Evaluation of AlphaFold2 Structures for Hit Identification across Multiple Scenarios.

The introduction of AlphaFold2 (AF2) has sparked significant enthusiasm and generated extensive discussion within the scientific community, particularly among drug discovery researchers. Although previous studies have addressed the performance of AF2 structures in virtual screening (VS), a more comprehensive investigation is still necessary considering the paramount importance of structural accuracy in drug design. In this study, we evaluate the performance of AF2 structures in VS across three common drug discovery scenarios: targets with holo, apo, and AF2 structures; targets with only apo and AF2 structures; and targets exclusively with AF2 structures. We utilized both the traditional physics-based Glide and the deep-learning-based scoring function RTMscore to rank the compounds in the DUD-E, DEKOIS 2.0, and DECOY data sets. The results demonstrate that, overall, the performance of VS on AF2 structures is comparable to that on apo structures but notably inferior to that on holo structures across diverse scenarios. Moreover, when a target has solely AF2 structure, selecting the holo structure of the target from different subtypes within the same protein family produces comparable results with the AF2 structure for VS on the data set of the AF2 structures, and significantly better results than the AF2 structures on its own data set. This indicates that utilizing AF2 structures for docking-based VS may not yield most satisfactory outcomes, even when solely AF2 structures are available. Moreover, we rule out the possibility that the variations in VS performance between the binding pockets of AF2 and holo structures arise from the differences in their biological assembly composition.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for Translational Research.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

The emerging roles of next-generation metabolomics in critical care nutrition.

Critical illness leads to millions of deaths worldwide each year, with a significant surge due to the COVID-19 pandemic. Patients with critical illness are frequently associated with systemic metabolic disorders and malnutrition. The idea of intervention for critically ill patients through enteral and parenteral nutrition has been paid more and more attention gradually. However, current nutritional therapies focus on evidence-based practice, and there have been lacking holistic approaches for nutritional support assessment. Metabolomics is a well-established omics technique in system biology that enables comprehensive profiling of metabolites in a biological system and thus provides the underlying information expressed and modulated by all other omics layers. In recent years, with the development of high-resolution and accurate mass spectrometry, metabolomics entered a new "generation", promoting its broader applications in critical care nutrition. In this review, we first described the technological development and milestones of next-generation metabolomics in the past 20 years. We then discussed the emerging roles of next-generation metabolomics in advancing our understanding of critical care nutrition, such as nutritional deficiency risk evaluation, metabolic mechanisms of nutritional therapies, and novel nutrition target identification.

Impact of cocrystal solution-state stability on cocrystal dissociation and polymorphic drug recrystallization during dissolution.

The present study aimed to investigate how cocrystal solution-state stability may affect the polymorphic drug formation and transition during dissolution. In this work, curcumin-resorcinol (CUR-RES), curcumin-hydroquinone (CUR-HYQ) and curcumin-phloroglucinol (CUR-PHL) cocrystals were employed for dissolution studies in three buffer systems to study the effects of solvent and cocrystal thermodynamic stability. The undissolved solids were collected at designed time points and characterized by powder X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. In pH 1.2 buffer, three cocrystals generated > 94% of metastable CUR form III with trace amount of stable CUR form I, while the phase purity of CUR form III recrystallized from buffers containing ethanol (EtOH) were decreased dramatically. For the same cocrystal, the cocrystal form maintained longer in the pH 1.2 buffer when compared with buffers containing EtOH. The phase purity of recrystallized CUR form III in the metastable cocrystal systems followed a linear relationship against CUR solubility, while the thermodynamically stable cocrystal resulted in a non-linear relationship. Due to different intermolecular interactions analyzed by 1H NMR, the stable cocrystal required a higher supersaturation level to precipitate pure CUR form III, in comparison to two metastable cocrystals. Our study offers important insights into mitigating the risk of recrystallization of drug polymorphs during cocrystal dissolution and demonstrates the potential use of cocrystals for drug polymorph preparation, both of which are crucial to the pharmaceutical cocrystal development and reformulation of existing drugs.

Impact of a pharmacist-led education and follow-up service on anticoagulation control and safety outcomes at a tertiary hospital in China: a randomised controlled trial.

OBJECTIVES: This study was designed to evaluate the impact of a pharmacist-led anticoagulation service on international normalised ratio (INR) control and other outcomes among patients receiving warfarin therapy at a tertiary hospital in Zhuhai, China. METHODS: In this randomised controlled trial, adult patients who were newly initiated on warfarin with intended treatment duration of at least 3 months were recruited. Participants were randomly allocated to receive the pharmacist-led education and follow-up service (PEFS) or usual care (UC). Anticoagulation control was calculated as the proportions of time within the target INR range (TTR) and time within the expanded target range (TER). KEY FINDINGS: A total of 152 participants (77 in the PEFS group and 75 in the UC group) were included. Within 180 days after hospital discharge, the PEFS group spent more TER than the UC group (54.4% versus 42.0%; P = 0.024), whereas the difference in TTR did not reach statistical significance (35.9% versus 29.5%; P = 0.203). No major bleeding events were observed, and the cumulative incidences of major thromboembolic events (6.5% versus 9.3%) and mortality (1.3% versus 1.3%) were similar between the two groups (P> 0.05). At 30 days postdischarge, the PEFS group had better warfarin knowledge by answering 57.5% of questions correctly, compared with the UC group (43.0%) (P = 0.003). CONCLUSIONS: The PEFS markedly enhanced anticoagulation control and warfarin knowledge but there was room for improvement. The expansion of pharmacists' clinical role and the development of more effective education and follow-up strategies are warranted to optimise anticoagulation management services in China.

Underdiagnosis of depression in an economically deprived population in Macao, China.

INTRODUCTION: Previous literature revealed an association between low income and depression. Despite the availability of effective treatments, depression is often underdiagnosed and undertreated. This study was designed to evaluate the prevalence of depressive symptoms and their impact on health-related quality of life (HRQoL) in a low-income population in Macao. METHODS: This cross-sectional study targeted the adult beneficiaries of local food bank program. The program was established to provide food assistance to the residents who had low income but were ineligible for government financial assistance. All data were collected through interview and questionnaires. The Patient Health Questionnaire (PHQ-9) was used for assessing depressive symptoms. Information about depression diagnosis was obtained by the self-report method. HRQoL levels were measured by the 12-item Short-Form Health Survey, Version 2.0. RESULTS: A total of 272 study participants were included for analysis. Based on the PHQ-9 scores, 27.6% of the participants suffered from moderate to severe depressive symptoms. Among them, 76% were not diagnosed with depression. Those with moderate to severe depressive symptoms had significantly lower levels of HRQoL (P < 0.001). Anxiety disorders (OR = 9.71, 95% CI = 2.36-40.06), migraine (OR = 3.88, 95% CI = 1.55-9.73), and poor to fair self-rated health (OR = 6.30, 95% CI = 1.95-20.40) were the independent factors associated with moderate to severe depressive symptoms. DISCUSSION: Underdiagnosis of depression was prevalent in this low-income population. There is a need to raise their awareness of mental disorders and improve their access to mental health services.

Potentially inappropriate prescribing and drug-drug interactions among elderly Chinese nursing home residents in Macao.

BACKGROUND: The ageing of the population has become a concern all over the world, including Macao. In general, older people are more prone to adverse drug events which can result from potentially inappropriate medication (PIM) use and drug-drug interactions (DDIs). OBJECTIVE: This study was designed to evaluate the prevalence of PIM use and DDIs among elderly nursing home residents in Macao, and to find out the factors associated with these drug-related problems. SETTING: This study was conducted in the largest nursing home in Macao, with a bed capacity of 168. METHOD: All data of this cross-sectional study were collected from medical charts and medication administration records. PIM use was determined by the screening tool of older person's prescription (STOPP) criteria and potential DDIs were detected using the preset criteria of two compendia, Drug-Reax and Lexi-Interact. Multivariate logistic regression analysis was performed to identify the independent factors associated with each drug-related problem. MAIN OUTCOME MEASURES: The proportions of elderly nursing home residents who regularly used PIMs and who were exposed to DDIs. RESULTS: A total of 114 elderly residents were eligible for PIM analysis. They consumed an average of 6.9 ± 3.1 different medications. About 46.5 % of them regularly used one or more PIMs. The prevalence of DDIs was 37.8 % among the 111 elderly residents who consumed at least two different medications. An increased number of drugs used was identified as the independent factor associated with PIM use and DDIs (p < 0.05). However, the use of STOPP-related PIMs did not appear to raise the likelihood of DDIs among the study population. CONCLUSION: Both PIM use and DDIs are common among elderly nursing home residents in Macao. Further studies should be conducted to evaluate the clinical outcomes of pharmacist-led interventions for elderly residents in the local nursing home setting.