[The effect of renal replacement therapy on the plasma concentration of antituberculosis drugs].

OBJECTIVE: To explore the effect of renal replacement therapy (RRT) on the plasma drug concentration of first-line antituberculosis drugs. METHODS: Thirty patients treated with continuous RRT and who were complicated with pulmonary tuberculosis from 2009 September to 2013 September were enrolled in the study. There were 19 males and 11 females, aged 18-75 years. They received RRT 3 times a week, 4 h each. The patients took isoniazid 300 mg and rifampin 450 mg one time every day, and pyrazinamide 40 mg · kg(-1) · d (-1) one time 24 h before RRT, 3 times every week. The plasma concentration of the drugs were monitored before and after each RRT for 4 weeks. RESULTS: Taken before RRT, the plasma concentration of isoniazid before RRP was (1.62 ± 0.44), (1.67 ± 0.38), (1.63 ± 0.41), (1.48 ± 0.38) mg/L respectively for 1-4 weeks; while that after RRT was (0.57 ± 0.22), (0.60 ± 0.24), (0.56 ± 0.20), (0.56 ± 0.15) mg/L (all P < 0.05). Taken before RRT, the plasma concentration of pyrazinamide before RRT was (16.08 ± 4.95), (16.32 ± 5.73), (14.89 ± 4.53), (13.81 ± 5.83) mg/L respectively for 1-4 weeks, while that after RRT was (3.73 ± 1.57), (3.57 ± 1.53), (3.22 ± 1.00), (2.81 ± 1.34) mg/L (all P < 0.05). Taken after RRT at once, the plasma concentration of pyrazinamide before RRT was (15.57 ± 3.47), (14.10 ± 2.27), (14.73 ± 2.36), (15.9 ± 3.02) mg/L respectively for 1-4 weeks, while that after RRT was (2.45 ± 1.14), (2.19 ± 1.07), (1.87 ± 1.52), (2.33 ± 1.30)mg/L. Taken before RRT, the plasma concentration of rifampin was (3.44 ± 1.17), (3.72 ± 1.24), (3.68 ± 1.16), (3.44 ± 1.22) mg/L respectively for 1-4 weeks (all P < 0.05), while that after RRT was (2.96 ± 1.10), (3.28 ± 1.04), (3.17 ± 1.02), (2.96 ± 1.05) mg/L (all P > 0.05). CONCLUSIONS: Continuous RRT has different effects on the plasma drug concentration of isoniazid and pyrazinamide. It almost has no effect on rifampin. To achieve the best plasma concentration and better anti-tuberculosis results, isoniazid and pyrazinamide should be taken after RRT, but rifampin before RRT.

A Systematic Thermal Analysis for Accurately Predicting the Extrusion Printability of Alginate-Gelatin-Based Hydrogel Bioinks.

Three-dimensional (3D) bioprinting has significant potential for addressing the global problem of organ shortages. Extrusion printing is a versatile 3D bioprinting technique, but its low accuracy currently limits the solution. This lack of precision is attributed largely to the complex thermal and dynamic properties of bioinks and makes it difficult to provide accurate estimations of the printed results. It is necessary to understand the relationship between printing temperature and materials' printability to address this issue. This paper proposes a quantitative thermal model incorporating a system's printing temperatures (syringe, ambient, and bioink) to facilitate accurate estimations of the printing outcomes. A physical model was established to reveal the relationship between temperature, pressure, and velocity in guiding the printing of sodium alginate-gelatin composite hydrogel (a popular bioink) to optimize its extrusion-based printability. The model considered the phenomenon of bioink die swells after extrusion. A series of extrusion experiments confirmed that the proposed model offers enhanced printing outcome estimations compared with conventional models. Two types of nozzles (32- and 23-gauge) were used to print several sets of lines with a linewidth step of 50 mm by regulating the extrudate's temperature, pressure, and velocity separately. The study confirmed the potential for establishing a reasonable, accurate open-loop linewidth control based on the proposed optimization method to expand the application of extrusion-based bioprinting further.

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety.

BACKGROUND: World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP). METHODS: AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort. RESULTS: By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually. CONCLUSIONS: Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Short-course Regimen for Subsequent Treatment of Pulmonary Tuberculosis: A Prospective, Randomized, Controlled Multicenter Clinical Trial in China.

PURPOSE: We designed a prospective, multicenter, randomized, controlled study to assess a 5-month regimen compared with the standard regimen on previously treated patients with pulmonary tuberculosis (TB). METHODS: We enrolled 917 sputum smear-positive patients undergoing additional treatment in 27 major tuberculosis hospitals in China. Patients were randomly assigned to a test group (n = 626)treated with a 5-month regimen of moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide or a reference group (n = 291) treated with an 8-month regimen of isoniazid, rifampicin, and streptomycin. All patients with a favorable response were followed up for 5 years after the end of treatment. FINDINGS: Of the study patients, 61 in the test group and 19 in the reference group had multidrug-resistant (MDR) TB. The treatment success rate in the study group was 74.12%, which was significantly higher than the 67.70% in the reference group (P = 0.04), whereas the treatment success rate of patients with MDR-TB was not significantly different between the test and reference groups (70.5% vs 63.1%, P =0.79). The adverse effects rates in the test and reference groups were 7.4% and 3.1%, respectively (P = .01). The difference in the TB recurrence rates between the group arm (9.6%) and the reference group (21.8%) was statistically significant (P < 0.001). IMPLICATIONS: The moxifloxacin, pasiniazid, rifabutin, ethambutol, and pyrazinamide test regimen yielded higher success and lower recurrence rates than the currently recommended isoniazid, rifampicin, and streptomycin regimen, but the rate of adverse effects was higher. ClinicalTrials.gov identifier: NCT02331823.

[Electrothermal acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting:a randomized controlled trial].

OBJECTIVE: To observe the effectiveness and safety of electrothermal acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in the cancerous patients of phlegm-stasis interaction in cisplatin-containing chemotherapy. METHODS: Sixty cases of phlegm-stasis interaction in cisplatin-containing chemotherapy were randomized into a trial group and a control group, 30 cases in each one. In the control group, the intravenous drip of granisetron hydrochloride injection was adopted, 3 mg before and after cisplatin-containing chemotherapy 30 min, continuously for 3 days. 43 to 45℃ electrothermal acupuncture at zusanli(ST 36) for 30 min was used on the basis of the treatment as the control group in the trial group,once a day for 3 days. CINV, anti-nausea effects, Karnofsky score, the syndrome score of phlegm-stasis interaction, and relevant indices of safety were observed on the 1st and 7th days of cisplatin-containing chemotherapy separately. RESULTS: 1.Regarding CINV and anti-nausea effect, CINV did not occur before chemotherapy in the patients of the two groups. On the 1st and 7th days of chemotherapy, CINV in the trial group were milder than those in the control group (both P<0.05).The anti-nausea effects in the trail group were better than those of the control group.2.Regarding Karnofsky score and the syndrome score of phlegm-stasis interaction, the improvements on the 7th days of chemotherapy in the trial group were better than those in the control group, indicating the significant differences (both P<0.05). 3.Regarding the safety indies, there was no adverse reaction during the treatment in the two groups. CONCLUSIONS: The electrothermal acupuncture effectively relieves CINV, and improves self-care dbility and the symptoms of phlegm-stasis interaction.

Discrepancies in Drug Susceptibility Test for Tuberculosis Patients Resulted from the Mixed Infection and the Testing System.

To find the potential reasons for the discrepancies in the drug susceptibility test (DST) of M. tuberculosis isolates, twenty paired isolates with disputed drug susceptibilities to isoniazid (INH) were selected according to the MGIT960 testing and Löwenstein-Jensen (L-J) proportion methods. Their MICs were confirmed again by broth microdilution method and by L-J proportion method. The spoligotyping results showed that, of all the 20 paired strains, 11 paired isolates belonged to the Beijing genotype and 6 paired isolates belonged to SIT1634, and that each of the remaining 3 paired isolates had two genotypes, namely, SIT1 and SIT1634. Those 3 paired isolates with different intrapair spoligotypes were further confirmed as mixed infection by the results that those three pairs of isolates with different 12 locus MIRU intrapair types and one pair carried different base pair at codon 315 (AGC versus AAC). Totally mutations in the katG gene were identified in 13 paired isolates. No mutations were found in the regulatory sequences and open reading frames (ORF) of the inhA and ahpC genes in any of the tested isolates. Those results showed that the different test systems and the mixed infection with particular genotypes of M. tuberculosis strains contributed to the drug susceptibility discrepancies.

[Study on the genotype of Mycobacterium tuberculosis isolates from hospitals in Tianjin].

OBJECTIVE: To explore the characteristics on molecular epidemiology of Mycobacterium tuberculosis isolates from hospitals in Tianjin area. METHODS: One hundred M. tuberculosis isolated strains were collected in succession from August 16th-December 25th, 2005 in Tianjin Haihe Hospital and genotyped by spoligotyping and multiple locus variable number-tandem repeat(VNTR). Data was analyzed by cluster software. Based on the concept of Beijing lineage, it was determinate two sub-groups: atypical Beijing strains and W strain/typical family strains by multiplex and real-time PCR. The associations of subgroups with drug resistance and age were assessed by the chi2 test. RESULTS: 96 M. tuberculosis strains were genotyped in which 91.7% (88/96) strains belonged to Beijing genotype (including 3 Beijing-like strains) by spoligtyping. VNTR typing could differentiate 60 genotypes among the 88 Beijing genotype strains. 93.2% of the Beijing lineage M. tuberculosis strains of this study belonged to W strain/typical Beijing family strains (82/88). No statistically significant differences were observed in the proportions of the two sub-groups in patients of different age, or drug resistance (P > 0.05). CONCLUSION: The M. tuberculosis Beijing genotype strains were dominated on tuberculosis hospital patients of Tianjin area. The discriminatory power of VNTR typing was higher than that of spoligtyping. The two sub-groups of Beijing lineage had been prevalent in Tianjin, however W strain/typical Beijing family strains were of preponderance.