Placoisoflavones A and B, two new cytotoxic isoflavonoids from Placolobium vietnamense N.D.Khôi & Yakovlev.

Two previously unreported isoflavonoids, placoisoflavones A and B (1 and 2), along with five known compounds, calopogonium isoflavone B (3), jamaicin (4), 6-methoxycalopogonium isoflavone A (5), vestitol (6), and caviunin (7) have been isolated from the stems of Placolobium vietnamense N.D.Khôi & Yakovlev. The structures of all isolated compounds were fully characterized using spectroscopic data and comparison with the previous literature. The cytotoxicity of all isolated compounds was evaluated against HepG2 cell line, and compound 1 showed the most potent cytotoxicity with an IC50 value of 8.0 µM.

Integrin α5ß1 contributes to cell fusion and inflammation mediated by SARS-CoV-2 spike via RGD-independent interaction.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infects host cells by engaging its spike (S) protein with human ACE2 receptor. Recent studies suggest the involvement of integrins in SARS-CoV-2 infection through interaction with the S protein, but the underlying mechanism is not well understood. This study investigated the role of integrin α5ß1, which recognizes the Arg-Gly-Asp (RGD) motif in its physiological ligands, in S-mediated virus entry and cell-cell fusion. Our results showed that α5ß1 does not directly contribute to S-mediated cell entry, but it enhances S-mediated cell-cell fusion in collaboration with ACE2. This effect cannot be inhibited by the putative α5ß1 inhibitor ATN-161 or the high-affinity RGD-mimetic inhibitor MK-0429 but requires the participation of α5 cytoplasmic tail (CT). We detected a direct interaction between α5ß1 and the S protein, but this interaction does not rely on the RGD-containing receptor binding domain of the S1 subunit of the S protein. Instead, it involves the S2 subunit of the S protein and α5ß1 homo-oligomerization. Furthermore, we found that the S protein induces inflammatory responses in human endothelial cells, characterized by NF-κB activation, gasdermin D cleavage, and increased secretion of proinflammatory cytokines IL-6 and IL-1ß. These effects can be attenuated by the loss of α5 expression or inhibition of the α5 CT binding protein phosphodiesterase-4D (PDE4D), suggesting the involvement of α5 CT and PDE4D pathway. These findings provide molecular insights into the pathogenesis of SARS-CoV-2 mediated by a nonclassical RGD-independent ligand-binding and signaling function of integrin α5ß1 and suggest potential targets for antiviral treatment.

New prenyl flavanone and diarylbutanol from Uvaria siamensis stem bark and their α-glucosidase inhibitory activity.

One new prenyl flavanone (1), (2S)-8-prenyl-5,6-dihydroxy-7-methoxyflavanone, and one new diarylbutanol (2), (7'S)-3'-hydroxy-linderagatin-A, were isolated from the stem bark of Uvaria siamensis (Annonaceae), along with five known compounds, eriodictyol (3), quercetin (4), paprazine (5), N-trans-caffeoyltyramine (6), and N-trans-feruloyltyramine (7). Their structures were determined through extensive spectroscopic analyses and comparison with the literature. The α-glucosidase inhibitory potential of 1-7 was evaluated. Compound 6 showed the highest inhibitory activity against α-glucosidase and exhibited superior potency compared to the positive control, with an IC50 value of 0.12 µM.

A theranostic abscisic acid-based molecular glue.

Molecular glues, capable of selectively controlling the interactions between specific pairs or groups of proteins and the associated downstream effects, have become a promising strategy for manipulating cellular functions and developing novel therapies for human diseases. Theranostics with both diagnostic and therapeutic capabilities acting at disease sites has become a powerful tool to achieve both functions simultaneously with high precision. To selectively activate molecular glues at the desired site and monitor the activation signals at the same time, here we report an unprecedented theranostic modular molecular glue platform integrating signal sensing/reporting and chemically induced proximity (CIP) strategies. We have demonstrated for the first time the integration of imaging and activation capacity with a molecular glue on the same platform to create a theranostic molecular glue. A theranostic molecular glue ABA-Fe(ii)-F1 was rationally designed by conjugating a NIR fluorophore dicyanomethylene-4H-pyran (DCM) with a CIP inducer abscisic acid (ABA) using a unique carbamoyl oxime linker. We have also engineered a new version of ABA-CIP with an enhanced ligand-responding sensitivity. We have validated that the theranostic molecular glue can sense Fe2+ and produce turn-on NIR fluorescence for monitoring as well as releasing the active inducer ligand to control cellular functions including gene expression and protein translocation. This novel molecular glue strategy paves the way to building a new class of molecular glues with theranostic capacity for research and biomedical applications.

ModAsian FINDRISC as a Screening Tool for People with Undiagnosed Type 2 Diabetes Mellitus in Vietnam: A Community-Based Cross-Sectional Study.

Purpose: Our study aims to evaluate the risk of developing type 2 diabetes mellitus in the next 10 years using ModAsian FINDRISC and additionally explore associated factors among the Vietnam population. Participants and Methods: A cross-sectional study was conducted on 2258 participants aged 25 years old or above in Thua Thien Hue Province, Vietnam. The sample size is calculated based on the estimated sensitivity, and participants were randomly selected from different geographical and socio-economic areas. All participants were thoroughly medically examined, taking blood lipid profile and fasting blood glucose, taking blood pressure, anthropometric indexes, 12-lead electrocardiogram, and behavioral factors were investigated using the Vietnamese version of the WHO STEPS toolkit. The risk of developing T2DM was made based on the ModAsian FINDRISC. Results: The incidence of developing type 2 diabetes mellitus among the study population was 4.21%. The group with a high or very high risk of developing type 2 diabetes mellitus in the next 10 years accounted for 2.52%. Body mass index (AUC = 0.840, 95% CI: 0.792-0.888), waist circumference (AUC = 0.824, 95% CI: 0.777-0.871), family history of diabetes mellitus (AUC = 0.751, 95% CI = 0.668-0.833), and history of antihypertensive medication use regularly (AUC = 0.708, 95% CI: 0.632-0.784) are the most associated factors of the ModAsian FINDRISC. Residential location (OR = 5.62, 95% CI: 1.91-16.54) and occupational status (OR = 0.35, 95% CI: 0.20-0.62) were significant factors associated with a high and very high risk of developing type 2 diabetes mellitus in the next 10 year. Conclusion: Screening for the risk of type 2 diabetes mellitus and implementing intervention programs focusing on controlling weight, waist circumference, and blood pressure are essential for reducing type 2 diabetes mellitus incidence and burden in Vietnam.

Comparing combined laser iridoplasty and surgical iridectomy with trabeculectomy in treatment of refractory acute primary angle closure without significant cataract: a randomized controlled trial.

OBJECTIVES: To compare the safety and efficacy of combined laser iridoplasty followed by surgical iridectomy (LI-SI) versus trabeculectomy in the management of medically unresponsive acute primary angle closure (APAC) with minimal cataract. PATIENTS AND METHODS: This was a randomized controlled trial conducted among patients with medically unresponsive APAC without significant cataract. Study participants were randomized into: LI-SI or unaugmented trabeculectomy. Primary outcome of the study was the rate of post-operative surgical complications in the first 3 months after surgery. Secondary outcome assessed at 1 year was whether treatment was completely successful (IOP < 21 mmHg without IOP lowering drops), or partially successful (IOP < 21 mmHg with IOP lowering drops). Failure was defined as IOP ≥ 21 mmHg with IOP lowering drops. RESULTS: The study included 67 eyes of 67 patients (59 females/8 males = 7.4/1) who were randomized into 2 groups: LI-SI (Group 1, 37 eyes), and trabeculectomy (Group 2, 30 eyes). There was no statistical difference between the two groups at baseline. Overall, there were more post-operative complications in Group 1 versus Group 2 (45.9% versus 33.3% - p = 0.23), although all responded well to medical treatment and resolved without sequelae. Complete success was found in 97.1% (34/35 eyes) in Group 1 and 92.6% in group 2 (p = 0.19, Fisher's exact test). CONCLUSIONS: There was a higher rate of post-operative complications after LI-SI compared to trabeculectomy performed for medically unresponsive APAC with minimal cataract. Both procedures had similar surgical outcomes at 1 year.

Opportunities and challenges for the development of M1 muscarinic receptor positive allosteric modulators in the treatment for neurocognitive deficits.

Targeting allosteric sites of M1 muscarinic acetylcholine receptors (M1 receptors) is a promising strategy to treat neurocognitive disorders, such as Alzheimer's disease and schizophrenia. Indeed, the last two decades have seen an impressive body of work focussing on the design and development of positive allosteric modulators (PAMs) for the M1 receptor. This has led to the identification of a structurally diverse range of highly selective M1 PAMs. In preclinical models, M1 PAMs have shown rescue of cognitive deficits and improvement of endpoints predictive of symptom domains of schizophrenia. Yet, to date only a few M1 PAMs have reached early-stage clinical trials, with many of them failing to progress further due to on-target mediated cholinergic adverse effects that have plagued the development of this class of ligand. This review covers the recent preclinical and clinical studies in the field of M1 receptor drug discovery for the treatment of Alzheimer's disease and schizophrenia, with a specific focus on M1 PAM, highlighting both the undoubted potential but also key challenges for the successful translation of M1 PAMs from bench-side to bedside.

Two new dimethylpyranoflavanones from the roots of Melodorum fruticosum.

Two previously unreported dimethylpyranoflavanones, pyronomelodorones A and B (1 and 2), along with five known compounds, 7-O-methyldihydrowogonin (3), 5,6,7-trimethoxyflavanone (4), 5,6-dihydroxy-7-methoxy-dihydroflavone (5), 5,7,8-trimethoxydihydroflavone (6), and pinostrobin (7), were isolated from the roots of Melodorum fruticosum. The structures of all isolates were fully characterized using spectroscopic data and comparison with the previous literature. All isolates were evaluated for their in vitro α-glucosidase inhibition and their cytotoxicity against KB, HepG2, and MCF7 cell lines. Among the isolates, compound 1 exhibited the most inhibitory activity against α-glucosidase and was superior to the positive control with an IC50 value of 1.32 µM. Compounds 1 and 2 showed weak cytotoxicity against the three human cancer cell lines, with IC50 values in the range of 53.3-79.0 µM.

Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients.

Purpose: The purpose of this study was to characterize the population-based pharmacokinetic (POP-PK) profile of imipenem in Vietnamese adult patients and to assess the probability of target attainment (PTA) of the pharmacokinetic/pharmacodynamic (PK/PD) parameter to determine the optimal dose. Patients and Methods: A POP-PK model of imipenem was developed in patients with severe infection from a 1500-bed general hospital in Vietnam, using MONOLIX 2019. After the initial dose infusion, 6 blood samples per patient were collected to measure plasma imipenem levels. Eight covariates (eg, age, weight) were investigated to ascertain their influence on imipenem's PK. Monte Carlo simulations were performed to determine the PTA for the time in which the total steady-state imipenem concentrations remained above the MIC (T>MIC) for 40% and 100% of the dosing interval. Results: The best fit to the PK data was a two-compartment model with inter-individual variability (IIV) in clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and peripheral volume of distribution (Vp). Only creatinine clearance was retained as a covariate on CL in the final model. The typical value of CL and Vc were estimated to be 4.79 L/h and 11.1 L, respectively. The between-subject variability in this population was noted to be high (>38%, especially for IIV on Q at 110%). Prolonged or continuous infusion demonstrated efficacy (40% T>MIC) against bacteria with a MIC of 4mg/L. To achieve 100% T>MIC or bacteria with MIC>4 mg/L, however, the number of doses must be increased while maintaining the same daily dose for the 3-hour prolonged infusion regimen. Conclusion: A population pharmacokinetic model of imipenem was developed for Vietnamese adult patients with severe illness. By using Monte Carlo simulation, the appropriate dose has been suggested based on the bacterial MIC value and the targeted PK/PD goal.

Quality of Life and Its Associated Factors Among Cancer Patients Receiving Chemotherapy at Oncology Hospitals in Vietnam After the Third Wave of the COVID-19 Pandemic.

Purpose: This study aimed to evaluate the health-related quality of life (HRQOL) of cancer patients receiving chemotherapy and identify associated factors affecting the HRQOL after the third wave of the COVID-19 pandemic in Vietnam. Patients and Methods: Patients with solid cancers receiving chemotherapy at two oncology hospitals in Vietnam during April and May 2021 were included. The European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3 was used to measure the HRQOL. Three questions were asked to explore patients' concern levels about contracting COVID-19, delaying chemotherapy, or not controlling cancer well. One question was used to explore whether patients were concerned about cancer progression or COVID-19 infection more, or equally, or had no concern about both. Multiple regression models were conducted to examine factors associated with the global health status (GHS) score. Results: Of 270 included patients, mean (Standard deviation [SD]) GHS was 56.7 (20.8). Among the functional statuses, social functioning (SF) had the lowest score of 63.6 (29.2). The symptoms with the highest means were insomnia and fatigue, obtaining the score of 38.5 (31.7) and 37.3 (29.2), respectively. The mean of financial difficulties was 54.1 (32.2). In univariate analysis, high concerns about contracting COVID-19, delaying chemotherapy, not controlling cancer well, or more concern about either cancer or COVID-19 over the other were associated with worse GHS, physical functioning, emotional functioning, and SF. In multivariate analysis, those concerns and no income were significantly related to lower GHS scores besides the non-modifiable factors, such as female gender and some cancer types. Conclusion: Patients at the high concern levels, or with more concern about either cancer or COVID-19 over the other had poorer HRQOL. Interventions to address the concerns are required to improve their HRQOL, particularly for women, those without income, or with some specific cancers.

Systematic bottom-up molecular coarse-graining via force and torque matching using anisotropic particles.

We derive a systematic and general method for parameterizing coarse-grained molecular models consisting of anisotropic particles from fine-grained (e.g., all-atom) models for condensed-phase molecular dynamics simulations. The method, which we call anisotropic force-matching coarse-graining (AFM-CG), is based on rigorous statistical mechanical principles, enforcing consistency between the coarse-grained and fine-grained phase-space distributions to derive equations for the coarse-grained forces, torques, masses, and moments of inertia in terms of properties of a condensed-phase fine-grained system. We verify the accuracy and efficiency of the method by coarse-graining liquid-state systems of two different anisotropic organic molecules, benzene and perylene, and show that the parameterized coarse-grained models more accurately describe properties of these systems than previous anisotropic coarse-grained models parameterized using other methods that do not account for finite-temperature and many-body effects on the condensed-phase coarse-grained interactions. The AFM-CG method will be useful for developing accurate and efficient dynamical simulation models of condensed-phase systems of molecules consisting of large, rigid, anisotropic fragments, such as liquid crystals, organic semiconductors, and nucleic acids.

Appendicular Lean Mass and Frailty among Geriatric Outpatients.

The objective of this observational study was to examine the association between appendicular lean mass and frailty in adults aged 60 years and older. This study was conducted in the Outpatient Department of the National Geriatric Hospital in Hanoi, Vietnam. Appendicular lean mass (kg) was assessed by using Dual energy X-ray absorptiometry scans. Frailty was defined according to Fried's frailty criteria. A total of 560 outpatients were included in the study, with a mean age of 70 years. The prevalence of frailty was 12.0%. Frail patients had significantly lower appendicular lean mass compared with non-frail outpatients (9.6 ± 2.0 kg vs. 11.7 ± 3.1 kg, p<0.001). On multivariable logistic regression models, higher appendicular lean mass was associated with significantly reduced odds for frailty (adjusted OR = 0.74, 95%CI 0.59 - 0.93). These findings suggest that the assessment of appendicular lean mass should be considered in older patients attending outpatient geriatric clinics.

Impact of left atrial enlargement on image quality in coronary computed tomography angiography.

PURPOSE: To assess the associations between simple measurements of left atrial (LA) size and image quality of coronary computed tomography angiography (CCTA). MATERIALS AND METHODS: Four hundred and nineteen patients who underwent CCTA were retrospectively examined. Image quality was measured by coronary artery attenuation and contrast-to-noise ratio (CNR) of the proximal coronary artery (mean values of right coronary artery and left main trunk). LA transverse (LA-TRA) and anterior-posterior (LA-AP) diameter were measured on non-contrast CT images of the chest. The relationships of coronary attenuation and CNR with LA diameters were assessed by Pearson's correlation or Spearman's rank correlation coefficient and multivariate linear regression analysis. Receiver operating characteristic curves were used to assess the predictive value of LA diameters for image quality. RESULTS: Both coronary artery attenuation value and CNR were independently correlated with LA-AP diameter (r = -0.38, for artery attenuation; r = -0.16, for CNR, both p < 0.001), and LA-TRA diameter (r = -0.2, p < 0.001, for artery attenuation; r = -0.11, p = 0.02, for CNR), respectively. With a cutoff value of 34 mm, the LA-AP diameter had a sensitivity of 85.2%, a specificity of 68.4% and an area under curve (AUC) of 0.77 for prediction of insufficient image quality (coronary artery attenuation less than 326 Hounsfield units). CONCLUSION: Coronary artery attenuation and CNR in CCTA decreased with larger LA size.

Effectiveness of Hyaluronic Acid Gel and Intrauterine Devices in Prevention of Intrauterine Adhesions after Hysteroscopic Adhesiolysis in Infertile Women.

STUDY OBJECTIVE: To compare the recurrence rate, post-treatment American Fertility Society (AFS) score, ongoing pregnancy rate, and endometrial thickness of 3 secondary prevention therapies in preventing recurrent intrauterine adhesions (IUAs) and increasing pregnancy rates in infertile women after hysteroscopic adhesiolysis. DESIGN: A retrospective study. SETTING: A private fertility hospital. PATIENTS: A total of 200 consecutive infertile women, with the desire to have a baby and were diagnosed as having IUAs detected by hysterosalpingogram, who underwent hysteroscopic adhesiolysis for IUAs from January, 2018 to May, 2020. INTERVENTIONS: Women who underwent hysteroscopic adhesiolysis received hormone therapy, and one of the 3 secondary preventions: hyaluronic acid (HA) gel alone, intrauterine devices (IUDs) alone, or HA gel + IUD. MEASUREMENTS AND MAIN RESULTS: Of the 200 women included in the final analysis, 121 received HA alone, 59 were treated with IUD alone, and 20 received HA gel + IUD combination. The mean post-treatment AFS score for IUAs was significantly lower in the HA gel + IUD group than the HA alone or the IUD alone groups (adjusted p = .01 and p = .02, respectively). Multivariable analysis revealed a significantly lower recurrence rate in the women after treatment with HA gel + IUD than HA alone (adjusted odds ratio, 0.19; 95% credible interval [CreI], 0.03-0.88). Women treated with HA gel + IUD also had reduced post-treatment AFS scores compared with HA alone (ß coefficients, -0.83; 95% CreI, -1.64 to -0.01). For ongoing pregnancy rates after in vitro fertilization, the adjusted odds ratio for HA gel + IUD vs HA alone was 2.03 (95% CreI, 0.44-11.00) and for IUD alone vs HA alone was 1.13 (95% CreI, 0.41-3.29), indicating nonsignificant differences. There were no differences observed in endometrial thickness on the day of embryo transfer among the 3 groups. CONCLUSION: The investigation of the primary outcome in reducing the recurrence rate IUA after treatment demonstrated that a combination of HA gel + IUD provides greater prevention of recurrent IUAs and may decrease post-treatment AFS scores for infertile women undergoing hysteroscopic adhesiolysis. However, for the secondary outcome of increasing pregnancy rates, there was no improvement in the ongoing pregnancy rates after in vitro fertilization.

Tools and Methods for Investigating Synthetic Metal-Catalyzed Reactions in Living Cells.

Although abiotic catalysts are capable of promoting numerous new-to-nature reactions, only a small subset has so far been successfully integrated into living systems. Research in intracellular catalysis requires an interdisciplinary approach that takes advantage of both chemical and biological tools as well as state-of-the-art instrumentations. In this perspective, we will focus on the techniques that have made studying metal-catalyzed reactions in cells possible using representative examples from the literature. Although the lack of quantitative data in vitro and in vivo has somewhat limited progress in the catalyst development process, recent advances in characterization methods should help overcome some of these deficiencies. Given its tremendous potential, we believe that intracellular catalysis will play a more prominent role in the development of future biotechnologies and therapeutics.

Solar-driven conversion of carbon dioxide over nanostructured metal-based catalysts in alternative approaches: Fundamental mechanisms and recent progress.

Solar-driven carbon dioxide (CO2) conversion has gained tremendous attention as a prominent strategy to simultaneously reduce the atmospheric CO2 concentration and convert solar energy into solar fuels in the form of chemical bonds. Numerous efforts have been devoted to diverse photo-driven processes for CO2 conversion, which utilized a multidisciplinary strategy. Among them, the architecture of nanostructured metal-based catalysts is emerging as an eminent solution for the design of catalysts of this field. In this work, we first provide fundamental mechanisms of photochemical, photoelectrochemical, photothermal, and photobio(electro)chemical CO2 reduction processes to achieve an in-deep understanding of vital aspects. Importantly, the recent progress in the catalyst design for each reaction system is discussed and highlighted. Based on these analyses, an overview of photo-driven CO2 reduction on metal-based catalysts for solar fuel production is also spotlighted. Finally, we analyze challenges and prospects for the strategic direction of developments in the field.

Paxillin binding to the PH domain of kindlin-3 in platelets is required to support integrin αIIbß3 outside-in signaling.

BACKGROUND: Kindlin-3 is essential for supporting the bidirectional signaling of integrin αIIbß3 in platelets by bridging the crosstalk between integrin αIIbß3 and the cytoplasmic signaling adaptors. OBJECTIVE: In this study, we identified a previously unrecognized paxillin binding site in the pleckstrin homology (PH) domain of kindlin-3 and verified its functional significance. METHODS: Structure-based approaches were employed to identify the paxillin binding site in the PH domain of kindlin-3. In addition, the bidirectional signaling of integrin αIIbß3 were evaluated in both human and mouse platelets. RESULTS: In brief, we found that a ß1-ß2 loop in the PH domain of kindlin-3, an important part of the canonical membrane phospholipid binding pocket, was also involved in mediating paxillin interaction. Interestingly, the binding sites of paxillin and membrane phospholipids in the PH domain of kindlin-3 were mutually exclusive. Specific disruption of paxillin binding to the PH domain by point mutations inhibited platelet spreading on immobilized fibrinogen while having no inhibition on soluble fibrinogen binding to stimulated platelets. In addition, a membrane-permeable peptide derived from the ß1-ß2 loop in the PH domain of kindlin-3 was capable of inhibiting platelet spreading and clot retraction, but it had no effect on soluble fibrinogen binding to platelets and platelet aggregation. Treatment with this peptide significantly reduced thrombus formation in mice. CONCLUSION: Taken together, these findings suggest that interaction between paxillin and the PH domain of kindlin-3 plays an important role in supporting integrin αIIbß3 outside-in signaling in platelets, thus providing a novel antithrombotic target.

Improving antibiotic prescribing for community-acquired pneumonia in a provincial hospital in Northern Vietnam.

OBJECTIVES: To test the effectiveness of a quality improvement programme to promote adherence to national quality standards (QS) for patients hospitalized with community-acquired pneumonia (CAP), exploring the factors that hindered improvements in clinical practice. METHODS: An improvement bundle aligned to the QS was deployed using plan-do-study-act methodology in a 600 bed hospital in northern Vietnam from July 2018 to April 2019. Proposed care improvements included CURB65 score guided hospitalization, timely diagnosis and inpatient antibiotic treatment review to limit the spectrum and duration of IV antibiotic use. Interviews with medical staff were conducted to better understand the barriers for QS implementation. RESULTS: The study found that improvements were made in CURB65 score documentation and radiology results available within 4 h (P < 0.05). There were no significant changes in the other elements of the QS studied. We documented institutional barriers relating to the health reimbursement mechanism and staff cultural barriers relating to acceptance and belief as significant impediments to implementation of the standards. CONCLUSIONS: Interventions led to some process changes, but these were not utilized by clinicians to improve patient management. Institutional and behavioural barriers documented may inhibit wider national uptake of the QS. National system changes with longer term support and investment to address local behavioural barriers are likely to be crucial for future improvements in the management of CAP, and potentially other hospitalized conditions, in Vietnam.

Testing early warning and response systems through a full-scale exercise in Vietnam.

BACKGROUND: Simulation exercises can functionally validate World Health Organization (WHO) International Health Regulations (IHR 2005) core capacities. In 2018, the Vietnam Ministry of Health (MOH) conducted a full-scale exercise (FSX) in response to cases of severe viral pneumonia with subsequent laboratory confirmation for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to evaluate the country's early warning and response capabilities for high-risk events. METHODS: An exercise planning team designed a complex fictitious scenario beginning with one case of severe viral pneumonia presenting at the hospital level and developed all the materials required for the exercise. Actors, controllers and evaluators were trained. In August 2018, a 3-day exercise was conducted in Quang Ninh province and Hanoi city, with participation of public health partners at the community, district, province, regional and national levels. Immediate debriefings and an after-action review were conducted after all exercise activities. Participants assessed overall exercise design, conduction and usefulness. RESULTS: FSX findings demonstrated that the event-based surveillance component of the MOH surveillance system worked optimally at different administrative levels. Detection and reporting of signals at the community and health facility levels were appropriate. Triage, verification and risk assessment were successfully implemented to identify a high-risk event and trigger timely response. The FSX identified infection control, coordination with internal and external response partners and process documentation as response challenges. Participants positively evaluated the exercise training and design. CONCLUSIONS: This exercise documents the value of exercising surveillance capabilities as part of a real-time operational scenario before facing a true emergency. The timing of this exercise and choice of disease scenario was particularly fortuitous given the subsequent appearance of COVID-19. As a result of this exercise and subsequent improvements made by the MOH, the country may have been better able to deal with the emergence of SARS-CoV-2 and contain it.

p-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation.

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p-Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA's actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.