IntroductionEarly prediction of dengue shock syndrome (DSS) is crucial for effective patient triage and management. However, the lack of consensus regarding the precise definition of the laboratory warning sign (WS) -"an increase in hematocrit concurrent with a rapid decrease in platelet count"- has made it difficult to utilize this WS for predicting DSS.MethodsA matched case - control study was conducted among adult dengue patients (aged ≥16 years) hospitalized within the first four days of illness between November 2022 and August 2023, with each DSS case was matched with three non-DSS ones.ResultsThere were 448 patients (112 DSS and 336 non-DSS) included in this study. An increase in hematocrit concurrent with a rapid decrease in platelet count was observed 1-2 days prior to the development of DSS. The cut-off value of an increase in hematocrit by ≥5% concurrent with a decrease in platelet count by ≥50% as compared with those of the previous day was found to be a predictor of DSS, with a sensitivity of 60.71% and a specificity of 83.04%. A DSS scoring system developed using these two cut-off values, along with the number of clinical WSs, can be used to predict the risk of DSS in adult patients. It achieved an area under the receiver operating characteristic curve (AUC) of 0.93 (95% CI: 0.90-0.96), sensitivity of 86.6%, and specificity of 87.8%. The Score enables triage of patients into low-, intermediate-, and high-risk groups for appropriate monitoring and management.ConclusionsThe WS "an increase in hematocrit concurrent with a rapid decrease in platelet count" can be defined as "an increase in hematocrit ≥5% concurrent with a decrease in platelet count ≥50% compared to the previous day". The DSS score, developed from traditional WSs, serves as a good predictor of DSS in adult patients.

Piperaquine resistance in Plasmodium falciparum has emerged in Southeast Asia and is strongly associated with mutations in the pfcrt gene and amplification of pfplasmepsin2/3. This study assessed the frequency of pfcrt mutations and pfplasmepsin2/3 gene amplifications across Southeast Asia over 25 years, which is critical for tracking resistant parasites. A total of 898 P. falciparum isolates collected from Thailand, Myanmar, Cambodia, Laos, and Vietnam between 1995 and 2023 were analyzed for pfcrt mutations, pfplasmepsin2 copy number, and microsatellite variation around the pfcrt locus. During the study period, pfcrt mutations in Cambodia across the study period showed that H97Y had the highest prevalence at 15%, followed by T93S at 8%, while I218F was common in 24% of specimens in Srisaket and Ubon in Thailand at 24.44%, followed by G353V at 20%, T93S at 17%, F145I at 13%, and H97Y at 4%. In Tak, Thailand, a mutation was found only in 1995 with 40% at I218F and the remaining wild-type. Yala in Thailand and Kayin State in Myanmar remained wild-type. Vietnam showed frequent T93S at 21%. The prevalence of pfcrt mutations observed in this study changed throughout the study period. Over 65% of parasites with pfcrt mutations at positions 93, 97, 145, 218, 343, and 353 also had pfplasmepsin2 amplification. Temporal analysis revealed that in Cambodia, pfplasmepsin2 CNV emerged first, peaking at 88% prevalence in 2015 after the introduction of DHA-piperaquine, with the subsequent increase of pfcrt mutations H97Y and G353V. In Eastern Thailand, both pfcrt mutations and pfplasmepsin2 CNV were highly prevalent, exceeding 70% during 2015-2018. In Vietnam, rapid increases in both markers were observed after 2012, reaching peak by 2017. Microsatellite analysis revealed reduced genetic diversity around mutant pfcrt alleles, indicating selective sweeps. This study demonstrates that frequencies of pfcrt mutations and pfplasmepsin2 amplification linked to piperaquine resistance have changed over time, highlighting the importance of ongoing genetic monitoring to inform strategies for preserving artemisinin-based combination therapy efficacy.

BACKGROUND:Drug-induced liver injury (DILI) management during tuberculous meningitis treatment may result in premature rifampicin and isoniazid withdrawal and contribute to poor outcomes. METHODS:Adults with tuberculous meningitis, enroled into the ACT HIV (N=520) and LAST ACT (N=720) corticosteroid trials (NCT03092817;NCT03100786), who developed DILI were randomised to strategy-1: continue all drugs, unless ALT ≥10x upper limit of normal [ULN], bilirubin ≥43µmol/L, or symptoms worsen; or strategy-2: stop pyrazinamide, unless ALT ≥5x ULN by day 6, bilirubin ≥43µmol/L, or symptoms worsen; or strategy-3: stop rifampicin, isoniazid, pyrazinamide, continue ethambutol, add levofloxacin and aminoglycoside. The primary outcome was the proportion of time, 60-days following DILI randomisation, during which neither rifampicin nor isoniazid were given (or the participant died). Secondary outcomes included acute liver failure, and death/new neurological events. RESULTS:Sixty-seven participants with DILI were randomised to strategy-1 (n=21), 2 (n=21), and 3 (n=25). Participants had fewer days without rifampicin and isoniazid in strategy-1 (median 7 days [1st-3rd quartile 0-31]) and 2 (9 days [0-21]) than strategy-3 (18 days [11-35]; p=0.022 and p=0.041). No participants developed liver failure. Strategy failure (requiring strategy-3 switch) occurred in 8/21 (38.1%) strategy-1 and 13/21 (61.9%) strategy-2. New neurological event or death after DILI randomisation, until 12 months from primary randomisation, occurred in 7/21 strategy-1, 9/21 strategy-2 and 14/25 strategy-3 (p=0.20 strategy 1 vs. 3; p=0.42 strategy 2 vs. 3). CONCLUSIONS:DILI management strategies that increase transaminase drug-stopping thresholds (10X ULN), or stop pyrazinamide alone, appeared safe and reduced rifampicin/isoniazid interruptions vs. standard approaches.

Adjunctive corticosteroids such as dexamethasone are recommended in tuberculous meningitis treatment, despite modest and heterogeneous survival benefit. Leukotriene A4 hydrolase (LTA4H) genotypes associate with distinct intracerebral inflammatory phenotypes and may determine corticosteroid response in tuberculous meningitis, with benefit observed in hyperinflammatory TT genotype but uncertain benefit in lower inflammation CC and CT genotypes. Here, in a phase 3, placebo-controlled trial of human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis, we randomized 613 LTA4H CC- and CT-genotype participants to 6–8 weeks of dexamethasone or placebo, aiming to show noninferiority of placebo (hazard ratio margin of 0.75) or its superiority. Given the significant survival benefit of dexamethasone previously seen in LTA4H TT-genotype individuals, TT-genotype participants all received open-label dexamethasone and were not randomized. A total of 89 TT-genotype participants received open-label dexamethasone. In CC- and CT-genotype participants, the primary endpoint of all-cause death or new neurological event over 12 months from randomization occurred in 108/305 (35.4 NCT03100786 ). In this phase 3 trial, human immunodeficiency virus-negative Vietnamese adults with tuberculous meningitis were stratified by LTA4H genotype to assess whether this influences corticosteroid response. However, outcomes were not significantly better according to genotype.

Background:Pulmonary TB (PTB) patients present with a wide range of pre-treatment Mycobacterium tuberculosis ( Mtb ) burdens, which predict poor treatment outcomes. We sought to identify immune pathways and biomarkers associated with pre-treatment Mtb burden. Methods:We conducted whole-blood RNA sequencing in 295 Vietnamese adults with PTB, quantifying bacterial load using GeneXpert Ct values. Weighted gene co-expression network analysis (WGCNA) identified gene modules, pathways, and hub genes associated with Mtb burden. Deconvolution analysis assessed contributions of immune cell types. Key findings were validated in independent PTB (n=171) and TB meningitis (TBM, n=281) cohorts, and publicly available animal datasets. We used non-linear regression for variable selection to identify gene predictors of Mtb burden and hurdle regression to model Mtb loads below the detection limit. Findings:Higher Mtb burden correlated with prolonged symptom duration, elevated neutrophil and monocyte counts, and severe lung pathology. WGCNA identified a 1,093-gene module associated with Mtb burden, characterized by coordinated innate-adaptive pathway interactions. Within this module, IFN-γ signaling participates in modulating the increase of innate signaling (Toll-like, Nod-like receptors, TNF) and the decrease of adaptive signaling (T- and B-cell receptor) pathways in high-burden patients. These responses were primarily driven by neutrophils and classical monocytes. CNIH4 emerged as the strongest hub-gene and a top predictor of bacterial burden, with consistent validation across independent PTB and TBM cohorts. Interpretation:Our study reveals systemic innate-adaptive immune dynamics underlying bacterial burden in PTB and identifies CNIH4 as a potential biomarker for treatment monitoring as well as a therapeutic target. Funding:National Institute of Health; Wellcome Trust, UK. Research in Context:Evidence before this study: We searched PubMed from Jan 1, 2000, to Dec 10, 2025, without language restrictions, for human studies examining the relationship between Mycobacterium tuberculosis (Mtb) burden and host blood transcriptional responses in pulmonary tuberculosis. Search terms were used in combination as follows: ("Tuberculosis, Pulmonary" OR "pulmonary tuberculosis" OR PTB) AND ("Mycobacterium tuberculosis" OR mycobacter*) AND ("bacterial load" OR "bacterial burden" OR "sputum smear" OR "smear grade" OR xpert OR genexpert OR "cycle threshold" OR ct OR "time to positivity" OR TTP OR CFU OR "molecular bacterial load" OR MBLA)) AND (blood OR "whole blood" OR "peripheral blood") AND (RNA-seq OR "RNA sequencing" OR transcriptom* OR "gene expression" OR microarray). We included studies of active pulmonary tuberculosis that measured quantitative or semi-quantitative bacterial burden and profiled host blood transcriptome-wide responses at baseline, reporting either differential expression by burden strata or associations between bacterial burden and host gene expression. We excluded studies limited to latent tuberculosis, animal or in vitro models, diagnostic or prognostic signature studies without bacterial burden measurement, studies focused on treatment response, and studies using targeted assays without transcriptome-wide profiling.This search identified 12 articles describing blood transcriptional signatures for tuberculosis diagnosis, prognosis, and treatment response. However, only one study directly examined the relationship between pre-treatment bacterial burden and whole-blood transcriptome-wide profiles. That study demonstrated differences in systemic gene expression between patients with higher and lower sputum mycobacterial load and proposed a 20-gene blood signature associated with bacterial burden. However, the analysis was limited by small sample size, lack of pathway-level and cellular interpretation or assessment of correlation between signature with bacterial load.Added value of this study: Our study advances existing evidence by leveraging the wide spectrum of pre-treatment bacterial burden observed in routine clinical populations, quantified using GeneXpert Ct values, and integrating this with whole-blood RNA sequencing in large, well-characterized clinical cohorts. Through network-based transcriptomic analysis, immune cell deconvolution, and non-linear modelling, we identify a bacterial burden-associated gene network characterized by enhanced innate inflammatory signaling and relative suppression of adaptive immune pathways, predominantly driven by neutrophils and classical monocytes and modulated by IFN-γ signaling. Within this network, CNIH4 emerges as a central hub gene and a robust predictor of bacterial burden, with consistent validation across independent pulmonary tuberculosis and tuberculous meningitis cohorts.Implications of all the available evidence: Taken together, the available evidence indicates that host blood transcriptional responses correlate with bacterial burden in pulmonary tuberculosis, but previous studies have provided limited insight into the underlying immune processes. Our findings strengthen the biological link between pre-treatment mycobacterial burden and systemic immune dysregulation, showing that higher bacterial burden is associated with transcriptional state marked by coordinated upregulation of innate immune responses and downregulation of adaptive immune pathways. These results support the use of host transcriptomic profiling as a biologically informative complement to sputum-based measures of bacterial burden and highlight burden-associated immune pathways, particularly CNIH4, as a potential target for treatment monitoring and host-directed therapeutic development.

Mục tiêu: Mô tả dịch tễ, tác nhân, tình hình đề kháng vancomycin và các yếu tố liên quan ở bệnh nhân nhiễm khuẩn do Enterococcus spp. Đối tượng và phương pháp nghiên cứu: Nghiên cứu cắt ngang mô tả (hồi cứu và tiến cứu) 216 trường hợp bệnh nhân nhiễm khuẩn do Enterococcus spp. điều trị tại bệnh viện Bệnh Nhiệt đới từ tháng 01/2021 đến tháng 08/2023. Các yếu tố liên quan nhiễm Enterococcus spp. kháng vancomycin (VRE) được xác định thông qua mô hình hồi quy logistic đơn biến và đa biến. Kết quả: Nhiễm khuẩn liên quan chăm sóc y tế do Enterococcus spp. chiếm tỉ lệ 87%, vượt trội hơn nhiều lần so với nguồn nhiễm khuẩn từ cộng đồng, với đường niệu là ổ nhiễm khuẩn thường gặp nhất. E. faecium là tác nhân phổ biến nhất (63%), kế đến là E. faecalis (36%). Tỉ lệ bệnh nhân nhiễm khuẩn do VRE nói chung là 34,3%, riêng E. faecium có tỉ lệ đề kháng vancomycin lên đến 45,8%. Phân tích đa biến cho thấy nhóm bệnh nhân từ 60 tuổi trở lên có nguy cơ nhiễm VRE cao gấp 1,91 lần (KTC 95%: 1,01 – 3,62) so với nhóm dưới 60 tuổi. Cơ địa đái tháo đường (aOR = 2,00; KTC 95%: 1,04 – 3,83) và tiền căn sử dụng vancomycin (aOR = 1,98; KTC 95%: 1,04 – 3,76) cũng là yếu tố nguy cơ độc lập dẫn đến nhiễm VRE. Tỉ lệ tử vong chung trong nghiên cứu là 38,4%. Kết luận: Nhiễm khuẩn do Enterococcus spp. gây ra gánh nặng lớn liên quan đến chăm sóc y tế với tỉ lệ tử vong cao và sự hiện diện của nhóm vi khuẩn kháng vancomycin. Tình trạng nhiễm VRE có mối liên quan độc lập với yếu tố tuổi cao, cơ địa đái tháo đường và tiền căn sử dụng vancomycin trước đó.

Abstract High-dose corticosteroids may cause reactivation or relapse of hepatitis B virus infection. We investigated the virologic and clinical consequences of 6-8 weeks dexamethasone in hepatitis B virus infected/exposed/unexposed HIV-negative adults with tuberculous meningitis enrolled into a placebo-controlled trial. Dexamethasone was not associated with viral reactivation or increased liver injury.

Background: Perceptions of death and dying has been attracting more attention in recent years with more advocacy on improving the end-of-life experiences and providing more support for families during these times. While these topics are important, Western views about death and dying have been more dominant, leaving a knowledge gap in how death and dying are perceived in Asian cultures. We used qualitative methods to explore how death and dying was perceived in Vietnamese culture, and examine the implications for related practices, including minimally invasive tissue sampling. Methods: We conducted 59 in-depth interviews and five focus group discussions with key informants, healthcare professionals, community stakeholders and relatives of recently deceased people. We used a form of thematic analysis and explored the perceptions of death and dying, with particular focus on the concepts of a good death and the meaning of the body in Vietnamese culture. Results: Perceptions and attitudes surrounding death and dying varied, from an acceptance attitude to a fearful and anxious view when talking about death. A good death was usually perceived as dying at home and surrounded by family, with no worries or regrets for both the deceased and the family, and keeping an intact body. The body has a sacred meaning to the family that is handled with great care and respect. Conclusion: Death and dying in Vietnamese culture is a communal affair with a considerable role of the family on the dying experience of the person. Any related practices, such as end-of-life care or minimally invasive tissue sampling, should consider the cultural aspects to improve its acceptability.

OBJECTIVES:To characterize tuberculous meningitis (TBM)-associated hyponatraemia and better understand its causality, progression, and influence on treatment outcomes. METHODS:208 Vietnamese adults with TBM, consecutively enrolled into two trials of adjunctive dexamethasone (ACT-HIV:NCT03092817; LAST-ACT:NCT03100786), had at least one measurement of plasma sodium, urinary sodium, serum osmolality, or urine osmolality during treatment. Fluid status was assessed by fluid balance and inferior vena cava ultrasound. TBM severity and clinical endpoints by 12 months were recorded. RESULTS:176/190 (92.6%) participants with plasma sodium measured at presentation had hyponatraemia, with lower sodium associated with more severe TBM, and increased CSF inflammation. Pre-defined causality criteria applied to 34 participants with complete data suggested 7/34 (20.6%) had cerebral salt wasting (CSW) and 27/34 (79.4%) had the syndrome of inappropriate anti-diuretic hormone (SIADH). Dexamethasone therapy (vs. placebo) was associated with higher plasma sodium during the first 30 days, irrespective of baseline plasma sodium, however these associations did not reach statistical significance. During treatment, lower plasma sodium and higher 24-hour urinary outputs strongly predicted death and neurological events at 3 and 12 months. CONCLUSIONS:Hyponatraemia was strongly associated with more severe TBM and intracerebral inflammation. Persistent hyponatraemia and increasing urinary output during treatment associate with worse clinical outcomes.

Hand, foot and mouth disease (HFMD) complications rarely develop in adults. We present a case of a 21-year-old woman with an acute onset of impaired consciousness, ptosis, and limb weakness. She had a history of close contact with an HFMD patient, fever, vesicles on her hands and nasopharynx, and decreased limb muscle power. The results of the head and spinal cord MRI and RT-PCR of cerebrospinal fluid and throat, skin lesion, and anal swabs confirmed enterovirus 71-induced encephalomyelitis. She received a single dose of IVIG therapy and fully recovered. Our report further confirms the possibilities of HFMD with severe neurological complications in adults. A history of contact with HFMD patients and lesions on the skin and mucosa, even unobvious, help diagnose the disease. Confirming central nervous system involvement requires cerebrospinal fluid analysis and brain and spinal cord MRI. Prompt IVIG treatment could help reduce fever, skin lesions, and recovery time.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, with a fatality rate of 20% to 50% in treated individuals. Although corticosteroid therapy can increase survival in HIV-negative people with TBM, better antimicrobial and host-directed therapies are required to improve outcome. There is, therefore, a need to better understand local immunopathologic pathways. Despite its power in identifying disease-specific cellular profiles, single-cell RNA sequencing (scRNA-seq) has been underutilized in cerebral samples in brain infection. We employed scRNA-seq to analyze fresh pretreatment cerebrospinal fluid (CSF) from 4 TBM patients, along with paired PBMCs. While 29 cell subtypes were present in both tissues, their relative abundance varied significantly. In particular, CSF was enriched with highly inflammatory microglia-like macrophages, GZMK+CD8+ effector-memory T (TEM) cells, and CD56bright NK cells. The latter 2 subsets exhibited reduced cytotoxicity compared with their blood-enriched counterparts, namely cytotoxic GNLY+CD8+ TEM and CD56dim NK cells, respectively. Across multiple cell types, inflammatory signaling pathways were increased and oxidative phosphorylation was decreased in CSF compared to PBMCs. This study highlights the value of scRNA-seq for exploring CSF immunopathogenesis in TBM patients and offers a resource for future studies investigating the pathophysiology of TBM and other brain infections, including potentially targetable cell populations linked with immune-mediated pathology.

Nontuberculous mycobacteria are environmental mycobacteria that rarely cause human disease, especially in the central nervous system. Central nervous system infection by Mycobacterium avium complex, the most common pathogen among nontuberculous mycobacteria species, is rare and seldom reported, even in those with advanced human immunodeficiency virus infection. We describe a case of Mycobacterium avium complex meningitis with cerebral hemorrhage in an human immunodeficiency virus uninfected man in Vietnam. A 56-year-old Vietnamese man with hypertension was hospitalized with a 5-day history of headache, dizziness, low-grade fever, and unresponsive to 5 days of oral antibiotics. A brain magnetic resonance imaging, performed on day 12, showed hydrocephalus and lacunar infarct. The patient did not improve with 8 days of empirical treatment with ceftriaxone, vancomycin, dexamethasone, and meropenem, and was transferred to a referral hospital for tropical diseases. At the second hospital admission, a cerebrospinal fluid analysis showed a white cell count of 22,518 cells/μL with 81

AIMS:Resistance to the artemisinins and the artemisinin-based combination therapy (ACT) partner drugs has developed in Southeast Asia, and artemisinin resistance has also emerged in eastern Africa. Triple ACTs (triple artemisinin-based combination therapies, TACT), consisting of two partner drugs with different mechanisms of action and similar pharmacokinetic profiles, combined with an artemisinin derivative can help to delay or prevent artemisinin resistance and prolong the useful lifetime of the partner drugs. This study aims to characterize the pharmacokinetic properties of a recommended TACT, artemether-lumefantrine plus amodiaquine, using data from two large clinical trials. METHODS:We analysed data from two randomized, controlled intervention trials conducted between 2015 and 2020 in one African country and two Southeast Asian countries, in which artemether-lumefantrine was administered alone (n = 443) or together with amodiaquine (n = 442) to patients with uncomplicated P. falciparum malaria. Both studies included a sub-cohort with dense pharmacokinetic sampling, combined with sparse data in the other patients. Concentration-time data of artemether, dihydroartemisinin, lumefantrine, desbutyllumefantrine, amodiaquine and desethylamodiaquine were analysed using nonlinear mixed-effects modelling. RESULTS:Pharmacokinetic models were developed for all drugs and demonstrated good predictive performance and goodness-of-fit diagnostics. Coadministered amodiaquine was not a significant covariate on pharmacokinetic properties of artemether-lumefantrine. Model-predicted Cmax and AUC (median [95% confidence interval, CI]) for artemether were 256 (159-407) ng/mL and 2850 (1820-4920) h·ng/mL for artemether-lumefantrine alone, and 230 (123-391) ng/mL and 2800 (1570-4570) h·ng/mL for artemether-lumefantrine-amodiaquine. For dihydroartemisinin, values were 135 (54.5-214) ng/mL and 1870 (813-3015) h·ng/mL for artemether-lumefantrine alone, and 116 (40.8-186) ng/mL and 1580 (547-2680) h·ng/mL for artemether-lumefantrine-amodiaquine. For lumefantrine, values were 15.2 (2.90-31.3) μg/mL and 600 (275-1230) h·μg/mL for artemether-lumefantrine alone, and 14.1 (2.72-31.4) μg/mL and 586 (269-1070) h·μg/mL for artemether-lumefantrine-amodiaquine. Day 7 concentrations of lumefantrine were 452 (215-1240) and 438 (204-1030) μg/mL for artemether-lumefantrine alone and artemether-lumefantrine-amodiaquine, respectively. All geometric mean ratios (GMRs) for the drug-drug interaction (DDI) effect on key pharmacokinetic parameters of artemether, dihydroartemisinin and lumefantrine fell within the 0.80-1.25 range, with the majority of the corresponding 90% CI also contained within this range. This indicates no clinically relevant DDIs between artemether-lumefantrine and amodiaquine. CONCLUSIONS:The DDI effect of amodiaquine on the pharmacokinetics of artemether-lumefantrine is expected to be minimal, the based on the current analysis. However, further large-scale clinical trials are needed to confirm this finding.

Abstract Background Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of a gold standard. Current microbiological tests lack sensitivity and clinical diagnostic approaches are subjective. We therefore built a diagnostic model that can be used before microbiological test results are known. Methods We included 659 individuals aged $$\ge 16$$ ≥ 16 years with suspected brain infections from a prospective observational study conducted in Vietnam. We fitted a logistic regression diagnostic model for TBM status, with unknown values estimated via a latent class model on three mycobacterial tests: Ziehl–Neelsen smear, Mycobacterial culture, and GeneXpert. We additionally re-evaluated mycobacterial test performance, estimated individual mycobacillary burden, and quantified the reduction in TBM risk after confirmatory tests were negative. We also fitted a simplified model and developed a scoring table for early screening. All models were compared and validated internally. Results Participants with HIV, miliary TB, long symptom duration, and high cerebrospinal fluid (CSF) lymphocyte count were more likely to have TBM. HIV and higher CSF protein were associated with higher mycobacillary burden. In the simplified model, HIV infection, clinical symptoms with long duration, and clinical or radiological evidence of extra-neural TB were associated with TBM At the cutpoints based on Youden’s Index, the sensitivity and specificity in diagnosing TBM for our full and simplified models were 86.0% and 79.0%, and 88.0% and 75.0% respectively. Conclusion Our diagnostic model shows reliable performance and can be developed as a decision assistant for clinicians to detect patients at high risk of TBM. Summary Diagnosis of tuberculous meningitis is hampered by the lack of gold standard. We developed a diagnostic model using latent class analysis, combining confirmatory test results and risk factors. Models were accurate, well-calibrated, and can support both clinical practice and research.

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a global health burden. While M. tuberculosis is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that lead to differential disease across organs. Attention has focused on differences in T cell responses in the control of M. tuberculosis in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood-brain barrier, here we characterized the antibody profiles across the blood and brain compartments in TBM and determined whether M. tuberculosis-specific humoral immune responses differed between M. tuberculosis infection of the lung (pulmonary TB) and TBM.Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different M. tuberculosis antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n = 10) versus TBM (n = 60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4) and the capacity of M. tuberculosis-specific antibodies to bind to Fc receptors or C1q and to activate innate immune effector functions (complement and natural killer cell activation; monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB.In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against M. tuberculosis, characterized by an enrichment of M. tuberculosis-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited M. tuberculosis-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared with individuals with pulmonary TB, despite having lower IgG titres and Fc gamma receptor-binding capacity.Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs versus brain) and demonstrate a highly compartmentalized M. tuberculosis-specific antibody response within the CSF in TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease. Mycobacterium tuberculosis causes pulmonary tuberculosis and tuberculosis meningitis, but the mechanisms by which the latter develops are unknown. Spatola et al. show that antibodies against Mycobacterium tuberculosis in the brain may play a role in the development and severity of tuberculosis meningitis.

The emergence of Plasmodium falciparum parasites resistant to artemisinins compromises the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line malaria treatment. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other genetic variations. Here, we present population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. Besides the PfK13 SNPs, several polymorphisms, including nonsynonymous SNPs (N1131I and N821K) in PfRad5 and an intronic SNP in PfWD11 (WD40 repeat-containing protein on chromosome 11), appear to be associated with artemisinin resistance, possibly as new markers. There is also a defined set of genes whose steady-state levels of mRNA and/or splice variants or antisense transcripts correlate with artemisinin resistance at the base level. In vivo transcriptional responses to artemisinins indicate the resistant parasite's capacity to decelerate its intraerythrocytic developmental cycle (IDC), which can contribute to the resistant phenotype. During this response, PfRAD5 and PfWD11 upregulate their respective alternatively/aberrantly spliced isoforms, suggesting their contribution to the protective response to artemisinins. PfRAD5 and PfWD11 appear under selective pressure in the Greater Mekong Sub-region over the last decade, suggesting their role in the genetic background of the artemisinin resistance.

BACKGROUND:Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections. METHODS:The expression of 3 genes (dual specificity phosphatase 3 [DUSP3], guanylate-binding protein [GBP5], krupple-like factor 2 [KLF2]) was analyzed by RNA sequencing of archived whole blood from 4 cohorts of Vietnamese adults: 281 with TBM, 279 with pulmonary tuberculosis, 50 with other brain infections, and 30 healthy controls. Tuberculosis scores (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC). RESULTS:GBP5 was upregulated in TBM compared to other brain infections (P < .001), with no difference in DUSP3 and KLF2 expression. The diagnostic performance of GBP5 alone (AUC, 0.74; 95% confidence interval [CI], .67-.81) was slightly better than the 3-gene tuberculosis score (AUC, 0.66; 95% CI, .58-.73) in TBM. Both GBP5 expression and tuberculosis score were higher in participants with human immunodeficiency virus (HIV; P < .001), with good diagnostic performance of GBP5 alone (AUC, 0.86; 95% CI, .80-.93). CONCLUSIONS:The 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in individuals with HIV. Validation in large prospective diagnostic study is now required.

Mục tiêu: Xác định tần suất, mô tả đặc điểm dịch tễ, lâm sàng, cận lâm sàng, phân bố tác nhân vi sinh và độ nhạy cảm vi khuẩn các trường hợp viêm phổi liên quan thở máy (VPLQTM), nhiễm trùng tiểu liên quan thông tiểu (CAUTI) trên các bệnh nhân can thiệp thở máy xâm lấn và đặt thông tiểu tại khoa Nhiễm Việt Anh bệnh viện Bệnh Nhiệt đới (BNBNĐ) năm 2022. Phương pháp: Nghiên cứu cắt ngang có theo dõi dọc các trường hợp người lớn trên 16 tuổi có can thiệp thở máy, đặt thông tiểu trên 48 giờ. Kết quả: Tần suất VPLQTM là 37/1000 ngày thở máy, thường gặp nhất là P.aeruginosa, có tỉ lệ nhạy Piperacillin/ Tazobactam 86%. Sử dụng kháng sinh tĩnh mạch từ thời điểm thở máy có thể làm giảm nguy cơ xuất hiện viêm phổi thở máy (OR 0,18, KTC 95%: 0,06-0,5,5 p=0,002). Tần suất CAUTI là 21/1000 ngày thông tiểu, thường gặp nhất là E.coli, tỉ lệ nhạy Carbapenem 85%, thời gian đặt thông tiểu dài và số lần đặt thông tiểu trên 2 lần làm tăng nguy cơ CAUTI (p<0,01). Kết luận: VPLQTM và CAUTI tại khoa có tần suất cao. Phần lớn các vi khuẩn phân lập được còn nhạy với các kháng sinh đang sử dụng. Rút ngắn thời gian can thiệp xâm lấn có thể làm giảm được nguy cơ nhiễm trùng bệnh viện.