Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.

Uric acid regulates α-synuclein transmission in Parkinsonian models.

Ample evidence demonstrates that α-synuclein (α-syn) has a critical role in the pathogenesis of Parkinson's disease (PD) with evidence indicating that its propagation from one area of the brain to others may be the primary mechanism for disease progression. Uric acid (UA), a natural antioxidant, has been proposed as a potential disease modifying candidate in PD. In the present study, we investigated whether UA treatment modulates cell-to-cell transmission of extracellular α-syn and protects dopaminergic neurons in the α-syn-enriched model. In a cellular model, UA treatment decreased internalized cytosolic α-syn levels and neuron-to-neuron transmission of α-syn in donor-acceptor cell models by modulating dynamin-mediated and clathrin-mediated endocytosis. Moreover, UA elevation in α-syn-inoculated mice inhibited propagation of extracellular α-syn which decreased expression of phosphorylated α-syn in the dopaminergic neurons of the substantia nigra leading to their increased survival. UA treatment did not lead to change in markers related with autophagolysosomal and microglial activity under the same experimental conditions. These findings suggest UA may control the pathological conditions of PD via additive mechanisms which modulate the propagation of α-syn.

Antibiotics use patterns in end-of-life cancer patients and medical staff's perception of antimicrobial stewardship programs.

BACKGROUND/AIMS: While most cancer patients with end-of-life (EOL) care receive antibiotic treatments, antibiotic use should be decided appropriately considering the benefits, side effects, resistance, and cost effects. Antimicrobial stewardship programs (ASP) are important for patients with EOL care, but there is limited study analyzing actual antibiotic use in EOL care and the perceptions of Korean medical staff. METHODS: Electronic medical records of 149 deceased cancer patients hospitalized in the medical hospitalist units at Asan Medical Center in Seoul from May 2019 to September 2021 were reviewed. Basic information, antibiotic use, duration, and changes were investigated. We surveyed medical staff's perceptions of antibiotics in cancer patients with EOL. RESULTS: Of the 149 cancer patients with EOL care, 146 (98.0%) agreed with physician orders for life-sustaining treatment (POLST). In total, 143 (95.9%) received antibiotics, 110 (76.9%) received combination antibiotic treatment, and 116 (81.1%) were given antibiotics until the day of death. In a survey of 60 medical staff, 42 (70.0%) did not know about ASP, and 24 (40.0%) thought ASP was important in EOL care. Nineteen doctors (31.7%) discussed the use or discontinuation of antibiotics with patients or caregivers when writing POLST, but only 8 patients (5.6%) stopped antibiotics after POLST. CONCLUSION: Most cancer patients with EOL care continue to receive antibiotics until just before their death. A careful approach is needed, considering the benefits and side effects of antibiotic use, and the patient's right to self-decision. It is necessary to actively improve awareness of ASP and its importance for medical staff.

Enhanced catalytic oxidation of naproxen via activation of peroxymonosulfate by Fe-based metal-organic framework aerogels functionalized with Ag nanoparticles.

In this study, Ag3PO4 and Fe-based metal-organic frameworks (MOFs)-functionalized three-dimensional (3D) porous gelatin aerogels (Ag/Fe@GMA) were fabricated and used as adsorbents and catalysts for the activation of peroxymonosulfate (PMS) for naproxen (NPX) removal from water. The morphology, crystallinity, surface functional groups, and surface chemical element compositions of the fabricated Ag/Fe@GMA was evaluated using various analytical techniques. Our results showed that as an adsorbent, Ag/Fe@GMA showed a 18.0 % higher NPX adsorption capacity compared with the pristine aerogels. This can be attributed to the well-embedded Ag3PO4 and MOFs, indicating a stronger interaction between functionalized aerogels and NPX. After adsorption, 99.9 % of total NPX removal was achieved within 15 min by activating PMS and effectively generating •OH and •SO4- in water. The PMS/Ag/Fe@GMA aerogel system also showed high removal performance for rhodamine B (99.5 %) and tetracycline (93.7 %). Moreover, the Ag/Fe@GMA aerogels showed excellent reusability to achieve 95.7 % NPX removal efficiency after six times of recycling. This study revealed that the Ag/Fe@GMA aerogels had good potential for PMS activation and NPX removal. In particular, as an alternative to powdery materials, 3D shape of Ag/Fe@GMA with excellent reusability facilitates its application in the treatment of water contaminated with organic contaminants.

Factors Affecting the Length of Stay in the Emergency Department in Psychiatric Emergency Patients in the COVID-19 Pandemic Context.

To reduce overcrowding in emergency departments (ED), which is a serious international problem, it is important to reduce the length of ED stay (ED LOS) of emergency patients. In particular, due to the COVID 19 pandemic, psychiatric emergency patients spent much longer in ED. This study was conducted to identify the characteristics of psychiatric emergency patients who visited the ED during the COVID-19 pandemic and to identify factors affecting ED LOS. This retrospective study was conducted on adult patients aged 19 years or older who visited a psychiatric emergency center operated by an ED from 1 May 2020 to 31 April 2021 because of the COVID-19 pandemic. In this study, the average ED LOS of psychiatric emergency patients was 7.8 h. Factors affecting ED LOS for over 12 h were isolation (OR = 2.39, CI = 1.409-4.052), unaccompanied police officers (OR = 2.106, CI = 1.338-3.316), night-time visits (OR = 2.127, CI = 1.357-3.332), use of sedatives (OR = 1.671, CI = 1.030-2.713), and restraints (OR = 1.968, CI = 1.172-4.895). The ED LOS of psychiatric emergency patients is longer than that of general emergency patients, and a long ED LOS causes ED overcrowding. To reduce the ED LOS of psychiatric emergency patients, they must be accompanied by a police officer when visiting the ED, and the treatment process should be reorganized so that a psychiatrist can promptly intervene. Furthermore, it is necessary to reorganize the isolation guidelines and admission criteria for mental emergency patients.

Genome-wide identification of copy neutral loss of heterozygosity reveals its possible association with spatial positioning of chromosomes.

Loss of heterozygosity (LOH) is a genetic alteration that results from the loss of one allele at a heterozygous locus. In particular, copy neutral LOH (CN-LOH) events are generated, for example, by mitotic homologous recombination after monoallelic defection or gene conversion, resulting in novel homozygous locus having two copies of the normal counterpart allele. This phenomenon can serve as a source of genome diversity and is associated with various diseases. To clarify the nature of the CN-LOH such as the frequency, genomic distribution and inheritance pattern, we made use of whole-genome sequencing data of the three-generation CEPH/Utah family cohort, with the pedigree consisting of grandparents, parents and offspring. We identified an average of 40.7 CN-LOH events per individual taking advantage of 285 healthy individuals from 33 families in the cohort. On average 65% of them were classified as gonosomal-mosaicism-associated CN-LOH, which exists in both germline and somatic cells. We also confirmed that the incidence of the CN-LOH has little to do with the parents' age and sex. Furthermore, through the analysis of the genomic region including the CN-LOH, we found that the chance of the occurrence of the CN-LOH tends to increase at the GC-rich locus and/or on the chromosome having a relatively close inter-homolog distance. We expect that these results provide significant insights into the association between genetic alteration and spatial position of chromosomes as well as the intrinsic genetic property of the CN-LOH.

Role of an unclassified Lachnospiraceae in the pathogenesis of type 2 diabetes: a longitudinal study of the urine microbiome and metabolites.

Recent investigations have revealed that the human microbiome plays an essential role in the occurrence of type 2 diabetes (T2D). However, despite the importance of understanding the involvement of the microbiota throughout the body in T2D, most studies have focused specifically on the intestinal microbiota. Extracellular vesicles (EVs) have been recently found to provide important evidence regarding the mechanisms of T2D pathogenesis, as they act as key messengers between intestinal microorganisms and the host. Herein, we explored microorganisms potentially associated with T2D by tracking changes in microbiota-derived EVs from patient urine samples collected three times over four years. Mendelian randomization analysis was conducted to evaluate the causal relationships among microbial organisms, metabolites, and clinical measurements to provide a comprehensive view of how microbiota can influence T2D. We also analyzed EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data from a prospective longitudinal Korean community-based cohort. Our data revealed that GU174097_g, an unclassified Lachnospiraceae, was associated with T2D (ß = -189.13; p = 0.00006), and it was associated with the ketone bodies acetoacetate and 3-hydroxybutyrate (r = -0.0938 and -0.0829, respectively; p = 0.0022 and 0.0069, respectively). Furthermore, a causal relationship was identified between acetoacetate and HbA1c levels (ß = 0.0002; p = 0.0154). GU174097_g reduced ketone body levels, thus decreasing HbA1c levels and the risk of T2D. Taken together, our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone body levels.

Clinical Features and Risk Factors of Adrenal Insufficiency in Patients With Cancer Admitted to the Hospitalist-Managed Medical Unit.

BACKGROUND: The symptoms of adrenal insufficiency (AI) overlap with the common effects of advanced cancer and chemotherapy. Considering that AI may negatively affect the overall prognosis of cancer patients if not diagnosed in a timely manner, we analyzed the incidence, risk factors, and predictive methods of AI in cancer patients. METHODS: We retrospectively analyzed the medical records of 184 adult patients with malignancy who underwent a rapid adrenocorticotrophic hormone stimulation test in the medical hospitalist units of a tertiary hospital. Their baseline characteristics and clinical features were evaluated, and the risk factors for AI were identified using logistic regression analysis. RESULTS: Of the study patients, 65 (35%) were diagnosed with AI, in whom general weakness (63%) was the most common symptom. Multivariate logistic regression showed that eosinophilia (adjusted odds ratio [aOR], 4.28; 95% confidence interval [CI], 1.10-16.63; P = 0.036), history of steroid use (aOR, 2.37; 95% CI, 1.10-5.15; P = 0.028), and history of megestrol acetate use (aOR, 2.71; 95% CI, 1.38-5.33; P = 0.004) were associated with AI. Baseline cortisol levels of 6.2 µg/dL and 12.85 µg/dL showed a specificity of 95.0% and 95.4% for AI diagnosis, respectively. CONCLUSION: AI was found in about one-third of patients with cancer who showed general symptoms that may be easily masked by cancer or chemotherapy, suggesting that clinical suspicion of AI is important while treating cancer patients. History of corticosteroids or megestrol acetate were risk factors for AI and eosinophilia was a pre-test predictor of AI. Baseline cortisol level appears to be a useful adjunct marker for AI.

Differences in dietary patterns related to metabolic health by gut microbial enterotypes of Korean adults.

Diet has a profound impact on the progression of metabolic syndrome (MetS) into various diseases. The gut microbiota could modulate the effect of diet on metabolic health. We examined whether dietary patterns related to MetS differed according to gut microbial enterotypes among 348 Korean adults aged 18-60 years recruited between 2018∼2021 in a cross-sectional study. The enterotype of each participant was identified based on 16S rRNA gut microbiota data. The main dietary pattern predicting MetS (MetS-DP) of each enterotype was derived using reduced-rank regression (RRR) models. In the RRR models, 27 food group intakes assessed by a semi-quantitative food frequency questionnaire and MetS prediction markers including triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio and homeostatic model assessment for insulin resistance (HOMA-IR) were used as predictor and response variables, respectively. The MetS-DP extracted in Bacteroides enterotype (B-type) was characterized by high consumption of refined white rice and low consumption of eggs, vegetables, and mushrooms. The MetS-DP derived among Prevotella enterotype (P-type) was characterized by a high intake of sugary food and low intakes of bread, fermented legumes, and fermented vegetables. The MetS-DP of B-type was positively associated with metabolic unhealthy status (OR T3 vs. T1 = 3.5; 95% CI = 1.5-8.2), comparing the highest tertile to the lowest tertile. Although it was not significantly associated with overall metabolic unhealthy status, the MetS-DP of P-type was positively associated with hyperglycemia risk (OR T3 vs. T1 = 6.2; 95% CI = 1.6-24.3). These results suggest that MetS-DP may differ according to the gut microbial enterotype of each individual. If such associations are found to be causal, personalized nutrition guidelines based on the enterotypes could be recommended to prevent MetS.

Taxonomic Composition and Diversity of the Gut Microbiota in Relation to Habitual Dietary Intake in Korean Adults.

We investigated associations of habitual dietary intake with the taxonomic composition and diversity of the human gut microbiota in 222 Koreans aged 18-58 years in a cross-sectional study. Gut microbiota data were obtained by 16S rRNA gene sequencing on DNA extracted from fecal samples. The habitual diet for the previous year was assessed by a food frequency questionnaire. After multivariable adjustment, intake of several food groups including vegetables, fermented legumes, legumes, dairy products, processed meat, and non-alcoholic beverages were associated with major phyla of the gut microbiota. A dietary pattern related to higher α-diversity (HiαDP) derived by reduced rank regression was characterized by higher intakes of fermented legumes, vegetables, seaweeds, and nuts/seeds and lower intakes of non-alcoholic beverages. The HiαDP was positively associated with several genera of Firmicutes such as Lactobacillus, Ruminococcus, and Eubacterium (all p < 0.05). Among enterotypes identified by principal coordinate analysis based on the ß-diversity, the Ruminococcus enterotype had higher HiαDP scores and was strongly positively associated with intakes of vegetables, seaweeds, and nuts/seeds, compared to the two other enterotypes. We conclude that a plant- and fermented food-based diet was positively associated with some genera of Firmicutes (e.g., Lactobacillus, Ruminococcus, and Eubacterium) reflecting better gut microbial health.

Metabolic tracking of isoflavones in soybean products and biosamples from healthy adults after fermented soybean consumption.

Fermentation may enhance the nutritional properties of foods by increasing metabolite bioactivity or bioavailability. This study explored the effect of fermentation on isoflavone bioavailability and metabolism. Isoflavone metabolites were tracked in foods and biospecimens of healthy adults after fermented soybean (FS) or non-fermented soybean (NFS) consumption in a randomized, controlled, crossover intervention study. The change in soybean isoflavones caused by fermentation resulted in faster absorption and higher bioavailability after consumption of FS. Although the urinary level of total isoflavone metabolites was similar after the consumption of the two diets, urinary genistein 7-O-sulfate was derived as a discriminant metabolite for the FS diet by partial least squares discriminant analysis. This study suggests that an isoflavone conjugate profile might be a more appropriate marker than total isoflavone levels for discriminating between the consumption of FS and NFS diets.

Comparative genomic analysis of inbred rat strains reveals the existence of ancestral polymorphisms.

In an alignment of closely related genomic sequences, the existence of discordant mutation sites, which do not reflect the phylogenetic relationship of the genomes, is often observed. Although these discordant mutation sites are thought to have emerged by ancestral polymorphism or gene flow, their frequency and distribution in the genome have not yet been analyzed in detail. Using the genome sequences of all protein coding genes of 25 inbred rat strains, we analyzed the frequency and genome-wide distribution of the discordant mutation sites. From the comparison of different substrains, it was found that these loci are not substrain specific, but are common among different groups of substrains, suggesting that the discordant sites might have mainly emerged through ancestral polymorphism. It was also revealed that the discordant sites are not uniformly distributed along chromosomes, but are concentrated at certain genomic loci, such as RT1, major histocompatibility complex of rats, and olfactory receptors, indicating that genes known to be highly polymorphic tend to have more discordant sites. Our results also showed that loci with a high density of discordant sites are also rich in heterozygous variants, even though these are inbred strains.

Analysis of the Sensing Margin of Silicon and Poly-Si 1T-DRAM.

Recently, one-transistor dynamic random-access memory (1T-DRAM) cells having a polysilicon body (poly-Si 1T-DRAM) have attracted attention as candidates to replace conventional one-transistor one-capacitor dynamic random-access memory (1T-1C DRAM). Poly-Si 1T-DRAM enables the cost-effective implementation of a silicon-on-insulator (SOI) structure and a three-dimensional (3D) stacked architecture for increasing integration density. However, studies on the transient characteristics of poly-Si 1T-DRAM are still lacking. In this paper, with TCAD simulation, we examine the differences between the memory mechanisms in poly-Si and silicon body 1T-DRAM. A silicon 1T-DRAM cell's data state is determined by the number of holes stored in a floating body (FB), while a poly-Si 1T-DRAM cell's state depends on the number of electrons trapped in its grain boundary (GB). This means that a poly-Si 1T-DRAM can perform memory operations by using GB as a storage region in thin body devices with a small FB area.

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. METHODS: We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. FINDINGS: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. INTERPRETATION: Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. FUNDING: Ministry of Health and Welfare, South Korea.

Probing the speciation of quaternary ammonium polybromides by voltammetric tribromide titration.

The speciation of quaternary ammonium polybromides (QBr2n+1) was quantitatively determined by voltammetric tribromide titration on a Pt ultramicroelectrode (UME). The concentration of Br3- in a QBr2n+1-water mixed solution (QBr2n+1-WMS) was electrochemically estimated by measuring the steady state current associated with the electro-reduction of Br3- in a linear sweep voltammogram (LSV). The pBr3- titration curves of QBr2n+1-WMSs show 2-4 plateaus, each of which relates to the formation of QBr2n+1 from Br3- and Br2. The values of pBr3- at these plateaus can be regarded as corrected equilibrium constants of QBr2n+1, K'eq(n), which is Keq(n)/γ±, where γ± is a mean activity coefficient in QBr2n+1-WMS. Based on the estimated K'eq(n), fractional diagrams of QBr2n+1 were obtained, which gave information on QBr2n+1 speciation.

Exposure to cigarette smoke disturbs adipokines secretion causing intercellular damage and insulin resistance in high fructose diet-induced metabolic disorder mice.

A large amount of fructose intake along with smoking is associated with increased incidence of diseases linked to metabolic syndrome. More research is necessary to understand the complex mechanism that ultimately results in metabolic syndrome and the effect, if any, of high fructose dietary intake and smoking on individual health. In this study, we investigated changes in ER-Golgi network and disturbance to secretion of adipokines induced by cigarette smoking (CS) and excess fructose intake and their contribution to the disruption of metabolic homeostasis. We used high fructose-induced metabolic disorder mice model by feeding them with high fructose diet for 8 weeks. For CS exposure experiment, these mice were exposed to CS for 28 days according to OECD guideline 412. Our results clearly showed that the immune system was suppressed and ER stress was induced in mice with exposure to CS and fed with high fructose. Furthermore, their concentrations of adipokines including leptin and adiponectin were aberrant. Such alteration in secretion of adipokines could cause insulin resistance which may lead to the development of type 2 diabetes.

Potential effect of compounds isolated from Coffea arabica against UV-B induced skin damage by protecting fibroblast cells.

Ultraviolet (UV) radiation has adverse effects on extracellular matrix (ECM) proteins, leading to formation of wrinkles a hallmark of premature skin aging. The adverse effects of UV radiation are associated with induction of matrix metalloproteinases (MMPs) expression and degradation of collagen and elastin. The present study investigated anti-wrinkle effects of chlorogenic acid (CGA), pyrocatechol (PC) and 3,4,5-tricaffeoyl quinic acid (TCQ), isolated from beans of Coffea arabica, against UV-B stimulated mouse fibroblast cells (CCRF) by measuring expression levels of MMP-1, 3, 9, and type-I procollagen. The three compounds were isolated and purified from coffee grounds using column chromatography and structural examination was evaluated by nuclear magnetic resonance (NMR) analysis. Among the three isolated compounds, CGA effectively suppressed the expression of the MMP-1, 3, and 9 and increased synthesis of type-I procollagen as compared UV-B-stimulated CCRF cells. In addition, CGA dose-dependently inhibited intracellular reactive oxygen species (ROS) production in CCRF cells stimulated by UV radiation. Moreover, CGA displayed a good sun protection factor (SPF) and in vitro DNA damage protection together with inhibition of enzyme xanthine oxidase. The enzyme inhibitory kinetic behavior of CGA was determined by Lineweaver-Burk plot, displayed a mixed type enzyme inhibition with 260.3±4.5µM, Ki value. The results indicate that CGA has potential to be used as a preventive agent against premature skin aging induced by UV radiation.

The Effects of Gymnema sylvestre in High-Fat Diet-Induced Metabolic Disorders.

This study used an integrated approach to investigate the effects of Gymnema sylvestre (GS) extract as a functional dietary supplement with a high-fat diet. This approach examined insulin resistance, the dysfunction of adipose tissue, and liver steatosis. Male C57BL/6J mice were fed a normal chow or high-fat diet (HFD) for the acute and chronic study, in addition to GS in different doses (100, 250 and 500[Formula: see text]mg/kg body weight). Their body composition changes, serum lipid and glucose parameters, adipose and liver tissue histology, and gene expression were measured. It was found that GS significantly suppressed the increase of body weight, serum levels of lipid, insulin and leptin, and adipose tissue, and liver inflammation. GS also demonstrated hypoglycemic effects due to the amylase inhibition activity. Our results support the existence of a relationship between the HFD induced insulin resistance, adipose dysfunction and liver steatosis. In conclusion, GS works as a functional dietary supplement with preventative effects against metabolic disorder.

Laboratory-based surveillance of hospital-acquired respiratory virus infection in a tertiary care hospital.

Of 7,772 laboratory-confirmed cases of respiratory viral infection among hospitalized patients, 22.8% were categorized as having hospital-acquired infection. The overall incidence of hospital-acquired respiratory viral infection was 3.9 (95% confidence interval, 3.7-4.1) cases per 1,000 admitted patients. Rhinovirus was the most common virus (30.3%), followed by influenza virus (17.6%) and parainfluenza virus (15.6%).

Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: study protocol for a prospective, multicenter, randomized, open-label, phase II trial.

BACKGROUND: Linezolid, an oxazolidinone, substantially improves treatment outcomes of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We started a trial to test whether the use of linezolid instead of ethambutol could increase the rate of sputum culture conversion as of 8 weeks of treatment in patients with drug-susceptible tuberculosis. METHODS/DESIGN: This is a phase II, multicenter, randomized study with three arms. We are enrolling patients with pulmonary tuberculosis without rifampicin resistance screened by the Xpert MTB/RIF® assay. The standard treatment arm uses isoniazid (6 months), rifampicin (6 months), pyrazinamide (2 months), and ethambutol (2 months). Experimental arm 1 uses linezolid (600 mg/day) for 4 weeks instead of ethambutol. Experimental arm 2 uses linezolid (600 mg/day) for 2 weeks instead of ethambutol. The primary outcome is the sputum culture conversion rate on liquid media after 2 months of treatment. Secondary outcomes include the sputum culture conversion rate on solid media after 2 months of treatment, time to sputum culture conversion on liquid and solid media, cure rate, and treatment success rate. The frequencies of total adverse events (AEs) and serious AEs will be described and documented. Based on an α = 0.05 level of significance, a power of 85%, a 15% difference in the culture conversion rate after 2 months between the control arm and experimental arm 1 (75% vs. 90%), a 10% default (loss to follow-up) rate, and a 10% culture failure, the required number per arm was calculated to be 143 (429 in total). DISCUSSION: This trial will reveal the effectiveness and safety of 2 or 4 weeks of use of linezolid instead of ethambutol for patients with drug-susceptible pulmonary tuberculosis. If a new regimen including linezolid shows a higher culture conversion rate by week 8, and is safe, it could be tested as a 4-month antituberculosis treatment regimen in the future. TRIAL REGISTRATION: ClincalTrials.gov, NCT01994460 . Registered on 13 November 2013.