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• Etest method is useful for in vitro testing of combination antifungal therapy. • A combination of caspofungin and triazoles was effective for Candida infections. • Caspofungin and triazole combination was effective for Candida. glabrata with FKS mutation. Increased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. In this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). For Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata , direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. A combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the performance of QuantiFERON-TB Gold Plus (QFT-Plus) on Mycobacterium tuberculosis (MTB) infection test among registered village doctors from China.Methods: MTB infection of the registered village doctors in Zhongmu County were tested using QFT-Plus and two other interferon-gamma release assays (IGRAs) in parallel: QuantiFERON-TB Gold In-Tube (QFT) and T-SPOT.TB (T-SPOT). Retests were carried out for baseline positives at 3 and 6 months later, respectively.Results: A total of 616 village doctors were included in the baseline examination. The positivity of QFT, QFT-Plus and T-SPOT was 27.91% (168/602), 31.22% (187/599) and 27.70% (169/610), respectively. The concordance between QFT and QFT-Plus was 94.81% (Kappa coefficient: 0.87) and between T-SPOT and QFT-Plus was 88.93% (Kappa coefficient: 0.73). Reversions were frequently observed for all three assays. With respect to QFT-Plus, the quantitative results of reversions in the serial testing were mostly distributed in an "uncertain range" zone (0.2-0.7 IU/mL). Similar patterns of distribution were observed for QFT and T-SPOT as well.Conclusion: Village doctors should gain more attention as an at-risk group for TB infection control in rural China. Our results support, by means of serial testing, a good agreement between QFT-Plus and QFT in Chinese population. [ABSTRACT FROM AUTHOR]

Background: An improved understanding of the gut microbiota could lead to better strategies for the diagnosis, therapy and prophylaxis of tuberculosis (TB). The impact of both Mycobacterium tuberculosis (Mtb) infection and anti-TB treatment on the gut microbiota has rarely been studied.Methods: We characterized the diversity and composition of the gut microbiota in pulmonary TB patients as well as the effects of anti-TB drugs on the gut microbiota.Results: Pulmonary Mtb infection led to a minor decrease in the α diversity of the gut microbiota when compared to healthy controls, which mainly resulted from changes in the relative abundance of the members of genus Bacteroides. Anti-TB therapy caused a rapid, significant alteration in the community structure. The relative abundance of members of genus Clostridiales of the phylum Firmicutes significantly decreased during anti-TB treatment, while many members of genus Bacteroides, including Bacteroides OTU230 and Bacteroides fragilis, were among the taxa that increased. OTU8 and OTU2972 assigned to family Erysipelotrichaceae of the phylum Firmicutes showed a dramatic increase 1 week after the start of therapy, while the other members of this family decreased.Conclusions: Pulmonary TB and anti-TB treatment caused a distinct dysbiosis of the gut microbiota. Our study contributes valuable information implying potential links between the gut microbiota and TB. [ABSTRACT FROM AUTHOR]

T cells are strongly regulated by oxidizing environments and amino acid restriction. How T cells reprogram metabolism to adapt to these extracellular stress situations is not well understood. Here, we show that oxidizing environments and amino acid starvation induce ATF4 in CD4+ T cells. We also demonstrate that Atf4 -deficient CD4+ T cells have defects in redox homeostasis, proliferation, differentiation, and cytokine production. We further reveal that ATF4 regulates a coordinated gene network that drives amino acid intake, mTORC1 activation, protein translation, and an anabolic program for de novo synthesis of amino acids and glutathione. ATF4 also promotes catabolic glycolysis and glutaminolysis and oxidative phosphorylation and thereby provides precursors and energy for anabolic pathways. ATF4-deficient mice mount reduced Th1 but elevated Th17 immune responses and develop more severe experimental allergic encephalomyelitis (EAE). Our study demonstrates that ATF4 is critical for CD4+ T cell-mediated immune responses through driving metabolic adaptation. • Oxidizing environments and amino acid starvation induce ATF4 in CD4+ T cells • ATF4 increases mTORC1 activation plus intake and de novo synthesis of amino acids • ATF4 enhances glycolysis, glutaminolysis, and oxidative phosphorylation • ATF4 deficiency leads to decreases in Th1 but increases in Th17 immune responses. Oxidizing environments and availability of extracellular amino acids are major mechanisms that regulate T cell proliferation and function. Yang et al. demonstrate that ATF4 drives metabolic reprogramming, which allows CD4+ T cells to adapt to these stresses. [ABSTRACT FROM AUTHOR]

Summary: IL-22 has been suggested to play an important role in immune response against Mycobacterium tuberculosis infection. However, the exact role of IL-22 in human tuberculosis (TB) infection remains unclear and the regulatory mechanism of IL-22 response in human TB is unknown. In this study, we observed that successful anti-tuberculosis treatment induced an enhanced and sustained M. tuberculosis antigen-specific IL-22 response, correlated with the decrease of the frequencies of CD19+CD5+CD1d+ regulatory B cells. We also found that depletion of CD19+ B cells significantly enhanced M. tuberculosis antigen-specific IL-22 production by peripheral blood mononuclear cells. More importantly, we observed that purified CD19+ B cells, and more efficiently, CD19+CD5+CD1d+ regulatory B cells, suppressed IL-22 production. In summary, we showed here for the first time that effective anti-tuberculosis treatment restores M. tuberculosis antigen-specific IL-22 response through a novel mechanism by reducing the frequencies of CD19+CD5+CD1d+ regulatory B cells in human TB. [Copyright &y& Elsevier]

• Three new multidrug-resistant tuberculosis (MDR-TB)/ pre-extensive drug-resistant tuberculosis (pre-XDR-TB) regimens, five drugs for 9 months. • The first cohort of short-course regimens for MDR-TB in China. • Of 99 assessable participants, 92.9% had a favorable outcome. • Culture conversion was 82.5% at month 2 and 97.9% at month 6. • Majority of adverse effects were manageable and reversible. Long, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB). We conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen. A total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants. The primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs. [Display omitted] [ABSTRACT FROM AUTHOR]

• The first trial to explore all-oral short regimens for MDR-TB in China. • Two optimized regimens, designed according to local conditions. • Similar high culture conversion in the early stage in both regimens. • High treatment success rate for patients who completed the treatment. • Good adherence in the pandemic of COVID-19. Multidrug-resistant tuberculosis (MDR-TB) patients have been suffering long, ineffective, and toxic treatment until short-course injectable-free regimens emerged. However, the new WHO-recommended regimens might be less feasible in the real-world setting. Here, we evaluated two optimized all-oral short-course regimens in China. From April 2019 to August 2020, we conducted a prospective nonrandomized controlled trial and consecutively included 103 MDR-TB patients diagnosed with pulmonary MDR-TB in Shenzhen, China. A 4-5 drug regimen of 9-12 months was tailored to the strain's resistance patterns, patients' affordability, and tolerance to drugs. This was an interim analysis, focusing on the early treatment period. 53.4% (55/103) of patients were prescribed linezolid, fluoroquinolone (FQ), clofazimine, cycloserine, and pyrazinamide, followed by a regimen in which clofazimine was replaced by bedaquiline (35/103, 34.0%). The culture conversion rate was 83.1% and 94.4% at two and four months, respectively, with no significant difference between bedaquiline-free and bedaquiline-containing cases and between FQ-susceptible and FQ-resistant cases. Among 41 patients who completed treatment, 40 (97.6%) patients had a favorable outcome and no relapse was observed. Peripheral neuropathy and arthralgia/myalgia were the most frequent AEs (56.3%, 58/103). 18 AEs caused permanent discontinuation of drugs, mostly due to pyrazinamide and linezolid. Optimized all-oral short-course regimens showed satisfactory efficacy and safety in early treatment stage. Further research is needed to confirm these results. [ABSTRACT FROM AUTHOR]

Wind pressure serves as the fundamental base for architectural design, particularly the reference wind pressure value, which affects the reliability and economy of high-rise, towering, and large-span structures. To facilitate the calculation of reference wind pressure values for design reference periods, load codes from various countries offer probabilistic distribution models for wind speed or reference wind pressure. However, the application of a uniform load probabilistic distribution model for calculating the reference wind pressure for the reference period often results in overestimation or underestimation of the reference wind pressure. To this end, this study collected annual maximum wind speed data from 34 meteorological stations in Liaoning Province, a region in Northeast China, and established extreme value type I, extreme value type III, lognormal, and generalized extreme value distribution models for the annual maximum wind speeds using the maximum likelihood method and method of moment, respectively. The goodness-of-fit test was conducted utilizing the Kolmogorov–Smirnov method. The results showed that the extreme value type III model and the method of moment achieved the best goodness-of-fit for the probabilistic distribution of annual maximum wind speeds. Based on the measured wind direction data corresponding to the annual maximum wind speed, joint probability density functions and cumulative probability density functions of wind speed and wind direction were established. Finally, the influence of different load statistical periods on the reference wind pressure was analyzed. [ABSTRACT FROM AUTHOR]

Abstract Diagnosis of cervical tuberculous lymphadenitis (CTL), the most commonly occurring form of extrapulmonary tuberculosis, remains as a challenge in clinic. Detection of the presence of Mycobacterium tuberculosis (Mtb) in fine needle aspiration cytology (FNAC) samples is one golden criterion to confirm the CTL diagnosis. Due to the non-specific clinical presentation, CTL might be confused with other lymph node enlargement diseases; therefore empirical treatment with non-anti-TB antibiotics is often initially administered. However, it is still unclear whether this diagnostic antibiotic treatment affects the positivity of Mtb detection in FNAC. The demographics and clinical characteristics of 732 lymph node enlargement patients who had underwent FNAC were retrospectively analyzed and 605 (82.65%) of them were diagnosed as CTL. A total of 279 CTL cases (279/605, 46.11%) with completion of three Mtb tests (AFB, NAAT, and Mtb culture) in FNAC samples were selected for analyzing the effect of empirical antibiotic treatment on the positivity of Mtb tests. Compared to CTL patients without antibiotic treatment prior to FNAC, patients received empirical non anti-TB treatment had significantly lower positivity for acid fast bacilli staining (adjusted OR 0.11, 95% CI 0.06–0.21), nucleic acid amplification test (NAAT) (adjusted OR 0.38, 95% CI 0.21–0.71), and Mtb culture (adjusted OR 0.11, 95% CI 0.06–0.19). In conclusion, this study demonstrated that empirical non anti-TB antibiotic treatment reduced the opportunity to confirm CTL by microbiological analysis. Patients with cervical lymph node enlargement should undergo FNAC for Mtb tests prior to initiation of empirical non anti-TB treatment. Highlights • CTL accounted for the most cases of cervical lymph node enlargement. • CTL patients with typical tuberculous cytopathology tended to be found with higher positivity of Mtb in molecular and culture methods. • Empirical non-anti-TB antibiotic treatment reduced the opportunity to confirm CTL by microbiological analysis. [ABSTRACT FROM AUTHOR]