INTRODUCTION:The optimal treatment for tuberculous meningitis (TBM) remains inconclusive. This study intends to compare the efficacy and safety of available drug therapies for treating TBM from the perspective of mortality, neurological events, and adverse events. METHODS:PubMed (21/6/2025), Cochrane (21/6/2025), Embase (21/6/2025), and Web of Science (21/6/2025) were searched for randomized controlled trials (RCTs) of TBM. Risk of Bias 2.0 was used for the quality assessment of the included studies. R4.2.3 "gemtc" package was used for data analysis, and Stata 15.0 was utilized to assess publication bias. Odds ratios (ORs) with 95% credible intervals (95% CrIs) were calculated as effect sizes. RESULTS:Twenty-nine RCTs involving 4,640 TBM patients were included. The results showed that when combined with the standard treatment, prednisone might reduce TBM mortality [OR (95% CrI) = 0.26 (0.07, 0.78)]; both methylprednisolone [OR (95% CrI) = 0.13 (0, 0.98)] and prednisone [OR (95% CrI) = 0.18 (0.02, 0.76)] were likely to reduce the incidence of tuberculoma and other extracranial tuberculosis; prednisolone might increase the risk of neurological events [OR (95% CrI) = 5.98 (2.03, 20.7)], while standard-dose rifampicin was less likely to cause neurological events [OR (95% CrI) = 0.25 (0.06, 0.78)]; dexamethasone might increase the incidence of gastrointestinal events [OR (95% CrI) = 1.72 (1.04, 2.91)]; levofloxacin was more likely to cause hepatic events [OR (95% CrI) = 1.79 (1.05, 3.14)]. CONCLUSIONS:Prednisone, levofloxacin, and linezolid, rather than high-dose rifampicin, may reduce TBM mortality compared with standard-dose rifampicin. Prednisolone increases the risk of neurological events.

[This corrects the article DOI: 10.3389/fcimb.2025.1726935.].

IntroductionTuberculous meningitis (TBM), the most severe form of Mycobacterium tuberculosis infection, is characterized by high mortality and neurological sequelae, largely attributed to blood-brain barrier (BBB) disruption. While recent studies identified GSDMD-mediated endothelial pyroptosis as a key mechanism of inflammatory BBB damage, the full molecular landscape in TBM remains unclear.MethodsThis study employed an integrated multi-omics approach, combining bulk and single-cell RNA sequencing of clinical and murine datasets with experimental validation, to identify central mediators of BBB dysfunction in TBM.ResultsWe identified and validated three genes – MARCKS, CD274 (PD-L1), and IL17RA – as significantly upregulated in TBM. Single-cell analysis of a murine TBM model demonstrated predominant MARCKS expression in CNS microglia, a finding further supported by elevated MARCKS protein levels in peripheral blood mononuclear cells from patients. However, validation in human TBM brain tissue remains warranted. Functional enrichment and correlation analyses positioned MARCKS at the nexus of inflammatory signaling and cytoskeletal regulation, showing strong associations with key effectors of the GSDMD pyroptosis pathway (CASP4, CD14, NINJ1). Our data further indicate a robust co‑expression pattern between MARCKS and key effectors of the GSDMD pathway (CASP5, TLR4, and CASP1), suggesting that MARCKS‑mediated cytoskeletal destabilization and GSDMD‑dependent lytic pore formation may act in concert to promote BBB disruption. Nevertheless, this proposed mechanistic interplay requires direct experimental verification.DiscussionOur findings nominate MARCKS as a novel mechanistic hub linking neuroinflammation to barrier pathology in TBM, revealing potential therapeutic targets for adjunctive barrier‑stabilizing strategies.

Background:Drug-resistant tuberculosis (DR-TB) undermines global TB control, yet how resistant Mycobacterium tuberculosis strains interact with the lung microbiome, phage communities, and local host immunity remains poorly defined. Methods:In a prospective cohort of 130 pulmonary TB patients (49 DR-TB, 81 drug-susceptible TB [DS-TB] patients), bronchoalveolar lavage fluid (BALF) was subjected to paired metagenomic and transcriptomic profiling. Microbial and bacteriophage community structures were assessed by diversity metrics and differential abundance testing, whereas host responses were characterized by gene expression, pathway enrichment, and immune cell deconvolution. A Random Forest model was trained to evaluate the diagnostic potential of host transcriptional signatures. Results:DR-TB airways presented distinct microbial beta diversity, with enrichment of Streptococcus spp. and streptococcal-targeting phages (e.g., Javan variants, phi-Ssu5SJ28rum). Transcriptomic analysis revealed 494 differentially expressed genes, which were associated with increased oxidative phosphorylation, suppressed ion channel and transporter activity, and enrichment of extracellular matrix remodeling pathways. Immune profiling demonstrated a significant reduction in γδ T cells in DR-TB patients (P = 0.0059). An 8-gene host-derived signature (ARHGEF5, PTGES3L, GAL3ST1, RANBP17, ACTA2_AS1, CBY3, MAMSTR, and LOC102031319) discriminated DR-TB from DS-TB with high accuracy (AUC = 0.837). Conclusion:This dual-omics study defines the airway niche of DR-TB as a convergence of microbial dysbiosis, phage imbalance, and host immune-metabolic dysfunction. By uncovering DR-TB-specific microbial and transcriptional signatures, and deriving a predictive host-based classifier, our findings provide mechanistic insights and highlight novel opportunities for microbiome- and host-directed interventions in drug-resistant tuberculosis.

BackgroundM. abscessus (Mabs) is one of the principal pathogenic strains among nontuberculous mycobacterial. Mabs infections pose a significant global public health challenge, leading to substantial morbidity and mortality. However, a standard treatment regimen has not yet been established. The goal of this study was to provide clear insights into constructing regimens.MethodsWe evaluated the efficacy of 7 clinically available drugs against Mabs under various environments through microplate alamar blue assay (MABA), biofilm assays, Wayne model and nutrient-starvation model. The checkerboard assay was employed to assess drug-drug interactions. Finally, we assessed the efficacy, degree of organ damage, and prevalence of resistant strains associated with different triple-drug combinations in a BALB/c mouse model.ResultsBedaquiline (BDQ) was active against replicating and nonreplicating planktonic bacteria. Moxifloxacin (MFX) was potent in preventing biofilm formation and inhibiting the viability of biofilm-resident bacteria. ABM (Azithromycin-Bedaquiline-Moxifloxacin) and CBM (Clofazimine-Bedaquiline-Moxifloxacin) combinations were effective in bacillary load reduction and organ injury alleviation in BALB/c mouse model.ConclusionsABM and CBM regimens show great promise against Mabs in vivo. We strongly recommend carrying out additional clinical trials to explore their efficacy.

Aim: Non-tuberculous mycobacteria (NTM) are ubiquitous in the natural environment. Globally, incidence of non-tuberculous mycobacterial disease is on the rise. To date, over 190 species of NTM have been identified, many of which possess inherent natural resistance to antibiotics, developing new drugs is a challenging process with a high risk of failure. The repurposing of existing drugs may be a quick and effective approach. This study investigates the combined effects of bedaquiline (BDQ) and nintedanib (a multi-target tyrosine kinase inhibitor) on NTM, with the aim of providing a novel therapeutic approach against NTM. Methods and Results: The number of colony-forming units (CFUs) in macrophages was determined to assess the antibacterial activity of nintedanib against Mycobacterium avium and Mycobacterium abscessus. To evaluate the efficacy of nintedanib in combination with BDQ in a mouse model of pulmonary infection. The mechanism of the synergistic antibacterial effect of nintedanib and BDQ was investigated using assays of immune cells and immune factors, ATP measurement, transcriptomic sequencing and RT-PCR. Nintedanib significantly enhanced the intracellular antibacterial activity of BDQ against M. avium and M. abscessus. In mice infection model, nintedanib enhanced the efficacy of BDQ, reducing the extent of inflammatory damage and fibrosis in the mice's lung tissue. The mechanism by which nintedanib enhances the antibacterial activity of BDQ is as follows: on the one hand, it boosts adaptive immunity in mice, promoting anti-inflammatory and tissue-repairing immune responses; on the other hand, it enhances BDQ's ability to inhibit ATP production and disrupts bacterial metabolic pathways. Conclusion: In vitro and in vivo studies have shown that nintedanib enhances the antibacterial activity of BDQ, accelerates pathogen clearance and reduces lung damage. Nintedanib adjuvant therapy modulates the body's adaptive immune response, promoting resolution of inflammation and tissue repair. Nintedanib may enhance the efficacy of BDQ by interfering with bacterial ATP synthesis and metabolic pathways. These findings highlight the potential of BDQ combined with nintedanib for the treatment of NTM infections and provide a crucial theoretical basis for the development of more effective therapeutic strategies for NTM infections.

BACKGROUND:Human Immunodeficiency Virus (HIV) and tuberculosis (TB) co-infection poses a significant challenge to public health systems due to its complex clinical management and high mortality. This study aimed to reveal the specific mechanisms through which knowledge influences practice in HIV/TB co-infection management among healthcare providers (HCPs) using structural equation modeling (SEM). METHODS:An exploratory cross-sectional study using convenience sampling was conducted from May to June 2025 involving healthcare providers (HCPs) across various medical institutions in Beijing, which included university-affiliated tertiary hospitals, specialized hospitals, and community health centers. RESULTS:A total of 565 valid questionnaires were collected, with 364 (64.42%) completed by medical doctors. The knowledge, attitude, and practice scores were 18.51 ± 7.75 (possible range: 0-30), 43.64 ± 5.51 (possible range: 10-50), and 30.75 ± 7.44 (possible range: 8-40), respectively. Spearman correlation analysis revealed significant positive correlations between knowledge and attitude (r = 0.500, P < 0.001), between attitude and practice (r = 0.584, P < 0.001) and between knowledge and practice (r = 0.592, P < 0.001). SEM analysis indicated that knowledge had a direct influence on both attitudes (β = 0.458, P = 0.002) and practices (β = 0.491, P = 0.011), while attitudes influenced practices (β = 0.272, P = 0.008). Furthermore, knowledge indirectly affected practices through attitudes (β = 0.124, P = 0.005). CONCLUSION:In our sample, respondents demonstrated limited knowledge, generally positive attitudes, and moderately adequate practices regarding HIV and TB co-infection. These preliminary findings suggest that targeted educational interventions designed to enhance knowledge may effectively improve both attitudes and practical behaviors, though more rigorous research is needed to confirm these relationships.

Background:Mycobacterial infections represent a major cause of morbidity and mortality in HIV-infected individuals. This study evaluated diagnostic techniques for mycobacterial identification and compared clinicopathological features between HIV-positive and HIV-negative patients. Methods:We analyzed 88 tissue samples (with 41 matched blood and 28 sputum samples) using histopathology (HE and acid-fast staining), bacterial culture, MTB-PCR (sputum/biopsy), PCR-reverse dot blot hybridization (RDBH), and metagenomic pathogen detection technology (MetaPath™). Logistic regression analyses were performed to identify factors affecting detection rates. Results:Mycobacterial infection was detected in 95.5% (84/88) of patients. Among HIV-positive patients (n=63), 46% (29/63) had Mycobacterium tuberculosis (MTB) infections, and 44% (28/63) had non-tuberculous mycobacteria (NTM) infections, significantly higher than the 20% (5/25) NTM rate in HIV-negative patients. Univariate analysis identified HIV-positive status (p=0.009), lymph node involvement (p=0.020), and positive MetaPath™ results (p=0.002) as significant predictors of detection, while multivariate analysis confirmed these as independent factors (p=0.036; p=0.042; p=0.006). Lymph nodes were the most common infection site in HIV-positive patients (42.9%, 27/63), while lung tissue predominated in HIV-negative patients (48%, 12/25). MetaPath™ demonstrated superior sensitivity and specificity for detecting both MTB and NTM. Biopsy samples provided higher diagnostic accuracy than sputum or blood for lung and lymph node infections, but not for brain. In HIV-positive patients, NTM infections showed significantly more granuloma formation (p=0.032) and foam cells (p=0.005), but less necrosis (p=0.0005) compared to MTB infections. No significant differences were observed in HIV-negative patients. Conclusions:MetaPath™ is a highly effective diagnostic tool for mycobacterial infections, particularly in tissue biopsies. HIV-positive status, lymph node involvement, and MetaPath™ positivity independently predict mycobacterial detection. HIV-positive patients exhibit distinct clinicopathological features, emphasizing the need for tailored diagnostic and therapeutic approaches based on immune status.

IntroductionTo evaluate the performance of oral fluid (OF) for quantitative detection of SARS-CoV-2 nucleic acid and IgG antibody, and explore its application value, we compared OF with traditional samples using multiple detection methods.MethodsReal-time PCR (RT-PCR) and digital PCR (dPCR) were used to detect SARS-CoV-2 nucleic acid in 213 paired OF and throat swab samples from COVID-19 cases. Chemiluminescence was applied to detect IgG antibody in paired OF and serum samples, while colloidal gold method was used specifically for OF.ResultsRT-PCR results showed that the positivity rates of OF and throat swabs were 80.75% (172/213) and 88.73% (189/213) respectively (p < 0.001). Using throat swabs as the reference, the sensitivity of OF for nucleic acid detection by RT-PCR was 87.83% (172/189). For 108 paired samples analyzed by dPCR, the positivity rate of OF was 86.11% (93/108), slightly higher than that by RT-PCR (85.19%, 92/108). Notably, in some cases, the viral load in OF exceeded that in throat swabs, accounting for 38.89% (N gene) to 41.67% (ORF1ab gene) of the tested samples.ConclusionAs a non-invasive, convenient, safe, and self-collectible biological sample, OF shows high consistency in detection efficacy compared with traditional throat swabs and serum. It thus holds important application value for the diagnosis, monitoring, and epidemic prevention and control of COVID-19.

OBJECTIVE:To evaluate the clinical value of nanopore sequencing technology (NST) for the early diagnosis and resistance guidance of Mycoplasma pneumoniae (MP) infection in children. METHODS:We analyzed four pediatric patients with MP pneumonia. Sputum specimens were subjected to NST, and results were compared with serological MP-IgM testing, nucleic acid detection, and chest CT. RESULTS:In all four cases, MP-IgM yielded false-negative or weakly positive results within the first 5 days. In contrast, NST provided a definitive diagnosis within 24 hours of admission, detecting MP with sequence reads ranging from 14 to 3024 and simultaneously identifying the macrolide-resistant A2063G mutation in the 23S rRNA gene. This led to a confirmed diagnosis 3-7 days earlier than serological methods. Blood cultures were negative in all cases. CONCLUSION:NST overcomes the limitations and delay of traditional methods, enabling rapid and accurate diagnosis of MP infection and concurrent detection of resistance mutations. Its integration into clinical practice may significantly improve the management of pediatric MP pneumonia.

The management of Mycobacterium abscessus (MAB) infection presents formidable challenges, necessitating the development of innovative antimicrobial agents and more efficacious combination therapies. The objective of this study was to investigate the in vitro, intracellular, and in vivo antibacterial activity of sudapyridine (WX-081) in combination with clarithromycin (CLR), clofazimine (CFZ), rifabutin (RFB), and linezolid (LZD) against MAB. In vitro, the interaction between WX-081 and other drugs was assessed using the checkerboard method against MAB. Synergistic or additive effects were observed when combining WX-081 with other drugs against all strains tested. The intracellular activity of WX-081 in combination with CLR, CFZ, RFB, and LZD against the MAB reference strain in J774A.1 cells was evaluated. The combination of WX-081 and CFZ or RFB exhibited potent inhibitory activity against MAB in macrophages. To evaluate pharmacodynamics, immunosuppressed BALB/c mice were infected with MAB to establish a murine model for assessing two-drug and three-drug combinations. In vivo studies demonstrated that the combination of WX-081 with CLR or both CLR and CFZ displayed antibacterial activity and significantly prevented mouse mortality. Our study demonstrates that the concurrent use of WX-081 with CLR or CLR plus CFZ holds significant promise as a clinical intervention for MAB infection.

Mycobacterium avium complex (MAC) is one of the principal pathogenic strains among nontuberculous mycobacteria. Current antibiotics have poor microbiological responses, and repurposed antibiotics are a way to meet clinical needs. Herein, the anti-MAC activity of carrimycin (CAM), a new macrolide, was evaluated in vitro and in vivo. Antimicrobial susceptibility testing was performed on two reference strains and 15 clinical isolates of MAC. The synergy between CAM and nine clinically used antibiotics was determined using a checkerboard assay. The activity of CAM against MAC residing inside macrophages and BALB/c mice were also evaluated. Although CAM exhibited weak anti-MAC activity in vitro, with MICs over 8 mg/L, the in vivo activity was potent. CAM treatment significantly reduced bacillary load, alleviated the severity of injury, and improved total T lymphocyte numbers in organs. Additionally, a synergy between CAM and clofazimine was found in vitro and in vivo. No antagonism was found between CAM and other eight antibiotics used in this study. In conclusion, CAM is a potential candidate and should be studied further in clinical trials.IMPORTANCEThe treatment of Mycobacterium avium complex (MAC) infections is a formidable challenge worldwide due to lack of effective drugs. In this paper, we firstly reported a promising candidate drug carrimycin (CAM). For M. intracellulare, the activity of CAM was compared with classical drug azithromycin (AZM). For M. avium, CAM also showed potent activity in vivo. Additionally, the combination of CAM and CFZ reduced more bacillary load than single drugs in vivo. Our study also indicated that we should take pharmacokinetic characteristics and drug interactions into account when evaluating the efficacy of drugs.

Background:Anti-tuberculosis drug-induced liver injury (ATB-DILI) is a common adverse reaction associated with tuberculosis (TB) treatment, significantly impacting treatment adherence and therapeutic outcomes. However, large-scale studies on hospitalized patients in China remain limited. Purpose:To characterize the clinical features and liver injury patterns in hospitalized TB patients with ATB-DILI and to identify risk factors associated with severe ATB-DILI. Methods:We retrospectively reviewed 28,753 hospitalized TB patients at Beijing Chest Hospital from 2014 to 2023. ATB-DILI was diagnosed in 567 patients (2.0%) based on serum biochemical criteria and causality assessment. Demographic, clinical, and laboratory data were analyzed to characterize liver injury types and identify risk factors for severe cases. Subgroup analyses based on liver injury patterns were performed to further evaluate the association between age and severe ATB-DILI. Results:Overall, 567 cases with ATB-DILI (2.0%) were analyzed. Hepatocellular injury was the most common type (71.4%), followed by cholestatic (13.8%) and mixed (14.8%) injury patterns. Most patients (68.4%) were asymptomatic and diagnosed via routine biochemical monitoring; jaundice occurred in 18.2%. Patients with hepatocellular damage were significantly younger, while those with cholestatic injury were older (p < 0.001). Severe ATB-DILI occurred in 46 patients (8.1%), with advanced age (≥60 years) identified as an independent risk factor (OR = 2.45, 95% CI: 1.33-4.52, p = 0.004). Subgroup analysis showed that this association between age and severe ATB-DILI was significant in the hepatocellular injury type (unadjusted OR = 3.59, 95% CI: 1.61-8.02, p = 0.002), while no statistically significant association was observed in cholestatic or mixed types, which may reflect limited statistical power in these subgroups. Conclusion:Routine liver function monitoring and age-specific risk assessment are essential for early identification and management of ATB-DILI in hospitalized TB patients.

ABSTRACT In the global response to the current mpox epidemic, understanding immune memory to the vaccinia virus and cross‐immunity to the mpox virus (MPXV) among people living with HIV (PLWH) is critical. Blood samples were collected from PLWH born between 1949 and 2002 without MPXV infection, as well as from sex‐ and age‐matched healthy donors (HD). Note that 62% and 56% of vaccinated PLWH born before 1980 had antibodies against the vaccinia virus Tiantan (VTT) strain and MPXV, respectively, though these seropositivity rates were lower than in HD (84% vs. 80%). Neutralizing antibodies were detected in 9% of PLWH, compared to 32% in HD. Notably, in PLWH with CD4 T‐cell counts below 500 cells/mm3, VTT‐IgG and MPXV‐IgG titers, as well as VTT‐specific memory B cells, were significantly reduced. In PLWH with CD4 T‐cell counts below 350 cells/mm3, CD4+ memory T‐cell responses were diminished, particularly in IFN‐γ and TNF‐α responses. In contrast, CD8+ T‐cell responses to MPXV were comparable in PLWH regardless of CD4 T‐cell counts. These findings highlight the diminished humoral and CD4+ T‐cell responses in PLWH, particularly in those with lower CD4 T‐cell counts, and underscore the necessity for targeted vaccination strategies in this population.

Background: This retrospective analysis aims to investigate the clinical characteristics of students infected with the SARS-CoV-2 Omicron variant in three Beijing schools. Additionally, we explore the dynamic trends of nucleic acid cycle threshold values (Ct values) and serum antibody titers throughout the disease course. Methods: Demographic, clinical, nucleic acid Ct values, and antibody titer data were collected from cases in a COVID-19 cluster in Beijing Ditan Hospital, Capital Medical University, spanning from September 6 to October 1, 2022. Results: A total of 107 students infected with Omicron (BA.5.2 and BA.2.76) were identified across three schools. Primary clinical manifestations included fever and upper respiratory symptoms (85/107, 79.4 %), with the majority being classified as mild cases (96/107, 89.7 %). Notably, middle school students in the second school exhibited a higher peak body temperature compared to college students in the first and third schools (39.5 degrees C vs. 38.4 degrees C, adjusted P = 0.005; 39.5 degrees C vs. 38.6 degrees C, adjusted P = 0.002). Analysis of dynamic changes in Ct values revealed the lowest median Ct value in nasopharyngeal swabs on the third day of illness, reaching 35 after 9-11 days. Oropharyngeal swab nucleic acid median Ct value reached 35 approximately 3-5 days post-onset. Serum antibody detection showed continuous negativity of IgM antibody titers from days 1-10, while IgG antibody titers were positive on the first day and increased rapidly after one week. Conclusions: The three COVID-19 cluster school outbreaks primarily resulted from Omicron infections, with no severe or fatal cases observed. Clinically, the selection of different types of SARSCoV-2 nucleic acid swabs for virus detection can be tailored based on the infection's course.

To explore the feasibility and effectiveness of an alternating shift pattern in two-hour segments in the state of emergency management of public health events. A cross-sectional research design was conducted in our study. The nursing staff working in the admission ward of suspected or confirmed patients with COVID-19 in December 2022 were selected as subjects by the whole-group sampling method. We adopted a shift pattern of alternating shifts every two-hour in the isolation wards. The vital signs parameters were captured by uniformly wearing the multi-signs sensing devices, and the questionnaires collected the symptoms. Sixty-seven female participants, with a mean age of 33.09 ± 5.96 years, were included in this study. Measurements of body temperature (T), blood oxygen saturation (SpO2), respiratory rate (RR), and heart rate (HR) while wearing personal protective equipment (PPE) all remained within normal limits. None of the nurses reported sweating, dizziness, blurred vision, palpitations, or dyspnea. Statistical analysis showed significant differences between the critical care group and the non-critical care group in terms of age (P = 0.041), working duration (P = 0.036), and the total number of entries into isolation areas for nursing care (rounds) (P = 0.007). However, there were no statistically significant differences in vital signs based on age, work duration, or body mass index (BMI). The data indicated a notable increase in body temperature compared to other vital sign parameters with increasing work time while wearing PPE. Body temperature approached the upper limit when working close to 2 h long. The alternating shift pattern in two-hour segments can effectively maintain the physical well-being of nurses wearing PPE without increasing the burden on nursing staff or the wastage of protective materials. This approach is recommended for addressing similar public health events in the future.

Background The dynamics of viral shedding and the specific fi c humoral response against monkeypox virus (MPXV) have not been well characterized in patients across their disease course during hospitalisation. The aim of this study was to determine the viral load and the levels of antibodies against MPXV using longitudinal paired-collected samples from hospitalized patients. Methods Patients who were hospitalised with mpox were recruited at Beijing Ditan Hospital Capital Medical University in China between June 2 and September 23, 2023. Paired samples, including samples from skin lesions, the oropharynx, saliva, faeces, urine, plasma, and serum, were serially collected at days 1, 3, 7, and 14 after admission until discharge. Not all of the patients had samples obtained at all of the timepoints. All the samples were analysed via quantitative PCR. Virus isolation was performed by using clinical samples and Vero cells. The presence of IgM, IgA, IgG, and neutralising antibodies (NAbs) against MPXV was evaluated. The fi rst collected plasma sample was taken when the patient was hospitalised, and the levels of cytokines and chemokines were measured in the sample. The demographic data, smallpox vaccination status, history of known exposure to MPVX, HIV status and other clinical data were collected using a standard case report form. Findings A total of 510 specimens were serially collected from 39 recruited people with mpox. Among all the samples, the skin lesions had the highest viral DNA detection rates and viral loads, and the saliva samples had the second highest rates and viral loads. One day before discharge, 85% of the dry scrabs (median Ct 28.2, range 19.0-38.3) - 38.3) and 70% of the saliva samples (median Ct 32.4, range 24.5-38.1) - 38.1) were positive for viral DNA, Of which, 23.1% of dry scrabs were positive in viral culture. The rate of viral DNA detection in the oropharyngeal, saliva, and faecal samples decreased with time, while the rates in the plasma, serum, and urine samples increased quickly before 10 days post symptom onset (PSO). The median days of appearance of MPXV-IgM, MPXV-IgA, MPXV-IgG, and NAb were at 8 (interquartile range [IQR] 7-9), - 9), 9 (7-10), - 10), 12 (9-15), - 15), and 12 (9-15) - 15) PSO, respectively. The IgM, IgA, IgG, and NAb titres increased with time. Between days 11 and 21 PSO, the NAb titres were lower in people living with HIV (PWH) than in people living without HIV (PWOH). Increased NAb titres were associated with decreased viral loads in the saliva (r = 0.28, p = 0.025), faeces (r = 0.35, p = 0.021), plasma (r = 0.30, p = 0.0044), and serum samples (r = 0.37, p = 0.001). Compared with PWOH, PWH had higher plasma levels of MIP-1 alpha, alpha , MIP-1 beta, beta , G-CSF, IL-4, and FGF-basic. Interpretation The high positive viral culture rate of clinical samples of patients when they are discharged from the hospital indicates that effective public health management strategies are needed for people with mpox. The low NAb titres and high levels of cytokines in PWH shows that earlier treatment is needed to control inflammation fl ammation in high-risk populations. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences, Fundamental Research Funds for the Central Universities for Peking Union Medical College, National Key R&D Program of China. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ABSTRACTSudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which shows anti-tuberculosis and non-tuberculous mycobacteria (NTM) activities but, unlike BDQ, did not prolong QT interval in animal model studies. This study evaluated the antibacterial activity of this novel compound against Mycobacterium avium, Mycobacterium abscessus, and Mycobacterium chelonae in vitro and in vivo. The minimum inhibitory concentration (MIC) of WX-081 against three kinds of non-tuberculous mycobacteria (NTM) clinical strains was determined using microplate-based alamarBlue assay (MABA), and the antibacterial activity of WX-081 against NTM in J774A.1 cells and mice was evaluated. MIC ranges of WX-081 against clinical strains of M. avium and M. abscessus were 0.05–0.94 μg/mL, 0.88–7.22 μg/mL (M. abscessus subsp. abscessus), and 0.22–8.67 μg/mL (M. abscessus subsp. massiliense), respectively, which were slightly higher than those of BDQ. For M. avium, M. abscessus, and M. chelonae, WX-081 can reduce the intracellular bacterial load by 0.13–1.18, 0.18–1.50, and 0.17–1.03 log10 colony forming units (CFU)/mL, respectively, in a concentration-dependent manner. WX-081 has bactericidal activity against three NTM species in mice. WX-081 exhibited anti-NTM activity to the same extent as BDQ both in vivo and in vitro. WX-081 is a promising clinical candidate and should be studied further in clinical trials.IMPORTANCEDue to the rapidly increased cases globally, non-tuberculous mycobacteria (NTM) disease has become a significant public health problem. NTM accounted for 11.57% of all mycobacterial isolates in China, with a high detection rate of Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium chelonae during 2000–2019. Treatment of NTM infection is often challenging, as natural resistance to most antibiotics is quite common among different NTM species. Hence, identifying highly active anti-NTM agents is a priority for potent regimen establishment. The pursuit of new drugs to treat multidrug-resistant tuberculosis may also identify some agents with strong activity against NTM. Sudapyridine (WX-081) is a structural analog of bedaquiline (BDQ), which was developed to retain the anti-tuberculosis efficacy but eliminates the severe side effects of BDQ. This study initially evaluated the antimicrobial activity of this novel compound against M. avium, M. abscessus, and M. chelonae in vitro, in macrophages and mice, respectively.

Objective: We aimed to investigate dysregulated metabolic pathways and identify diagnostic and therapeutic targets in patients with Methods: In our prospective cohort study, plasma samples were collected from healthy individuals, diabetic (DM) patients, untreated TB-only (TB-0)/TB-DM patients (TB-DM-0), and cured TB (TB-6)/TB-DM patients (TB-DM-6) to measure the levels of amino acids, fatty acids, and other metabolites in plasma using high-throughput targeted quantification methods. Results: Significantly different biological processes and biomarkers were identified in DM, TB-DM-0, and TB-DM-6 patients. Moreover, quinolinic acid (QA) showed excellent predictive accuracy for distinguishing between DM patients and TB-DM-0 patients, with an AUC of 1 (95% CI 1-1). When differentiating between TB-DM-0 patients and TB-DM-6 patients, the AUC was 0.9297 (95% CI 0.8460-1). Compared to those in DM patients, the QA levels were significantly elevated in TB-DM-0 patients and decreased significantly after antituberculosis treatment. We simultaneously compared healthy controls and untreated tuberculosis patients and detected an increase in the level of QA in the plasma of tuberculosis patients, which decreased following treatment. Conclusion: These findings improve the current understanding of tuberculosis treatment in patients with diabetes. QA may serve as an ideal diagnostic biomarker for TB-DM patients and contribute to the development of more effective treatments.