Microbiota and mycobiota in bronchoalveolar lavage fluid of silicosis patients.

BACKGROUND: The contribution of bronchoalveolar lavage fluid (BALF) microbiota and mycobiota to silicosis has recently been noticed. However, many confounding factors can influence the accuracy of BALF microbiota and mycobiota studies, resulting in inconsistencies in the published results. In this cross-sectional study, we systematically investigated the effects of "sampling in different rounds of BALF" on its microbiota and mycobiota. We further explored the relationship between silicosis fatigue and the microbiota and mycobiota. METHODS: After obtaining approval from the ethics board, we collected 100 BALF samples from 10 patients with silicosis. Demographic data, clinical information, and blood test results were also collected from each patient. The characteristics of the microbiota and mycobiota were defined using next-generation sequencing. However, no non-silicosis referent group was examined, which was a major limitation of this study. RESULTS: Our analysis indicated that subsampling from different rounds of BALF did not affect the alpha- and beta-diversities of microbial and fungal communities when the centrifuged BALF sediment was sufficient for DNA extraction. In contrast, fatigue status significantly influenced the beta-diversity of microbes and fungi (Principal Coordinates Analysis, P = 0.001; P = 0.002). The abundance of Vibrio alone could distinguish silicosis patients with fatigue from those without fatigue (area under the curve = 0.938, 95% confidence interval [CI] 0.870-1.000). Significant correlations were found between Vibrio and haemoglobin levels (P < 0.001, ρ = -0.64). CONCLUSIONS: Sampling in different rounds of BALF showed minimal effect on BALF microbial and fungal diversities; the first round of BALF collection was recommended for microbial and fungal analyses for convenience. In addition, Vibrio may be a potential biomarker for silicosis fatigue screening.

[Epidemiological Characteristics and Drug Resistance of Microbial Pathogens of Patients With Silicosis Combined With Pulmonary Infection].

Objective: To investigate the epidemiological characteristics of patients with silicosis combined with pulmonary infection in recent years, to study the distribution and the drug susceptibility of fungal and bacterial pathogens in their sputum samples, and to provide references for the prevention and treatment of silicosis and the appropriate drug use. Methods: The clinical data and drug sensitivity test results of patients with silicosis combined with pulmonary infection diagnosed at the Department of Occupational Diseases, West China Fourth Hospital, Sichuan University were retrospectively analyzed. Results: A total of 318 patients with silicosis combined with pulmonary infection who received treatment between January 2017 and December 2020 were enrolled. All the patients had positive microorganism test results. All participants were male. Their median age at the time of onset was 51.00 years and the median time of exposure to silica dust at work was 12.40 years. They worked mostly in construction, non-ferrous metal mining, and coal mining. The main types of work they did were pneumatic drilling, coal digging, and mining. The positive detection rates for the first, second and third phases of silicosis were 27.54%, 28.32%, and 32.97%, respectively. A total of 341 strains of fungal and bacterial pathogens were isolated, of which, 54.1% were fungi, including 114 strains (35.8%) of Candida albicans, and 53.1% were bacteria, including 168 strains (52.8%) of gram-negative bacteria, most of which being Klebsiella pneumoniae (30.2%). There was only 1 strain (0.3%) of gram-positive bacteria, namely Staphylococcus hemolyticus. Gram-negative bacilli were most resistant to ampicillin and highly sensitive to penicillin G and ofloxacin. Conclusion: Among patients with silicosis combined with pulmonary infection, the incidence of pulmonary infection increases along with the progress of silicosis. Microorganism analysis reveals high detection rates for fungi and the bacteria detected are predominantly gram-negative bacteria. The overall prospect for drug resistance rate was not optimistic.

Ferrocene-Based Polymeric Nanoparticles Carrying Doxorubicin for Oncotherapeutic Combination of Chemotherapy and Ferroptosis.

Mono-chemotherapy has significant side effects and unsatisfactory efficacy, limiting its clinical application. Therefore, a combination of multiple treatments is becoming more common in oncotherapy. Chemotherapy combined with the induction of ferroptosis is a potential new oncotherapy. Furthermore, polymeric nanoparticles (NPs) can improve the antitumor efficacy and decrease the toxicity of drugs. Herein, a polymeric NP, mPEG-b-PPLGFc@Dox, is synthesized to decrease the toxicity of doxorubicin (Dox) and enhance the efficacy of chemotherapy by combining it with the induction of ferroptosis. First, mPEG-b-PPLGFc@Dox is oxidized by endogenous H2 O2 and releases Dox, which leads to an increase of H2 O2 by breaking the redox balance. The Fe(II) group of ferrocene converts H2 O2 into ·OH, inducing subsequent ferroptosis. Furthermore, glutathione peroxidase 4, a biomarker of ferroptosis, is suppressed and the lipid peroxidation level is elevated in cells incubated with mPEG-b-PPLGFc@Dox compared to those treated with Dox alone, indicating ferroptosis induction by mPEG-b-PPLGFc@Dox. In vivo, the antitumor efficacy of mPEG-b-PPLGFc@Dox is higher than that of free Dox. Moreover, the loss of body weight in mice treated mPEG-b-PPLGFc@Dox is lower than in those treated with free Dox, indicating that mPEG-b-PPLGFc@Dox is less toxic than free Dox. In conclusion, mPEG-b-PPLGFc@Dox not only has higher antitumor efficacy but it reduces the damage to normal tissue.

Direct-acting antiviral agent use and gastrointestinal safety in patients with chronic hepatitis C: a pharmacovigilance study based on FDA Adverse Event Reporting System.

BACKGROUND: Gastrointestinal adverse drug reactions (GADRs) of direct-acting antiviral agents (DAAs) in patients with chronic hepatitis C are underestimated. AIM: This study aimed to comprehensively evaluate the gastrointestinal safety of DAAs in patients with chronic hepatitis C. METHOD: The US FDA Adverse Event Reporting System database was searched for GADR cases reported from 01 to 2012 to 30 September 2021. Twelve DAA types used for hepatitis C virus were included. The top 30 GADRs were assessed based on the use of DAAs, number of cases, and clinical features. A case-non-case disproportionality approach was used to confirm pharmacovigilance signals, whereby reporting odds ratios (ROR) with 95% CI were calculated. RESULTS: Nausea (70.01/1000), diarrhoea (39.10/1000), and vomiting (31.68/1000) accounted for the highest number of cases. The pooled median time-to-onset of the top 30 GADRs was 13 days (Q1-Q3: 2-38) and the proportion of drug discontinuation was 19.17%. The highest number of DAA-related cases involved ledipasvir/sofosbuvir (21.86%), sofosbuvir/velpatasvir (21.77%), and sofosbuvir (13.41%). When DAAs were considered as a class drug, after adjusting for age, sex, concomitant diseases and drugs that potentially induced GADRs, significant RORs for specific GADRs were noted, including abdominal discomfort (1.62, 95% CI 1.32-1.99), constipation (1.54, 95% CI 1.26-1.89), dyspepsia (1.25, 95% CI 1.01-1.55), abdominal distension (1.36, 95% CI 1.05-1.75), faeces discoloured (1.77, 95% CI 1.15-2.73), and gastric ulcer (2.37, 95% CI 1.28-4.41). CONCLUSION: Clinicians should have a deeper understanding of GADRs to improve the gastrointestinal tolerance of patients with chronic hepatitis C.

Oral mycobiota and pancreatic ductal adenocarcinoma.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is essential for survival. Preliminary research demonstrated significant associations between structural alternation of mycobiota and PDAC. In this study, we investigated the associations between oral mycobiota and PDAC. We further explored mycobiota biomarkers for PDAC detection. We enrolled 34 PDAC patients and 35 matched healthy controls from West China hospital in Southwest China. Demographic data, clinical information, and salivary samples were collected. Mycobiota characteristics were defined using Internal Transcribed Spacer (ITS) ribosomal RNA sequencing. We found that the PDAC patients had significant increase in fungal abundance (P < 0.001) and significant decrease in fungal diversity (P < 0.001) in comparison to the healthy controls. A higher abundance of Basidiomycota and Unclassifed_p_Ascomycota was associated with an increased risk of PDAC. With each increase of abundance of g__unclassified_k__Fungi and g__unclassified_p__Ascomycota in PDAC patients, the risk of pancreatic cancer increased by 1.359 odds and 1.260 odds, respectively. Aspergillus (AUC = 0.983, 95% CI 0.951-1.000) and Cladosporium (AUC = 0.969, 95% CI 0.921-1.000) achieved high classification powers to distinguish PDAC patients from the healthy controls. The rapid, inexpensive tests of ITS1 sequencing of mycobiota and PCR detection of potential fungal biomarkers make it promising for the clinical practice to use oral microbes for PDAC early detection and prevention. Results of our study provide evidence that salivary mycobiota may provide insights into cancer risk, prevention, and detection.

[A review on voluntary or involuntary eye movement classification methods based on electro-oculogram and their applications].

The eye-computer interaction technology based on electro-oculogram provides the users with a convenient way to control the device, which has great social significance. However, the eye-computer interaction is often disturbed by the involuntary eye movements, resulting in misjudgment, affecting the users' experience, and even causing danger in severe cases. Therefore, this paper starts from the basic concepts and principles of eye-computer interaction, sorts out the current mainstream classification methods of voluntary/involuntary eye movement, and analyzes the characteristics of each technology. The performance analysis is carried out in combination with specific application scenarios, and the problems to be solved are further summarized, which are expected to provide research references for researchers in related fields.

Anti-tumor Necrosis Factor-Alpha Therapy and Hypoglycemia: A Real-World Pharmacovigilance Analysis.

INTRODUCTION: An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet. OBJECTIVE: The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use. METHODS: Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels. RESULTS: In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable. CONCLUSIONS: Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation.

In vitro protoscolicidal effects of lithocholic acid on protoscoleces of Echinococcus granulosus and its mechanism.

Surgery has been found to be the best choice of treatment for hydatidosis. However, leakage of cyst contents during surgery is the foremost reason for recurrence of hydatidosis. In this study, we investigated the in vitro efficacy of lithocholic acid (LCA) against Echinococcus granulosus protoscoleces. The protoscoleces were divided into a control group, an albendazole (ABZ) positive control group and LCA intervention groups at concentrations of 0.5, 1, 2, and 3 mmol/L and stained with 0.1% eosin for observation using an inverted microscope; the protoscolecal ultrastructure was examined with SEM and TEM; the activities of ROS, SOD, and caspase-3 were investigated using an ROS kit, SOD kit, and caspase-3 kit, respectively; the contents of HO-1 and NQO-1 were analyzed by enzyme-linked immunosorbent assay; and the expression level of cytochrome c (Ctyc) was analyzed by western blotting. Results: As the concentration of LCA increased, the survival rate of protoscoleces gradually decreased. The microstructure shows that the external shape and internal structure were gradually deformed and collapse. SOD, GSH, HO-1 and NQO-1 decreased more significantly in the 3 mmol/L LCA group. However, ROS levels gradually increased. LCA treatment for 3 days at all concentrations significantly increased caspase-3 activity and expression in a dose-dependent manner. LCA decreased the level of Ctyc protein in vitro. LCA demonstrated a parasiticidal effect on the protoscoleces of Echinococcus granulosus in vitro. LCA may induce apoptosis of E. granulosus protoscoleces by oxidative stress and mitochondrial pathways.

Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis.

Background: The information is relatively scarce regarding the occurrence of drug-induced acute kidney injury (AKI) when anti-coronavirus disease 2019 (COVID-19) drugs are prescribed for patients with diabetes mellitus (DM). Objective: The objective of this study was to evaluate a pharmacovigilance signal for AKI upon the use of common drugs prescribed for COVID-19 treatment, especially in patients with DM. Methods: The FDA Adverse Event Reporting System (FAERS) database were used, and data from the first quarter of 2020 to the third quarter of 2021 were retrieved. A disproportionality analysis was performed to determine whether AKI was more frequently reported with anti-COVID-19 drugs compared to that with other drugs in different populations. Further, reporting odds ratios (RORs) and their 95% confidence intervals (CIs) were used to calculate disproportionality. Results: We identified 33,488 COVID-19 patients and 2397 COVID-19 patients with DM. AKI was the most frequent adverse drug reaction (ADR) reported in this patient population. The primary suspected drugs related to AKI in more than half of the reports (75.60%, 127/168) were four common anti-COVID-19 drugs (remdesivir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir). Compared with other drugs in the same time window, remdesivir and lopinavir/ritonavir were associated with an increased risk of AKI in all COVID-19 patients (ROR: 3.97, 95% CI: 3.51-4.50; ROR: 4.02, 95% CI: 3.11-5.19, respectively). In COVID-19 patients with DM, remdesivir was significantly associated with AKI (ROR: 5.65, 95% CI: 4.06-7.87); meanwhile, there was a new AKI signal associated with tocilizumab (ROR: 2.37, 95% CI: 1.19-4.72). After sensitivity analyses in COVID-19 patients with DM, consistent results for remdesivir were observed; however, the AKI signals for tocilizumab were unstable. Conclusion: Our study confirmed the association of AKI with the usage of common anti-COVID-19 drugs (especially remdesivir and tocilizumab) in DM patients. These safety signals suggested more individualized treatments for COVID-19 patients with comorbidities. Cross-disciplinary collaborative is needed to improve current strategy of clinical treatment and develop new approaches to management.

Efficacy and safety of vinorelbine and cisplatin regimen of different doses and intensities for neoadjuvant chemotherapy in patients with locally advanced esophageal carcinoma.

BACKGROUND: There are few studies focused on comparing the toxicity, postoperative complication rate, and survival among patients with locally advanced esophageal squamous cell cancer receiving a different dose and intensity of vinorelbine plus cisplatin for neoadjuvant chemoradiotherapy (nCRT) followed by surgery. METHODS: In total, 78 patients diagnosed with locally advanced esophageal squamous cell cancer that had received a vinorelbine and cisplatin (VP)1 or VP2 regimen for nCRT followed by surgery in Taizhou Hospital of Zhejiang Province between June 2008 and December 2016 were retrospectively analyzed. The VP1 regimen involved cisplatin 75 mg/m2 on day 1, and vinorelbine 25 mg/m2 on days 1 and 8, for two cycles. The VP2 regimen involved cisplatin 25 mg/m2 on days 1 to 4, and vinorelbine 25 mg/m2 on days 1 and 8, for two cycles. The rate of adverse events, postoperative complications, and survival were compared between the two groups. RESULTS: The median overall survival (OS) was 97.6 months (85.6-109.7) in the VP2 group, which was not significantly different to that of the VP1 group [hazard ratio (HR), 1.008 (0.999-1.108); P=0.509]. The main toxicity was hematologic adverse events. The VP2 group had significantly higher rates of all grades of anemia, leukopenia, neutropenia, and thrombocytopenia (all P<0.05), as well as grade 3 or 4 of leukopenia and neutropenia (P<0.05) compared to the VP1 group. Regarding postoperative complications, the VP2 group had a significantly higher rate of pulmonary infection than the VP1 group (P<0.05). CONCLUSIONS: Compared with VP2, VP1 showed comparable efficacy in terms of survival, with less hematologic toxicity and postoperative pulmonary infection. Therefore, we recommended that VP1 over VP2 to be the optimized VP neoadjuvant chemotherapy regimen for locally advanced esophageal squamous cell cancer.

TcpC secreting uropathogenic E. coli promoted kidney cells to secrete MIP-2 via p38 MAPK pathway.

Pyelonephritis is an infection of the upper urinary tract with characteristic histological change to neutrophil infiltration in the kidney. The majority of pyelonephritis is caused by uropathogenic Escherichia (E.) coli (UPEC) bearing distinct virulence factors. Toll/interleukin­1 receptor domain­containing protein C (TcpC) encoded by E. coli is an important virulence factor in the majority of strains of UPEC and inhibits macrophage­mediated innate immunity, which serves an essential role in the pathogenesis of pyelonephritis. In the present study, it was demonstrated that TcpC induced kidney cells to produce macrophage inflammatory protein­2 (MIP­2; also known as C­X­C motif chemokine 2). MIP­2 concentration in kidney homogenates from TcpC­secreting UPEC CFT073 (TcpCwt) murine pyelonephritis models was significantly higher compared with that in kidney homogenates from tcpC knockout CFT073 (TcpC­/­) models. In vitro, TcpCwt dose­dependently promoted MIP­2 secretion in HEK­293 cells. The concentration of MIP­2 in culture supernatants of HEK­293 co­cultured with TcpCwt was profoundly higher compared with that of HEK­293 co­cultured with TcpC­/­. In the presence of anti­TcpC antibody, the enhancement effect of TcpCwt on MIP­2 production was completely abrogated, suggesting that the enhanced production of MIP­2 was mediated by secreted TcpC. Furthermore, it was demonstrated that TcpC­/­ treatment had no effect on the p38 mitogen activated protein kinase (MAPK) signaling pathway, while TcpCwt treatment resulted in the activation of p38 MAPK in HEK­293 cells, as indicated by a simultaneous increase in p38 and phosphorylated­p38. In addition, inhibition of p38 MAPK with SB203580 significantly decreased MIP­2 concentration and neutrophil recruitment activity in the supernatants of HEK­293 cells co­cultured with TcpCwt. This indicates that TcpC may promote MIP­2 production in kidney cells through the p38 MAPK signaling pathway. Taken together, the data of the present study demonstrated that TcpC can induce MIP­2 production, which may contribute to the characteristic histological change associated with pyelonephritis. This data has provided novel evidence to further clarify the pathogenesis of pyelonephritis and novel directions on the pathogenicity of TcpC­secreting UPEC.

Berberine Protects Human Umbilical Vein Endothelial Cells against LPS-Induced Apoptosis by Blocking JNK-Mediated Signaling.

Endothelial dysfunction is a critical factor during the initiation of atherosclerosis. Berberine has a beneficial effect on endothelial function; however, the underlying mechanisms remain unclear. In this study, we investigated the effects of berberine on lipopolysaccharide- (LPS-) induced apoptosis in human umbilical vein endothelial cells (HUVECs) and the molecular mechanisms mediating the effect. The effects of berberine on LPS-induced cell apoptosis and viability were measured with 5-ethynyl-2'-deoxyuridine staining, flow cytometry, and Cell Counting Kit-8 assays. The expression and/or activation of proapoptotic and antiapoptotic proteins or signaling pathways, including caspase-3, poly(ADP-ribose) polymerase, myeloid cell leukemia-1 (MCL-1), p38 mitogen-activated protein kinase, C-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase, were determined with western blotting. The malondialdehyde levels, superoxide dismutase (SOD) activity, and production of proinflammatory cytokines were measured with enzyme-linked immunosorbent assays. The results demonstrated that berberine pretreatment protected HUVECs from LPS-induced apoptosis, attenuated LPS-induced injury, inhibited LPS-induced JNK phosphorylation, increased MCL-1 expression and SOD activity, and decreased proinflammatory cytokine production. The effects of berberine on LPS-treated HUVECs were prevented by SP600125, a JNK-specific inhibitor. Thus, berberine might be a potential candidate in the treatment of endothelial cell injury-related vascular diseases.