with specific classes of medications and antibiotics as well as patient factors resulting in increased risk for HOI. Further work is needed to better understand the risk factors for COI.Karim Khader, PhD, BioFire Diagnostics: Grant/Research Support.


Several reports of unheeded complications secondary to the current mass international rollout of SARS-COV-2 vaccines, one of which is myocarditis occurring with the FDA fully approved vaccine, Pfizer, and others.Certain miRNAs (non-coding RNA sequences) are involved in the pathogenesis in viral myocarditis, and those miRNAs are interestingly upregulated in severe COVID-19. We hypothesize that the use of mRNA-based vaccines may be triggering the release of host miRNAs or that trigger the occurrence of myocarditis. This is based on the finding of altered host miRNA expression promoting virus-induced myocarditis.In conclusion, miRNAs are likely implicated in myocarditis associated with mRNA vaccines. Our hypothesis suggests the use of miRNA as a biomarker for the diagnosis of mRNA vaccine-induced myocarditis. Additionally, the interplay between viral miRNA and the host immune system could alter inflammatory profiles, hence suggesting the use of therapeutic inhibition to prevent such complications. Many lives were lost since the emergence of COVID-19 (coronavirus disease 2019) pandemic in China 2019. The resultant global health crisis has compelled health authorities all over the world to allow emergency authorization to many vaccines before full FDA (Food and drug agency) approval. However, a major setback of such emergency authorization was the rise of unexpected complications.One of the most serious complications of the COVID-19 vaccines is post-vaccination myocarditis associated with the mRNA vaccines  vaccines such as Janssen. Patients who developed myocarditis presented with chest pain and elevated troponin levels after receiving the second dose of the mRNA vaccine. Most of their symptoms resolved without treatment  proteins and self-antigens, triggering an abnormal immune response reaction  expression mediates the pathogenesis of viral myocarditis. miRNAs are short non-coding RNAs that regulate gene expression during cellular processes, and they are known to mediate inflammation, myocardial remodeling, and reverse remodeling. They are either host-generated after exposure of tissues to viral DNA/RNA or directly derived from the manipulation of the host cellular machinery to viral DNA and RNA.These two sources of miRNAs might be hypothetically induced by mRNA vaccines and might mean that recognizing and screening certain miRNA levels following administration of mRNA vaccines might help in predicting the occurrence of mRNA vaccine-induced myocarditis. . Its level is elevated in plasma during myocarditis and could be used as a noninvasive biomarker for diagnosing myocarditis -induced viral myocarditis, macrophage infiltration and miRNA-155, which regulates the differentiation of macrophages, were found to be hallmark features of viral myocarditis. miRNA-155 silencing might affect macrophage polarization and shifting of the inflammatory mediator's balance, resulting in an increase in alternatively activated macrophages (M2) and a decrease in classically activated macrophages (M1) in the heart. Subsequently, the risks associated with viral myocarditis decrease. Hence, antagonizing miR-155 is a potential therapeutic target against viral myocarditis  during the inflammatory phase. Furthermore, suppression of miRNA-155 reduced weight loss caused by systemic illness and reduced the number of circulating leukocytes induced by CVB3 infection . miRNA-141-3p is known to decrease myocardial inflammation by suppressing STAT4  on echocardiography in the non-injected mice, and increased LVEF and LVFS  in miR-141-3p agomir-injected mice. MiRNA-141-3p overexpression  to evade the host immune response.More than 250 v-miRNAs exist. The majority of which are present in the DNA viruses of the herpes virus family. The detection of v-miRNAs in RNA viruses is controversial. A few reports suggested that non-canonical miRNA-like small RNAs are produced during RNA virus infections. However, these small RNAs lack the canonical stem-loop structure of miRNAs, and thus their biogenesis and function are not well understood  the RNA viruses consist of positive or negative sense or double-stranded RNA (dsRNA) and replicate in the host cell cytoplasm, which is inaccessible to the miRNA biogenesis machinery in the nuclei. (b) Excision of pre-miRNA from the primary transcript might destroy RNA-based viral genomes. c-the generated v-miRNA may target the viral genome itself, cleaving the viral genome. To date, viruses involved in myocarditis were not found to release such types of v-miRNAs. However, below are the main cellular effects of the currently discovered v-miRNAs  miRNA-BART5 (Bamhi fragment A rightward transcript), which controls proliferation and establishes latent infection by targeting PUMA. PUMA (The p53 upregulated modulator of apoptosis) is known to modulate apoptosis by p53. So, by suppressing PUMA, EBV miRNAs alter the susceptibility to apoptotic agents and improve host cell survival  v-miRNAs reduce the expression of C/EBPβ p20 (Enhancer binding protein), a known negative regulator of IL-6 and IL-10 cytokines. This results in regulation of cytokine signaling in infected cells and overexpression of pro-inflammatory IL-6 leading to tissue damage  miRNAs target host genes involved in the antiviral immune response. miRNA-UL112 blocks the natural killer (NK) cell-mediated recognition of virus-infected cells, by inhibiting MICB expression (MHC class I chain-related protein B), which is a stress-induced ligand essential for NK-cell activity  RNA that is upregulated in cardiac tissue in response to cardiomyocyte inflammation. It affects signaling pathways involved in cardiomyocyte growth, autophagy, calcium handling, and contractility. Thus, miRNA-132 appears as a potentially promising molecular pathophysiological target in myocarditis and heart failure (HF) treatment. CDR132L is a miRNA-132 inhibitor. It is a synthetic nucleic acid antisense oligonucleotide (ASO) inhibitor with a phosphorylated backbone.A prospective, randomized, double-blind, placebo-controlled, dose-ranging study of intravenous antagonist of miRNA-132-3p  was performed by Täubel and colleagues on 28 HF patients, with left ventricular ejection fraction between ≥ 30% and < 50%, or amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) > 125 ng/L at screening, and they were randomized to receive CDR132L  or placebo . Dose-dependent CDR132L treatment reduced miRNA-132 in plasma. Patients given CDR132L ≥ 1 mg/kg displayed a median 23.3% NT-proBNP reduction, versus a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraged positive trends for relevant cardiac fibrosis biomarkers. CDR132L was safe and well tolerated, without dose-limiting toxicity. The suggested dose level is 1 mg/kg of CDR132L. Both, direct inhibition and indirect inhibition of miRNAs were proven useful . It silences miRNA-21 that promotes cardiac fibrosis, diminishing fibroblast proliferation, and collagen type 1 production and crosslinking that cause heart fibrosis.In a randomized clinical trial conducted by Gavin A Lewis et al., to evaluate the efficacy of pirfenidone in the treatment of heart failure patients with preserved ejection fraction, pirfenidone and placebo were compared in the treatment of HFpEF (Heart Failure with preserved Ejection Fraction) in 47 participants of mean age 78 and mean myocardial extracellular volume 30%, shown by cardiac imaging 30%.The results showed a reduction in myocardial fibrosis in 52 weeks. 100 capsules of pirfenidone were taken and resulted in a mean reduction of 0.06%. There was an improvement in 8 out of 10 KCCQ (Cardiomyopathy Questionnaire (Kansas City scores)), including clinical improvements and log NT-proBNP reduction.The reduction in log NT-proBNP with pirfenidone was due to left ventricular myocardial stiffness improvement secondary to myocardial fibrosis regression. The decrease in myocardial fibrosis with log NT-proBNP reduction provided further evidence of its effect in decreasing heart fibrosis and treating HFpEF through non-coding miRNA silencing. The drug is effective in the structure but not the hemodynamic changes occurring in Heart failure. So, RAAS  inhibitors should be studied for cardiac hemodynamic effects, synergistically with pirfenidone (Aimo et al. *Another modulator of miRNA levels is using RNA helicase; Wang and colleagues studied the effect of RNA helicases on miRNA expression in breast tissue and found similar effects of RNA helicases to miRNA antagonists on tissue levels of deleterious miRNA-21 involved in the development of breast cancer (Wang et al. Figure In conclusion, miRNA upregulation or downregulation by mRNA vaccines might explain the myocarditis observed from mRNA vaccines. This might explain why younger male individuals are at a higher risk of myocarditis as they have larger muscle mass, expressing higher circulating levels of myocarditis-producing miRNAs. Key miRNAs, such as miRNA-155, are highly expressed in skeletal muscles. Recognizing this fact allows risk stratification of this complication before receiving mRNA vaccines, via sarcopenia index calculation or testing for target miRNAs serum levels. miRNAs can also be therapeutic by developing antisense miRNAs blocking the action of the implicated miRNAs and thus preventing the myocarditis process.It is also to be noted that there is a trend toward the future use of mRNA technology for developing vaccines against other infectious agents and cancer. The early identification of the mechanisms involved in the pathogenesis of complications induced by those vaccines can help in avoiding and treating similar complications when those vaccines are targeting other disorders such as HIV or malignancies (Pardi et al.


Herpesviruses belong to large double-stranded DNA viruses. They are under a wide range of hosts and establish lifelong infection, which creates a burden on human health and animal health. Innate immunity is the host’s innate defense ability. Activating the innate immune signaling pathway and producing type I interferon is the host’s first line of defense against infectious pathogens. Emerging evidence indicates that the cGAS-STING signaling pathway plays an important role in the innate immunity in response to herpesvirus infections. In parallel, because of the constant selective pressure imposed by host immunity, herpesvirus also evolves to target the cGAS-STING signaling pathway to inhibit or escape the innate immune responses. In the current review, we insight on the classical cGAS-STING signaling pathway. We describe the activation of cGAS-STING signaling pathway during herpesvirus infections and strategies of herpesvirus targeting this pathway to evade host antiviral response. Furthermore, we outline the immunotherapy boosting cGAS-STING signaling pathway. Herpesviridae family comprises three subfamilies: alphaherpesvirinae, betaherpesvirinae, and gammaherpesvirinae, composed of 115 viruses , stimulator of interferon genes (STING) , 17. SubIn the current review, we insight on the classical cGAS-STING signaling pathway. Then we describe the activation of cGAS-STING signaling pathway during herpesvirus infections and strategies of herpesvirus targeting this pathway to inhibit and evade the host antiviral response. Finally, we outline the immunotherapy enhancing cGAS-STING signaling pathway.cGAS-STING signaling pathway is one of the important pattern recognition and effector pathways in host innate immunity. The signaling of classical cGAS-STING signaling pathway is generally thought to consist of three main phases: nucleic acid-sensing, intracellular signal transduction, and immune response activation Figure 1Viral DNA is sensed by specific sensor proteins which mainly present in the cytoplasm of host cells. Sensor proteins recognize viral DNA and activate an innate immune response against the virus . cGAS isSTING is an important junctional protein in the cGAS-STING signaling pathway and is the downstream ligand of cGAMP. STING utilizes its amino-terminal transmembrane domain to anchor it to the ER membrane, with the carboxyl terminus projecting into the cytoplasm . With orThe recruited IRF3 forms a dimer after phosphorylation by TBK1. It then enters the nucleus to induce transcription of IFN-I . TriggerThe cGAS-STING signaling pathway is activated during herpesvirus infections Figure 2The cGAS-STING signaling pathway is critical to drive the initial IFN-I response and limite herpesvirus infection. Multiple herpesviruses have been shown to trigger this pathway, including herpes simplex virus-1 (HSV-1), oncolytic herpes simplex viruses (oHSV), pseudorabies virus (PRV), human cytomegalovirus (HCMV), mouse cytomegalovirus (MCMV), Kaposi’s sarcoma-associated herpesvirus (KSHV) , 67–72. In addition to being directly activated by viral DNA, the cGAS-STING signaling pathway can undergo different modifications for optimal signaling of HSV-1 infection, including ubiquitination and phosphorylation. E3 ubiquitin ligases, TRAF6 and RINCK , promotes ubiquitination and activation of cGAS in IFN-I production during HSV-1 infection. IFN-β production is inhibited in TRAF6-knockdown cells infected with HSV-1. IFN-I production also is inhibited the RINCK−deletion cells upon HSV-1 infection, which is associated with the phosphorylation of TBK1 and IRF3 , 74. TRIifnb1, ifvn4, and isg56. Following HSV-1 infection, CSK phosphorylates STING at Y240 and Y245 after the phosphorylation of STING at S366 by TBK1  is a newly identified intranuclear DNA sensing protein. hnRNPA2B1 binds intranuclear viral DNA and transfers it to the cytoplasm during HSV-1 infection. It then activates TBK1 to promote the expression of downstream antiviral genes . ZCCHC3, by TBK1 . β-arres by TBK1 . A recenlication .Herpesviruses are remarkable pathogens, which encode at least 70 functional proteins. The member known to encode the largest number proteins is HCMV that encode about 170 proteins. They can efficiently utilize their proteins and host components to evade host immunity and achieve proliferation and egress. With the in-depth study of herpesvirus-host interactions, we have understood how herpesviruses evade the cGAS-STING signaling pathway Figure 2via the conserved herpesvirus protein ICP27. ICP27 targets TBK1 and STING in the cGAS-SING signaling pathway. The activity of TBK1 is important for this process   . MCMV m1nd IRF3) .The proteins of several gammaherpesviruses have been reported to inhibit the cGAS-STING signaling pathway. The viral IFN regulatory factor 1 (vIRF1) of KSHV was shown to be an important negative regulator of STING. vIRF1 blocks the interactions of STING with TBK1 and then inhibits the phosphorylation and activation of STING to suppress cGAS-STING-mediated antiviral immunity . The latThe cGAS-STING signaling pathway is indispensable for the sensing of herpesvirus in host innate immunity, which makes this pathway an important candidate target for the therapy of herpesvirus infections. In fact, numerous studies have explored the immunotherapy targeting cGAS-STING signaling pathway, especially in tumor and cancer treatment, showing great therapeutic potential. Immunotherapy boosting the cGAS-STING pathway mainly includes STING agonist, improved delivery system and combination therapy. We outline these therapeutic approaches below, which may provide new ideas for against herpesvirus infections.Cyclic dinucleotides (CDNs) have been verified as a class of cGAS-STING signaling pathways agonist involved in the immune system in prokaryotic cells and mammalian cells. CDNs consist of cyclic di-GMP (cdGMP), cyclic di-AMP (cdAMP), cyclic AMP-GMP (cGAMP) . cGAMP iExcept for natural CDNs, synthetic CDNs with better properties are developed in recent years, such as ADU-S100 and ADU-V19. ADU-S100 (ML RR-S2 CDN), also known as MIW815, is a dithio CDN with high affinity to human STING. Therefore, it becomes the first STING agonist to enter clinical trials for advanced metastatic solid tumors or lymphomas. ADU-V19 (RR-S2 cGAMP) is similar to ADU-S100 and targets human STING .Recent studies indicate that non-CDN agonists also play an important pharmacological role in immunotherapy targeting the cGAS-STING signaling pathway. 5,6-dimethylxanthenone-4-acetic acid, also named DMXAA or ASA404, is a flavonoid. DMXAA is a STING non-CDN agonist and is found to be selective for STING. In T cells of B6 mice, the IFN-I response is considerably enhanced after treatment with DMXAA . HowevercGAS-STING agonists are usually soluble, susceptible to enzymatic hydrolysis, and negatively charged, limiting their therapeutic efficacy . TherefoLiposome is the first FDA-approved nano-biotherapeutic carrier. Liposome nano-delivery systems containing STING agonists can target specific cells for cell activation. Liposome nanoparticles encapsulating cdGMP target to draining lymph nodes. The therapeutic efficacy of the nano-delivery system is considerably improved in murine compared with cdGMP alone . Polymerin vivo  and acid-sensitive acetylated dextran (Ace-DEX) polymer microparticle (Ace-DEX MP) . TMPs arin vivo .Hydrogel is another common delivery system that forms viscoelastic gels by binding and retaining water. Cross-linked hyaluronic acid (HA) hydrogel loaded with 2’, 3’-cdAM (PS)2  significantly enhances the therapeutic effect of tumors . cGAMP-lSTING agonists and optimized delivery systems target and activate the cGAS-STING signaling pathway to promote immunotherapy of tumors and other diseases. However, a growing body of research has shown that combination immunotherapy targeting the cGAS-STING signaling pathway maximizes the efficacy of STING agonists in immunotherapy of disease and reduce drug negative impacts.Appropriate adjuvants play a major role in enhancing the specific immunity of vaccines. To increase the effectiveness of vaccines, various adjuvants have been developed to promote innate immunity. Among them, STING agonists have shown potential as adjuvants in vaccinology. STINGVAX (ML-RR-S2-CDA) is believed to be the first cancer vaccine to utilize a STING agonist as an adjuvant, which comprises cancer cells secreting granulocyte-macrophage colony-stimulating factor and ADU-S100 . STINGVASynergistic administration reduces the required dose of each drug and narrows the side effects of drugs. STING agonists combined with other chemotherapy drugs have achieved good efficacy in anti-tumor. DMXAA synergistically promotes cell death in mouse sarcomas when treated with cyclophosphamide . The comUsually, immune checkpoint blockers (ICBs) target cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PD-1) or its ligand PD-L1 . CombinaIn the current review, we describe the cGAS-STING signaling pathway in herpesvirus infections and outline the immunotherapy boosting this pathway. The cGAS-STING signaling pathway is essential for immunological defense of the host against herpesvirus infections. In parallel, herpesviruses also evolves to target the cGAS-STING signaling pathway to inhibit or escape the host innate immune response, thereby promoting their replication. Given the importance of the cGAS-STING signaling pathway in the sensing of herpesvirus in innate immunity, it is an attractive antiviral strategy to develop and utilize immunotherapy that enhances the cGAS-STING signaling pathway. In addition, since our review is limited to the classical cGAS-STING signaling pathway in herpesvirus infections, exploring the potential crosstalk between this pathway and other pathways of the innate immune system during viral or other pathogenic infections may be a matter of great interest in the future, such as MAPK pathway and autophagy.LZ, LD, and ZX provided ideas. LD wrote the manuscript and designed the figures. ZX, FL, JZ, ZJ, HD, SL, XS, YG, and LZ reviewed and modified the manuscript. All authors contributed to the article and approved the submitted version.This article was supported by the Sichuan Province’s “14th Five-Year Plan” Sichuan Pig Major Science and Technology Project (No. 2021ZDZX0010) and the Key R&D Program in Rural Areas of Sichuan Provincial Department of Science and Technology (No. 2020YFN0147).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.


Inflammatory diseases are composed of numerous disorders and conditions that are characterized by inflammation, such as inflammatory bowel disease, hepatitis, and rheumatoid arthritis . In pathLin et al. demonstrated that lncRNA DLEU2 in the intestinal mucosa was dysregulated upon gut inflammation and could act as a diagnostic biomarker for ulcerative colitis . They identified DLEU2 as an anti-inflammatory lncRNA which inhibits gut inflammation by negatively regulating the NF-κB signaling pathway . Huang et al. reported that MHR (monocyte to high-density lipoprotein ratio) and MAR (monocyte to apolipoprotein A1 ratio) were ideal pro-inflammatory markers to reflect bone homeostasis imbalance caused by chronic inflammation in the bone microenvironment of postmenopausal women with type 2 diabetes mellitus . These researchers expanded the Research Topic of biomarkers to inflammatory diseases.Diagnostic biomarkers are useful in the therapeutics of diseases at multiple aspects along the patient’s diagnostic and treatment course. There are various inflammatory biomarkers including cytokines/chemokines, acute phase proteins, immune-related effectors, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, transcription factors, and growth factors . Lin et Qi et al. reported that inhibition of K-RasG13D mutation promoted cancer stemness and inflammation via RAS/ERK pathway . This finding may be important for understanding the effects of K-RasG13D mutation on promoting cancer stemness and inflammation when employing targeted therapies to K-RasG13D mutations in clinical practice. Promyelocytic leukemia zinc finger protein (PLZF) is a transcription factor that acts in regulating a variety of biological processes, such as spermatogenesis, stem cell maintenance, immune regulation, and invariant natural killer T cell (iNKT) development. Hu et al. demonstrated that PLZF, upregulated in mice with non-alcoholic fatty liver disease, was an essential regulator of hepatic lipid and glucose metabolism . PLZF activates SREBP-1c gene transcription by binding directly to the promoter, inducing repressor-to-activator conversion.Finding the right therapeutic targets is the most important approach in anti-inflammatory drug discovery. Many targets are responsible for the anti-inflammatory actions, such as inhibition of cytokine signaling, decreasing leucocyte activation, chemotaxis, and recruitment. Researchers have characterized several targets in this Research Topic. K-Ras is a well-studied oncogene. Schepetkin et al. designed, synthesized, and evaluated several novel analogs of O-substituted tryptanthrin oxime derivatives as c-Jun N-terminal kinase (JNK) inhibitors. Some of these compounds had a high affinity for JNK1-3 and potently inhibited LPS-induced nuclear NF-κB/AP-1 activation and IL-6 production in human monocytic cells . Ginsenoside Rc (Rc) is a major component of Panax ginseng. Tang et al. reported that Rc potentially ameliorated inflammatory response and barrier function to protect the gut from DSS-induced colitis . Zhong et al. showed that Rc alleviated acetaminophen-induced hepatotoxicity by relieving inflammation and oxidative stress . Both studies indicated that Rc could be a ligand of FXR by binding with the protein domain. Thus, signaling inhibitors and ligands of nuclear receptors may represent novel anti-inflammatory therapies for the inhibition of multiple cytokines and inflammatory signaling pathways.Target-based small molecule drug discovery is an important research direction for inflammatory diseases. in vivo to manage inflammatory diseases in the future. Further studies would identify the patients who would benefit from a particular anti-inflammatory drug action, making treatment for disease state more personalized and effective.Overall, we identified a series of attractive diagnostic biomarkers, therapeutic targets, and compounds for the intervention of inflammatory diseases . These b


Dicranum scoparium and the Antarctic flowering plant Colobanthus quitensis. These TCMBs are encoded by smaller RNA components of putative two-component viruses related to plant benyviruses. Similar to the RNA2 of benyviruses, TCMB-containing RNAs have the 5′-terminal coat protein gene and include the RNA helicase gene which is followed by two small overlapping cistrons encoding hydrophobic proteins with a distant sequence similarity to the TGB2 and TGB3 proteins. Unlike TGB, TCMB also includes a fourth 5′-terminal gene preceding the helicase gene and coding for a protein showing a similarity to the double-stranded RNA-binding proteins of the DSRM AtDRB-like superfamily. Additionally, based on phylogenetic analysis, we suggest the involvement of replicative beny-like helicases in the evolution of the BMB and TCMB movement genetic modules.Previous studies have shown that the RNA genomes of some plant viruses encode two related genetic modules required for virus movement over the host body, containing two or three genes and named the binary movement block (BMB) and triple gene block (TGB), respectively. In this paper, we predict a novel putative-related movement gene module, called the tetra-cistron movement block (TCMB), in the virus-like transcriptome assemblies of the moss  Martellivirales (family Virgaviridae), Tymovirales (families Alphaflexiviridae and Betaflexiviridae) and Hepelivirales (family Benyviridae). They have a positive-sense, single-stranded genome consisting of one to four RNA segments . Am. AmC. quORF2 is followed by an intergenic region of 73 nucleotides in length and an ORF3, which codes for a small protein with a charged N-terminal half and a cysteine-rich C-terminal region . This cyThe NCBI BLAST analysis showed that the predicted Cq-VLRA2 ORF4 protein is quite similar to Ds-ORF3 (vDRB) protein and contains a single DSRM with signatures specific for DSRM_AtDRB-like proteins  and the Beet necrotic yellow vein virus (BNYVV) has six ORFs, namely, the CP gene terminated by a leaky stop codon, the CP read-through protein gene, the TGB and the cistron coding for a cysteine-rich protein having a silencing suppressor activity  both virus-like RNAs have considerable similarity to the benyvirus TGB-containing RNA 2. Indeed, RNA 2 of the type benyvirus activity  12,20];,20;Beet Dicranum scoparium TSA database in an attempt to find Ds-RNA1 expected to code for virus replicase as in the case of BNYVV. As an initial query, we used a 150 amino acid-long segment of the BNYVV replicase (GDD domain). A BLAST search revealed a single TSA contig (HANF01090670) of 305 nucleotides in length which codes for a protein segment containing a GDD motif typical for the RNA-dependent RNA polymerase (RdRp) domain and having more than 60% protein identity to BNYVV replicase protein (data not shown). To assemble the expected Ds-RNA 1, the transcriptome sequencing data for D.scoparium SRA experiment ERX3824048 linked to the TSA project were used. The assembled full-length sequence of the contig comprised 6624 nt, excluding the poly(A) tail. ORF prediction showed that the contig contains a single cistron encoding viral replicase (Assuming the similarity of Ds-VLRA 2 and Cq-VLRA 2 to benyvirus RNA 2  in gene eplicase  flanked eplicase .−6); a viral helicase 1 domain ; papain-like proteinase domain , and RdRp core motif with GDD signature . The MTR domain is known to be conserved in a wide range of single-stranded RNA viruses, including the orders Martellivirales, Tymovirales and Hepelivirales [ORF1 protein of Ds-VLRA 1  containsivirales . All repivirales  conserveivirales .C.quitensis SRA data (SRX814890) in order to assemble a Cq-RNA1 complete nucleotide sequence. However, only a rather short nucleotide sequence encoding a part of RdRp domain (including the GDD signature), which showed significant similarity to the Ds-VLRA1 protein and moderate similarity to benyvirus replicases, has been assembled (data not shown). This failure to identify the full-length Cq-RNA1 could likely result from the insufficient coverage of the used sequencing data.We further used encoded amino acid and nucleotide sequences of Ds-VLRA1 as queries for searches of D. scoparium and Antarctic flowering plant C. quitensis represent a conserved array of four overlapping genes named the “Tetra-Cistron Movement Block” (TCMB), which is related to the well-characterized transport modules TGB and BMB, consisting of three and two genes, respectively [Sweet potato chlorotic stunt virus  encodes an RNAse III with conserved dsRNA-binding domain (cd10845) [Flockhouse virus (FHV), which can infect both insect and plant cells, contains a dsRNA-binding domain of another type (superfamily cl12995) [https://riboviria.org/ accessed on 26 May 2022) revealed additional dsRNA-binding domains of superfamily cl00054 in ORF2 of beny-like RNAs encoding viral replicase as an ORF1. These include a motif of the DSRM_RNAse_III_family , as well as some other motifs . These observations demonstrate that dsRNA-binding proteins are encoded by a variety of plant viruses, including those with beny-like replicons.The transport gene module found in RNAs of viral origin identified in the transcriptomes of moss ectively ,2,5,7. Tcd10845) ,29, whercl12995) . Our seaD. scoparium and C. quitensis viruses may possess a similar activity. As the cell-to-cell movement of Potato virus X depends on silencing suppressor activity of TGB1 protein [In many viruses infecting plant and non-plant hosts, dsRNA-binding domains are found in proteins that play a role in subverting host antiviral responses ,32. Part protein , we spec protein ,22 repre protein . Similar protein ,24. In a protein ,15, and  protein ,21, vDRBHepeviridae [Hepelivirales [C.quitensis [An important clue to the pathways of evolutionary origin of TGB, BMB and TCMB, to our mind, can be provided by phylogenetic analysis of their encoded helicases. Evidently, phylogenetic analysis suggests that the BMB and TCMB helicases form a common branch, which is closer to benyvirus TGB helicases and less similar to potex- and hordei-like TGB helicases . Moreoveeviridae , which teviridae , comprisivirales . Taking uitensis , TCMB miFurthermore, the phylogenetic analysis of TCMB-encoded helicases may shed new light on the evolutionary shift between TGB3-containing and TGB3-lacking transport modules. As suggested earlier, the TGB3 gene could be either acquired by a BMB-like transport module to give rise to a TGB-like module consisting of three genes, or, alternatively, lost by a TGB-like module that resulted in the appearance of a BMB-like transport system employing two MPs ,5,6. As D. scoparium (this study) and another moss-infecting virus, Leucodon julaceus associated beny-like virus [The predictions of moss ssRNA-containing beny-like virus infecting ke virus , raise tke virus ,42, whicIn conclusion, the identification of the TCMB transport system that contains, compared to TGB/BMB, an additional vDRB-encoding gene opens new directions in the experimental analysis of both transport modules of this type and the functions of virus-encoded dsRNA-binding proteins, as well as further phylogenetic analyses aimed at the reconstruction of the evolutionary history of movement proteins encoded by plant virus genomes.


We excluded RCTs investigating vaccination with an additional vaccine unless outcomes from a follow-up period before the second vaccination were reported. Results: Our search identified 16 RCTs including 34,197 participants. Vaccination with BCG caused an estimated 44% decrease in risk for respiratory infections (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.39–0.82) with substantial heterogeneity between trials (I2 = 77%). There was evidence for a protective effect on all-cause mortality of 21% if follow-up was restricted to one year . We did not find evidence for an effect when we considered longer follow-up . Infection-related mortality after BCG vaccination was reduced by 33% , mortality for sepsis by 38% . There was no evidence for a protective effect of BCG vaccination on infections of any origin , COVID-19 , sepsis  or hospitalization . Conclusions: According to these results, depending on the setting, vaccination with BCG provides time-limited partial protection against non-tuberculosis respiratory infections and may reduce mortality. These findings underline BCG’s potential (1) in pandemic preparedness against novel pathogens especially in developing countries with established BCG vaccination programs but limited access to specific vaccines; (2) in reducing microbial infections, antimicrobial prescriptions and thus the development of antimicrobial resistance. There is a need for additional RCTs to clarify the circumstances under which BCG’s non-specific protective effects are mediated.Background: Vaccines induce antigen-specific immunity, which provides long-lived protection from the target pathogen. Trials from areas with high incidence rates for infectious diseases indicated that the tuberculosis vaccine Bacillus Calmette-Guérin (BCG) induces in addition non-specific immunity against various pathogens and thereby reduces overall mortality more than would have been expected by just protecting from tuberculosis. Although recent trials produced conflicting results, it was suggested that BCG might protect from non-tuberculosis respiratory infections and could be used to bridge the time until a specific vaccine against novel respiratory diseases like COVID-19 is available. Methods: We performed a systematic search for randomized controlled trials (RCTs) published between 2011 and December 9 Bacillus Calmette-Guérin (BCG) is an attenuated bacterial vaccine developed against the respiratory infectious disease tuberculosis. According to the current World Health Organization (WHO) policy, it is mainly used in tuberculosis-endemic countries to protect children against the disease ,2. BesidThe sudden occurrence of “Coronavirus disease 2019” (COVID-19), a severe and potentially lethal respiratory disease caused by the novel coronavirus SARS-CoV-2, and its spread as a global pandemic triggered intensive scientific efforts to develop a SARS-CoV-2 specific vaccine, which was perceived as the most effective way out of the pandemic. To bridge the time until a SARS-CoV-2 specific vaccine was available, it had been suggested to evaluate BCG’s potential in providing non-specific protection, in particular in people with a high risk for COVID-19 . More thAlthough COVID-19-specific vaccines are available by now, there is a need for an assessment of BCG’s NSE and its potential as a bridge vaccination due to (1) its wide availability, especially in developing countries which often suffer from timely access to specific vaccines and medical supplies; (2) its potential to activate the immune system against various pathogens, like emerging vaccine resistant SARS-CoV-2 immune escape mutants or novel pathogens in future pandemics. Moreover, BCG-mediated trained immunity may reduce microbial infections in general, thereby lessening drug prescriptions and the development of antimicrobial resistance; it may also reduce the risk for all-cause mortality.We aimed to evaluate the effects of BCG vaccination on the risk for non-tuberculosis respiratory infections, COVID-19, non-tuberculosis infections of any origin, sepsis, mortality, and hospitalizations. For this purpose, we systematically identified RCTs published between 2011 and 9 December 2022, which compared the effects of BCG vaccination against no vaccination, assessed their potential for bias, and quantified the estimated effects by meta-analysis.We performed a systematic review and meta-analysis of RCTs reporting NSE of vaccination with BCG. The study protocol is registered in PROSPERO (CRD 42021255017).A systematic literature search was conducted in four electronic databases  and three electronic clinical trial registers  from 1 January 2011 to 9 December 2022 . In addiWe included studies that met the following criteria: (1) RCTs; (2) conducted among children and/or adults; (3) comparing BCG vaccination with placebo/no vaccination; (4) reporting effects of BCG vaccination on non-tuberculosis related respiratory infections, non-tuberculosis related infections of any origin, non-tuberculosis related sepsis, non-tuberculosis related mortality ; non-tuberculosis related hospitalizations . Trials conducted in participants with interfering comorbidities, e.g., patients with bladder cancer for which BCG is used as a therapeutic option, and trials investigating combinations of interventions were excluded . If triaStudy characteristics and outcome data were recorded by one reviewer (GT) using a standardized data collection form. Another reviewer checked the data (MD). If methods or study design were described in several publications, all publications were used to inform data extraction. If publications with additional analyses for a given trial were available, the publication providing most information was considered.Two reviewers  evaluated independently the risk of bias for each included study using the Cochrane Collaboration’s tool for assessing the risk of bias . Any dis2-tests and quantified heterogeneity using the I2 statistic; a p-value < 0.05 was considered significant ..2 = 0%; 2 = 0%; p = 0.96)  (I = 0.96) D. Result2 = 0%; p = 0.70) and the results with fixed effect and random effects models were identical , suggesting more pronounced BCG-mediated NSE in non-tuberculosis respiratory infections (1) in adolescents or adults, (2) in low-birth-weight children or morbid participants, (3) in trials conducted in Western Europe or Australia, (4) in trials with a follow-up period smaller or equal to six months, (5) and in trials collecting outcome data by medical diagnosis compared to participant-reported data. Meta-analysis for the outcomes non-tuberculosis respiratory infections , COVID-19 , infections of any origin , and mortality  showed moderate to substantial heterogeneity between the trials . We perfFor all-cause mortality, there was evidence for a statistically significant difference between subgroups with different health status, suggesting more pronounced BCG-mediated NSE on mortality in low birth-weight children or morbid participants compared to others .Our meta-analysis indicates that vaccination with BCG caused an estimated 44% decrease in risk for non-tuberculosis respiratory infections . Additional analyses revealed evidence for a protective effect after BCG vaccination of 21% on all-cause mortality if follow-up was restricted to one year ; there was no evidence for an effect when longer follow-up was considered . In particular, mortality for infections  and mortality for sepsis  were significantly reduced after BCG vaccination. For COVID-19 , infections of any origin , and sepsis , there was no evidence for a protection after BCG vaccination. Regarding hospitalization , hospitalization for infections , and hospitalization for respiratory infections , we found no evidence for improvement after BCG vaccination. Subgroup analyses suggested better protection of non-tuberculosis respiratory infections after BCG vaccination in adolescents or adults as compared to infants; in participants with impaired health including low-birth-weight children as compared to others; in trials from Western Europe or Australia as compared to trials from Africa, Indonesia, India, South America; in trials with a follow-up period shorter or equal to six months; and in trials with outcome collection by a medical diagnosis instead of participant-reported data. Regarding all-cause mortality, subgroup analyses indicated better protection in low-birth-weight children or morbid participants as compared to others.Based on the few RCTs included and the large number of potential effect modifiers and confounders, results of our subgroup-analysis must be interpreted with caution. The trials indicating less pronounced NSE for respiratory infections in infants include only three RCTs ,33,44; tThe effect of routine childhood vaccinations on overall mortality was first systematically analyzed in observational studies in Guinea-Bissau. A large cohort study revealed that BCG vaccination was associated with a significantly lower mortality ratio of 0.55 95% CI 0.36–0.85) . These p6–0.85 . Our meta-analysis is based on data from 16 RCTs reporting NSE of BCG; 13 of them were published after 2017 and, to our knowledge, not included in previous meta-analyses, six of these 13 report mortality data. Based on this evidence, we did not find a significant reduction in all-cause mortality after BCG vaccination . However, restriction to a follow-up of twelve months excluded one RCT , which cThe persistence of NSE of BCG has been analyzed in mechanistic studies demonstrating epigenetic reprogramming of monocytes, leading to increased cytokine production in response to non-related pathogens for up to three months after BCG vaccination, and enduring changes in pattern recognition receptors after one year. In healthy humans, non-specific Th1 and Th17 responses were enhanced for at least one year after vaccination . In addiWhereas the previous meta-analysis quantified the impact of NSE of BCG on all-cause mortality in children, we focused our meta-analysis on non-tuberculosis respiratory infections and COVID-19 and considered additional age groups. Approximately 40 ongoing RCTs on this subject are a unique chance to elucidate the question of whether, and under which circumstances, BCG protects from COVID-19 . HoweverSeveral effective COVID-19 specific vaccines exist by now. Nevertheless, the question of whether BCG can protect from respiratory infections in general is still highly relevant. (1) BCG’s ability to train the immune system and thereby protect antigen-independent against infections might provide an effective shield against vaccine-resistant mutants, which are able to circumvent antigen-specific immunological memory. Thus, BCG might be valuable to bridge time until an antigen-specific vaccine against a dangerous vaccine-resistant mutant is developed . 2) BCG BCG2]. TWith rising resistance to antimicrobial interventions worldwide, improving the host response to infections becomes increasingly important. This meta-analysis summarizes the recent available RCT-data on BCG-mediated NSE and indicates time-limited and partial protection from respiratory infections. There was no evidence for a protective NSE of BCG vaccination on COVID-19. Yet, the BCG-mediated NSE described here have the potential to short-term prevent viral spread and reduce pandemic-related mortality, thus being of strategic importance in pandemic preparedness. Especially in developing countries with established BCG vaccination programs, BCG is easily accessible for revaccinations in pandemic emergencies which could positively influence the course of a future pandemic. Moreover, BCG-mediated NSE reduce microbial infections in general, thereby decreasing antimicrobial prescriptions and thus the development of antimicrobial resistance.Our findings indicated a protective NSE on mortality within one year after BCG vaccination and support the current WHO policy of providing BCG vaccination to all infants on the first day of life in areas of high infectious disease incidence . However