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Abstract The notion of topological insulators (TIs), characterized by an insulating bulk and conducting topological surface states, can be extended to higher-order topological insulators (HOTIs) hosting gapless modes localized at the boundaries of two or more dimensions lower than the insulating bulk. In this work, by performing high-resolution angle-resolved photoemission spectroscopy (ARPES) measurements with submicron spatial and spin resolution, we systematically investigate the electronic structure and spin texture of quasi-one-dimensional (1D) HOTI candidate Bi4Br4. In contrast to the bulk-state-dominant spectra on the (001) surface, we observe gapped surface states on the (100) surface, whose dispersion and spin-polarization agree well with our ab-initio calculations. Moreover, we reveal in-gap states connecting the surface valence and conduction bands, which is a signature of the hinge states inside the (100) surface gap. Our findings provide compelling evidence for the HOTI phase of Bi4Br4. The identification of the higher-order topological phase promises applications based on 1D spin-momentum locked current in electronic and spintronic devices.

The relationship between the charge density wave and excitonic correlations in a layered compound 1T-TiSe2 has remained controversial. Here, the authors observe a photo-induced dimensional crossover of the charge density wave and conclude that excitonic correlations are responsible for its out-of-plane phase coherence.

ABSTRACTIn preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

Introduction The burden of Mycobacterium avium complex (MAC) lung disease is increasing globally and treatment outcome is in general poor. Therapeutic drug monitoring has the potential to improve treatment outcome by ensuring adequate drug exposure. However, very limited population-based studies exist for MAC lung disease. This study aims to describe the distribution of drug exposure for key antimycobacterial drugs at population level, and to analyse them in relationship to treatment outcome in patients with MAC lung disease.Methods and analysis A prospective cohort aiming to include 100 adult patients diagnosed with and treated for MAC lung disease will be conducted in Shanghai Pulmonary Hospital, China. Blood samples will be collected after 1 month MAC treatment for measurement of macrolides, rifamycin, ethambutol, amikacin and/or fluoroquinolones, using a validated liquid-chromatography tandem mass spectrometry method. Respiratory samples will be collected at inclusion and once every 3 months for mycobacterial culture until treatment completion. Minimum inhibitory concentration (MIC) determination will be performed using a commercial broth microdilution plate. In addition to mycobacterial culture, disease severity and clinical improvement will be assessed from the perspective of lung function, radiological presentation and self-reported quality of life. Whole genome sequencing will be performed for any longitudinal isolates with significant change of MIC to explore the emergence of drug resistance-conferring mutations. The relationship between drug exposure and treatment outcome will be analysed and potential confounders will be considered for adjustment in multivariable models. Meanwhile, the associations between drug exposure in relation to MIC and markers of treatment response will be explored using Cox proportional hazards or binary logistic regression models, as appropriate.Ethics and dissemination This study has been approved by the ethics committee of Shanghai Pulmonary Hospital (No. K22-149Z). Written and oral informed consent will be obtained from all participants. The study results will be submitted to a peer-reviewed journal.Trial registeration number NCT05824988.

Abstract Background The positive rate of pathogenic examination about tuberculosis is low. It is still difficult to achieve early diagnosis for some TB patients. The value of Interferon-gamma release assays (IGRA) in the diagnosis of active tuberculosis remains controversial. The purpose of this multicenter prospective study was to verify and validate the role of TBAg/PHA ratio (TB-specific antigen to phytohaemagglutinin) of T-SPOT.TB assay in diagnosing ATB. Methods We prospectively enrolled 2390 suspected pulmonary tuberculosis patients with positive T-SPOT assay results from three tertiary hospitals. Results A total of 1549 ATB (active tuberculosis) patients (including 1091 confirmed and 458 probable ATB) and 724 non-tuberculosis (non-TB) patients with positive T-SPOT results were included. The results of this study showed that ESAT-6 and CFP-10 in the T-SPOT.TB assay were significantly higher in the ATB group compared with the non-TB group, while PHA was lower in the ATB group. Results of ESAT-6, CFP-10 and PHA show a certain diagnostic performance, but moderate sensitivity and specificity. The TBAg/PHA ratio, a further calculation of ESAT-6, CFP-10 and PHA in T-SPOT.TB assay showed improved performance in the diagnosis of active Tuberculosis. If using the threshold value of 0.2004, the specificity and sensitivity of TBAg/PHA ratio in distinguishing ATB from non-TB were 92.3% and 74.4%, PPV was 95.4, PLR was 9.6. Conclusion By recalculating the results of T-SPOT.TB Assay, the TBAg/PHA ratio shows high prospect value in the diagnosis of active tuberculosis in high prediction areas.

Objectives The value of QuantiFERON-TB Gold In-Tube (QFT-GIT) in the diagnosis of TB varies by population, comorbidities, and other factors. In this study, we aimed to investigate factors that influence false-negative results of QFT-GIT test in the diagnosis of TB as well as the impact of different cutoffs on the diagnostic value. Methods A total of 3562 patients who underwent QFT-GIT tests at Shanghai Pulmonary Hospital were enrolled retrospectively between May 2016 and May 2017. False-negative and false-positive results were analyzed using different clinical stratifications. The optimal cutoff values were established under different clinical conditions. Results Positive QFT-GIT results greatly shortened the time taken to diagnose smear-negative TB. The factors of age, smear and culture results, site of TB, comorbidity with tumors, white blood cell count, neutrophil count, and CD4/CD8 ratio were significantly correlated with false-negative QFT-GIT results (p < 0.05). Personalized cutoff values were established according to different influencing factors. The results showed high consistency between the smear-negative and total populations. Conclusion QFT-GIT can facilitate the early diagnosis of smear-negative TB. The diagnostic performance of the QFT-GIT test in the diagnosis of active TB was shown to be affected by many clinical factors. Personalized cutoff values may have superior value in the identification of active tuberculosis under different conditions.

It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control Mycobacterium tuberculosis (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.

BACKGROUND: The treatment of patients with MDR- and XDR-TB is usually more complex, toxic and costly and less effective than treatment of other forms of TB. However, there is little information available on risk factors for poor outcomes in patients with MDR- and XDR-TB in China. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively analyzed the clinical records of HIV-negative TB Patients with culture-proven MDR- or XDR-TB who were registered from July 2006 to June 2011 at five large-scale Tuberculosis Specialized Hospitals in China. Among 1662 HIV-seronegative TB cases which were culture-positive for M. tuberculosis complex and had positive sputum-smear microscopy results, 965 cases (58.1%) were DR-TB, and 586 cases (35.3%) were classified as having MDR-TB, accounting for 60.7% of DR-TB. 169 cases (10.2%) were XDR-TB, accounting for 17.5% of DR-TB, 28.8% of MDR-TB. The MDR-TB patients were divided into XDR-TB group (n=169) and other MDR-TB group (non-XDR MDR-TB) (n=417). In total, 240 patients (40.95%) had treatment success, and 346 (59.05%) had poor treatment outcomes. The treatment success rate in other MDR-TB group was 52.2%, significantly higher than that in the XDR-TB group (13%, P