The association between antibody responses and prolonged viable SARS-CoV-2 shedding in immunocompromised patients: a prospective cohort study.

Immunocompromised COVID-19 patients were prospectively enrolled from March to November 2022 to understand the association between antibody responses and SARS-CoV-2 shedding. A total of 62 patients were analyzed and the results indicated a faster decline in genomic and subgenomic viral RNA in patients with higher neutralizing and S1-specific IgG antibodies (both P < 0.001). Notably, high neutralizing antibody levels were associated with a significantly faster decrease in viable virus cultures (P = 0.04). Our observations suggest the role of neutralizing antibodies in prolonged virus shedding in immunocompromised patients, highlighting the potential benefits of enhancing their humoral immune response through vaccination or monoclonal antibody treatments.

Virological characteristics and the rapid antigen test as deisolation criteria in immunocompromised patients with COVID-19: A prospective cohort study.

There are limited data supporting current Centers for Disease Control and Prevention guidelines for the isolation period in moderate to severely immunocompromised patients with coronavirus disease 2019 (COVID-19). Adult COVID-19 patients who underwent solid organ transplantation (SOT) or received active chemotherapy against hematologic malignancy were enrolled and weekly respiratory samples were collected. Samples with positive genomic real-time polymerase chain reaction results underwent virus culture and rapid antigen testing (RAT). A total of 65 patients (40 with hematologic malignancy and 25 SOT) were enrolled. The median duration of viable virus shedding was 4 weeks (interquartile range: 3-7). Multivariable analysis revealed that B-cell depletion (hazard ratio [HR]: 4.76) was associated with prolonged viral shedding, and COVID-19 vaccination (≥3 doses) was negatively associated with prolonged viral shedding (HR: 0.22). The sensitivity, specificity, positive predictive value, and negative predictive value of RAT for viable virus shedding were 79%, 76%, 74%, and 81%, respectively. The negative predictive value of RAT was only 48% (95% confidence interval [CI]: 33-65) in the samples from those with symptom onset ≤20 days, but it was as high as 92% (95% CI: 85-96) in the samples from those with symptom onset >20 days. About half of immunocompromised COVID-19 patients shed viable virus for ≥4 weeks from the diagnosis, and virus shedding was prolonged especially in unvaccinated patients with B-cell-depleting therapy treatment. RAT beyond 20 days in immunocompromised patients had a relatively high negative predictive value for viable virus shedding.

Comparison of Plasma Metabolites From Patients With Non-Small Cell Lung Cancer by Erlotinib Treatment and Skin Rash.

Erlotinib is a necessary anticancer treatment for non-small cell lung cancer (NSCLC) patients yet it causes severe side effects such as skin rash. In this study, researchers compared the untargeted compound profiles before and after erlotinib administration to observe changes in blood metabolites in NSCLC patients. The levels of 1005 substances changed after taking erlotinib. The levels of 306 and 699 metabolites were found to have increased and decreased, respectively. We found 5539 substances with peak area differences based on the presence of skin rash. Carbohydrate, amino acid, and vitamin metabolic pathways were altered in response to the onset of erlotinib-induced skin rash. Finally, this study proposed using plasma metabolites to identify biomarker(s) induced by erlotinib, as well as target molecule(s), for the treatment of dermatological toxic effects.

Evaluation of antiviral drugs against newly emerged SARS-CoV-2 Omicron subvariants.

Ongoing emergence of SARS-CoV-2 Omicron subvariants and their rapid worldwide spread pose a threat to public health. From November 2022 to February 2023, newly emerged Omicron subvariants, including BQ.1.1, BF.7, BA.5.2, XBB.1, XBB.1.5, and BN.1.9, became prevalent global strains (>5% global prevalence). These Omicron subvariants are resistant to several therapeutic antibodies. Thus, the antiviral activity of current drugs such as remdesivir, molnupiravir, and nirmatrelvir, which target highly conserved regions of SARS-CoV-2, against newly emerged Omicron subvariants need to be evaluated. We assessed the antiviral efficacy of the drugs using the half-maximal inhibitory concentration (IC50) against human isolates of 23 Omicron subvariants and four former SARS-CoV-2 variants of concern (VOCs) and compared it with the antiviral efficacy of these drugs against the SARS-CoV-2 reference strain (hCoV/Korea/KCDC03/2020). Maximal IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir were 1.9 (BA.2.75.2), 1.2 (B.1.627.2), and 1.4 (BA.2.3), respectively, compared to median IC50 values of the reference strain. Moreover, median IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir against the Omicron variants were 0.96, 0.4, and 0.62, respectively, similar to the 1.02, 0.88, and 0.67, respectively, median IC50-fold changes for previous VOCs. Although K90R and P132H in Nsp 5, and P323L, A529V, G671S, V405F, and ins823D in Nsp 12 mutations were identified, these amino acid substitutions did not affect drug antiviral activity. These results indicate that current antivirals retain antiviral efficacy against newly emerged Omicron subvariants. It is important to continue active surveillance and testing of new variants for drug resistance to enable early identification of drug-resistant strains.

Can nirmatrelvir/ritonavir treatment shorten the duration of COVID-19 isolation?

Background: The impact of nirmatrelvir/ritonavir treatment on shedding of viable virus in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Methods: A prospective cohort study evaluating mildly ill COVID-19 patients was conducted. Virologic responses were compared between nirmatrelvir/ritonavir-treatment and supportive care groups. Risk factors and relevant clinical factors for shedding of viable virus were investigated. Results: A total of 80 COVID-19 patients were enrolled and 222 sputum specimens were collected. Ten patients were dropped during follow-up, and 33 patients in the nirmatrelvir/ritonavir and 37 in the supportive care groups were compared. The median age was 67 years, and 67% were male. Clinical characteristics were similar between groups. Viral loads decreased significantly faster in the nirmatrelvir/ritonavir group compared with the supportive care group (P < 0.001), and the slope was significantly steeper (-2.99 ± 1.54 vs. -1.44 ± 1.52; P < 0.001). The duration of viable virus shedding was not statistically different between groups. In the multivariable analyses evaluating all collected specimens, male gender (OR 2.51, 95% CI 1.25-5.03, P = 0.010), symptom score (OR 1.41, 95% CI 1.07-1.87, P = 0.015), days from symptom onset (OR 0.72, 95% CI 0.59-0.88, P = 0.002), complete vaccination (OR 0.09, 95% CI 0.01-0.87, P = 0.038), and BA.2 subtype (OR 0.49, 95% CI 0.26-0.91, P = 0.025) were independently associated with viable viral shedding, while nirmatrelvir/ritonavir treatment was not. Conclusion: Nirmatrelvir/ritonavir treatment effectively reduced viral loads of SARS-CoV-2 Omicron variants but did not decrease the duration of viable virus shedding.

Engineered small extracellular vesicles displaying ACE2 variants on the surface protect against SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry is mediated by the interaction of the viral spike (S) protein with angiotensin-converting enzyme 2 (ACE2) on the host cell surface. Although a clinical trial testing soluble ACE2 (sACE2) for COVID-19 is currently ongoing, our understanding of the delivery of sACE2 via small extracellular vesicles (sEVs) is still rudimentary. With excellent biocompatibility allowing for the effective delivery of molecular cargos, sEVs are broadly studied as nanoscale protein carriers. In order to exploit the potential of sEVs, we design truncated CD9 scaffolds to display sACE2 on the sEV surface as a decoy receptor for the S protein of SARS-CoV-2. Moreover, to enhance the sACE2-S binding interaction, we employ sACE2 variants. sACE2-loaded sEVs exhibit typical sEVs characteristics and bind to the S protein. Furthermore, engineered sEVs inhibit the entry of wild-type (WT), the globally dominant D614G variant, Beta (K417N-E484K-N501Y) variant, and Delta (L452R-T478K-D614G) variant SARS-CoV-2 pseudovirus, and protect against authentic SARS-CoV-2 and Delta variant infection. Of note, sACE2 variants harbouring sEVs show superior antiviral efficacy than WT sACE2 loaded sEVs. Therapeutic efficacy of the engineered sEVs against SARS-CoV-2 challenge was confirmed using K18-hACE2 mice. The current findings provide opportunities for the development of new sEVs-based antiviral therapeutics.

Gyejibokryeong-Hwan improves recovery of injured muscles in mouse model of muscle contusion.

OBJECTIVE: To investigate the effects of Gyejibokryeong-Hwan (Guizhifuling-wan, GBH) on muscle injury in a mouse model of muscle contusion. METHODS: C57/BL6 mouse biceps femoris muscles were injured using the drop-mass method and injured animals were treated orally with GBH (50, 100, or 500 mg/kg) once a day for 7 d. Open field and treadmill running tests were performed to assess functional recovery from muscle injury. The production of pro-inflammatory cytokines was examined by enzyme-linked immunosorbent assay and Western blotting analysis. Expression of the muscle regeneration biomarkers, myoblast determination (MyoD), myogenic factor 5 (Myf5), and smooth muscle actin (α-SMA), in the biceps femoris muscle was investigated at the protein and mRNA level by Western blotting and real time-PCR, respectively. Histological analysis was performed using hematoxylin and eosin staining. Finally, myosin heavy chain production was investigated in differentiated C2C12 myoblasts in the presence of GBH. RESULTS: GBH treatment markedly improved locomotion and running behavior. GBH significantly inhibited the secretion of monocyte chemoattractant protein-1 into the bloodstream in muscle-contused animals. The levels of MyoD, Myf5, and α-SMA protein and mRNA were significantly up-regulated by GBH in injured muscle tissue. Histological studies suggested that GBH facilitated recovery from muscle damage. However, GBH did not induce the production of myosin heavy chain in vitro. CONCLUSION: Overall, the present study suggested that GBH improves the recovery of the injured muscles in the mouse model of muscle contusion.

Exogenous Transforming Growth Factor-ß in Brain-Induced Symptoms of Central Fatigue and Suppressed Dopamine Production in Mice.

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is one of the most refractory diseases in humans and is characterized by severe central fatigue accompanied with various symptoms that affect daily life, such as impaired memory, depression, and somatic pain. However, the etiology and pathophysiological mechanisms of CFS remain unknown. To investigate the pathophysiological role of transforming growth factor (TGF)-ß1, we injected a cytokine into the lateral ventricle of a C57BL/6 mouse. The intracranial injection of TGF-ß1 increased the immobility duration in a forced swimming test (FST) and time spent at the closed arm in elevated plus maze (EPM) analysis. The mice injected with TGF-ß1 into their brain showed increased sensitivity to pain in a von Frey test, and had a decreased retention time on rotarod and latency time in a bright box in a passive avoidance test. In addition, the serum levels of muscle fatigue biomarkers, lactate dehydrogenase (LDH) and creatine kinase (CK), were significantly increased after administration of TGF-ß1. Intracranial injection of TGF-ß1 significantly reduced the production of tyrosine hydroxylase (TH) in the ventral tegmental area, accompanied by a decreased level of dopamine in the striatum. The suppression of TH expression by TGF-ß1 was confirmed in the human neuroblastoma cell line, SH-SY5Y. These results, which show that TGF-ß1 induced fatigue-like behaviors by suppressing dopamine production, suggest that TGF-ß1 plays a critical role in the development of central fatigue and is, therefore, a potential therapeutic target of the disease.

So-Ochim-Tang-Gamibang, a Traditional Herbal Formula, Ameliorates Depression by Regulating Hyperactive Glucocorticoid Signaling In Vitro and In Vivo.

So-ochim-tang-gamibang (SOCG) is a Korean traditional medicine; it has previously been shown to be safe and effective against depression. Persistently increased levels of circulating glucocorticoids have been considered as a pathological mechanism for depression and associated with decreased neurotrophic factors in the hippocampus. This study investigated whether SOCG controls the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and the molecular mechanisms underlying its effects in vivo and in vitro. Wistar Kyoto (WKY) rats were subjected to restraint stress, where SOCG was orally administered to the animals for 2 weeks. An open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were performed to explore the antidepressant activity of SOCG in WKY rats. Plasma levels of HPA axis hormones were measured by ELISA or western blotting analysis. The expression levels or activation of HPA axis-related signaling molecules such as brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), extracellular regulated kinase (ERK), and glucocorticoid receptors (GRs) in the brain were determined by real-time PCR and western blotting analysis. Furthermore, a corticosterone- (CORT-) induced cell injury model was established using SH-SY5Y cells to explore the antidepressive effects of SOCG in vitro. The results of the OFT, FST, and SPT revealed that SOCG ameliorated depressive-like behaviors in the WKY rats. The blood plasma levels of HPA axis hormones such as CORT, CORT-releasing hormone (CRH), and adrenocorticotrophic hormone were downregulated by SOCG. On the other hand, SOCG upregulated the phosphorylation of CREB and ERK in both the rat hippocampus and CORT-treated SH-SY5Y cells. Moreover, it also increased the GR expression. These results suggested that SOCG may improve depression by controlling hyperactive glucocorticoid signaling via the downregulation of HPA axis hormones and upregulation of GR.

Dietary Epigallocatechin-3-Gallate Alters the Gut Microbiota of Obese Diabetic db/db Mice: Lactobacillus Is a Putative Target.

Obesity results in the progression of metabolic disorders, and especially type 2 diabetes mellitus (T2DM), and the gut microbiota have been implicated in the development of T2DM. This study investigated the effect of epigallocatechin-3-gallate (EGCG) on structural changes to the gut microbiota of obese diabetic db/db mice. db/db mice were subjected to a control and EGCG (10, 50, and 100 mg/kg) diet for 8 weeks. Glucose homeostasis and the structure and composition of the gut microbiota were measured. EGCG inhibited the increases in body weight and fasting blood glucose levels. Similarly, it resulted in remarkable improvements in glucose tolerance. Based on lipid profiles, EGCG decreased serum cholesterol and low-density lipoprotein (LDL) levels, and increased the high-density lipoprotein/LDL ratio. In addition, upon fecal microbiota analysis, this compound significantly increased the Firmicutes:Bacteroidetes ratio at the phylum level and increased Lactobacillus abundance at the genus level. Especially, its administration increased abundances of the Lactobacillus gasseri, Lactobacillus intestinalis, and Lactobacillus reuteri. We also found that EGCG increased Christensenellaceae abundance and decreased Enterobacteriaceae and Proteobacteria abundance at the family level. EGCG improves glucose homeostasis in diabetic mice. Its beneficial effects on glucose homeostasis are likely associated with alterations to the gut microbiota. Furthermore, the enrichment of probiotics (Lactobacillus) might be a potential mechanism underlying the effects of EGCG on glucose homeostasis.

Administration of Wasabia koreana Ameliorates Irritable Bowel Syndrome-Like Symptoms in a Zymosan-Induced Mouse Model.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with complex pathophysiology involving the brain-gut axis. To assess the effects of Wasabia koreana (WK) on IBS, we employed a mouse model of colonic zymosan injection presenting with diarrhea-predominant IBS-like symptoms. Oral WK administration significantly diminished stool score, suppressed colon length and weight change, and minimized body weight loss without affecting food intake. In WK-treated mice, the submucosal thickening and epithelial lining of the colon were inhibited and were similar to those of naïve mice. Infiltration of mast cells into the colon and serum tumor necrosis factor-α levels were markedly suppressed. These effects were comparable to those of sulfasalazine, an anti-inflammatory drug. Furthermore, the number of visceral pain-related behaviors was significantly decreased, and locomotion activities measured in the elevated plus maze and open field tests were significantly increased by WK in a dose-dependent manner compared with amitriptyline, an antidepressant. These changes were accompanied by reduced FosB2 expression in the brain. Taken together, these data suggest that WK may have potential as a medicinal food for IBS by acting on inflammatory diarrhea and neural activity.