Cyclosporine A-induced systemic metabolic perturbations in rats: A comprehensive metabolome analysis.

A better understanding of cyclosporine A (CsA)-induced nephro- and hepatotoxicity at the molecular level is necessary for safe and effective use. Utilizing a sophisticated study design, this study explored metabolic alterations after long-term CsA treatment in vivo. Rats were exposed to CsA with 4, 10, and 25 mg/kg for 4 weeks and then sacrificed to obtain liver, kidney, urine, and serum for untargeted metabolomics analysis. Differential network analysis was conducted to explore the biological relevance of metabolites significantly altered by toxicity-induced disturbance. Dose-dependent toxicity was observed in all biospecimens. The toxic effects were characterized by alterations of metabolites related to energy metabolism and cellular membrane composition, which could lead to the cholestasis-induced accumulation of bile acids in the tissues. The unfavorable impacts were also demonstrated in the serum and urine. Intriguingly, phenylacetylglycine was increased in the kidney, urine, and serum treated with high doses versus controls. Differential correlation network analysis revealed the strong correlations of deoxycytidine and guanosine with other metabolites in the network, which highlighted the influence of repeated CsA exposure on DNA synthesis. Overall, prolonged CsA administration had system-level dose-dependent effects on the metabolome in treated rats, suggesting the need for careful usage and dose adjustment.

Metabolic phenotyping and global functional analysis facilitate metabolic signature discovery for tuberculosis treatment monitoring.

Tracking alterations in polar metabolite and lipid levels during anti-tuberculosis (TB) interventions is an emerging biomarker discovery and validation approach due to its sensitivity in capturing changes and reflecting on the host status. Here, we employed deep plasma metabolic phenotyping to explore the TB patient metabolome during three phases of treatment: at baseline, during intensive phase treatment, and upon treatment completion. Differential metabolites (DMs) in each period were determined, and the pathway-level biological alterations were explored by untargeted metabolomics-guided functional interpretations that bypassed identification. We identified 41 DMs and 39 pathways that changed during intensive phase completion. Notably, levels of certain amino acids including histidine, bile acids, and metabolites of purine metabolism were dramatically increased. The altered pathways included those involved in the metabolism of amino acids, glycerophospholipids, and purine. At the end of treatment, 44 DMs were discovered. The levels of glutamine, bile acids, and lysophosphatidylinositol significantly increased compared to baseline; the levels of carboxylates and hypotaurine declined. In addition, 37 pathways principally associated with the metabolism of amino acids, carbohydrates, and glycan altered at treatment completion. The potential of each DM for diagnosing TB was examined using a cohort consisting of TB patients, those with latent infections, and controls. Logistic regression revealed four biomarkers (taurine, methionine, glutamine, and acetyl-carnitine) that exhibited excellent performance in differential diagnosis. In conclusion, we identified metabolites that could serve as useful metabolic signatures for TB management and elucidated underlying biological processes affected by the crosstalk between host and TB pathogen during treatment.

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management.

The spread of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, has strongly motivated the research and development of new anti-TB drugs. New strategies to facilitate drug combinations, including pharmacokinetics-guided dose optimization and toxicology studies of first- and second-line anti-TB drugs have also been introduced and recommended. Liquid chromatography-mass spectrometry (LC-MS) has arguably become the gold standard in the analysis of both endo- and exo-genous compounds. This technique has been applied successfully not only for therapeutic drug monitoring (TDM) but also for pharmacometabolomics analysis. TDM improves the effectiveness of treatment, reduces adverse drug reactions, and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window. Based on TDM, the dose would be optimized individually to achieve favorable outcomes. Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs, aiding in the discovery of potential biomarkers for TB diagnostics, treatment monitoring, and outcome evaluation. This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades. Besides, we discussed the advantages and disadvantages of this technique in practical use. The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted. Lastly, we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies (pharmacometrics, drug and vaccine developments, machine learning/artificial intelligence, among others) to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

Newly detected paediatric melioidosis cases in a single referral children's hospital in Ho Chi Minh City indicate the probable underrecognition of melioidosis in South Vietnam.

BACKGROUND: The epidemiology of melioidosis in Vietnam, a disease caused by the soil bacterium Burkholderia pseudomallei, remains unclear. This study aimed to detect paediatric melioidosis in South Vietnam and describe clinical features and the geographic distribution. METHODS: We introduced a simple laboratory algorithm for detecting B. pseudomallei from clinical samples at Children's Hospital 2 in Ho Chi Minh City in July 2015. A retrospective observational study of children <16 y of age with culture-confirmed melioidosis between July 2015 and August 2019 was undertaken. RESULTS: Thirty-five paediatric cases of melioidosis were detected, with cases originating from 13 of 32 provinces and cities in South Vietnam. The number of paediatric melioidosis cases detected from a certain region correlated with the overall number of inpatients originating from the respective geographic area. Suppurative parotitis (n=15 [42.8%]) was the most common clinical presentation, followed by lung infection (n=10 [28.6%]) and septicaemia (n=7 [20%]). Fourteen (40%) children had disseminated disease, including all cases of lung infection, four cases with central nervous system symptoms and four (11.4%) deaths. CONCLUSIONS: The patients' origin indicates a wide distribution of melioidosis in South Vietnam. It seems probable that cases not only in children, but also in adults, remain grossly undiagnosed. Further awareness raising and laboratory capacity strengthening are needed in this part of the country.

Alterations of lipid-related genes during anti-tuberculosis treatment: insights into host immune responses and potential transcriptional biomarkers.

Background: The optimal diagnosis and treatment of tuberculosis (TB) are challenging due to underdiagnosis and inadequate treatment monitoring. Lipid-related genes are crucial components of the host immune response in TB. However, their dynamic expression and potential usefulness for monitoring response to anti-TB treatment are unclear. Methodology: In the present study, we used a targeted, knowledge-based approach to investigate the expression of lipid-related genes during anti-TB treatment and their potential use as biomarkers of treatment response. Results and discussion: The expression levels of 10 genes (ARPC5, ACSL4, PLD4, LIPA, CHMP2B, RAB5A, GABARAPL2, PLA2G4A, MBOAT2, and MBOAT1) were significantly altered during standard anti-TB treatment. We evaluated the potential usefulness of this 10-lipid-gene signature for TB diagnosis and treatment monitoring in various clinical scenarios across multiple populations. We also compared this signature with other transcriptomic signatures. The 10-lipid-gene signature could distinguish patients with TB from those with latent tuberculosis infection and non-TB controls (area under the receiver operating characteristic curve > 0.7 for most cases); it could also be useful for monitoring response to anti-TB treatment. Although the performance of the new signature was not better than that of previous signatures (i.e., RISK6, Sambarey10, Long10), our results suggest the usefulness of metabolism-centric biomarkers. Conclusions: Lipid-related genes play significant roles in TB pathophysiology and host immune responses. Furthermore, transcriptomic signatures related to the immune response and lipid-related gene may be useful for TB diagnosis and treatment monitoring.

Pretomanid resistance: An update on emergence, mechanisms and relevance for clinical practice.

Pretomanid (PA-824), a novel anti-tuberculosis (TB) nitroimidazoxazine, has been approved for multi-drug-resistant TB treatment for a few years. Pretomanid has been demonstrated to be highly active against Mycobacterium tuberculosis when combined with other anti-TB drugs. This review provides an update of the current knowledge on the modes of action, resistance mechanisms, emergence of drug resistance, and status of antimicrobial susceptibility testing for pretomanid and its relevance for clinical practice. Pretomanid resistance has been reported in in-vitro and animal models but not yet in clinical trials. Pretomanid-resistance-associated mutations have been reported in the fbiA, fbiB, fbiC, fbiD, ddn and fgd1 genes. However, understanding of in-vivo molecular resistance mechanisms remains limited, and complicates the development of accurate antimicrobial susceptibility testing methods for pretomanid. As such, no reference method for antimicrobial susceptibility testing of pretomanid has been established to guide clinical use. Further studies linking specific mutations, in-vitro susceptibility, drug exposure and resistance mechanisms to treatment failure with pretomanid should be prioritized.

Early diagnostic indicators of dengue versus other febrile illnesses in Asia and Latin America (IDAMS study): a multicentre, prospective, observational study.

BACKGROUND: Improvements in the early diagnosis of dengue are urgently needed, especially in resource-limited settings where the distinction between dengue and other febrile illnesses is crucial for patient management. METHODS: In this prospective, observational study (IDAMS), we included patients aged 5 years and older with undifferentiated fever at presentation from 26 outpatient facilities in eight countries (Bangladesh, Brazil, Cambodia, El Salvador, Indonesia, Malaysia, Venezuela, and Viet Nam). We used multivariable logistic regression to investigate the association between clinical symptoms and laboratory tests with dengue versus other febrile illnesses between day 2 and day 5 after onset of fever (ie, illness days). We built a set of candidate regression models including clinical and laboratory variables to reflect the need of a comprehensive versus parsimonious approach. We assessed performance of these models via standard measures of diagnostic values. FINDINGS: Between Oct 18, 2011, and Aug 4, 2016, we recruited 7428 patients, of whom 2694 (36%) were diagnosed with laboratory-confirmed dengue and 2495 (34%) with (non-dengue) other febrile illnesses and met inclusion criteria, and were included in the analysis. 2703 (52%) of 5189 included patients were younger than 15 years, 2486 (48%) were aged 15 years or older, 2179 (42%) were female and 3010 (58%) were male. Platelet count, white blood cell count, and the change in these variables from the previous day of illness had a strong association with dengue. Cough and rhinitis had strong associations with other febrile illnesses, whereas bleeding, anorexia, and skin flush were generally associated with dengue. Model performance increased between day 2 and 5 of illness. The comprehensive model (18 clinical and laboratory predictors) had sensitivities of 0·80 to 0·87 and specificities of 0·80 to 0·91, whereas the parsimonious model (eight clinical and laboratory predictors) had sensitivities of 0·80 to 0·88 and specificities of 0·81 to 0·89. A model that includes laboratory markers that are easy to measure (eg, platelet count or white blood cell count) outperformed the models based on clinical variables only. INTERPRETATION: Our results confirm the important role of platelet and white blood cell counts in diagnosing dengue, and the importance of serial measurements over subsequent days. We successfully quantified the performance of clinical and laboratory markers covering the early period of dengue. Resulting algorithms performed better than published schemes for distinction of dengue from other febrile illnesses, and take into account the dynamic changes over time. Our results provide crucial information needed for the update of guidelines, including the Integrated Management of Childhood Illness handbook. FUNDING: EU's Seventh Framework Programme. TRANSLATIONS: For the Bangla, Bahasa Indonesia, Portuguese, Khmer, Spanish and Vietnamese translations of the abstract see Supplementary Materials section.

Clinical and aetiological study of hand, foot and mouth disease in southern Vietnam, 2013-2015: Inpatients and outpatients.

BACKGROUND: Hand, foot and mouth disease (HFMD) has been associated with large outbreaks among young children in the Asia-Pacific Region since 1997, including cases of severe illness and death. Severe illness is often associated with enterovirus A71 (EV-A71). Vietnam experienced a large sustained outbreak of 200000 hospitalized cases and over 200 deaths in 2011-12, the large majority occurring in southern Vietnam. METHODS: A prospective observational study was conducted in the outpatient clinics, infectious diseases wards, and paediatric intensive care units of the three main referral centres for the treatment of HFMD in southern Vietnam. Demographic data, basic laboratory parameters, and clinical data were recorded, and molecular diagnostic tests were performed. RESULTS: Between July 2013 and July 2015, a total of 1547 children were enrolled. Four serotypes of enterovirus A (EV-A71, Coxsackievirus (CV) A6, A10, and A16) were responsible for 1005 of 1327 diagnosed cases (75.7%). An unexpected dominance of EV-A71 was found among both inpatients and outpatients, as well as a strong association with severe illness. CV-A6 and CV-A10 emerged in Vietnam during the study period and replaced CV-A16. CV-A10 was associated with different clinical and laboratory characteristics. During admission, 119 children developed a more severe illness. It was found that children with a skin rash showed less progression of severity, but when a rash was present, a macular rash was significantly associated with an increased risk of progression. CONCLUSIONS: This study represents the most comprehensive descriptive HFMD study from Vietnam to date. Co-circulation and replacement of different serotypes has implications for vaccine development and implementation. These findings from a severely affected country add to our understanding of the presentation, progression, and aetiology of HFMD.

Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo.

The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Commun.2014, 450, 1063). Herein, we establish structure-activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL. However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.

Evaluation of the value of blood gas in thoraco-abdominal postoperation in newborns admitted to rehabilitation Department of Children N0 II hospital

A retrospective study of the value of blood gas in prognosis of early respiratory failure postoperation was performed on 50 newborns admitted to Children N0 II hospital, HCM city from 2000 to 2002. Examination of blood gas 24 hours before and after operation in 50 newborns. The results as followed: the lower PaCO2 and CRIB score were the good predictor for non respiratory failure in postoperating patients. This study suggested, tests of blood gas before and after operation should be done routinely to predict early respiratory failure for the newborns in NICU