Rationale Current recommendations for the treatment of rifampicin- and multidrug-resistant tuberculosis include bedaquiline (BDQ) used for 6 months or longer. Evidence is needed to inform the optimal duration of BDQ. Objectives We emulated a target trial to estimate the effect of three BDQ duration treatment strategies (6, 7–11, and ⩾12 mo) on the probability of successful treatment among patients receiving a longer individualized regimen for multidrug-resistant tuberculosis. Methods To estimate the probability of successful treatment, we implemented a three-step approach comprising cloning, censoring, and inverse probability weighting. Measurements and Main Results The 1,468 eligible individuals received a median of 4 (interquartile range, 4–5) likely effective drugs. In 87.1% and 77.7% of participants, this included linezolid and clofazimine, respectively. The adjusted probability of successful treatment was 0.85 (95% confidence interval [CI], 0.81–0.88) for 6 months of BDQ, 0.77 (95% CI, 0.73–0.81) for 7–11 months, and 0.86 (95% CI, 0.83–0.88) for ⩾12 months. Compared with 6 months of BDQ, the ratio of treatment success was 0.91 (95% CI, 0.85–0.96) for 7–11 months and 1.01 (95% CI, 0.96–1.06) for ⩾12 months. Naive analyses that did not account for bias revealed a higher probability of successful treatment with ⩾12 months (ratio, 1.09 [95% CI, 1.05–1.14]). Conclusions BDQ use beyond 6 months did not increase the probability of successful treatment among patients receiving longer regimens that commonly included new and repurposed drugs. When not properly accounted for, immortal person–time bias can influence estimates of the effects of treatment duration. Future analyses should explore the effect of treatment duration of BDQ and other drugs in subgroups with advanced disease and/or receiving less potent regimens.
BackgroundRecent World Health Organisation guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline- and/or delamanid as part of their multidrug regimen.MethodsPatients with a positive baseline culture were included. Six-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods.ResultsCulture conversion was observed in 83.8% (526/628) of patients receiving an all-oral regimen and 85.5% (425/497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95%CI: 0.88–1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients.ConclusionsAmong individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.
BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.
During full load shop tests under natural gas, two multistage centrifugal compressors exhibited subsynchronous vibrations. Both of them are low flow, high pressure, high rotational speed compressors, and are fitted with tilting pad bearings, and dry gas seals. A rotating stall problem was firstly eliminated by a modification of the diffuser geometry. Then, aerodynamic excitations caused the rotors to operate at their stability limit, and high vibration levels were observed at the first natural frequency. A complete rotordynamics analysis was performed in order to model precisely all the fluid-structure interactions. Modifications of the rotor designs were implemented, consisting in optimizing conveniently the bearing pads, replacing the toothed labyrinth seals of the balance pistons by damping honeycomb seals, fitting them with improved shunt hole systems. In addition, the dry gas seals were found to have been damaged, due to thermal effects, and further modifications were implemented to eliminate this problem. Final full load tests demonstrated a satisfactory behaviour of both centrifugal compressors.
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