Anti-Dengue Screening on Several Vietnamese Medicinal Plants: Experimental Evidences and Computational Analyses.

Worldwide, medicinal plants have been known for economic and geographical advantages, thus possibly holding potentiality against dengue hemorrhagic fever. The methanol/water extracts from different parts of fourteen Vietnam-based plant species were subjected for experimental screening on anti-dengue activity using baby hamster kidney cells (BHK21) and plaque reduction neutralisation test (PRNT). Firstly, the methanol/water extracts were tested against serotype dengue virus DENV-1. Seven out from nineteen extracts show the PRNT50 values less than 31.25 µg/mL. Four of the above extracts namely from Euphorbia hirta, Cordyline terminalis, Carica papaya, and Elaeagnus latifolia were chosen for testing against the serotype DENV-2. All of them exhibit good activity with the PRNT50 values less than 31.25 µg/ml, which were further fractionated to obtain hexane, ethyl acetate and butanol fractions. Anti-dengue virus activity of the fractions against four serotypes DENV-1, -2, -3 and -4 was evaluated. As results, the ethyl acetate fraction of Elaeagnus latifolia is highly active against all four serotype viruses. The structural formulae of its nine constituents were input for molecular docking simulation. The docking-based order for static inhibitability is 6-3L6P>7-3L6P>9-3L6P>2-3L6P>3-3L6P≈5-3L6P>9-3L6P>1-3L6P>8-3L6P; QSARIS-based analysis reveals the biocompatibility of the most promising ligands (4-7); ADMET-based analysis expects their pharmacological suitability. Exceptional finding on 2-3LKW hydrophilic interaction at Lys43 (with the associated Gibbs free energy of -10.3 kcal mol-1 ) raises an open explanation for inhibitory effects. The results encourage further investigations for more in-depth mechanisms and drug development, such as in vitro enzyme assays or in vitro clinical trials with natural substances from E. latifolia.

The efficacy, safety and immunogenicity Nanocovax: results of a randomized, double-blind, placebo-controlled Phase 3 trial.

BackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, (NCT04683484) the vaccine was found to be safe and induce a robust immune response in healthy adult participants. MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19. FindingsUp to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax. Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1. Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant. InterpretationNanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%. FundingResearch was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788.

The impact of hyperandrogenism on the outcomes of ovulation induction using gonadotropin and intrauterine insemination in women with polycystic ovary syndrome / 대한생식의학회지

Objective@#This study aimed to investigate the impact of hyperandrogenism (HA) on the outcomes of ovulation induction (OI) using gonadotropin and intrauterine insemination (IUI) in patients with polycystic ovary syndrome (PCOS). @*Methods@#This was a retrospective cohort study including 415 patients undergoing OI using gonadotropin and IUI treatment between January 2018 and December 2020 at a single infertility center. Baseline characteristics, clinical and laboratory parameters, and pregnancy outcomes were investigated. @*Results@#Among the study population, there were 105 hyperandrogenic (25.3%) and 310 non-hyperandrogenic patients (74.7%). The live birth rate was lower in the HA group than in the non-HA group, but this difference did not reach statistical significance due to the limited sample size (14.3% vs. 21.0%, relative risk=0.68; 95% CI, 0.41–1.14, p=0.153). No predictive factors for live birth were identified through logistic regression analysis. @*Conclusion@#HA did not negatively affect the outcomes of OI using gonadotropin and IUI cycles in Vietnamese women with PCOS. The result may not be applicable elsewhere due to the large variation in the characteristics of women with PCOS across races and populations.

Prevalence of Advanced HIV Disease, Cryptococcal Antigenemia, and Suboptimal Clinical Outcomes Among Those Enrolled in Care in Vietnam.

BACKGROUND: People living with advanced HIV disease are at high risk of morbidity and mortality. We assessed the prevalence of cryptococcal antigenemia (CrAg) and clinical outcomes among patients newly presenting with CD4 ≤100 cells/µL in Vietnam. SETTING: Twenty-two public HIV clinics in Vietnam. METHODS: During August 2015-March 2017, antiretroviral therapy (ART)-naïve adults presenting for care with CD4 ≤100 cells/µL were screened for CrAg. Those who consented to study enrollment were followed up for up to 12 months and assessed for clinical outcomes. RESULTS: Of 3504 patients with CD4 results, 1354 (38.6%) had CD4 ≤100 cells/µL, of whom 1177 (86.9%) enrolled in the study. The median age was 35 years (interquartile range 30-40); 872 (74.1%) of them were men, and 892 (75.8%) had CD4 <50 cells/µL. Thirty-six patients (3.1%) were CrAg-positive. Overall, 1151 (97.8%) including all who were CrAg-positive initiated ART. Of 881 patients (76.5%) followed up for ≥12 months, 623 (70.7%) were still alive and on ART at 12 months, 54 (6.1%) had transferred to nonstudy clinics, 86 (9.8%) were lost to follow-up, and 104 (11.8%) had died. Among all 1177 study participants, 143 (12.1%) died, most of them (123, 86.0%) before or within 6 months of enrollment. Twenty-seven patients (18.9%) died of pulmonary tuberculosis, 23 (16.1%) died of extrapulmonary tuberculosis, 8 (5.6%) died of Talaromyces marneffei infection, and 6 (4.2%) died of opioid overdose. Eight deaths (5.8%) occurred among the 36 CrAg-positive individuals. CONCLUSIONS: Late presentation for HIV care was common. The high mortality after entry in care calls for strengthening of the management of advanced HIV disease.

Chevalierinol A and B, two new neolignan sesquiterpenoids from Magnolia chevalieri.

Two new neolignan sesquiterpenoids, chevalierinol A (1) and chevalierinol B (2), were isolated from the ethyl acetate extract of Magnolia chevalieri leaves, together with twelve known compounds (3-14). Their structures were elucidated by analysis of spectroscopic data including 1D, 2D and mass spectra and compared with the reported data. Compounds 1, 3, 4, 6, 7, 10 were evaluated for their inhibitory effect against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophage cells.

Modeling α-Synuclein Propagation with Preformed Fibril Injections

The aggregation of α-synuclein (α-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Postmortem analyses of α-syn pathology, especially that of PD, have suggested that aggregates progressively spread from a few discrete locations to wider brain regions. The neuron-to-neuron propagation of α-syn has been suggested to be the underlying mechanism by which aggregates spread throughout the brain. Many cellular and animal models has been created to study cell-to-cell propagation. Recently, it has been shown that a single injection of preformed fibrils (PFFs) made of recombinant α-syn proteins into various tissues and organs of many different animal species results in widespread α-syn pathology in the central nervous system (CNS). These PFF models have been extensively used to study the mechanism by which aggregates spread throughout the brain. Here, we review what we have learned from PFF models, describe the nature of PFFs and the neuropathological features, neurophysiological characteristics, and behavioral outcomes of the models.

Exploring characteristics of the corner sections of a domain wall trap nanostructure with the two-field direction method.

A 2D polycrystalline permalloy domain wall trap nanostructure with a thickness of 20 nm was studied. The structure was alternatively designed and patterned using QCAD/L-Edit software and focused-ion beam technique. With this design, a magnetic domain wall can be created and propagated with a sequence of two-field directions in a Lorentz microscopy. The trap consists of two horizontal nanowires and three 90°-tilted ones. Each nanowire has an in-plane dimension of 200 × 1000 nm2. The trap corners were curved to allow a created domain wall that easily moves through the structure. A head-to-head domain-wall aims to create using a continuous field, this created wall can be propagated in the trap using a sequence of two-field directions. The designed trap was simulated using the Object Oriented Micro-Magnetic Framework software. Lorentz microscopy and simulation results indicate that the propagation of a domain wall is strongly affected by the precise roughness behavior of the trap elements. Domain wall pinning and transformation of wall chirality are sensitively correlated to the corner sections of the trap structure and field directions at a certain regime. Using the two-field direction method enables us to explore characteristics of the corner sections of the patterned trap nanostructure. This study is vital to fabricate an optimal nano-trap which supports a reproducible domain wall motion. This also suggests a useful method for the domain wall propagation using sequences of two-field directions. This work provides a better understanding of wall creation and propagation in polycrystalline permalloy curved nanowires which are of interest for concepts of nonvolatile data storage devices.

Comparison of HIV Testing among Children and Adults with Tuberculosis, Vietnam.

HIV testing among persons with tuberculosis (TB) results in high-yield identification of persons infected with HIV. To evaluate differences in HIV testing among children versus adults with TB in Vietnam, we collected and analyzed age-disaggregated facility and aggregated provincial data from the National Tuberculosis Program. HIV testing was incompletely documented for >70% of children, whereas adult testing data were >90% complete. Standardized training of personnel for universal HIV testing and documentation for children with TB could improve HIV case-detection and permit linking of children with HIV to antiretroviral treatment to prevent morbidity and mortality.

Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A.

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 µg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 µg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-µg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 µg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 µg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 µg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.

A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam.

BACKGROUND: Drug resistant typhoid fever is a major clinical problem globally. Many of the first line antibiotics, including the older generation fluoroquinolones, ciprofloxacin and ofloxacin, are failing. OBJECTIVES: We performed a randomised controlled trial to compare the efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20 mg/kg/day) as a once daily oral dose for 7 days for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. METHODS: An open-label multi-centre randomised trial with pre-specified per protocol analysis and intention to treat analysis was conducted. The primary outcome was fever clearance time, the secondary outcome was overall treatment failure (clinical or microbiological failure, development of typhoid fever-related complications, relapse or faecal carriage of S. typhi). PRINCIPAL FINDINGS: We enrolled 358 children and adults with suspected typhoid fever. There was no death in the study. 287 patients had blood culture confirmed typhoid fever, 145 patients received gatifloxacin and 142 patients received azithromycin. The median FCT was 106 hours in both treatment arms (95% Confidence Interval [CI]; 94-118 hours for gatifloxacin versus 88-112 hours for azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.80-1.26]). Overall treatment failure occurred in 13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43-2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were resistant to nalidixic acid and 58% (153/263) were multidrug resistant. CONCLUSIONS: Both antibiotics showed an excellent efficacy and safety profile. Both gatifloxacin and azithromycin can be recommended for the treatment of typhoid fever particularly in regions with high rates of multidrug and nalidixic acid resistance. The cost of a 7-day treatment course of gatifloxacin is approximately one third of the cost of azithromycin in Vietnam. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN67946944.

Tetrodotoxin for moderate to severe cancer pain: a randomized, double blind, parallel design multicenter study.

Cancer pain is a serious public health issue and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker. This randomized, placebo-controlled, parallel design study of subcutaneous tetrodotoxin, in patients with moderate or severe unrelieved cancer pain persisting despite best available treatment, involved 22 centers across Canada. The design called for tetrodotoxin administered subcutaneously over Days 1-4 with a period of observation to Day 15 or longer. All patients could enroll into an open-label extension efficacy and safety trial. The primary endpoint was the proportion of analgesic responders in each treatment arm. Eighty-two patients were randomized, and results on 77 were available for analysis. There was a nonstatistically significant trend toward more responders in the active treatment arm based on the primary endpoint (pain intensity difference). However, analysis of secondary endpoints, and an exploratory post hoc analysis, suggested there may be a robust analgesic effect if a composite endpoint is used, including either fall in pain level, or fall in opioid dose, plus improvement in quality of life. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but one patient experienced a serious, adverse event, truncal and gait ataxia. This trial suggests tetrodotoxin may potentially relieve moderate to severe, treatment-resistant cancer pain in a large proportion of patients, and often for prolonged periods following treatment, but further study is warranted using a composite primary endpoint.

An open-label, multi-dose efficacy and safety study of intramuscular tetrodotoxin in patients with severe cancer-related pain.

Cancer pain is a prevalent and serious public health issue, and more effective treatments are needed. This study evaluates the analgesic activity of tetrodotoxin, a highly selective sodium channel blocker, in cancer pain. A Phase IIa, open-label, multicenter, dose-escalation study of intramuscular tetrodotoxin was conducted in patients with severe, unrelieved cancer pain. The study design called for six ascending dose levels of intramuscular tetrodotoxin, administered over a four-day treatment period in hospitalized patients, with six patients to be enrolled within each successive dose level. Twenty-four patients underwent 31 courses of treatment at doses ranging from 15 to 90 microg daily, administered in divided doses, over four days. Most patients described transient perioral tingling or other mild sensory phenomena within about an hour of each treatment. Nausea and other toxicities were generally mild, but two patients experienced a serious adverse event, truncal and gait ataxia, that resolved over days. Seventeen of 31 treatments resulted in clinically meaningful reductions in pain intensity, and relief of pain persisted for up to two weeks or longer. Two patients had opioids held due to narcosis concurrent with relief of pain. Somatic, visceral, or neuropathic pain could all respond, but it was not possible to predict which patients were more likely to have an analgesic effect. Tetrodotoxin was overall safe. It effectively relieved severe, treatment-resistant cancer pain in the majority of patients and often for prolonged periods after treatment. It may have a novel mechanism of analgesic effect. Further study is warranted.