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The most frequent adverse event associated with bedaquiline (BDQ) is the QTc interval prolongation; however, there was no biomarkers that could be used to predict the occurrence of QTc prolongation in BDQ-treated patients. In this study, we employed the ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) to generate metabolic profiling for the discovery of potential predictive urine biomarkers of QTc prolongation in these patients. Untargeted metabolomic technique was used to concentrate the differential metabolic pathway, and targeted metabolomic technique was subsequently performed to identify predictive biomarkers for QTc prolongation. A total of 45 rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) patients were enrolled in our study, including 15 RR/MDR-TB patients with QTc interval prolongation (QIP) and 30 RR/MDR-TB patients with QTc interval un-prolongations (QIU). Untargeted technique revealed that the lipid metabolism was the most differential metabolic pathway between two groups. Further targeted technique identified four differential metabolites, including betaine, LPE (18:2), LPE (20:3), and LPE (20:4). The combined analysis of metabolisms revealed that the combined use of LPE (20:3) and LPE (20:4) had the best performance for predicting the occurrence of QTc prolongation in TB patients, yielding a sensitivity of 87.4% and a specificity of 78.5%. In addition, with the progression of BDQ treatment, the LPEs exhibited persistent difference in the BDQ-treated TB patients experiencing QTc interval prolongation. In conclusion, our data demonstrate that the combined use of LPE (20:3) and LPE (20:4) yields promising performance for predicting the occurrence of QTc interval prolongation in BDQ-treated patients.

BackgroundLatent tuberculosis (TB) infection can progress to active TB, which perpetuates community transmission that undermines global TB control efforts. Clinically, interferon-γ release assays (IGRAs) are commonly used for active TB case detection. However, low IGRA sensitivity rates lead to false-negative results for a high proportion of active TB cases, thus highlighting IGRA ineffectiveness in differentiating MTB-infected individuals from healthy individuals.MethodsParticipants enrolled at Beijing Chest Hospital from May 2020-April 2022 were assigned to healthy control (HC), LTBI, IGRA-positive TB, and IGRA-negative TB groups. Screening cohort MTB antigen-specific blood plasma chemokine concentrations were measured using Luminex xMAP assays then were verified via testing of validation cohort samples.ResultsA total of 302 individuals meeting study inclusion criteria were assigned to screening and validation cohorts. Testing revealed significant differences in blood plasma levels of CXCL9, CXCL10, CXCL16, CXCL21, CCL1, CCL19, CCL27, TNF-α, and IL-4 between IGRA-negative TB and HC groups. Levels of CXCL9, CXCL10, IL-2, and CCL8 biomarkers were predictive for active TB, as reflected by AUC values of ≥0.9. CXCL9-based enzyme-linked immunosorbent assay sensitivity and specificity rates were 95.9% (95%CI: 91.7-98.3) and 100.0% (92.7-100.0), respectively. Statistically similar AUC values were obtained for CXCL9 and CXCL9-CXCL10 assays, thus demonstrating that combined analysis of CXCL10 and CXCL9 levels did not improve active TB diagnostic performance.ConclusionThe MTB antigen stimulation-based CXCL9 assay may compensate for low IGRA diagnostic accuracy when used to diagnose IGRA-negative active TB cases and thus is an accurate and sensitive alternative to IGRAs for detecting MTB infection.

ObjectiveTuberculosis diagnosis requires rapid, simple and highly sensitive methods. Clustered regularly interspaced short palindromic repeats (CRISPRs) and associated protein (Cas) systems are increasingly being used for clinical diagnostic applications, due to their high flexibility, sensitivity and specificity. We developed a sensitive Mycobacterium tuberculosis (MTB) complex polymerase chain reaction (PCR)-CRISPR/Cas13a detection method (CRISPR-MTB) and then evaluated its performance in detecting MTB in clinical specimens.MethodsThe conserved MTB IS1081 sequence was used to design CRISPR-derived RNAs (crRNAs) and T7 promoter sequencing-containing PCR primers for use in the CRISPR-MTB assay, then assay performance was evaluated using 401 clinical specimens.ResultsThe CRISPR-MTB assay provided a low limit of detection of 1 target sequence copy/μL and excellent specificity. Furthermore, use of the assay to detect MTB in bronchoalveolar lavage fluid (BALF), sputum and pus samples provided superior sensitivity (261/268, 97.4%) as compared to sensitivities of acid-fast bacilli (130/268, 48.5%) and mycobacterial culture (192/268, 71.6%) assays, and comparable or greater sensitivity to that of GeneXpert MTB/RIF (260/268, 97.0%).ConclusionThe CRISPR-MTB assay, which provides excellent sensitivity and specificity for MTB detection in sputum, BALF and pus samples, is a viable alternative to conventional tests used to diagnose TB in resource-limited settings.

Gazing is important during communication, which is a type of body language that differs from culture to culture. The present study investigated the influence of direct and averted gaze directions on the perceived duration of gazing among same-race and other-race faces. The gaze direction effect, in which direct-gazing faces were perceived to be longer than averted-gazing faces were, was found in the same-race condition but not in the other-race condition. The results could promote our understanding of the underlying mechanism of the gaze direction effect based on the perception of interpersonal social interaction.

BackgroundApart from bactericidal effects, anti-tuberculosis drugs can interfere with the host’s immune system. In this study, we analyzed the role of delamanid (DLM), an inhibitor of mycolic acid synthesis of mycobacterial cell wall, on human macrophages.MethodsBased on a cohort of multidrug-resistant tuberculosis (MDR-TB) patients treated with DLM, the levels of C-reaction protein (CRP) and cytokines in the plasma were monitored using immunoturbidimetric assay and flow cytometry, respectively. We investigated the role of DLM on CXCL10 expression in U937 cell model using the following methods: cell viability assay, reverse transcription-quantitative polymerase chain reaction, enzyme linked immunosorbent assay, immunoblot, and transwell co-culture assay.ResultsA total of 23 MDR-TB patients were included, comprising of 13 patients treated with optimized background therapeutic regimen (OBR) plus DLM regimen (OBR+DLM) and 10 patients treated with OBR plus placebo. DLM administration was associated with a significant reduce in circulating CRP level. Correspondingly, after treatment, the level of CXCL10 in patients treated with OBR+DLM was significantly lower than that with control. Using cell model, DLM dramatically suppressed CXCL10 expression, which majorly depended on inhibiting the JAK/STAT pathway, and impaired the migration of PBMCs.ConclusionOur data firstly demonstrate that DLM suppresses CXCL10 expression via regulation of JAK2/STAT1 signaling and correlates with reduced inflammation in MDR-TB patients. DLM could be used as a potential drug for immunotherapy of patients with overactive immune response due to CXCL10.

Natural products from microorganisms are important sources for drug discovery. With the development of high-throughput sequencing technology and bioinformatics, a large amount of uncharacterized biosynthetic gene clusters (BGCs) in microorganisms have been found, which show the potential for novel natural product production. Nine BGCs containing PKS and/or NRPS in Streptomyces globisporus C-1027 were transcriptionally low/silent under the experimental fermentation conditions, and the products of these clusters are unknown. Thus, we tried to activate these BGCs to explore cryptic products of this strain. We constructed the cluster-situated regulator overexpressing strains which contained regulator gene(s) under the control of the constitutive promoter ermE*p in S. globisporus C-1027. Overexpression of regulators in cluster 26 resulted in significant transcriptional upregulation of biosynthetic genes. With the separation and identification of products from the overexpressing strain OELuxR1R2, three ortho-methyl phenyl alkenoic acids (compounds 1–3) were obtained. Gene disruption showed that compounds 1 and 2 were completely abolished in the mutant GlaEKO, but were hardly affected by deletion of the genes orf3 or echA in cluster 26. The type II PKS biosynthetic pathway of chain-extended cinnamoyl compounds was deduced by bioinformatics analysis. This study showed that overexpression of the two adjacent cluster-situated LuxR regulator(s) is an effective strategy to connect the orphan BGC to its products.

False negative interferon-γ release assay (IGRA) results constitute the major dilemma for the diagnosis of tuberculosis (TB) infections. Herein, we conducted a cohort study to compare the host immunological response to TB-specific antigens between active TB patients with positive and negative IGRA results and control groups. A total of 274 laboratory-confirmed TB patients were included in our analysis, consisting of 221 were IGRA positive and 53 were IGRA negative. Patients with the elderly were identified as an independent risk factor for negative IGRA results. In addition, the elevated level of IL-4 and the decreased levels of IFN-γ, IL-2, IL-6, IL-1β, and IL-12 in IGRA negative TB relative to IGRA positive TB group, demonstrating a significant difference in Th1/Th2 paradigm between two groups. The IFN-γ&IL-2 based assay could correctly identify 247 out of 307 MTB-infected individuals [271 TB patients and 36 individuals with latent TB infection (LTBI)], demonstrating a sensitivity of 80.5%. Then the IFN-γ and IL-4 were applied to distinguish healthy control and IGRA-negative group. When using the stepwise algorithm, the sensitivity for detecting Mycobacterium tuberculosis (MTB) infections was significantly increased from 80.5% to 89.6%. Additionally, patients with negative IGRA results had a conversion to culture-negative status longer than those with positive IGRA results. In conclusion, a stepwise algorithm outperforms IGRA assays to accurately identify MTB infections by the combination IFN-γ, IL-2, and IL-4. Further study is needed to evaluate the accuracy of our diagnostic algorithm in the LTBI population.

A reduction in visual performance is among the serious consequences of acute alcohol intake. Contrast sensitivity (CS) is a fundamental feature of visual function. Here, we investigated the negative effect of a moderate dose of alcohol on CS across a wide range of spatial frequencies and with multiple levels of external noise and clarified the corresponding mechanisms in the context of a perceptual template model (PTM). To avoid the effect of alcohol washout, a quick contrast sensitivity function (qCSF) method was used to assess the visual performance of subjects before and 30 min after a moderate dose of alcohol intake. We found that (1) CS was significantly disrupted by acute alcohol intake; (2) alcohol-induced CS loss was dependent on spatial frequency and external noise; and (3) increased internal additive noise and an impaired perceptual template accounted for alcohol-induced CS loss. These results help us better understand the negative effect of alcohol consumption and provide guidance for driver safety studies.

It is critical to address the relationship between density label of Bangerter filters and expected visual acuity, and how filters modulate contrast sensitivity (CS) at different spatial frequency and external noise levels. In the current study, the monocular visual acuity and CS at ten spatial frequencies and three noise levels were measured in normal subjects wearing no filters, 0.8, 0.4, or 0.2 Bangerter filters. Compared with the baseline condition (no filter worn), Bangerter filters degraded both visual acuity and contrast sensitivity function (CSF) in zero-noise conditions, but the reduction of both visual functions did not correlate with each other at any filter level. In addition, the stronger the filter was, the worse both visual functions became. In contrast, when external noise was present, filters improved the contrast sensitivity at low frequencies but deteriorated it at intermediate and high spatial frequencies. The perceptual template model was used to reveal the corresponding mechanism accounted for filter-induced visual function changes. Although the internal process in visual system should not be affected by the filters, the measurement of parameters was biased. To be specific, (1) the internal additive noise was elevated at all frequencies; (2) the perceptual template was improved at low spatial frequencies but impaired at intermediate spatial frequencies; and (3) the changes in both factors were highly dependent on filter intensity. We conclude that Bangerter filters influence visual acuity and contrast sensitivity differently and that their effect on contrast sensitivity depends on spatial frequency and noise.

ObjectivesIn this study, we conducted a systematic review to determine tuberculosis (TB) incidence due to immunotherapy with programmed cell death protein-1 (PD-1)/PD ligand (PD-L1) blockade in cancer patients.MethodsWe searched PubMed, Cochrance Library, Excerpt Medica Database (Embase), ClinicalTrials.gov, Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI), Wanfang and China Science and Technology Journal Database to identify studies between January 1, 2000 and April 30, 2021, on the reports of TB cases in patients treated with PD-1/PD-L1 blockade. Methodological quality of eligible studies was assessed, and random-effect model meta-analysis was performed to generate the pooled incidence estimate of TB cases in patients undergoing PD-1/PD-L1 therapy.ResultsWe initially identified 745 records, of which 27 studies ultimately met the inclusion criteria and were included in our meta-analysis. A total of 35 TB cases occurred among patients treated with PD-1/PD-L1 blockade. Nivolumab (51.4%) was the most frequently used PD-1/PD-L1 blockade for cancer treatment. In addition, pulmonary TB was the most common form of tuberculosis seen in 77.1% cases. Clinical outcomes were recorded in 18 patients, of whom 77.8% were cured or achieved remission, and 22.2% were died of TB. Pooled analysis determined that the TB rate in this population was 2,000 cases per 100,000 persons, and the estimated rate for TB associated with PD-1/PD-L1 blockade was 35 times higher than that in the general population.ConclusionTo conclude, our results demonstrate that the clinical use of PD-1/PD-L1 inhibitors significantly increases risk of TB reactivation. An extremely high mortality rate due to TB disease is noted in the patients with PD-1/PD-L1 blockade.

In this study, our aims were to comparatively analyze the power of variable number tandem repeat (VNTR) typing to discriminate isolates within subspecies and to identify a potential genetic marker for better molecular typing of Mycobacterium abscessus complex (MABC) strains. A total of 103 clinical MABC isolates were collected from a nationwide cross-sectional study in China. Eighteen VNTR loci were chosen to genotype the MABC isolates. Of the 103 clinical MABC isolates, there were 76 (73.8%) M. abscessus subsp. abscessus (MAA) and 27 (26.2%) M. abscessus subsp. massiliense (MAM) isolates. Among the patients with MAA lung diseases, the percentage of patients older than 45 years (67.1%) was significantly higher than that of patients with MAM lung diseases [33.3%, adjusted odds ratio (aOR) = 0.36, 95% CI = 0.13–0.98, p = 0.046]. Fifteen VNTR loci were designated as being “highly discriminant” in our sample, except for TR109. The total of 103 MABC isolates were fully discriminated into 103 unique patterns by an 18-locus VNTR set [Hunter–Gaston Discriminatory Index (HGDI) = 1.000], of which the inclusion of the top 12 loci yielded a comparative HGDI value (HGDI = 0.9998). Remarkably, the order of the diversity of the VNTR loci showed significant difference between the MAA and MAM isolates. TR137 and TR2, two loci with high diversity indices for the MAA isolates, only yielded poor discriminatory power for the MAM isolates; the allelic diversity (h) values were 0.0000 and 0.2621, respectively. A detailed analysis of TR137 in combination with the other 17 VNTR loci showed that the combination of TR137–TR2 could fully distinguish MAA from MAM isolates. In conclusion, our data revealed that MAA is more prone to affect elderly patients. Additionally, the population structure of the MABC isolates circulating in China has high diversity. The combined use of the TR137 and TR2 loci provides a simple criterion for the precise identification of MABC to the subspecies level.

Binocular summation is generally defined as the superiority of binocular over monocular performance. Here, we investigated how external noise modulates the effect of binocular summation on the contrast sensitivity function (CSF) and clarified the corresponding mechanisms with a perceptual template model (PTM). The contrast sensitivity (CS) over 10 spatial frequencies and three external noise levels was assessed under one binocular and two monocular viewing conditions. The binocular summation ratio (BSR) was calculated by dividing the area under the log CSF (AULCSF), or the CS of using both eyes, by that of only using the “good eye” (BSRG) or the “bad eye” (BSRB), respectively. We found that: (1) based on the AULCSF, the BSRB was higher than the BSRG; (2) based on the AULCSF, the BSR was more pronounced under zero-noise than under low-noise conditions, but the BSR was not higher than 1 under high-noise conditions due to a large individual difference; (3) based on the CS, with increasing spatial frequencies, the BSRB steadily increased; (4) both decreased internal additive noise and an improved perceptual template accounted for the gain in binocular summation. These results help us better understand the features of binocular CS and shed light on the clinical studies on populations with monocular CS loss.

Source memory is one of the cognitive abilities that are most vulnerable to aging. Luckily, the brain plasticity could be modulated to counteract the decline. The repetitive transcranial magnetic stimulation (rTMS), a relatively non-invasive neuro-modulatory technique, could directly modulate neural excitability in the targeted cortical areas. Here, we are interested in whether the application of rTMS could enhance the source memory performance in healthy older adults. In addition, event-related potentials (ERPs) were employed to explore the specific retrieval process that rTMS could affect. Subjects were randomly assigned to either the rTMS group or the sham group. The rTMS group received 10 sessions (20 min per session) of 10 Hz rTMS applying on the right dorsolateral prefrontal cortex (i.e., F4 site), and the sham group received 10 sessions of sham stimulation. Both groups performed source memory tests before and after the intervention while the electroencephalogram (EEG) was recorded during the retrieval process. Behavioral results showed that the source memory performance was significantly improved after rTMS compared with the sham stimulation; ERPs results showed that during the retrieval phase, the left parietal old/new effect, which reflected the process of recollection common to both young and old adults, increased in the rTMS group compared with the sham stimulation group, whereas the late reversed old/new effect specific to the source retrieval of older adults showed similar attenuation after intervention in both groups. The present results suggested that rTMS could be an effective intervention to improve source memory performance in healthy older adults and that it selectively facilitated the youth-like recollection process during retrieval. This study was registered in the Chinese Clinical Trial Registry (ChiCTR) with the identifier chictr-ire-15006371.

It is well known that extensive practice of a perceptual task can improve visual performance, termed perceptual learning. The goal of the present study was to evaluate the dependency of visual improvements on the features of training stimuli (i.e., spatial frequency). Twenty-eight observers were divided into training and control groups. Visual acuity (VA) and contrast sensitivity function (CSF) were measured and compared before and after training. All observers in the training group were trained in a monocular grating detection task near their individual cutoff spatial frequencies. The results showed that perceptual learning induced significant visual improvement, which was dependent on the cutoff spatial frequency, with a greater improvement magnitude and transfer of perceptual learning observed for those trained with higher spatial frequencies. However, VA significantly improved following training but was not related to the cutoff spatial frequency. The results may broaden the understanding of the nature of the learning rule and the neural plasticity of different cortical areas.

Increasing evidence suggests that functional brain connectivity is an important determinant of cognitive aging. However, the fundamental concept of inter-individual variations in functional connectivity in older individuals is not yet completely understood. It is essential to evaluate the extent to which inter-individual variability in connectivity impacts cognitive performance at an older age. In the current study, we aimed to characterize individual variability of functional connectivity in the elderly and to examine its significance to individual cognition. We mapped inter-individual variability of functional connectivity by analyzing whole-brain functional connectivity magnetic resonance imaging data obtained from a large sample of cognitively normal older adults. Our results demonstrated a gradual increase in variability in primary regions of the visual, sensorimotor, and auditory networks to specific subcortical structures, particularly the hippocampal formation, and the prefrontal and parietal cortices, which largely constitute the default mode and fronto-parietal networks, to the cerebellum. Further, the inter-individual variability of the functional connectivity correlated significantly with the degree of cognitive relevance. Regions with greater connectivity variability demonstrated more connections that correlated with cognitive performance. These results also underscored the crucial function of the long-range and inter-network connections in individual cognition. Thus, individual connectivity–cognition variability mapping findings may provide important information for future research on cognitive aging and neurocognitive diseases.

Hyperlipidemia, one of the cardiovascular (CV) risk factors, is associated with an increase in the risk for dementia. Repetitive transcranial magnetic stimulation (rTMS) was applied over the right dorsolateral prefrontal cortex (DLPFC) to modulate serum lipid levels in older adults. Participants received 10 sessions of rTMS or sham stimulation intervention within 2 weeks. The serum lipid and thyroid hormone-related endocrine levels were assessed before and after the treatment. We found that rTMS significantly decreased serum lipid levels, including the total cholesterol (CHO) and triglyceride (TG); meanwhile, it also increased the thyroid-stimulating hormone (TSH) as well as thyroxine (T4) levels. This suggests that rTMS modulated the serum lipid metabolism by altering activity in the hypothalamo-pituitary-thyroid (HPT) axis. The trial was registered on the website of Chinese Clinical Trial Registry (http://www.chictr.org.cn).

The speed of moving stimuli can bias duration perception. Here, we investigated whether words describing different speeds influence subjective duration estimation in a temporal bisection task. Duration estimations of two different types of speed words (fast- vs. slow speed words) were compared. We found that the time bisection point (TBP) was significantly lower for fast-speed words than for slow-speed words, suggesting that the durations of fast speed words were overestimated compared to the slow-speed words. In contrast, fast- and slow-speed words did not significantly differ in just noticeable differences (JND) and Weber fractions, indicating that the types of speed words did not influence the sensitivity of duration estimation. These results provide new evidence to support the theory of embodied cognition in the context of implicit meaning of a speed word. [ABSTRACT FROM AUTHOR]