Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort.

BACKGROUND: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid. METHODS: Multicentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent. RESULTS: Among 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure. CONCLUSIONS: AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations. CLINICAL TRIALS REGISTRATION: NCT02754765

Novel UV‐B Phototherapy With a Light‐Emitting Diode Device Prevents Atherosclerosis by Augmenting Regulatory T‐Cell Responses in Mice

Background Ultraviolet B (UV‐B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV‐B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses. Methods and Results Based on light‐emitting diode technology, we developed novel devices that can emit 282 nm UV‐B, which we do not receive from natural sunlight, 301 nm UV‐B, and clinically available 312 nm UV‐B. We irradiated 6‐week‐old male atherosclerosis‐prone Apoe−/− (apolipoprotein E‐deficient) mice with specific wavelengths of UV‐B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry‐based lipidomics. Irradiation of 282 nm UV‐B but not 301 or 312 nm UV‐B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti‐inflammatory CD4+ Foxp3 (forkhead box P3)+ regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV‐B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin. Conclusions We demonstrated that 282 nm UV‐B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T‐cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV‐B phototherapy could be an attractive approach to treat atherosclerosis