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Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.
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Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/inmunología , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/inmunología , Leucotrieno A4/genética , Leucotrieno A4/inmunología , Leucotrieno B4/genética , Leucotrieno B4/inmunología , Lipoxinas/inmunología , Mitocondrias/metabolismo , Infecciones por Mycobacterium/genética , Mycobacterium marinum , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Transducción de Señal , Transcripción Genética , Tuberculosis Meníngea/genética , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra/embriología , Pez Cebra/inmunologíaRESUMEN
BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).
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Antirretrovirales , Antituberculosos , Dexametasona , Glucocorticoides , Infecciones por VIH , Tuberculosis Meníngea , Adulto , Humanos , Dexametasona/efectos adversos , Dexametasona/uso terapéutico , Método Doble Ciego , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Seropositividad para VIH/complicaciones , Seropositividad para VIH/tratamiento farmacológico , Tuberculosis Meníngea/complicaciones , Tuberculosis Meníngea/tratamiento farmacológico , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Quimioterapia Combinada/efectos adversos , Antirretrovirales/efectos adversos , Antirretrovirales/uso terapéuticoRESUMEN
Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
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Epóxido Hidrolasas/genética , Enfermedades de los Peces/genética , Lepra/genética , Tuberculosis/genética , Animales , Modelos Animales de Enfermedad , Enfermedades de los Peces/inmunología , Predisposición Genética a la Enfermedad , Humanos , Lepra/inmunología , Tuberculosis/inmunología , Pez CebraRESUMEN
BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.
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Acrilamidas , Compuestos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Acrilamidas/uso terapéutico , Acrilamidas/administración & dosificación , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Biomarcadores de Tumor/genética , Supervivencia sin Progresión , Adulto , Anciano de 80 o más Años , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Indoles , PirimidinasRESUMEN
Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.
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Deficiencia de Dihidropirimidina Deshidrogenasa , Dihidrouracilo Deshidrogenasa (NADP) , Genotipo , Humanos , Dihidrouracilo Deshidrogenasa (NADP)/genética , Masculino , Femenino , Persona de Mediana Edad , Deficiencia de Dihidropirimidina Deshidrogenasa/diagnóstico , Deficiencia de Dihidropirimidina Deshidrogenasa/genética , Anciano , Técnicas de Genotipaje/métodos , Adulto , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéuticoRESUMEN
The major human genes regulating Mycobacterium tuberculosis-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression in humans are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling. We hypothesized that common variants in CNBP, REL, and BHLHE40 were associated with IL-12 and IL-10 production from dendritic cells, and that these variants also influence adaptive immune responses to bacillus Calmette-Guérin (BCG) vaccination and TB susceptibility. We characterized the association between common variants in CNBP, REL, and BHLHE40, innate immune responses in dendritic cells and monocyte-derived macrophages, BCG-specific T cell responses, and susceptibility to pediatric and adult TB in human populations. BHLHE40 single-nucleotide polymorphism (SNP) rs4496464 was associated with increased BHLHE40 expression in monocyte-derived macrophages and increased IL-10 from peripheral blood dendritic cells and monocyte-derived macrophages after LPS and TB whole-cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL-2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and rs842618 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618 was associated with increased risk for TB meningitis. In summary, we found that genetic variations in REL and BHLHE40 are associated with IL-12 and IL-10 cytokine responses and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.
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Mycobacterium bovis , Mycobacterium tuberculosis , Proteínas Proto-Oncogénicas c-rel/genética , Tuberculosis , Adulto , Vacuna BCG , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Niño , Proteínas de Homeodominio , Humanos , Interleucina-10/genética , Interleucina-12/genética , Tuberculosis/genéticaRESUMEN
The COVID-19 pandemic was caused by the SARS-CoV-2 virus, marking one of the most catastrophic global health crises of the 21st century. Throughout this period, widespread use and improper disposal of personal protective equipment (PPE) emerged as a pressing environmental issue, significantly impacting various life forms. During the COVID-19 pandemic, there was a high rate of PEP disposal. An alarming 1.6 × 106 tons of plastic waste each day has been generated since the onset of the outbreak, predominantly from the inadequate disposal of PPE. The mismanagement and subsequent degradation of discarded PPE significantly contribute to increased non-biodegradable micro(nano)plastic (MNP) waste. This pollution has had profound adverse effects on terrestrial, marine, and aquatic ecosystems, which have been extensively of concern recently. Accumulated MNPs within aquatic organisms could serve as a potential route for human exposure when consuming seafood. This review presents a novel aspect concerning the pollution caused by MNPs, particularly remarking on their role during the pandemic and their detrimental effects on human health. These microplastic particles, through the process of fragmentation, transform into nanoparticles, persisting in the environment and posing potential hazards. The prevalence of MNP from PPE, notably masks, raises concerns about their plausible health risks, warranting global attention and comprehensive exploration. Conducting a comprehensive evaluation of the long-term effects of these processes and implementing effective management strategies is essential.
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COVID-19 , Equipo de Protección Personal , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Contaminación Ambiental/prevención & control , Microplásticos/análisis , SARS-CoV-2 , Plásticos , NanopartículasRESUMEN
Millions of people worldwide are infected with filarial nematodes, responsible for lymphatic filariasis (LF) and other diseases causing chronic disablement. Elimination programs have resulted in a substantial reduction of the rate of infection in certain areas creating a need for improved diagnostic tools to establish robust population surveillance and avoid LF resurgence. Glycans from parasitic helminths are emerging as potential antigens for use in diagnostic assays. However, despite its crucial role in host-parasite interactions, filarial glycosylation is still largely, structurally, and functionally uncharacterized. Therefore, we investigated the glycan repertoire of the filarial nematode Brugia malayi. Glycosphingolipid and N-linked glycans were extracted from several life-stages using enzymatic release and characterized using a combination of MALDI-TOF-MS and glycan sequencing techniques. Next, glycans were purified by HPLC and printed onto microarrays to assess the host anti-glycan antibody response. Comprehensive glycomic analysis of B. malayi revealed the presence of several putative antigenic motifs such as phosphorylcholine and terminal glucuronic acid. Glycan microarray screening showed a recognition of most B. malayi glycans by immunoglobulins from rhesus macaques at different time points after infection, which permitted the characterization of the dynamics of anti-glycan immunoglobulin G and M during the establishment of brugian filariasis. A significant level of IgG binding to the parasite glycans was also detected in infected human plasma, while IgG binding to glycans decreased after anthelmintic treatment. Altogether, our work identifies B. malayi glycan antigens and reveals antibody responses from the host that could be exploited as potential markers for LF.
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Brugia Malayi , Filariasis Linfática , Animales , Filariasis Linfática/diagnóstico , Filariasis Linfática/parasitología , Humanos , Inmunoglobulina G , Macaca mulatta , PolisacáridosRESUMEN
Water pollution remains a pressing environmental issue, with diverse pollutants such as heavy metals, pharmaceuticals, dyes, and aromatic hydrocarbon compounds posing a significant threat to clean water access. Historically, biomass-derived activated carbons (ACs) have served as effective adsorbents for water treatment, owing to their inherent porosity and expansive surface area. Nanocomposites have emerged as a means to enhance the absorption properties of ACs, surpassing conventional AC performance. Biomass-based activated carbon nanocomposites (ACNCs) hold promise due to their high surface area and cost-effectiveness. This review explores recent advancements in biomass-based ACNCs, emphasizing their remarkable adsorption efficiencies and paving the way for future research in developing efficient and affordable ACNCs. Leveraging real-time communication for ACNC applications presents a viable approach to addressing cost concerns.
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Carbón Orgánico , Frutas , Nanocompuestos , Verduras , Purificación del Agua , Nanocompuestos/química , Carbón Orgánico/química , Purificación del Agua/métodos , Frutas/química , Adsorción , Verduras/química , Contaminantes Químicos del Agua/química , BiomasaRESUMEN
BACKGROUND: The purpose of this study was to assess if single nucleotide polymorphisms (SNPs) in lung mucins MUC5B and MUC5AC are associated with Mycobacterium tuberculosis outcomes. METHODS: Independent SNPs in MUC5B and MUC5AC (genotyped by Illumina HumanOmniExpress array) were assessed for associations with tumor necrosis factor (TNF) concentrations (measured by immunoassay) in cerebral spinal fluid (CSF) from tuberculous meningitis (TBM) patients. SNPs associated with CSF TNF concentrations were carried forward for analyses of pulmonary and meningeal tuberculosis susceptibility and TBM mortality. RESULTS: MUC5AC SNP rs28737416 T allele was associated with lower CSF concentrations of TNF (P = 1.8 × 10-8) and IFN-γ (P = 2.3 × 10-6). In an additive genetic model, rs28737416 T/T genotype was associated with higher susceptibility to TBM (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.03-1.49; P = .02), but not pulmonary tuberculosis (OR, 1.11, 95% CI, .98-1.25; P = .10). TBM mortality was higher among participants with the rs28737416 T/T and T/C genotypes (35/119, 30.4%) versus the C/C genotype (11/89, 12.4%; log-rank P = .005) in a Vietnam discovery cohort (n = 210), an independent Vietnam validation cohort (n = 87; 9/87, 19.1% vs 1/20, 2.5%; log-rank P = .02), and an Indonesia validation cohort (n = 468, 127/287, 44.3% vs 65/181, 35.9%; log-rank P = .06). CONCLUSIONS: MUC5AC variants may contribute to immune changes that influence TBM outcomes.
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Mycobacterium tuberculosis , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/genética , Tuberculosis Meníngea/complicaciones , Citocinas/genética , Genotipo , Factor de Necrosis Tumoral alfa/genética , Polimorfismo de Nucleótido Simple , Mucina 5AC/genéticaRESUMEN
BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24â h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6)â h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3)â h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7)â h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0)â h·mg·L-1). Our multivariate models indicated that younger age (especially <2â years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
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Antituberculosos , Isoniazida , Niño , Adolescente , Humanos , Preescolar , Antituberculosos/uso terapéutico , Isoniazida/uso terapéutico , Pirazinamida/uso terapéutico , Etambutol/uso terapéutico , Rifampin/uso terapéuticoRESUMEN
The chiral surface states of Weyl semimetals have an open Fermi surface called a Fermi arc. At the interface between two Weyl semimetals, these Fermi arcs are predicted to hybridize and alter their connectivity. In this Letter, we numerically study a one-dimensional (1D) dielectric trilayer grating where the relative displacements between adjacent layers play the role of two synthetic momenta. The lattice emulates 3D crystals without time-reversal symmetry, including Weyl semimetal, nodal line semimetal, and Chern insulator. Besides showing the phase transition between Weyl semimetal and Chern insulator at telecom wavelength, this system allows us to observe the Fermi arc reconstruction between two Weyl semimetals, confirming the theoretical predictions.
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PURPOSE: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. METHODS: The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. RESULTS: As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys ) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). CONCLUSION: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. TRIAL REGISTRATION: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.
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Citocromo P-450 CYP3A , Tomografía Computarizada por Tomografía de Emisión de Positrones , Masculino , Femenino , Humanos , Índice de Masa Corporal , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/farmacología , Radioisótopos de Flúor , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología , Tomografía de Emisión de Positrones/métodos , Receptores de GABA/metabolismoRESUMEN
The need for novel healthcare treatments and drugs has increased due to the expanding human population, detection of newer diseases, and looming pandemics. The development of nanotechnology offers a platform for cutting-edge in vivo non-invasive monitoring and point-of-care-testing (POCT) for rehabilitative disease detection and management. The advancement and uses of nanobiosensors are currently becoming more common in a variety of scientific fields, such as environmental monitoring, food safety, biomedical, clinical, and sustainable healthcare sciences, since the advent of nanotechnology. The identification and detection of biological patterns connected to any type of disease (communicable or not) have been made possible in recent years by several sensing techniques utilizing nanotechnology concerning biosensors and nanobiosensors. In this work, 2218 articles are drawn and screened from six digital databases out of which 17 were shortlisted for this review by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) technique. As a result, this study uses a systematic methodology to review some recently developed extremely sensitive nanobiosensors, along with their biomedical, point-of-care diagnostics (POCD), or healthcare applications and their capabilities, particularly for the prediction of some fatal diseases based on a few of the most recent publications. The potential of nanobiosensors for medicinal, therapeutic, or other sustainable healthcare applications, notably for ailments diagnostics, is also recognized as a way forward in the manifestation of future trends.
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Técnicas Biosensibles , Nanotecnología , Humanos , Nanotecnología/métodos , Pandemias , Inocuidad de los Alimentos , Atención a la SaludRESUMEN
The alarming impact of antibiotic resistance sparked the quest for complementary treatments to overcome the confrontation over resistant pathogens. Metallic nanoparticles, especially silver nanoparticles (Ag NPs) have gained a much attention because of their remarkable biological characteristics. Moreover, their medicinal properties can be enhanced by preparing the composites with other materials. This article delves a comprehensive review of biosynthesis route for Ag NPs and their nanocomposites (NCs) with in-depth mechanism, methods and favorable experimental parameters. Comprehensive biological features Ag NPs such as antibacterial, antiviral, antifungal have been examined, with a focus on their potential uses in biomedicine and diagnostics has also been discussed. Additionally, we have also explored the hitches and potential outcomes of biosynthesis of Ag NPs in biomedical filed.
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Nanopartículas del Metal , Nanocompuestos , Plata , Antibacterianos , AntiviralesRESUMEN
In the quest of improving the photocatalytic efficiency of photocatalysts, the combination of two and more semiconductors recently has garnered significant attention among scientists in the field. The doping of conductive metals is also an effective pathway to improve photocatalytic performance by avoiding electron/hole pair recombination and enhancing photon energy absorption. This work presented a design and fabrication of porphyrin@g-C3N4/Ag nanocomposite using acid-base neutralization-induced self-assembly approach from monomeric porphyrin and g-C3N4/Ag material. g-C3N4/Ag material was synthesized by a green reductant of Cleistocalyx operculatus leaf extract. Electron scanning microscopy (SEM), X-ray diffraction (XRD), FT-IR spectroscopy, and UV-vis spectrometer were utilized to analyse the properties of the prepared materials. The prepared porphyrin@g-C3N4/Ag nanocomposite showed well integration of porphyrin nanostructures on the g-C3N4/Ag's surface, in which porphyrin nanofiber was of the diameter in nanoscales and the length of several micrometers, and Ag NPs had an average particle size of less than 20 nm. The photocatalytic behavior of the resultant nanocomposite was tested for the degradation of Rhodamine B dye, which exhibited a remarkable RhB photodegrading percentage. The possible mechanism for photocatalysis of the porphyrin@g-C3N4/Ag nanocomposite toward Rhodamine B dye was also proposed and discussed.
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Nanocompuestos , Porfirinas , Espectroscopía Infrarroja por Transformada de Fourier , Colorantes , ElectronesRESUMEN
The increase of microplastic contamination in Vietnam is a growing concern due to various domestic, agricultural, and industrial activities. The use of plastic mulch and sludge application in agricultural farmland, textile production, daily consumer items, cleaning agents, and health/personal care products contribute significantly to the increasing microplastic pollution in the aquatic ecosystem. The concentration of microplastics reported in surface water ranged from 0.35 to 519,000 items m-3, with fibers and fragments being the most prevalent shapes. Notably, the high concentration of microplastics was observed in lakes, canals, and megacities such as Ha Noi and Ho Chi Minh City, which poses potential health risks to the local community via drinking-water supply and food chains. As an emerging pollutant, MPs are the transport vectors for contaminants in environmental matrices that act as a carrier of hazardous pollutants, release toxic compounds, and evenly aggregate/accumulate in biota. Recent studies have reported the presence of microplastics in various marine organisms, including fish and shellfish, highlighting the risk of ingestion of these particles by humans and wildlife. Thus, it is imperative to monitor microplastic contamination in the ecosystem to provide helpful information for the government and local communities. Efforts should be taken to reduce microplastic pollution at the source to minimize potential effects on ecological and health safety. This review paper emphasizes the urgent need for further research on microplastic pollution in Vietnam and highlights potential solutions to mitigate this emerging environmental threat. KEYWORKS: single-use plastics; microplastics; ecosystems; plastic waste; health risk; ecological and health safety; pollution mitigation.
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Ecosistema , Contaminantes Ambientales , Animales , Humanos , Microplásticos/toxicidad , Plásticos , Vietnam , Cadena AlimentariaRESUMEN
The production of plastic has exponentially increased in recent years, leading to the release of millions of tons of plastic waste into the environment annually. This waste can break down into smaller micro- and nanoplastics (MNPs) that are toxic and reactive to life forms, including humans. MNPs are particularly concerning for marine biologists and environmental scientists due to their toxic impacts on aquatic organisms, including algae, which are the foundation of the food chain. The review provides a comprehensive overview of the (eco)toxicity assessment of MNPs on aquatic algal communities, highlighting the novel insights gained into the ecotoxicity of various MNPs on algae and the associated health risks for aquatic ecosystems, food chains, and humans. This article also discusses current challenges and future research opportunities to address these challenges, making it a valuable contribution to the field of environmental science. Overall, this work is one of the first efforts to comprehensively assess the effects of MNPs on aquatic algae, emphasizing the significant risks that MNPs pose to essential ecosystems and human health.
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Microplásticos , Contaminantes Químicos del Agua , Humanos , Microplásticos/toxicidad , Contaminantes Químicos del Agua/análisis , Ecosistema , Organismos Acuáticos , Plantas , Plásticos/toxicidadRESUMEN
Gender dysphoria refers to the suffering an individual experiences when his or her sex at birth does not correspond to the expression of his or her gender. Gender-affirmation surgery is a procedure that can alleviate this suffering. For 20 years, GrS Montreal has been Canada's only center dedicated exclusively to this type of surgery. Thanks to its expertise, quality of care, state-of-the-art infrastructure and convalescent home, GrS Montreal receives patients from all over the world. This article describes the particularities of this center and puts into perspective the evolution of this type of surgery.
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Disforia de Género , Cirugía de Reasignación de Sexo , Personas Transgénero , Humanos , Masculino , Femenino , Recién Nacido , Disforia de Género/cirugía , Canadá , Hospitales PrivadosRESUMEN
Background: In Vietnam, cervical cancer is a significant public health concern for women. Unfortunately, despite the availability of the HPV vaccine, low vaccination rates persist. Objectives: This study investigates the discrepancy between urban and rural areas in the willingness to receive HPV vaccination with or without fees. Methods: A cross-sectional study was conducted on a sample of 648 women aged between 15 and 49, living in two urban and two rural Vietnamese districts of Can Tho, between May and December 2021. Results: The overall vaccination rate was 4%, with urban women having a higher rate of 4.9% compared to rural women at 3.1%. Among unvaccinated women, those from rural areas expressed a significantly higher desire to receive the free vaccine (91.4%) than urban women (84.4%). However, the intention to vaccinate declined when rural women and urban women were advised to pay the cost (63.4% and 57.1%, respectively). A strong correlation was found between a positive attitude and intention for vaccination, irrespective of its price or free availability. Education and access to information about the HPV vaccine were also identified as the most significant factors influencing the intention to vaccination among urban and rural women. Conclusion: The low HPV vaccination rates among women aged 15-49 living in both urban and rural regions of Vietnam are a notable public health concern. These outcomes emphasize the critical need for effective programs of vaccine laterization, as an introduction to the offer of affordable and accessible HPV vaccines for women in Can Tho, Vietnam.