Isoprenoid flavonoids isolated from Sophora davidii and their activities induces apoptosis and autophagy in HT29 cells.

Four previously undescribed isoprenoid flavonoids (2-5) were isolated from Sophora davidii, along with five known analogues. The structures of the compounds were established through comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR, and absolute configurations determined by theoretical calculations, including ECD and NMR calculation. The cytotoxic effects of the isolated compounds on human HT29 colon cancer cells were evaluated using the MTT assay, compound 1 exhibited cytotoxicity against human HT29 colon cancer cells with an IC50 value of 8.39 ± 0.09 µM. Studies conducted with compound 1 in HT29 cells demonstrated that it may induce apoptosis and autophagy in HT29 by promoting the phosphorylation of P38 MAPK and inhibiting the phosphorylation of Erk MAPK.

Effects of Different Doses of Esketamine on Pain Sensitivity of Patients Undergoing Thyroidectomy: A Randomized Controlled Trial.

INTRODUCTION: Several factors may lead to increased postoperative pain sensitivity, of which remifentanil-induced hyperalgesia (RIH) is one of the main factors. High-dose remifentanil exposure during anesthesia may induce RIH. Esketamine may prevent RIH by antagonizing N-methyl-D-aspartate (NMDA) receptors, thereby reducing the postoperative pain sensitivity. This study examined the effects of different esketamine doses on pain sensitivity in patients undergoing thyroidectomy and determined the optimal dose. METHODS: This study included 117 patients who received elective thyroidectomy. They were randomized into four groups: saline group (group C), esketamine 0.2 mg·kg-1 group (group RK1), esketamine 0.4 mg·kg-1 group (group RK2), and esketamine 0.6 mg·kg-1 group (group RK3). Five minutes before anesthesia induction, the same volume of study drugs were injected respectively in groups C, RK1, RK2, and RK3. Remifentanil was pumped at the same rate of 0.3 µg·kg-1·min-1 during surgery to ensure uniformity. This study's primary outcomes were the mechanical pain thresholds measured before surgery, as well as at 30 min, 6 h, 24 h, and 48 h after surgery. Hyperalgesia, rescue analgesia, numerical rating scale (NRS) score, and adverse reactions were recorded. RESULTS: Compared with baseline, the mechanical pain threshold was significantly decreased in group C [(94.67 ± 22.85) versus (112.00 ± 36.62) versus (161.33 ± 53.28) g, P < 0.001 at 30 min, P < 0.001 at 6 h] and group RK1 [(102.86 ± 24.17) versus (114.29 ± 41.05) versus (160.00 ± 54.98) g, P < 0.001 at 30 min, P < 0.001 at 6 h] around the surgical incision, and in group C [(112.00 ± 31.78) versus (170.67 ± 56.26) g, P < 0.001 at 30 min, (118.67 ± 34.42) versus (170.67 ± 56.26) g, P = 0.001 at 6 h] and group RK1 [(114.29 ± 45.17) versus (175.71 ± 54.80) g, P = 0.001 at 30 min, (121.43 ± 38.46) versus (175.71 ± 54.80) g, P = 0.002 at 6 h] on the forearm at 30 min and 6 h after surgery; compared with group C, the mechanical pain threshold was higher in group RK2 [(142.76 ± 50.06) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (145.52 ± 49.83) versus (112.00 ± 36.62) g, P < 0.001 at 6 h] and group RK3 [(140.00 ± 40.68) versus (94.67 ± 22.85) g, P < 0.001 at 30 min, (150.67 ± 56.50) versus (112.00 ± 36.62) g, P = 0.010 at 6 h] around the surgical incision, and in group RK2 [(149.66 ± 39.50) versus (112.00 ± 31.78) g, P = 0.006 at 30 min, (156.55 ± 47.23) versus (118.67 ± 34.42) g, P = 0.005 at 6 h] and group RK3 [(145.33 ± 51.18) versus (112.00 ± 31.78) g, P = 0.018 at 30 min, (154.67 ± 47.54) versus (118.67 ± 34.42) g, P = 0.008 at 6 h] on the forearm at 30 min and 6 h after surgery. Group RK3 had more glandular secretions than the other three groups (P = 0.042). CONCLUSIONS: Intravenous injection of esketamine 0.4 mg·kg-1 before anesthesia induction is a suitable dose to reduce pain sensitivity in patients undergoing thyroidectomy without increasing adverse reactions. However, future research needs to be extended to other populations. TRIAL REGISTRATION: Registered at the Chinese Clinical Trials Registry http://www.chictr.org.cn/ (09/06/2022, ChiCTR-2200060741).

Nimotuzumab plus induction chemotherapy followed by radiotherapy/concurrent chemoradiotherapy plus nimotuzumab for locally advanced nasopharyngeal carcinoma: protocol of a multicentre, open-label, single-arm, prospective phase II trial.

Epidermal growth factor receptor (EGFR) is a therapeutic target in nasopharyngeal carcinoma (NPC). The optimal combined modality of optimal combined modality of anti--EGFR monoclonal antibodies, induction chemotherapy (ICT), concurrent chemotherapy and radiotherapy for NPC remains poorly defined. None of previous studies have developed subsequent treatment strategies on the basis of stratification according to the efficacy following ICT plus anti-EGFR mAbs. This study aims to increase treatment intensity for patients with poor efficacy of ICT and reduce treatment toxicity for patients with favourable efficacy of ICT by assessing whether the efficacy of this treatment regimen is non-inferior to ICT plus concurrent chemoradiotherapy (historic controls). INTRODUCTION: METHODS AND ANALYSIS: Pathology-confirmed WHO type II/III NPC patients at clinical stage III-IVA (eighth American Joint Committee on Cancer/Union for International Cancer Control staging system) will be included in the study. They will receive ICT plus nimotuzumab (NTZ), followed by radiotherapy plus NTZ or concurrent chemoradiotherapy plus NTZ (stratified based on the efficacy of ICT plus NTZ). The primary endpoint is 3-year failure-free survival rate; while the secondary endpoints are 3-year overall survival rate, distant metastasis-free survival rate and locoregional recurrence-free survival rate, and short-term remission rate of tumour and treatment toxicity. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Our findings will be disseminated in a peer-reviewed journal. Implementation strategies are in place to ensure privacy and confidentiality of participants. TRIAL REGISTRATION NUMBER: ChiCTR2000041139.

A Prospective Study on Defining the Indications of Prophylactic Level IB Radiotherapy in Nasopharyngeal Carcinoma Based on a Risk Score Model.

OBJECTIVE: The aim of the study was to investigate clinical evidence for defining the indications of prophylactic level IB radiotherapy (RT) in nasopharyngeal carcinoma (NPC). METHODS: We conducted a phase 2 prospective study in 116 newly diagnosed patients with NPC treated by intensity-modulated RT. Whether level IB was irradiated is based on the risk score model (RSM). Two groups based on RSM were obtained: low risk and high risk. Omission of level IB irradiation was conducted in the low-risk group, otherwise level IB was contoured as part of the treatment target. Grade 2 or worse xerostomia at 12 months was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-H&N35 questionnaire. RESULTS: At a median follow-up of 16 months (range, 1-26 months), none of the patients developed failures at level IB. The 1-year overall survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 98.3%, 97.2%, and 95.8%, respectively. At 12 months xerostomia side-effects were reported in 90 of 116 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the low-risk group than in the high-risk group. CONCLUSION: Omission of level IB irradiation was feasible for patients with low-risk IB lymph nodes metastasis.

Liver Metastasis Occurring within Four Months of Early Breast Cancer Diagnosis: A Case Report and Literature Review.

Liver metastasis commonly occurs; however, the luminal-type liver metastasis rarely develops at the early stage of breast cancer, posing key challenges in screening patients, giving early targeted treatment, and providing an opportunity to prolong survival. A 44-year-old female was diagnosed with breast cancer (pT2N0M0, IIa) and luminal B type postoperatively. The latest guidelines indicated four cycles of albumin-paclitaxel and cyclophosphamide chemotherapy. After 4 months of treatment, the patient was found to have hypoechoic nodules in the liver due to other diseases and was thereby diagnosed with breast cancer with liver metastasis. The latest guidelines did not recommend routine imaging and hematological examination of asymptomatic early breast cancer during follow-up. We suggest that follow-up should be strengthened for high-risk patients to maximize their benefits from early diagnosis and treatment.

[Regulation of TRIP13 on Proliferation and Apoptosis of B-Cell Lymphoma Cells and Its Mechanism].

OBJECTIVE: To explore the regulatory effect of TRIP13 on the proliferation and apoptosis of B-cell lymphoma cells and its possible molecular mechanism by knocking down/overexpressing TRIP13 on the cell lines Granta-519 and JVM-2. METHODS: Lentiviral transfection technology was used to construct Granta-519 and JVM-2 cells with knocked down or overexpressed TRIP13 and their control cells. The efficiency of transfection was determined by fluorescence microscopy. The efficiency of knockdown and overexpression was evaluated by real-time quantitative PCR and Western blot. The proliferation was detected by CCK-8 assay. The apoptosis was detected by the Annexin V-APC single staining. The cell cycle was detected by the PI staining. The expression levels of P53, MDM4, and BCL-2 were evaluated by Western blot. RESULTS: After TRIP13 was knocked down, the proliferation ability of Granta-519 and JVM-2 cells was significantly reduced, and the apoptosis rate significantly increased. After TRIP13 was overexpressed, the proliferation ability of Granta-519 and JVM-2 cells was significantly enhanced, and the apoptosis was significantly reduced. After TRIP13 was knocked down, Granta-519 cells had obvious G1 phase arrest, and JVM-2 cells had obvious G1 and G2/M phase arrest. After TRIP13 was knocked down in Granta-519 cells, the expression of BCL-2 protein decreased, while MDM4 protein increased. After TRIP13 was overexpressed, the expression of MDM4 protein decreased. After TRIP13 was overexpressed in JVM-2 cells, the expression of BCL-2 protein increased. CONCLUSION: TRIP13 promotes the proliferation of B-cell lymphoma cells, inhibits their apoptosis, and affects their proliferation and apoptosis by participating in the regulation of the cell cycle. TRIP13 promotes the expression of BCL-2 proteins and inhibits the expression of MDM4 protein in B-cell lymphoma cells.

MicroRNA-139-5p upregulation is associated with diabetic endothelial cell dysfunction by targeting c-jun.

Dysfunction of endothelial cells (ECs) and their progenitor cells is an important feature of diabetic vascular disease. MicroRNA (miR)-139-5p is involved in inhibiting the metastasis and progression of diverse malignancies. However, the role of miR-139-5p in ECs still remains unclarified. Here we demonstrated that miR-139-5p expression was elevated in endothelial colony-forming cells (ECFCs) isolated from patients with diabetes, ECs derived from the aorta of diabetic rodents, and human umbilical vein endothelial cells (HUVECs) cultured in high glucose media. MiR-139-5p mimics inhibited tube formation, migration, proliferation, and down-regulated expression of c-jun, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF)-B, in ECFCs and HUVECs, respectively; moreover, miR-139-5p inhibitors reversed the tendency. Further, gain- and-loss function experiments and ChIP assay indicated that miR-139-5p regulate functions of ECFCs by targeting c-jun-VEGF/PDGF-B pathway. In vivo experiments (Matrigel plug assay and hindlimb ischemia model) showed that miR-139-5p downregulation further promoted ECFC-mediated angiogenesis and blood perfusion. In conclusion, diabetes-mediated high miR-139-5p expression inhibits the c-jun-VEGF/PDGF-B pathway, thus decreasing ECFCs migration, tube formation and proliferation, which subsequently reduces ECs survival. Therefore, miR-139-5p might be an important therapeutic target in the treatment of diabetic vasculopathy in the future.

The Role of Epstein-Barr Virus in Adults With Bronchiectasis: A Prospective Cohort Study.

BACKGROUND: Epstein-Barr virus (EBV) is implicated in the progression of chronic obstructive pulmonary disease. We aimed to determine whether EBV correlates with bronchiectasis severity, exacerbations, and progression. METHODS: We collected induced sputum in healthy controls and spontaneous sputum at 3-6-month intervals and onset of exacerbations in bronchiectasis patients between March 2017 and October 2018. EBV DNA was detected with quantitative polymerase chain reaction. RESULTS: We collected 442 sputum samples from 108 bronchiectasis patients and 50 induced sputum samples from 50 healthy controls. When stable, bronchiectasis patients yielded higher detection rates of EBV DNA (48.1% vs 20.0%; P = .001), but not viral loads (mean log10 load, 4.45 vs 4.76; P = .266), compared with controls; 64.9% of patients yielded consistent detection status between 2 consecutive stable visits. Neither detection rate (40.8% vs 48.1%; P = .393) nor load (mean log10 load, 4.34 vs 4.45; P = .580) differed between the onset of exacerbations and stable visits, nor between exacerbations and convalescence. Neither detection status nor viral loads correlated with bronchiectasis severity. EBV loads correlated negatively with sputum interleukin-1ß (P = .002), CXC motif chemokine-8 (P = .008), and tumor necrosis factor-α levels (P = .005). Patients initially detected with, or repeatedly detected with, EBV DNA had significantly faster lung function decline and shorter time to next exacerbations (both P < .05) than those without. Detection of EBV DNA was unrelated to influenza virus and opportunistic bacteria (all P > .05). The EBV strains detected in bronchiectasis patients were phylogenetically homologous. CONCLUSIONS: Patients with detection of EBV DNA have a shorter time to bronchiectasis exacerbations. EBV may contribute to bronchiectasis progression.

The Roles of Bacteria and Viruses in Bronchiectasis Exacerbation: A Prospective Study.

BACKGROUND: Exacerbations are crucial events during bronchiectasis progression. OBJECTIVES: To explore the associations between bacterial, viral, and bacterial plus viral isolations and bronchiectasis exacerbations. METHODS: In this prospective study, we enrolled 108 patients who were followed up every 3-6 months and at onset of exacerbations between March 2017 and November 2018. Spontaneous sputum was split for detection of bacteria (routine culture) and viruses (quantitative polymerase chain reaction). Symptoms and lung function were assessed during exacerbations. RESULTS: The median exacerbation rate was 2.0 (interquartile range: 1.0-2.5) per patient-year. At any visit, viral isolations (V+) occurred more frequently during onset of exacerbations [odds ratio (OR): 3.28, 95% confidence interval (95%CI): 1.76-6.12], as did isolation of new bacteria (NB+) (OR: 2.52, 95%CI: 1.35-4.71) and bacterial plus viral isolations (OR: 2.24, 95%CI: 1.11-4.55). Whilst coryza appeared more common in exacerbations with V+ than in exacerbations with no pathogen isolations and those with NB+, lower airway symptoms were more severe in exacerbations with NB+ (P<.05). Sputum interleukin-1ß levels were higher in exacerbations with NB+ than in exacerbations with no pathogen isolations and those with V+ (both P<.05). Significantly more coryza symptoms correlated with bacterial plus viral isolations at exacerbations (P=.019). Compared with V+ alone, bacterial with and without viral isolations tended to yield more severe lower airway symptoms, but not sputum cytokine levels at exacerbations. CONCLUSIONS: Viral isolations, isolation of new bacteria and bacterial plus viral isolation are associated with bronchiectasis exacerbations. Symptoms at exacerbations might inform clinicians the possible culprit pathogens.

The Roles of Bacteria and Viruses in Bronchiectasis Exacerbation: A Prospective Study.

Background: Exacerbations are crucial events during bronchiectasis progression. Objectives: To explore the associations between bacterial, viral, and bacterial plus viral isolations and bronchiectasis exacerbations. Methods: In this prospective study, we enrolled 108 patients who were followed up every 3-6 months and at onset of exacerbations between March 2017 and November 2018. Spontaneous sputum was split for detection of bacteria (routine culture) and viruses (quantitative polymerase chain reaction). Symptoms and lung function were assessed during exacerbations. Results: The median exacerbation rate was 2.0 (interquartile range: 1.0-2.5) per patient-year. At any visit, viral isolations (V+) occurred more frequently during onset of exacerbations [odds ratio (OR): 3.28, 95% confidence interval (95%CI): 1.76-6.12], as did isolation of new bacteria (NB+) (OR: 2.52, 95%CI: 1.35-4.71) and bacterial plus viral isolations (OR: 2.24, 95%CI: 1.11-4.55). Whilst coryza appeared more common in exacerbations with V+ than in exacerbations with no pathogen isolations and those with NB+, lower airway symptoms were more severe in exacerbations with NB+ (P < .05). Sputum interleukin-1ß levels were higher in exacerbations with NB+ than in exacerbations with no pathogen isolations and those with V+ (both P < .05). Significantly more coryza symptoms correlated with bacterial plus viral isolations at exacerbations (P = .019). Compared with V+ alone, bacterial with and without viral isolations tended to yield more severe lower airway symptoms, but not sputum cytokine levels at exacerbations. Conclusions: Viral isolations, isolation of new bacteria and bacterial plus viral isolation are associated with bronchiectasis exacerbations. Symptoms at exacerbations might inform clinicians the possible culprit pathogens.

Contexto: Las exacerbaciones son eventos cruciales durante la progresión de la bronquiectasia. Objetivos: Analizar las asociaciones entre el aislamiento de bacterias, virus y virus y bacterias juntas y las exacerbaciones de las bronquiectasias. Métodos: En este estudio prospectivo se incluyó a 108 pacientes a los que se siguió cada 3-6 meses y al comienzo de las exacerbaciones entre marzo de 2017 y noviembre de 2018. La muestra de esputo espontáneo se dividió para la detección de bacterias (cultivo de rutina) y virus (reacción en cadena de la polimerasa cuantitativa). Se evaluaron los síntomas y la función pulmonar durante las exacerbaciones. Resultados: La mediana de la tasa de exacerbación fue de 2,0 (rango intercuartil: 1,0-2,5) por paciente/año. En cualquier visita, los aislamientos de virus (V+) tuvieron lugar con mayor frecuencia durante el inicio de las exacerbaciones (odds ratio [OR]: 3,28; intervalo de confianza del 95% [IC 95%]: 1,76-6,12), al igual que el aislamiento de nuevas bacterias (NB+) (OR: 2,52; IC 95%: 1,35-4,71) y los aislamientos de bacterias y virus juntos (OR: 2,24; IC 95%: 1,11-4,55). Mientras que la coriza parecía más común en las exacerbaciones con V+ que en las exacerbaciones sin aislamientos de patógenos y en aquellas con NB+, los síntomas de las vías respiratorias inferiores fueron más graves en las exacerbaciones con NB+ (p < 0,05). Los niveles de interleucina-1ß en el esputo fueron más altos en las exacerbaciones con NB+ que en las exacerbaciones sin aislamiento de patógenos, y aquellas con V+ (ambos p < 0,05). De manera significativa, más síntomas de coriza se correlacionaron con aislamientos de bacterias y virus juntos durante las exacerbaciones (p = 0,019). Comparados con los V+ en solitario, los aislamientos de bacterias con y sin virus tienden a producir síntomas más graves en las vías respiratorias inferiores, pero no alteran los niveles de citocinas en el esputo durante las exacerbaciones. Conclusiones: Los aislamientos de virus, el aislamiento de nuevas bacterias y el aislamiento de bacterias y virus juntos están asociados a las exacerbaciones de las bronquiectasias. Los síntomas de las exacerbaciones pueden proporcionar información a los médicos sobre los posibles patógenos responsables.

The Clinical Outcomes and Toxicities of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma.

PURPOSE: To analyze the outcomes and toxicities of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) plus adjuvant chemotherapy (ACT) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Retrospective analysis of 163 patients with LA-NPC referred from August 2015 to December 2018 was carried out. All patients underwent platinum-based ICT followed by CCRT plus ACT. RESULTS: The median follow-up time was 40 months, ranging from 5 to 69 months. The 3-year disease-free survival (DFS), overall survival (OS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates were 80.8, 90.0, 91.6, and 87.4%, respectively. The most frequent acute grade 3/4 adverse events were leukopenia (66.8%), neutropenia (55.8%), mucositis (41.1%), thrombocytopenia (27.0%), and anemia (14.7%). CONCLUSION: ICT followed by CCRT plus ACT did not seemingly enhance DFS and OS in LA-NPC patients compared to the addition of ICT to CCRT (historical controls). In contrast, ICT followed by CCRT plus ACT had more acute adverse events than ICT followed by CCRT. Longer-term clinical studies are required to examine the treatment outcomes and late toxicities.

Sputum Exosomal microRNAs Profiling Reveals Critical Pathways Modulated By Pseudomonas aeruginosa Colonization In Bronchiectasis.

Background: Pseudomonas aeruginosa (PA) colonization confers poor prognosis in bronchiectasis. However, the biomarkers and biological pathways underlying these associations are unclear. Objective: To identify the roles of PA colonization in bronchiectasis by exploring for sputum exosomal microRNA profiles. Methods: We enrolled 98 patients with clinically stable bronchiectasis and 17 healthy subjects. Sputum was split for bacterial culture and exosomal microRNA sequencing, followed by validation with quantitative polymerase chain reaction. Bronchiectasis patients were stratified into PA and non-PA colonization groups based on sputum culture findings. We applied Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis to explore biological pathways corresponding to the differentially expressed microRNAs (DEMs) associated with PA colonization. Results: Eighty-two bronchiectasis patients and 9 healthy subjects yielded sufficient sputum that passed quality control. We identified 10 overlap DEMs for the comparison between bronchiectasis patients and healthy subjects, and between PA and non-PA colonization group. Both miR-92b-5p and miR-223-3p could discriminate PA colonization (C-statistic >0.60) and independently correlated with PA colonization in multiple linear regression analysis. The differential expression of miR-92b-5p was validated by quantitative polymerase chain reaction (P<0.05), whereas the differential expression of miR-223 trended towards statistical significance (P=0.06). These DEMs, whose expression levels correlated significantly with sputum inflammatory biomarkers (interleukin-1ß and interleukin-8) level, were implicated in the modulation of the nuclear factor-κB, phosphatidylinositol and longevity regulation pathways. Conclusion: Sputum exosomal microRNAs are implicated in PA colonization in bronchiectasis, highlighting candidate targets for therapeutic interventions to mitigate the adverse impacts conferred by PA colonization.

Health Perception and Behaviors in Adults With Bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic debilitating suppurative disease that significantly impacts quality of life. Clinical outcomes like exacerbations, are usually physician centered; however, the patients' experience, health-related behaviors, and expectations have frequently been neglected. In addition, patients' health perceptions may be influenced by their culture. OBJECTIVE: To determine the health perception and behavior in adults with bronchiectasis. METHODS: We performed semi-directive interviews, which were audiotaped, with 60 adults with bronchiectasis between April 2016 and December 2016. Our interview focused on issues related to symptom perception, access to health-care resources and patient-physician communication, medication adherence, outcomes and expectations, quality of life, and social relationships. RESULTS: The subjects with bronchiectasis developed varying patterns of symptom perception (ranging from highly distressing to barely disturbing) and had conflicting opinions on whether and when they should seek health-care services (ranging from active consultations to being totally passive or resistant to seek health care). We observed certain discrepancies between symptom perception and health-related behaviors. Overall, medication adherence was suboptimal, but the subjects were willing to participate in clinical trials and receive complementary alternative medications despite concerns regarding adverse effects of prolonged treatment. There were concerns about the adverse effects of bronchiectasis on fertility and infectiousness to others, although most subjects disregarded these issues. CONCLUSIONS: The diverse symptom perception and health-related behaviors highlighted the need for evaluation and intervention in bronchiectasis. These findings will provide rationales for refining future health care through comprehensive (particularly psychological) interventions worldwide.

Altered community compositions of Proteobacteria in adults with bronchiectasis.

Background: Bronchiectasis is a debilitating disease with chronic airway infection. Proteobacteria, the dominant phylum, can be detected with high-throughput sequencing. Objective: To stratify Proteobacteria compositions according to culture findings in bronchiectasis. Patients and methods: We sampled sputum, split for culture and 16srRNA sequencing, from 106 patients with stable bronchiectasis and 17 healthy subjects. Paired sputa from 22 bronchiectasis patients were collected during exacerbations and convalescence. Results: Forty-five, 41, and 20 patients with clinically stable bronchiectasis had isolated Pseudomonas aeruginosa (PA), other potentially pathogenic microorganisms, and commensals at the initial visit, respectively. The PA group (but not other groups) demonstrated significantly greater relative abundance of Proteobacteria, and lower Shannon-Wiener Diversity Index, Simpson Diversity Index, and richness compared with healthy subjects. Pseudomonas was the dominant genus that discriminated bronchiectasis patients (particularly in the PA group) from healthy subjects. Compared with baseline levels, Proteobacteria community compositions in the PA group, but not in other groups, were more resilient during exacerbations and convalescence. Conclusion: Proteobacteria community compositions could be partially reflected by conventional sputum bacterial culture. Significantly altered Proteobacteria community compositions - particularly, the increased relative abundance of Pseudomonas and diminished community diversity - represent critical targets for novel interventions to restore normal airway microen-vironment in patients with bronchiectasis.

Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis.

BACKGROUND: Defective airway host-defense (e.g., altered mucus properties, ciliary defects) contributes to the pathogenesis of bronchiectasis. This study aims to determine whether genetic mutations associated with defective airway host-defense are implicated in the pathogenesis of bronchiectasis. METHODS: Based on the systematic screening of 32 frequently reported bronchiectasis-associated genes, we performed next-generation sequencing (NGS) on peripheral blood samples from 192 bronchiectasis patients and 100 healthy subjects. The variant distribution frequency and pathogenicity of mutations were analyzed. RESULTS: We identified 162 rare variants in 192 bronchiectasis patients, and 85 rare variants among 100 healthy subjects. Among bronchiectasis patients, 25 (15.4%), 117 (72.2%) and 18 (11.1%) rare variants were associated with cystic fibrosis transmembrane receptor (CFTR), epithelial sodium channel, and primary ciliary dyskinesia genes, respectively. Biallelic CFTR variants were detected in four bronchiectasis patients but none of the healthy subjects. Carriers of homozygous p.M470 plus at least one CFTR rare variant were detected in 6.3% of bronchiectasis patients (n=12) and in 1.0% of healthy subjects (n=1, P=0.039). Twenty-six patients (16 with idiopathic and 6 with post-infectious bronchiectasis) harbored biallelic variants. Bronchiectasis patients with biallelic DNAH5 variants, or biallelic CFTR variants plus an epithelial sodium channel variant, tended to have greater disease severity. CONCLUSIONS: Genetic mutations leading to impaired host-defense might have implicated in the pathogenesis of bronchiectasis. Genetic screening may be a useful tool for unraveling the underlying causes of bronchiectasis, and offers molecular information which is complementary to conventional etiologic assessment for bronchiectasis.

Residual volume/total lung capacity ratio confers limited additive significance to lung clearance index for assessment of adults with bronchiectasis.

BACKGROUND: Mosaicism and hyperinflation are common pathophysiologic features of bronchiectasis. The magnitude of ventilation heterogeneity might have been affected by the degree of hyperinflation. Some studies have evaluated the discriminative performance of lung clearance index (LCI) in bronchiectasis patients, but the additive diagnostic value of hyperinflation metrics to LCI is unknown. OBJECTIVE: To compare LCI and the ratio of residual volume to total lung capacity (RV/TLC), along with the LCI normalized with RV/TLC, in terms of discriminative performance, correlation and concordance with clinical variables in adults with bronchiectasis. METHODS: Measurement items included chest high-resolution computed tomography, multiple-breath nitrogen washout test, spirometry, and sputum culture. We analyzed bronchodilator responses by stratifying LCI and RV/TLC according to their median levels (LCIHigh/RV/TLCHigh, LCILow/RV/TLCHigh, LCIHigh/RV/TLCLow, and LCILow/RV/TLCLow). RESULTS: Data from 127 adults with clinically stable bronchiectasis were analyzed. LCI had greater diagnostic value than RV/TLC in discriminating moderate-to-severe from mild bronchiectasis, had greater concordance in reflecting clinical characteristics (including the number of bronchiectatic lobes, radiological severity score, and the presence of cystic bronchiectasis). Normalization of LCI with RV/TLC did not contribute to greater discriminative performance or concordance with clinical variables. The LCI, before and after normalization with RV/TLC, correlated statistically with age, sex, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, and ventilation heterogeneity (all P<0.05). Different bronchodilator responses were not significant among the four subgroups of bronchiectasis patients, including those with discordant LCI and RV/TLC levels. CONCLUSION: LCI is superior to RV/TLC for bronchiectasis assessment. Normalization with RV/TLC is not required. Stratification of LCI and RV/TLC is not associated with significantly different bronchodilator responses.

Effect of Pregnane X Receptor*1B genetic polymorphisms on postoperative analgesia with fentanyl in Chinese patients undergoing gynecological surgery.

BACKGROUND: The purpose of the study was to investigate the effects of the pregnane X receptor (PXR)*1B polymorphisms on CYP3A4 enzyme activity and postoperative fentanyl consumption in Chinese patients undergoing gynecological surgery. METHODS: A total of 287 females of Han ethnicity, aged 20 to 50 years old, ASA I or II, scheduled to abdominal total hysterectomy or myomectomy under general anesthesia were enrolled. The analgesic model used was fentanyl consumption via patient-controlled intravenous analgesia (PCIA) in the post-operative period. Additionally, pain was assessed using a visual analog score (VAS). Pain scores, occurrence of adverse reactions and consumption of fentanyl were recorded during the 24 h postoperative period. The enzyme activity of CYP3A4 was evaluated by measuring the plasma ratio of 1'-hydroxymidazolam to midazolam 1 h after intravenous administration of 0.1 mg/kg midazolam. PXR genotyping was performed by direct DNA sequencing and the PXR * 1B haplotype was analyzed via PHASE V.2.1 software. RESULTS: The polymorphism frequency of PXR11156A > C/11193 T > C and 8055C > T were 49.6 and 49.3%, and the rate of PXR * 1B haplotype was 48.8% in our study. None of the pain scores, consumption of fentanyl 24 h post-operatively or enzyme activity of CYP3A4, showed differences among different genotypes. CONCLUSIONS: PXR11156A > C, PXR11193T > C, PXR8055C > T or the PXR * 1B haplotype do not appear to be important factors contributing to CYP3A4 activity and interindividual variations in postoperative fentanyl consumption in Han female patients undergoing gynecological surgery. TRIAL REGISTRATION: The DNA samples were obtained since 2007 to 2010 year in our hospital, there was no registration at that time. So this section is not applicable to our research.

Impulse Oscillometry and Spirometry Small-Airway Parameters in Mild to Moderate Bronchiectasis.

BACKGROUND: Both impulse oscillometry and spirometry can reflect small-airway disorders. The objective of this work was to investigate the diagnostic value of impulse oscillometry and spirometry small-airway parameters and their correlation with radiology, disease severity, and sputum bacteriology in mild to moderate bronchiectasis (bronchiectasis severity index <9) and to validate these findings in sensitivity analyses (mild bronchiectasis). METHODS: We recruited 94 subjects with mild to moderate bronchiectasis and 26 healthy subjects. The diagnostic value of small-airway parameters was compared using the receiver operating characteristic curve. Chest high-resolution computed tomography (HRCT), impulse oscillometry measurement, spirometry, and sputum culture were performed. Correlation between small-airway parameters and clinical indices was determined, adjusting for age, sex, body mass index, and smoking history. Sensitivity analyses were repeated when excluding subjects with bronchiectasis severity index ≥9 or HRCT score ≥13. RESULTS: Impulse oscillometry and spirometry small-airway parameters could discriminate mild to moderate bronchiectasis from healthy subjects and correlated significantly with HRCT score and the number of bronchiectatic lobes and the bronchiectasis severity index (all P < .01). Small-airway parameters were more aberrant in subjects with dyshomogeneity and cystic bronchiectasis but were independent of Pseudomonas aeruginosa isolation or the location of predominant bronchiectatic lobes. Spirometry, but not impulse oscillometry, small-airway parameters differed statistically between subjects with isolated peripheral-airway bronchiectasis and those with peripheral plus central-airway bronchiectasis (all P < .01). Subgroup analyses yielded similar findings, except for the lack of correlation between small-airway parameters and clinical parameters in subjects with HRCT score ≤6. CONCLUSIONS: Impulse oscillometry and spirometry small-airway parameters have similar diagnostic value in reflecting peripheral-airway disorders and correlate with the HRCT scores, the bronchiectasis severity index, and the number of bronchiectatic lobes in mild to moderate bronchiectasis. Assessment of small-airway parameters should be incorporated in future lung function investigations in bronchiectasis.

Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis.

Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity.