Beijing Genotype of Mycobacterium tuberculosis Is Significantly Associated with High-Level Fluoroquinolone Resistance in Vietnam

Consecutive fluoroquinolone (FQ)-resistant isolates (n = 109) identified at the Pham Ngoc Thach Hospital for Tuberculosis, Ho Chi Minh City, Vietnam, were sequenced in the quinolone resistance-determining regions of the gyrA and gyrB genes and typed by large sequence polymorphism typing and spoligotyping to identify the Beijing genotype of Mycobacterium tuberculosis. Beijing genotype prevalence was compared with 109 consecutive isolates from newly presenting patients with pulmonary tuberculosis from the hospital outpatient department. Overall, 82.6% (n = 90/109) of isolates had mutations in gyrAB. Nine novel mutations were identified in gyrB (S486F, N538T, T539P, D500A, D500H, D500N, G509A, E540V, and E540D). The influence of these novel gyrB mutations on FQ resistance is not proven. The Beijing genotype was significantly associated with FQ resistance (odds ratio [OR], 2.39 [95% confidence interval {CI}, 1.34 to 4.25]; P = 0.003). Furthermore, Beijing genotype FQ-resistant isolates were significantly more likely than FQ-resistant isolates of other genotypes to have gyrA mutations (OR, 7.75 [95% CI, 2.84 to 21.15]; P = 0.0001) and high-level (>8 μg/ml) FQ resistance (OR, 11.0 [95% CI, 2.6 to 47.0]; P = 0.001). The underlying mechanism of the association of the Beijing genotype with high-level FQ resistance in this setting remains to be determined. The association of the Beijing genotype with relatively high-level FQ resistance conferred by specific gyrA mutations reported here is of grave concern given the epidemic spread of the Beijing genotype and the current hopes for shorter first-line treatment regimens based on FQs.Fluoroquinolones (FQs) are the most promising antituberculous therapeutic agents to be developed in 40 years (9, 31). They are widely used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) despite the lack of clinical trials evaluating optimal doses, duration, and combinations (10, 28, 31). Gatifloxacin is currently in phase III trials as a first-line agent to shorten existing treatment regimens from 6 to 4 months (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385 [http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00216385","term_id":"NCT00216385"}}NCT00216385]), and moxifloxacin is in phase III trials as a first-line substitute for either ethambutol (ETH) (ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173 [http://clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00082173","term_id":"NCT00082173"}}NCT00082173]) or isoniazid (INH) (ISRCTN register number 85595810 [http://www.controlled-trials.com/ISRCTN85595810]; ClinicalTrials.gov identification number {"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417 [www.clinicaltrials.gov/show/{"type":"clinical-trial","attrs":{"text":"NCT00144417","term_id":"NCT00144417"}}NCT00144417]).There is concern about levels of preexisting FQ-resistant TB in regions with high drug resistance rates because these drugs are often available over the counter and are additionally prescribed as broad-spectrum antibiotics for the treatment of undiagnosed respiratory infections (4, 5, 11, 17, 23, 27, 29).Vietnam has some of the highest primary drug resistance rates for Mycobacterium tuberculosis in the world, with over 35% of primary isolates being resistant to one or more first-line drugs (21, 26). Despite this, MDR TB rates remain relatively low, at 2.7% nationally, and the National Tuberculosis Program has achieved World Health Organization (WHO) targets for the detection and cure of TB for the last 10 years (14). An expanded MDR TB management program (formally DOTS-PLUS) will be piloted in the near future; however, the success of standardized regimens will depend heavily on preexisting levels of resistance to the most effective second-line agents, the FQs. At present, no data exist on FQ-resistant TB in Vietnam.In mycobacteria, the FQs bind to DNA gyrase and inhibit DNA replication. Reports in the literature show that the majority (approximately 60%) of FQ-resistant M. tuberculosis isolates carry mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene, and a small number have mutations in the gyrB gene (10). It was previously postulated that efflux pump mechanisms account for FQ resistance in isolates with wild-type gyrAB genes (6).While adherence remains the single most important factor in the emergence of drug-resistant TB, a factor contributing to the high prevalence of INH and streptomycin (STR) resistance in the region may be the high prevalence of strains of Mycobacterium tuberculosis of the Beijing genotype (1-3). The Beijing genotype first attracted attention as being the genotype of the strain responsible (W strain) for several large outbreaks of MDR TB in the United States in the early 1990s (28). It is associated with drug resistance and MDR in Vietnam (1, 3).This study investigated the prevalence of the Beijing genotype among FQ-resistant isolates from southern Vietnam and the associated genotypic mutations and MICs of ofloxacin.     

Loneliness and the psychosis continuum: a meta-analysis on positive psychotic experiences and a meta-analysis on negative psychotic experiences

Abstract

There is an increase in interest in the relationships between loneliness and psychosis. The notion of psychosis continuum implies that psychotic experiences extend from clinical populations with psychotic disorders to non-clinical populations. This meta-analytic review aimed to examine the respective associations of loneliness with positive and negative psychotic experiences along the psychosis continuum. A systematic database search was conducted and a total of 30 studies were included in the first meta-analysis and 15 studies were included in the second meta-analysis. There was a medium association between loneliness and positive psychotic experiences (r?=?0.302, p?<?0.001). In particular, the association between loneliness and paranoia was robust (r?=?0.448, p?<?0.001). The second meta-analysis revealed a medium association between loneliness and negative psychotic experiences (r?=?0.347, p?<?0.001). The associations between loneliness and both positive and negative psychotic experiences were found to be smaller among clinical than non-clinical samples. The above findings provided evidence for the associations between loneliness and the two core dimensions of psychotic experiences along the phenomenological continuum. Future research should examine the dynamics of these relationships in both clinical and non-clinical samples, preferably using a single-symptom approach.     

High-flow nasal oxygen vs. standard flow-rate facemask pre-oxygenation in pregnant patients: a randomised physiological study

High-flow nasal oxygen has been shown to provide effective pre-oxygenation and prolong apnoeic time during intubation attempts in non-pregnant patients. We aimed to compare pre-oxygenation using high-flow nasal oxygen (30–70 l.min⁻¹ oxygen flow) via nasal prongs with standard 15 l.min⁻¹ oxygen breathing via a tight-fitting facemask. Forty healthy parturients were randomly allocated to these two groups, and furthermore each patient underwent the selected pre-oxygenation method with both 3-min tidal volume breathing and 30s tidal breathing followed by eight vital capacity breaths. With 3-min tidal volume breathing, the respective estimated marginal means for high-flow nasal oxygen and standard flow rate facemask pre-oxygenation were 87.4% (95%CI 85.5–89.2%) and 91.0% (95%CI 89.3–92.7%), p = 0.02; with eight vital capacity breaths the estimated marginal means were 85.9% (95%CI 84.1–87.7%) and 91.8% (95%CI 90.1–93.4%, p < 0.0001). Furthermore, high-flow nasal oxygen did not reliably achieve a mean end-tidal oxygen concentration ≥ 90% compared with the standard flow rate facemask. In this physiological study, high-flow nasal oxygen pre-oxygenation performed worse than standard flow rate facemask pre-oxygenation in healthy term parturients.     

The Landscape of Actionable Molecular Alterations in Immunomarker-Defined Large-Cell Carcinoma of the Lung

IntroductionPatients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized cancer treatment decisions.Patients and MethodsA consecutive cohort of 789 resected NSCLC cases were reviewed. Fifty-nine NSCLC cases lacking morphologic differentiation, accounting for 7.5% of all resected NSCLCs, were identified and further characterized by immunohistochemistry according to the 2015 WHO lung tumor classification. Molecular alterations were investigated by multiple technologies including target capture sequencing, immunohistochemistry, and fluorescence in situ hybridizations.ResultsOf 59 NSCLC cases lacking morphologic differentiation, 20 (33.9%) were reclassified as adenocarcinoma (LCC-AD), 14 (23.7%) as squamous cell carcinoma (LCC-SqCC), and 25 (42.4%) as LCC-Null. Approximately 92% of LCC-Null, 95% of LCC-AD, and 86% of LCC-SqCC harbored clinically relevant alterations. Alterations characteristic of adenocarcinoma (EGFR, KRAS, ALK receptor tyrosine kinase [ALK], ROS1, and serine/threonine kinase 11 [STK11]) were detected in the LCC-AD subgroup but not in LCC-SqCC, whereas squamous-lineage alterations (phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha [PIK3CA], SRY-box 2 [SOX2], fibroblast growth factor receptor 1 [FGFR1], and AKT1) were detected in the LCC-SqCC subgroup but not in the LCC-AD group. Although some LCC-Null tumors displayed a genetic profile similar to either adenocarcinoma or squamous-cell carcinoma, more than half of the LCC-Null group were completely devoid of recognizable lineage-specific genetic profiles. High programmed death ligand 1 expression and high frequency of cell cycle regulatory gene alterations were found in the LCC-Null group offering alternative options of targeted therapy.ConclusionsThis comprehensive molecular study provided further insight into the genetic architecture of LCC. The presence of clinically actionable alterations in a majority of the tumors allowed personalized treatment to emerge.     

Application of corona electrical discharge plasma on modifying the physicochemical properties of banana starch indigenous to Taiwan

Corona electrical discharge (CED) belongs to an atmospheric pressure cold plasma. In this study, raw banana starch (indigenous to Taiwan), which contained resistant starch and amylose at a level of 58.4 g/100 g and 14.5 g/100 g, respectively, was treated by CED at 30 kV/cm, 40 kV/cm, and 50 kV/cm for 3 minutes. After the CED treatment, starch analyses showed that there were no apparent changes in the resistant starch and amylose contents. Only surface and nonpenetrative damage caused by plasma etching at different voltage strengths were observed on the starch granules. The CED treatments reduced the total area of diffraction peak, gelatinization enthalpy (by −21% to −38%), and different pasting behaviors including peak viscosity, breakdown, final viscosity, and setback. The CED treatments were capable of increasing relative crystallinity and gelatinization temperature. This study revealed the potential of CED plasma technology as a tool to modify the characteristics of banana starch.