Functional metagenomic and metabolomics analysis of gut dysbiosis induced by hyperoxia

BackgroundInhaled oxygen is the first-line therapeutic approach for maintaining tissue oxygenation in critically ill patients, but usually exposes patients to damaging hyperoxia. Hyperoxia adversely increases the oxygen tension in the gut lumen which harbors the trillions of microorganisms playing an important role in host metabolism and immunity. Nevertheless, the effects of hyperoxia on gut microbiome and metabolome remain unclear, and metagenomic and metabolomics analysis were performed in this mouse study.MethodsC57BL/6 mice were randomly divided into a control (CON) group exposed to room air with fractional inspired oxygen (FiO2) of 21% and a hyperoxia (OXY) group exposed to FiO2 of 80% for 7 days, respectively. Fecal pellets were collected on day 7 and subjected to metagenomic sequencing. Another experiment with the same design was performed to explore the impact of hyperoxia on gut and serum metabolome. Fecal pellets and blood were collected and high-performance liquid chromatography with mass spectrometric analysis was carried out.ResultsAt the phylum level, hyperoxia increased the ratio of Firmicutes/Bacteroidetes (p = 0.049). At the species level, hyperoxia reduced the abundance of Muribaculaceae bacterium Isolate-037 (p = 0.007), Isolate-114 (p = 0.010), and Isolate-043 (p = 0.011) etc. Linear discriminant analysis effect size (LEfSe) revealed that Muribaculaceae and Muribaculaceae bacterium Isolate-037, both belonging to Bacteroidetes, were the marker microbes of the CON group, while Firmicutes was the marker microbes of the OXY group. Metagenomic analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Carbohydrate-Active enZYmes (CAZy) revealed that hyperoxia provoked disturbances in carbohydrate and lipid metabolism. Fecal metabolomics analysis showed hyperoxia reduced 11-dehydro Thromboxane B2-d4 biosynthesis (p = 1.10 × 10−11). Hyperoxia blunted fecal linoleic acid metabolism (p = 0.008) and alpha-linolenic acid metabolism (p = 0.014). We showed that 1-docosanoyl-glycer-3-phosphate (p = 1.58 × 10−10) was the most significant differential serum metabolite inhibited by hyperoxia. In addition, hyperoxia suppressed serum hypoxia-inducible factor-1 (HIF-1, p = 0.007) and glucagon signaling pathways (p = 0.007).ConclusionHyperoxia leads to gut dysbiosis by eliminating beneficial and oxygen strictly intolerant Muribaculaceae with genomic dysfunction of carbohydrate and lipid metabolism. In addition, hyperoxia suppresses unsaturated fatty acid metabolism in the gut and inhibits the HIF-1 and glucagon signaling pathways in the serum

Current status and progress in research on dressing management for diabetic foot ulcer

Diabetic foot ulcer (DFU) is a major complication of diabetes and is associated with a high risk of lower limb amputation and mortality. During their lifetime, 19%–34% of patients with diabetes can develop DFU. It is estimated that 61% of DFU become infected and 15% of those with DFU require amputation. Furthermore, developing a DFU increases the risk of mortality by 50%–68% at 5 years, higher than some cancers. Current standard management of DFU includes surgical debridement, the use of topical dressings and wound decompression, vascular assessment, and glycemic control. Among these methods, local treatment with dressings builds a protective physical barrier, maintains a moist environment, and drains the exudate from DFU wounds. This review summarizes the development, pathophysiology, and healing mechanisms of DFU. The latest research progress and the main application of dressings in laboratory and clinical stage are also summarized. The dressings discussed in this review include traditional dressings (gauze, oil yarn, traditional Chinese medicine, and others), basic dressings (hydrogel, hydrocolloid, sponge, foam, film agents, and others), bacteriostatic dressings, composite dressings (collagen, nanomaterials, chitosan dressings, and others), bioactive dressings (scaffold dressings with stem cells, decellularized wound matrix, autologous platelet enrichment plasma, and others), and dressings that use modern technology (3D bioprinting, photothermal effects, bioelectric dressings, microneedle dressings, smart bandages, orthopedic prosthetics and regenerative medicine). The dressing management challenges and limitations are also summarized. The purpose of this review is to help readers understand the pathogenesis and healing mechanism of DFU, help physicians select dressings correctly, provide an updated overview of the potential of biomaterials and devices and their application in DFU management, and provide ideas for further exploration and development of dressings. Proper use of dressings can promote DFU healing, reduce the cost of treating DFU, and reduce patient pain

The multimorbidity association of metabolic syndrome and depression on type 2 diabetes: a general population cohort study in Southwest China

BackgroundMetabolic syndrome(MetS) and depression are independently associated with type 2 diabetes (T2DM) risk. However, little is known about the combined effect of MetS and depression on the risk of T2DM. The present study aims to prospectively explore the impact of MetS and depression on T2DM susceptibility among the Chinese general population.Methods6489 general population without T2DM adults in Southwest China were recruited from 2010 to 2012. Depression and MetS were prospectively assessed using a 9-item Patient Health Questionnaire(PHQ-9) and Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition) (CDS2020) during 2016–2020, respectively. Modified Poisson regression models were conducted to estimate relative risk(RR) and 95% confidence intervals (95%CI) for independent and combined associations of MetS and depression with an incidence of T2DM.ResultsDuring a median follow-up of 6.6 years, 678 cases of T2DM were documented. Individuals with MetS were 1.33 times more likely to develop T2DM than those without MetS. The corresponding RR(95%CI) for depression with no depression was 1.45(1.22–1.72). Notably, compared with no MetS or depression, the multivariate-adjusted RR for a combined effect of MetS and depression on the risk of T2DM was 2.11(1.39–3.22). Moreover, an increased risk of T2DM was more apparent in those ≥ 60 years, males, and overweight.ConclusionsIndividuals with multimorbidity of MetS and depression are at a higher risk of T2DM compared with those with no MetS or depression

Acceptance and Preference for COVID-19 Vaccine among Japanese Residents at Early Stage of the Epidemic in Japan

Background: This study aimed to survey the attitudes toward COVID-19 vaccines and their acceptability among the Japanese public as soon as the United States Food and Drug Administration (FDA) authorized vaccines and their rollouts started around the world. Methods: An anonymous cross-sectional survey was conducted in Japan between 4 January and 5 March 2021. A questionnaire was administered to evaluate attitudes toward COVID-19 vaccines according to demographic characteristics, vaccine characteristics, and vaccine production. Results: A total of 1037 completed responses were received. More than half (63.5%) of the participants responded positively (extremely likely/likely) toward COVID-19 vaccines. The highest acceptance to be vaccinated was discovered among the youngest age group. As expected, participants who had never delayed acceptance or refused the vaccine in their history of vaccination had a significantly higher willingness to be vaccinated against COVID-19 (p < 0.001). Females (OR = 2.66, 95% CI: 1.99–3.58) and participants who had ever delayed acceptance or refuse the vaccine (OR = 3.49, 95% CI: 2.42–5.05) had higher odds of COVID-19 vaccine hesitancy. Participants with a postgraduate degree (OR = 0.64, 95% CI: 0.40–1.00) presented the highest willingness to be vaccinated against COVID-19. More than two-thirds (72.9%, 95% CI: 70.4%–75.8%) of the participants did not mind a booster dose required following primary vaccination. A total of 63.2% (95% CI: 60.0%–66.0%) of the participants only accepted a nearly 90% effective or above vaccine at preventing COVID-19. At the same, 86.4% (95% CI: 84.4%–88.4%) of the participants reported only accepting a vaccine with minor side effects. Conclusions: The moderate levels of COVID-19 vaccine acceptance found in the early phase of the pandemic demonstrate that it is important to improve the implementation of effective management for vaccine promotion and the acceptability of the vaccine to slow or delay transmission

Immune phenotype of patients with stage IV metastatic inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a rare but aggressive carcinoma characterized by severe erythema and edema of the breast, with many patients presenting in advanced metastatic disease. The inflammatory nature is not due to classic immune-mediated inflammation, but instead results from tumor-mediated blockage of dermal lymphatic ducts. Previous work has shown that expression of PD-L1 on tumor cells can suppress T cell activation in triple-negative (TN) non-IBC breast cancer. In the present work, we investigated immune parameters in peripheral blood of metastatic IBC patients to determine whether cellular components of the immune system are altered, thereby contributing to pathogenesis of the disease. These immune parameters were also compared to PD-1 and PD-L1 expression in IBC tumor biopsies. METHODS: Flow cytometry-based immune phenotyping was performed using fresh peripheral blood from 14 stage IV IBC patients and compared to 11 healthy age-similar control women. Immunohistochemistry for CD20, CD3, PD-1, and PD-L1 was performed on tumor biopsies of these metastatic IBC patients. RESULTS: IBC patients with Stage IV disease had lymphopenia with significant reductions in circulating T, B, and NK cells. Reductions were observed in all subsets of CD4+ T cells, whereas reductions in CD8+ T cells were more concentrated in memory subsets. Immature cytokine-producing CD56bright NK cells expressed higher levels of FcγRIIIa and cytolytic granule components, suggesting accelerated maturation to cytolytic CD56dim cells. Immunohistochemical analysis of tumor biopsies demonstrated moderate to high expression of PD-1 in 18.2% of patients and of PD-L1 in 36.4% of patients. Interestingly, a positive correlation was observed between co-expression levels of PD-L1 and PD-1 in tumor biopsies, and higher expression of PD-L1 in tumor biopsies correlated with higher expression of cytolytic granule components in blood CD4+ T cells and CD56dim NK cells, and higher numbers of CD8+ effector memory T cells in peripheral blood. PD-1 expression in tumor also correlated with increased infiltration of CD20+ B cells in the tumor. CONCLUSIONS: Our results suggest that while lymphocyte populations are severely compromised in stage IV IBC patients, an immune response toward the tumor had occurred in some patients, providing biological rationale to evaluate PD-1/PD-L1 immunotherapies for IBC

COVID-19 vaccination intention and vaccine characteristics influencing vaccination acceptance: a global survey of 17 countries

BACKGROUND: The availability of various types of COVID-19 vaccines and diverse characteristics of the vaccines present a dilemma in vaccination choices, which may result in individuals refusing a particular COVID-19 vaccine offered, hence presenting a threat to immunisation coverage and reaching herd immunity. The study aimed to assess global COVID-19 vaccination intention, vaccine characteristics influencing vaccination acceptance and desirable vaccine characteristics influencing the choice of vaccines. METHODS: An anonymous cross-sectional survey was conducted between 4 January and 5 March 2021 in 17 countries worldwide. Proportions and the corresponding 95% confidence intervals (CI) of COVID-19 vaccine acceptance and vaccine characteristics influencing vaccination acceptance were generated and compared across countries and regions. Multivariable logistic regression analysis was used to determine the factors associated with COVID-19 vaccine hesitancy. RESULTS: Of the 19,714 responses received, 90.4% (95% CI 81.8-95.3) reported likely or extremely likely to receive COVID-19 vaccine. A high proportion of likely or extremely likely to receive the COVID-19 vaccine was reported in Australia (96.4%), China (95.3%) and Norway (95.3%), while a high proportion reported being unlikely or extremely unlikely to receive the vaccine in Japan (34.6%), the U.S. (29.4%) and Iran (27.9%). Males, those with a lower educational level and those of older age expressed a higher level of COVID-19 vaccine hesitancy. Less than two-thirds (59.7%; 95% CI 58.4-61.0) reported only being willing to accept a vaccine with an effectiveness of more than 90%, and 74.5% (95% CI 73.4-75.5) said they would accept a COVID-19 vaccine with minor adverse reactions. A total of 21.0% (95% CI 20.0-22.0) reported not accepting an mRNA vaccine and 51.8% (95% CI 50.3-53.1) reported that they would only accept a COVID-19 vaccine from a specific country-of-origin. Countries from the Southeast Asia region reported the highest proportion of not accepting mRNA technology. The highest proportion from Europe and the Americas would only accept a vaccine produced by certain countries. The foremost important vaccine characteristic influencing vaccine choice is adverse reactions (40.6%; 95% CI 39.3-41.9) of a vaccine and effectiveness threshold (35.1%; 95% CI 33.9-36.4). CONCLUSIONS: The inter-regional and individual country disparities in COVID-19 vaccine hesitancy highlight the importance of designing an efficient plan for the delivery of interventions dynamically tailored to the local population

MicroRNA-211 Expression Promotes Colorectal Cancer Cell Growth In Vitro and In Vivo by Targeting Tumor Suppressor CHD5

Background: Chromodomain-helicase-DNA-binding protein 5 (CHD5) is a newly identified tumor suppressor that is frequently downregulated in a variety of human cancers. Our previous work revealed that the low expression of CHD5 in colorectal cancer is correlated with CHD5 promoter CpG island hypermethylation. In this study, we investigated the effect of microRNA-211 (miR-211)-regulated CHD5 expression on colorectal tumorigenesis. Methodology/Principal Findings: miR-211 was predicted to target CHD5 by TargetScan software analysis. A stably expressing exogenous miR-211 colorectal cancer cell line (HCT-116 miR-211) was generated using lentiviral transduction and used as a model for in vitro and in vivo studies. The expression level of miR-211 in HCT-116 miR-211 cells was upregulated by 16-fold compared to vector control cells (HCT-116 vector). Exogenous miR-211 directly binds to the 39-untranslated region (39-UTR) of CHD5 mRNA, resulting in a 50 % decrease in CHD5 protein level in HCT-116 miR-211 cells. The levels of cell proliferation, tumor growth, and cell migration of HCT-116 miR-211 cells were significantly higher than HCT-116 vector cells under both in vitro and in vivo conditions, as determined using the methods of MTT, colony formation, flow cytometry, scratch assay, and tumor xenografts, respectively. In addition, we found that enforced expression of miR-211 in HCT-116 cells was able to alter p53 pathway-associated regulatory proteins, such as MDM2, Bcl-2, Bcl-xL, and Bax. Conclusion/Significance: Our results demonstrate that CHD5 is a direct target of miR-211 regulation. Enforced expression o