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BACKGROUND: The healthcare systems in Asia vary greatly due to the socio-economic and cultural diversities which impact haemophilia management. METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.
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Hemofilia A , Humanos , Hemofilia A/terapia , Hemofilia A/epidemiología , Asia/epidemiología , Prevalencia , Atención a la Salud , Hemofilia B/terapia , Hemofilia B/epidemiologíaRESUMEN
The Asia-Pacific Plasma Leaders' Network (APPLN) plays a crucial role in addressing the regional shortage of plasma-derived medicinal products (PDMPs), particularly in low- and middle-income countries (LMICs). It provides a platform for experts to share their expertise and drive multi-stakeholder collaborations. While several PDMPs are acknowledged by the World Health Organization (WHO) as life-saving therapeutics on the Model List of Essential Medicine for treating various chronic and acute life-threatening diseases, there are still many inadequacies in the availability and affordability of PDMPs. These challenges arise from insufficient domestic supplies of plasma suitable for fractionation, as well as a lack of technical and financial capabilities to implement contract or domestic plasma fractionation programmes. At two separate dialogue forums organized by the APPLN in 2023, experts discussed the unmet needs of PDMPs for individuals living with haemophilia and immunodeficiencies in the region. They also highlighted the limited access to early diagnosis and patient-centred care in several LMICs. To address these issues, there is an urgent need to increase the availability of high-quality domestic plasma for fractionation. Adopting a stepwise approach to utilize unused recovered plasma and establishing contract fractionation programmes could be viable strategies to potentially enhance PDMP availability in LMICs. However, achieving this goal requires improving existing domestic infrastructures for blood collection, implementing adequate policy reforms and fostering competent local leadership. Ultimately, there is no 'one-size-fits-all' strategy for securing safe plasma proteins for all patients in need. Collaborative efforts are essential for achieving progressive self-sufficiency in PDMPs.
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Four previously undescribed compounds named phyllancosides A and B (1 and 2), and phyllancochines A and B (3 and 4) together with ten known compounds (5-14) were isolated from the aerial parts of Phyllanthus cochinchinensis Spreng. Their chemical structures were elucidated on the basis of comprehensive analysis of IR, HR-ESI-MS, 1D and 2D NMR spectra. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) spectra. Compounds 3, 4, and 10 showed antimicrobial activity against E. faecalis, S. aureus, and B. cereus with the MIC values in range of 32-256â µg/mL. Compound 11 inhibited E. faecalis and B. cereus, and 7 inhibited S. aureus with the MIC values in range of 64-128â µg/mL. In addition, compounds 1, 3, 4, 8, and 9 showed significantly NO production inhibitory activity in LPS activated RAW 264.7 cells with IC50 values ranging from 36.57 to 56.34â µM.
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Antiinfecciosos , Lipopolisacáridos , Animales , Ratones , Células RAW 264.7 , Estructura Molecular , Lipopolisacáridos/farmacología , Staphylococcus aureus , Óxido Nítrico , Componentes Aéreos de las Plantas/química , Antiinfecciosos/análisisRESUMEN
Three new oleanane-type triterpene saponins, named camphanosides A-C (1-3), along with five known compounds, chikusetsusaponin IVa (4), spinasaponin A 28-O-glucoside (5), (-)-epicatechin (6), (-)-epicatechin 3-O-gallate (7), and (-)-epigallocatechin 3-O-gallate (8) were isolated from the leaves Camellia phanii Hakoda & Ninh. Their structures were established by 1D and 2D-NMR and mass spectral analysis and chemical methods. Moreover, compounds 1-5 were also evaluated for α-glucosidase inhibitory activity. Compounds 1-3 exhibited moderate α-glucosidase inhibitory activity with IC50 values of 230.7±18.0, 251.4±22.7, and 421.4±25.6â µM, respectively.
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Camellia , Inhibidores de Glicósido Hidrolasas , Glicósidos , Ácido Oleanólico , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Camellia/química , alfa-Glucosidasas/metabolismo , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/aislamiento & purificación , Glicósidos/química , Glicósidos/farmacología , Glicósidos/aislamiento & purificación , Hojas de la Planta/química , Relación Estructura-Actividad , Conformación Molecular , Triterpenos/química , Triterpenos/farmacología , Triterpenos/aislamiento & purificación , Estructura MolecularRESUMEN
A chemical study of the methanol extract of the aerial parts of Achyranthes aspera led to the isolation of four new flavonoid C-glycosides (1-4) along with eight known analogs (5-12). Their structures were elucidated by a combination of spectroscopic data analysis, HR-ESI-MS, 1D and 2D NMR spectra. All the isolates were evaluated their NO production inhibitory activity in LPS-activated RAW264.7 cells. Compounds 2, 4, and 8-11 showed significant inhibition with IC50 values ranging from 25.06 to 45.25â µM, compared to that of the positive control compound, L-NMMA, IC50 value of 32.24â µM, whereas the remaining compounds were weak inhibitory activity with IC50 values over 100â µM. This is the first report of 7 from Amaranthaceae family, and 11 from the genus Achyranthes.
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Achyranthes , Flavonoides , Flavonoides/farmacología , Flavonoides/química , Achyranthes/química , Óxido Nítrico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Glicósidos/farmacología , Glicósidos/química , Estructura MolecularRESUMEN
A chemical investigation of K. heteroclite led to isolation of two new dibenzocyclooctadienes (1 and 2) together with 14 known compounds (3-16) by using multiple chromatographic techniques. New compounds (1 and 2) were obtained and identified by spectroscopic methods (HR-ESI-MS, 1D and 2D NMR, and ECD) as well as by comparison of their experimental data with those reported in the literatures. All the isolates were evaluated for their ability to modulate TNF-α production in lipopolysaccharide (LPS) stimulated RAW264.7 cells. Among them, compound 5 displayed the most inhibition against tumor necrosis factor (TNF)-α production with IC50 value of 6.16±0.14â µM. Whereas, compounds (1, 3, and 6) showed the significant inhibition (IC50 values ranging from 9.41 to 14.54â µM), and compounds (2, 4, 9, 10, 13, 15, and 16) exhibited moderate inhibition (IC50 values ranging from 19.27 to 40.64â µM) toward TNF-α production, respectively.
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Kadsura , Lignanos , Kadsura/química , Factor de Necrosis Tumoral alfa , Lignanos/farmacología , Lignanos/química , Antiinflamatorios/farmacología , Fenoles , Estructura MolecularRESUMEN
One new phenylpropanoid glycoside, tinosinen A (1) and 13 known compounds, tinosinen (2), citrusin B (3), picraquassioside C (4), erythro-guaiacylglycerol-ß-O-4'-coniferyl alcohol (5), erythro-guaiacylglycerol-8-O-4'-(sinapyl alcohol) ether (6), erythro-syringylglycerol-8-O-4'-(sinapyl alcohol) ether (7), seco-isolariciresinol 9-O-D-ß-glucopyranoside (8), tinosposide A (9), pinoresinol-4'-O-ß-D-glucopyranoside (10), syringaresinol-4'-O-ß-D-glucopyranoside (11), pinoresinol (12), syringaresinol (13), and lirioresino-ß-dimethyl ether (14) were isolated from the stems of Tinospora sinensis (Lour.) Merr. Their structures were established by detailed spectroscopic studies and comparisons with those reported in the literature. Compound 13 showed significant inhibitory NO production (IC50 value of 38.53 ± 1.90 µM) in RAW264.7 macrophages, LPS-stimulated. Compounds 3-7, 11, 12, and 14 inhibited NO production with IC50 values ranging from 38.53 to 99.07 µM.
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Tinospora , Tinospora/química , Óxido Nítrico , ÉteresRESUMEN
A new furostane saponin, ramosaponin (1), and four known furostane saponins, protodioscin (2), dehydrotomatoside (3), (25 R)-26-O-(ß-D-glucopyranosyl)-furost-5-ene-3ß,22α,26-triol 3-O-ß-D-glucopyranosyl-(1â4)-ß-D-galactopyranoside (4), and anguivioside A (5) were isolated from the methanol extract of Allium ramosum seeds. Their structures were identified based on spectroscopic evidence and comparison with those reported in the literature. All compounds were evaluated for reduction of lipid accumulation in HepG2 cell line. As a result, compound 1 showed significant lipid accumulation inhibitory activity with an IC50 value of 64.32 ± 3.87 µM.
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Allium , Saponinas , Allium/química , Saponinas/farmacología , Saponinas/química , Extractos Vegetales/química , Semillas , Lípidos , Estructura MolecularRESUMEN
BACKGROUND: An endotracheal tube cuff pressure between 20 and 30 cmH2O is recommended to prevent ventilator-associated respiratory infection (VARI). We aimed to evaluate whether continuous cuff pressure control (CPC) was associated with reduced VARI incidence compared with intermittent CPC. METHODS: We conducted a multicenter open-label randomized controlled trial in intensive care unit (ICU) patients within 24 hours of intubation in Vietnam. Patients were randomly assigned 1:1 to receive either continuous CPC using an automated electronic device or intermittent CPC using a manually hand-held manometer. The primary endpoint was the occurrence of VARI, evaluated by an independent reviewer blinded to the CPC allocation. RESULTS: We randomized 600 patients; 597 received the intervention or control and were included in the intention to treat analysis. Compared with intermittent CPC, continuous CPC did not reduce the proportion of patients with at least one episode of VARI (74/296 [25%] vs 69/301 [23%]; odds ratio [OR] 1.13; 95% confidence interval [CI] .77-1.67]. There were no significant differences between continuous and intermittent CPC concerning the proportion of microbiologically confirmed VARI (OR 1.40; 95% CI .94-2.10), the proportion of intubated days without antimicrobials (relative proportion [RP] 0.99; 95% CI .87-1.12), rate of ICU discharge (cause-specific hazard ratio [HR] 0.95; 95% CI .78-1.16), cost of ICU stay (difference in transformed mean [DTM] 0.02; 95% CI -.05 to .08], cost of ICU antimicrobials (DTM 0.02; 95% CI -.25 to .28), cost of hospital stay (DTM 0.02; 95% CI -.04 to .08), and ICU mortality risk (OR 0.96; 95% CI .67-1.38). CONCLUSIONS: Maintaining CPC through an automated electronic device did not reduce VARI incidence. CLINICAL TRIAL REGISTRATION: NCT02966392.
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Neumonía Asociada al Ventilador , Infecciones del Sistema Respiratorio , Humanos , Intubación Intratraqueal/efectos adversos , Tiempo de Internación , Neumonía Asociada al Ventilador/epidemiología , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/prevención & control , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/prevención & control , Ventiladores MecánicosRESUMEN
Developmental and epileptic encephalopathies (DEE) refers to a group of rare and severe neurodevelopmental disorders where genetic etiologies can play a major role. This study aimed to elucidate the genetic etiologies of a cohort of 53 Vietnamese patients with DEE. All patients were classified into known electroclinical syndromes where possible. Exome sequencing (ES) followed by a targeted analysis on 294 DEE-related genes was then performed. Patients with identified causative variants were followed for 6 months to determine the impact of genetic testing on their treatment. The diagnostic yield was 38.0% (20/53), which was significantly higher in the earlier onset group (<12 months) than in the later onset group (≥12 months). The 19 identified variants belonged to 11 genes with various cellular functions. Genes encoding ion channels especially sodium voltage-gated channel were the most frequently involved. Most variants were missense variants and located in key protein functional domains. Four variants were novel and four had been reported previously but in different phenotypes. Within 6 months of further follow-up, treatment changes were applied for six patients based on the identified disease-causing variants, with five patients showing a positive impact. This is the first study in Vietnam to analyze the genetics of DEE. This study confirms the strong involvement of genetic etiologies in DEE, especially early onset DEE. The study also contributes to clarify the genotype-phenotype correlations of DEE and highlights the efficacy of targeted ES in the diagnosis and treatment of DEE.
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Encefalopatías , Exoma , Pueblo Asiatico , Encefalopatías/genética , Exoma/genética , Pruebas Genéticas , Humanos , Mutación , Fenotipo , VietnamRESUMEN
Astronauts are always faced with serious health problems during prolonged spaceflights. Previous studies have shown that weightlessness significantly affects the physiological function of female astronauts, including a change in reproductive hormones and ovarian cells, such as granulosa and theca cells. However, the effects of microgravity on these cells have not been well characterized, especially in granulosa cells. This study aimed to investigate the effects of simulated microgravity (SMG) on the proliferation and morphology of porcine granulosa cells (pGCs). pGC proliferation from the SMG group was inhibited, demonstrated by the reduced O.D. value and cell density in the WST-1 assay and cell number counting. SMG-induced pGCs exhibited an increased ratio of cells in the G0/G1 phase and a decreased ratio of cells in the S and G2/M phase. Western blot analysis indicated a down-regulation of cyclin D1, cyclin-dependent kinase 4 (cdk4), and cyclin-dependent kinase 6 (cdk6), leading to the prevention of the G1-S transition and inducing the arrest phase. pGCs under the SMG condition showed an increase in nuclear area. This caused a reduction in nuclear shape value in pGCs under the SMG condition. SMG-induced pGCs exhibited different morphologies, including fibroblast-like shape, rhomboid shape, and pebble-like shape. These results revealed that SMG inhibited proliferation and induced morphological changes in pGCs.
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Células de la Granulosa/citología , Células de la Granulosa/fisiología , Simulación de Ingravidez , Ingravidez , Citoesqueleto de Actina/metabolismo , Animales , Biomarcadores , Ciclo Celular , Proliferación Celular , Células Cultivadas , Femenino , PorcinosRESUMEN
The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.
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Aciltransferasas/genética , Discapacidades del Desarrollo/genética , Proteínas Ligadas a GPI/deficiencia , Malformaciones del Sistema Nervioso/genética , Espasmos Infantiles/genética , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Preescolar , Discapacidades del Desarrollo/fisiopatología , Facies , Femenino , Pérdida Auditiva/genética , Pérdida Auditiva/fisiopatología , Humanos , Lactante , Riñón/anomalías , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/fisiopatología , Fenotipo , Espasmos Infantiles/fisiopatología , Trastornos de la Visión/genética , Trastornos de la Visión/fisiopatologíaRESUMEN
BACKGROUND: Approximately 6% of children hospitalized with severe falciparum malaria in Africa are also bacteremic. It is therefore recommended that all children with severe malaria should receive broad-spectrum antibiotics in addition to parenteral artesunate. Empirical antibiotics are not recommended currently for adults with severe malaria. METHODS: Blood cultures were performed on sequential prospectively studied adult patients with strictly defined severe falciparum malaria admitted to a single referral center in Vietnam between 1991 and 2003. RESULTS: In 845 Vietnamese adults with severe falciparum malaria admission blood cultures were positive in 9 (1.07%: 95% confidence interval [CI], .37-1.76%); Staphylococcus aureus in 2, Streptococcus pyogenes in 1, Salmonella Typhi in 3, Non-typhoid Salmonella in 1, Klebsiella pneumoniae in 1, and Haemophilus influenzae type b in 1. Bacteremic patients presented usually with a combination of jaundice, acute renal failure, and high malaria parasitemia. Four bacteremic patients died compared with 108 (12.9%) of 836 nonbacteremic severe malaria patients (risk ratio, 3.44; 95% CI, 1.62-7.29). In patients withâ >20% parasitemia the prevalence of concomitant bacteremia was 5.2% (4/76; 95% CI, .2-10.3%) compared with 0.65% (5/769; 0.08-1.2%) in patients withâ <20% parasitemia, a risk ratio of 8.1 (2.2-29.5). CONCLUSIONS: In contrast to children, the prevalence of concomitant bacteremia in adults with severe malaria is low. Administration of empirical antibiotics, in addition to artesunate, is warranted in the small subgroup of patients with very high parasitemias, emphasizing the importance of quantitative blood smear microscopy assessment, but it is not indicated in most adults with severe falciparum malaria.
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Antimaláricos , Artemisininas , Bacteriemia , Malaria Falciparum , Malaria , Adulto , África , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Bacteriemia/complicaciones , Bacteriemia/tratamiento farmacológico , Bacteriemia/epidemiología , Niño , Humanos , Malaria/tratamiento farmacológico , Malaria Falciparum/complicaciones , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Plasmodium falciparum , Vietnam/epidemiologíaRESUMEN
Tuberculous meningitis (TBM) is the most lethal form of tuberculosis infection, characterized by a dysregulated immune response that frequently leads to neurologic injury and death despite the best available treatment. The mechanisms driving the inflammatory response in TBM are not well understood. To gain insights into these mechanisms, we used a lipid mediator-profiling approach to investigate the regulation of a novel group of host protective mediators, termed specialized proresolving mediators (SPMs), in the cerebrospinal fluid (CSF) of adults with TBM. Herein, using CSF from patients enrolled into a randomized placebo-controlled trial of adjunctive aspirin treatment, we found distinct lipid mediator profiles with increasing disease severity. These changes were linked with an up-regulation of inflammatory eicosanoids in patients with severe TBM and a decrease in the production of a number of SPMs. CSF proresolving mediator concentrations were also associated with 80-d survival. In survivors, we found a significant increase in proresolving mediator concentrations, including the lipoxygenase 5-derived 13-series resolvin (RvT)2, RvT4, and 15-epi-lipoxin B4, compared with those who died. Of note, treatment of patients with high-dose aspirin led to a decrease in the concentrations of the prothrombic mediator thromboxane A2, reduced brain infarcts, and decreased death in patients with TBM. Together, these findings identify a CSF SPM signature that is associated with disease severity and 80-d mortality in TBM.-Colas, R. A., Nhat, L. T. H., Thuong, N. T. T., Gómez, E. A., Ly, L., Thanh, H. H., Mai, N. T. H., Phu, N. H., Thwaites, G. E., Dalli, J. Proresolving mediator profiles in cerebrospinal fluid are linked with disease severity and outcome in adults with tuberculous meningitis.
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Antituberculosos/uso terapéutico , Mediadores de Inflamación/líquido cefalorraquídeo , Tuberculosis Meníngea/líquido cefalorraquídeo , Tuberculosis Meníngea/tratamiento farmacológico , Adulto , Aspirina/administración & dosificación , Dexametasona/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Masculino , Placebos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Tuberculosis Meníngea/patologíaRESUMEN
Cobalt oxide clusters, ConOm+ (5 ≤ n ≤ 9 and 4 ≤ m ≤ 13), are produced by laser vaporization and studied by time-of-flight mass spectrometry. Specific stoichiometries are mass separated and photofragmented using 355 nm laser light. The preferred fragmentation channels of m = n-1, m = n-2, and m ≥ n species are investigated. Loss of oxygen molecules is the favorable dissociation channel of m ≥ n clusters. While ConOn-2+ clusters decay via the loss of a Co atom, the photofragmentation behavior of ConOn-1+ species interestingly can be divided into two regimes: the n ≤ 6 clusters tend to lose an oxygen atom, but for n > 6 they favorably dissociate via the loss of a cobalt atom. The geometric structures of selected m = n - 2 species are studied using density functional theory calculations. Dissociation energies for different evaporation channels are calculated and thermodynamically favorable channels are found to correspond to the experimental observations.
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Synthesis of reduced graphene oxide/TiO2 nanotubes (rGO/TNTs) composite is being attended. However, the synthesis of rGO/TNTs composite directly from graphite oxide with a greener approach is still challenging. In this study, we directly synthesized rGO/TNTs composite by a simple method from graphite oxide and titanium dioxide nanotube (TNTs) powder without involving any assistant agents. The formation of the graphene oxide (GO) was confirmed by X-ray diffraction (XRD) pattern, transmission electron microscope (TEM) image, Fourier-transform infrared (FTIR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). Besides, photoluminescence analysis (PL) was conducted to determine the defects of materials. The methylene blue (MB) photodegradation efficiency under visible light of rGO/TNTs composite achieved 80% after 180 min. In addition, the key of the photocatalytic mechanism of rGO/TNTs under visible light was systematically investigated via trapping experiments.
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Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection. Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/). Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone. Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care.
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Coinfección/mortalidad , Infecciones por VIH/complicaciones , Modelos Teóricos , Tuberculosis Meníngea/mortalidad , Adulto , Factores de Edad , Coinfección/microbiología , Coinfección/virología , Femenino , Infecciones por VIH/microbiología , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/aislamiento & purificación , Nomogramas , Estudios Observacionales como Asunto , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Factores de Tiempo , VietnamRESUMEN
Dengue can cause neurologic complications in addition to the more common manifestations of plasma leakage and coagulopathy. Posterior reversible encephalopathy syndrome has rarely been described in dengue, although the pathophysiology of endothelial dysfunction likely underlies both. We describe a case of dengue-associated posterior reversible encephalopathy syndrome and discuss diagnosis and management.
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Dengue/complicaciones , Síndrome de Leucoencefalopatía Posterior/etiología , Femenino , Humanos , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Síndrome de Leucoencefalopatía Posterior/diagnóstico por imagen , Síndrome de Leucoencefalopatía Posterior/tratamiento farmacológico , Vietnam/epidemiologíaRESUMEN
There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h-1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h-1 The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144-168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.
Asunto(s)
Anfotericina B/farmacocinética , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Ácido Desoxicólico/farmacocinética , Meningitis Criptocócica/tratamiento farmacológico , Meningitis Criptocócica/metabolismo , Adulto , Anciano , Anfotericina B/líquido cefalorraquídeo , Anfotericina B/uso terapéutico , Antifúngicos/líquido cefalorraquídeo , Ácido Desoxicólico/líquido cefalorraquídeo , Ácido Desoxicólico/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Masculino , Meningitis Criptocócica/líquido cefalorraquídeo , Persona de Mediana Edad , Método de Montecarlo , Estudios Prospectivos , Adulto JovenRESUMEN
Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h-1, from the peripheral to central compartment, 18.10 (8.25) h-1, from the central to CNS compartment, 35.43 (13.74) h-1, and from the CNS to central the compartment, 28.63 (10.03) h-1 Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg · h/liter in plasma (AUCplasma) and 982.9 (range, 781.0 to 1,185.9) mg · h/liter in cerebrospinal fluid (AUCCSF) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUCCSF/AUCplasma was 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution for C. neoformans The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.