Swietemicrolides A-D, mexicanolide-type limonoids from the bark of Swietenia macrophylla with in vitro cytotoxic and α-glucosidase inhibitory activities.

Four new mexicanolide-type limonoids, swietemicrolides A-D (1-4), together with three known compounds (5-7) were isolated from an ethyl acetate extract of the bark of Swietenia microphylla. 1 and 2 had 1,8-hemiacetal systems whilst 3 and 4 shared hexacyclic skeletons consisting of three fused five-membered rings. The structures of the isolated compounds were determined using spectroscopic methods. The five limonoids (1-5) were tested in vitro for their cytotoxic effects against two human cancer cell lines (KB carcinoma and A549 lung cancer cells) and α-glucosidase inhibitory activity. None of them showed significant cytotoxic activity, however, swietemicrolide C (3) exhibited strong effect towards α-glucosidase. Moreover, a possible biosynthetic pathway for compounds 1-4 was proposed to support a comprehensive understanding of the configurations of the new limonoids.

Characteristics of nonconventional hydrogen bonds and stability of dimers of chalcogenoaldehyde derivatives: a noticeable role of oxygen compared to other chalcogens.

In this work, twenty-four stable dimers of RCHZ with R = H, F, Cl, Br, CH3 or NH2 and Z = O, S, Se or Te were determined. It was found that the stability of most dimers is primarily contributed by the electrostatic force, except for the dominant role of the induction term in those involving a Te atom, which has been rarely observed. Both electron-donating and -withdrawing groups in substituted formaldehyde cause an increase in the strength of nonconventional Csp2-H⋯Z hydrogen bonds, as well as the dimers, in which the electron donating effect plays a more crucial role. The strength of nonconventional hydrogen bonds decreases in the following order: Csp2-H⋯O ≫ Csp2-H⋯S > Csp2-H⋯Se > Csp2-H⋯Te. Remarkably, a highly significant role of the O atom compared to S, Se and Te in increasing the Csp2-H stretching frequency and strength of the nonconventional hydrogen bonds and dimers is found. A Csp2-H stretching frequency red-shift is observed in Csp2-H⋯S/Se/Te, while a blue-shift is obtained in Csp2-H⋯O. When Z changes from O to S to Se and to Te, the Csp2-H blue-shift tends to decrease and eventually turns to a red-shift, in agreement with the increasing order of the proton affinity at Z in the isolated monomer. The magnitude of the Csp2-H stretching frequency red-shift is larger for Csp2-H⋯Te than Csp2-H⋯S/Se, consistent with the rising trend of proton affinity at the Z site and the polarity of the Csp2-H bond in the substituted chalcogenoaldehydes. The Csp2-H blue-shifting of the Csp2-H⋯O hydrogen bonds is observed in all dimers regardless of the electron effect of the substituents. Following complexation, the electron-donating derivatives exhibit a stronger Csp2-H blue-shift compared to the electron-withdrawing ones. Notably, the stronger Csp2-H blue-shift turns out to involve a less polarized Csp2-H bond and a decrease in the occupation at the σ*(Csp2-H) antibonding orbital in the isolated monomer.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Comorbidities of diabetes and hypertension in Vietnam: current burden, trends over time, and correlated factors.

BACKGROUND: Vietnam conducted the national Noncommunicable Disease Risk-Factor Surveillance (STEPs) surveys in the years 2010, 2015, and 2021. This study aims to use STEPs data to assess the burden of comorbidity between diabetes and hypertension, analyze trends over time, and identify factors associated with this comorbidity. METHODS: The study extracted data for the population aged 25-64 years old from three STEPs surveys. Survey weight was used for all estimations of prevalence and 95% CI. Correlated factors with comorbidity were examined by a multivariate logistics model. RESULTS: The prevalence of comorbidity in 2021 was about 3.92% among Vietnamese people aged 25-64. In the last 10 years, this prevalence has increased more than 8 times (from 0.44% to 3.92%). Sub-populations demonstrating the most significant changes included the male population, people living in urban areas, and older people. Significant factors correlated with comorbidity included demographic factors, body mass index (BMI), and clustering of 4 noncommunicable diseases (NCDs) behavioral risk factors (OR = 3.48, p < 0.05). CONCLUSION: The high comorbidity between hypertension and diabetes underscores the imperative for integrated treatment and management approaches in Vietnam. Coordinated care is essential for addressing the complex interplay between these two prevalent conditions.

REstrictive versus StandarD FlUid Management in Mechanically Ventilated ChildrEn Admitted to PICU: study protocol for a pilot randomised controlled trial (REDUCE-1).

INTRODUCTION: Intravenous fluid therapy is the most common intervention in critically ill children. There is an increasing body of evidence questioning the safety of high-volume intravenous fluid administration in these patients. To date, the optimal fluid management strategy remains unclear. We aimed to test the feasibility of a pragmatic randomised controlled trial comparing a restrictive with a standard (liberal) fluid management strategy in critically ill children. METHODS AND ANALYSIS: Multicentre, binational pilot, randomised, controlled, open-label, pragmatic trial. Patients <18 years admitted to paediatric intensive care unit and mechanically ventilated at the time of screening are eligible. Patients with tumour lysis syndrome, diabetic ketoacidosis or postorgan transplant are excluded. INTERVENTIONS: 1:1 random assignment of 154 individual patients into two groups-restrictive versus standard, liberal, fluid strategy-stratified by primary diagnosis (cardiac/non-cardiac). The intervention consists of a restrictive fluid bundle, including lower maintenance fluid allowance, limiting fluid boluses, reducing volumes of drug delivery and initiating diuretics or peritoneal dialysis earlier. The intervention is applied for 48 hours postrandomisation or until discharge (whichever is earlier). ENDPOINTS: The number of patients recruited per month and proportion of recruited to eligible patients are feasibility endpoints. New-onset acute kidney injury and the incidence of clinically relevant central venous thrombosis are safety endpoints. Fluid balance at 48 hours after randomisation is the efficacy endpoint. Survival free of paediatric intensive care censored at 28 days is the clinical endpoint. ETHICS AND DISSEMINATION: Ethics approval was gained from the Children's Health Queensland Human Research Ethics Committee (HREC/21/QCHQ/77514, date: 1 September 2021), and University of Zurich (2021-02447, date: 17 March 2023). The trial is registered with the Australia New Zealand Clinical Trials Registry (ACTRN12621001311842). Open-access publication in high impact peer-reviewed journals will be sought. Modern information dissemination strategies will also be used including social media to disseminate the outcomes of the study. TRIAL REGISTRATION NUMBER: ACTRN12621001311842. PROTOCOL VERSION/DATE: V5/23 May 2023.

Individualized precision dosing approaches to optimize antimicrobial therapy in pediatric populations.

INTRODUCTION: Severe infections continue to impose a major burden on critically ill children and mortality rates remain stagnant. Outcomes rely on accurate and timely delivery of antimicrobials achieving target concentrations in infected tissue. Yet, developmental aspects, disease-related variables, and host factors may severely alter antimicrobial pharmacokinetics in pediatrics. The emergence of antimicrobial resistance increases the need for improved treatment approaches. AREAS COVERED: This narrative review explores why optimization of antimicrobial therapy in neonates, infants, children, and adolescents is crucial and summarizes the possible dosing approaches to achieve antimicrobial individualization. Finally, we outline a roadmap toward scientific evidence informing the development and implementation of precision antimicrobial dosing in critically ill children.The literature search was conducted on PubMed using the following keywords: neonate, infant, child, adolescent, pediatrics, antimicrobial, pharmacokinetic, pharmacodynamic target, Bayes dosing software, optimizing, individualizing, personalizing, precision dosing, drug monitoring, validation, attainment, and software implementation. Further articles were sought from the references of the above searched articles. EXPERT OPINION: Recently, technological innovations have emerged that enabled the development of individualized antimicrobial dosing approaches in adults. More work is required in pediatrics to make individualized antimicrobial dosing approaches widely operationalized in this population.

Adverse influence of multilevel socioeconomic status on physical activity: results from a national survey in Vietnam.

BACKGROUND: This study aims to explore associations of individual- and provincial-level socioeconomic status (SES) and the combined interaction among these SES with individual physical activity (PA). METHOD: This analyze used data of 3068 Vietnamese people aged 18-65 years from the national representative STEPS survey in 2015 (STEPS2015). The survey collected PA-related data using the Global PA Questionnaire Version 2 and those on provicial-level characteristics from two surveys in 2014, namely the Intercensal Population and Housing Survey (IPHS) and The Vietnam Household Living Standard Survey (VLSS2014). Multilevel linear analyze was performed with individual and provincial characteristics as independent variables and the metabolic equivalent (MET) score - the indicator of individual PA - as the dependent variable. RESULTS: Male and female participants with insufficient PA accounted for 20.2 and 35.7%, respectively. Both individual- and provicial-level SES were inversely associated with the individual PA level. As the provincial-level monthly income increased by 1 million Vietnam Dongs, the total PA score of individuals residing in that province reduced by 1900 METS. A buffering effect was reported between provincial and individual SES, as the provincial average income increased, the differences in PA scores between different SES groups decreased. CONCLUSION: Our data suggest that Vietnamese individuals in low SES groups tended to be more physically active than those in high SES groups because their PA was largely related to work.

Prolonged Postoperative Vasoplegia in Pediatric Patients on Chronic Angiotensin II Blocker Treatment.

Prolonged postoperative vasoplegia is known to occur following cardiac surgery in patients on chronic angiotensin II receptor blocker (ARB) treatment in adults. The perioperative management of these drugs in the pediatric population is not well described and here we would like to highlight this fact. While ARBs are increasingly used in children and adolescents with hypertension, there is lack of data to guide optimal pre-surgical management in the pediatric age group. We report two cases of prolonged vasoplegia following cardiopulmonary bypass occurring in adolescent patients on chronic ARB therapy and the importance of cessation of these drugs preoperatively.

Adherence to standard medication infusion concentrations and its impact on paediatric intensive care patient outcomes.

AIM: To review compliance with the DERS, and to evaluate the impact on daily fluid balances as a standard outcome in paediatric intensive care. METHOD: A prospective audit of patients admitted to our tertiary level PICU over a 10day period. The audit tool collated information on patient's weight, diagnosis, medication infusions, whether standard concentrations were selected, daily fluid balance, target fluid balance, and renal support including use of diuretics. RESULTS: Seventy-seven (84%) of patients weighed less than 10kg. On average, there were seven medication infusions per patient and 98% of the medication infusions adhered to standard concentrations for medication infusions and DERS. In 2% of medication infusions staff opted not to use the DERS, or selected non-standard concentration, and 2% of patients had no labels on the syringe. 90% of patients had a minimal positive balance of 0.5mL/kg/h, averaged over 24h; 48% of patients received renal support and 16% of patients were 24h post cardiac surgery, where a negative fluid balance was recorded. It is standard practice post cardiac surgery to receive diuretics. Standard concentrations did not have a significant impact on patients' daily fluid balance. CONCLUSIONS: The use of standard concentrations and short infusions in PICU using DERS is feasible & achievable as demonstrated by high compliance, and does not have a negative impact on patient outcome, especially fluid balance.

Population pharmacokinetics of phenytoin in critically ill children.

The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration.