A comparison of GOLD 2019 and 2023 recommendations to contemporaneous real-world inhaler treatment patterns for chronic obstructive pulmonary disease management in Singapore.

Background: In 2019 and 2023, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) provided updated strategies for modifying the therapy of patients with chronic obstructive pulmonary disease (COPD) and high exacerbation risk. A key update since the 2019 guidelines recommends considering blood eosinophil count to guide decisions on inhaled corticosteroid (ICS) treatment. To evaluate the potential impact of these updated recommendations, this study aimed to assess how extensively future practice would diverge from contemporaneous prescribing practices at a single center in Singapore, assuming adherence to the 2019 and 2023 GOLD guidelines. Methods: Retrospective cohort analysis of the Changi General Hospital COPD data warehouse involving patients aged ≥40 years hospitalized for a COPD exacerbation (October 2018-April 2020) receiving long-acting muscarinic antagonist (LAMA), LAMA plus a long-acting beta2-agonist (LABA), or an ICS plus LABA at admission. The proportion of patients eligible for treatment escalations per GOLD 2019 and 2023 recommendations was calculated. Results: In total, 268 patients were included (mean age 73 years; 91% male). At admission, 19%, 59%, and 22% of patients were receiving LAMA, LAMA + LABA, and ICS + LABA, respectively. Overall, 226 patients would have been eligible for treatment escalation per GOLD 2019 or 2023 recommendations; 31 (13.7%) had treatment escalations consistent with GOLD 2019 guidelines and 34 (15%) received treatment escalations consistent with GOLD 2023 guidelines. A total of 205 patients (76.5%) remained on the same treatment regimen at hospital discharge as they were receiving at admission. Lower measured post-bronchodilator forced expiratory volume in 1 second was associated with treatment escalations that would have been GOLD-concordant (P=0.028), as was increased number of emergency department/hospital visits in the last year (P=0.048). Conclusions: Compared with real-world clinical practice, a significantly higher proportion of patients may be eligible for treatment escalation under the GOLD 2019 and 2023 eosinophil-directed algorithms.

Microbial conversion of agro-processing waste (peanut meal) to rhamnolipid by Pseudomonas aeruginosa: solid-state fermentation, water extraction, medium optimization and potential applications.

The high cost and severe foam in rhamnolipid fermentation are still bottlenecks for its industrial production and application. Non-foaming production of rhamnolipid by Pseudomonas aeruginosa FA1 was explored in solid-state fermentation using the agro-processing waste (peanut meal) as low-cost substrate. An environmental-friendly extraction method was developed to harvest rhamnolipid from solid-state culture. Strain FA1 produced 265.4 ± 8.2 mg rhamnolipid using 10 g peanut meal. HPLC-MS results revealed that 7 rhamnolipid homologues were produced, mainly including Rha-C8-C10 and Rha-Rha-C10-C10. Nitrate was the optimal nitrogen source. Peanut meal, MgSO4 and CaCl2 were significant factors for rhamnolipid production in solid-state fermentation. Rhamnolipid production was enhanced 31 % using the solid-state medium optimized by response surface method. The produced rhamnolipid reduced water surface tension to 28.1 ± 0.2 mN/m with a critical micelle concentration of 70 mg/L. The crude oil was emulsified with an emulsification index of 75.56 ± 1.29 %. The growth of tested bacteria and fungi was inhibited.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

Enhanced production of mono-rhamnolipid in Pseudomonas aeruginosa and application potential in agriculture and petroleum industry.

Differences in the rhamnolipid structures must result in its different activities, thus affecting its application effect. The rhlC gene in Pseudomonas aeruginosa SG was knocked out to construct strain P. aeruginosa SGΔrhlC. Rhamnolipid production was enhanced by 23.3% through knocking out rhlC gene. P. aeruginosa SGΔrhlC produced 14.22 g/L of rhamnolipid using glycerol and nitrate. Five kinds of mono-rhamnolipid but no di-rhamnolipid were produced by strain SGΔrhlC. The main rhamnolipid homologues were Rha-C10-C10, Rha-C10-C12:1 and Rha-C10-C12. Mono-rhamnolipid exhibited better antimicrobial activity to Escherichia coli, Staphylococcus aureus, Aspergillus niger and Penicillium chrysogenum. Rhamnolipid produced from strain SGΔrhlC showed greater emulsifying activity to crude oil with EI24 of 84.73%. Rhamnolipid produced from strain SGΔrhlC efficiently washed oily sludge at 35 °C. High-producing strain P. aeruginosa SGΔrhlC and its produced mono-rhamnolipid are more promising in agriculture and petroleum industry. This study is a step forward to the tailor-made biosynthesis and application of rhamnolipid.

VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions.

Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation ßGlu6 → ßVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.

AGLPM and QMDDQ peptides exert a synergistic action on memory improvement against scopolamine-induced amnesiac mice.

This study aimed to explore the synergistic action of pentapeptides Gln-Met-Asp-Asp-Gln (QMDDQ) and Ala-Gly-Leu-Pro-Met (AGLPM) on memory improvement against scopolamine-induced impairment in mice compared to those of either peptide alone. In behavioral tests, the codelivery of QMDDQ and AGLPM was superior to the individual supplements of either peptide alone not only in enhancing the memory ability at training trials but also in recovering the memory impairment in scopolamine-induced amnesiac mice in test trials. Furthermore, combination treatment with QMDDQ and AGLPM could significantly reduce the acetylcholinesterase (AChE) level and increase the acetylcholine (ACh) level in the hippocampus, and noticeably improve the pathological morphology of the neuron cells in hippocampal regions CA1 and CA2 and dentate gyrus (DG). The findings indicated that the combination treatment with QMDDQ and AGLPM could improve the memory function by regulating the cholinergic system.

Discriminant Analysis of Traditional Chinese Medicinal Properties Based on Holistic Chemical Profiling by 1H-NMR Spectrometry.

Medicinal property, which is closely related to drug chemical profiling, is the essence of traditional Chinese medicine (TCM) theory and has always been the focus of modern Chinese medicine. Based on dozens of classic and commonly used TCM herbs with recognized medicinal properties, the present study just aimed to investigate the feasibility and reliability of medicinal property discriminant by using 1H-NMR spectrometry, which provided a mass of spectral data showing holistic chemical profile for multivariate analysis and data mining, including principal component analysis (PCA), Fisher linear discriminant analysis (FLDA), and canonical discriminant analysis (CDA). By using FLDA for two-class recognition, a large majority of test herbs (59/61) were properly discriminated as cold or hot group, and the only two exceptions were Chuanbeimu (Fritillariae Cirrhosae Bulbus) and Rougui (Cinnamomi Cortex), suggesting that medicinal properties interrelate with flavor and body tropism, and all these factors together bring up medicinal property and efficacy. While by performing CDA, 98.4% of the original grouped herbs and 77.0% of the leave-one-out cross-validated grouped cases were correctly classified. The findings demonstrated that discriminant analysis based on holistic chemical profiling data by 1H-NMR spectrometry may provide a powerful alternative to have a deeper understanding of TCM medicinal property.

Xiyanping Plus Azithromycin Chemotherapy in Pediatric Patients with Mycoplasma pneumoniae Pneumonia: A Systematic Review and Meta-Analysis of Efficacy and Safety.

BACKGROUND: Xiyanping injection (XYP) is a well-known Chinese medicinal preparation reputed as a most effective alternative to antibiotics. XYP has been widely used in combination therapies to treat various infectious diseases, among which XYP plus azithromycin (AZM) chemotherapy is often used for the treatment of Mycoplasma pneumoniae pneumonia in pediatric patients (p-MPP) in China. OBJECTIVE: The present study just aimed to confirm whether XYP can improve the clinical efficacy and safety of AZM chemotherapy for p-MPP by performing meta-analysis and systematic review. METHODS: A meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The randomized controlled trials (RCTs) concerning XYP plus AZM chemotherapy for p-MPP were selected, for which the main outcomes included overall response rate (ORR), antipyretic time, cough disappearance time, lung wet Rales disappearance time, hospitalization duration, and adverse drug reactions (ADRs). Based on the data extracted, the meta-analysis was conducted by using a standard data extraction form. RESULTS: Nine RCTs involving 963 patients were included for meta-analysis. More concretely, the combination therapy showed the risk ratio (RR) and 95% confidence intervals (CI) of ORR and ADRs as (RR, 1.21 [95% CI, 1.15, 1.28]) and (RR, 0.37 [95% CI, 0.27, 0.51]), respectively. And other major outcomes were as follows: hospitalization durations (standard mean difference (SMD), -1.32 [95% CI, -1.48, -1.16]), antipyretic time (SMD, -1.26 [95% CI, -1.70, -0.83]), cough disappearance time (SMD, -1.07 [95% CI, -1.38, -0.75]), and the disappearance time of lung wet Rales (SMD, -0.83 [95% CI, -1.07, -0.60]). With statistically significant differences in various aspects, the combination therapy plus XYP displayed obvious advantages in contrast to AZM alone. CONCLUSION: Overall, XYP might reduce the incidence of ADRs and significantly improve the clinical efficacy for p-MPP receiving AZM chemotherapy.

Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations.

The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

Evaluation of MODS assay for rapid detection of Mycobacterium tuberculosis resistance to second-line drugs in a tertiary care tuberculosis hospital in China.

In this study we evaluated the performance of microscopic observation drug susceptibility (MODS) assay for rapid detection of Mycobacterium tuberculosis resistance to second-line drugs. 246 multidrug-resistant M. tuberculosis clinical isolates were used to compare MODS with the agar proportion method for rapid detection of resistance to 8 second-line drugs: ofloxacin, amikacin, kanamycin, capreomycin, ethionamide, cycloserine, ciprofloxacin and para-aminosalicylic acid. The sensitivity of the MODS for different drugs ranged from 88.1% to 100%, whereas the specificity ranged from 92.3% to 100%. Results for MODS assay were obtained in a median time of 7 days (range 5-18). Thus MODS assay could be used as a fast, reliable and inexpensive method for detection of M. tuberculosis resistance to second-line drugs in resource-limited settings.

Screening for differentially expressed genes in endophytic fungus strain 39 during co-culture with herbal extract of its host Dioscorea nipponica Makino.

Strain 39 is an endophytic fungus which was isolated from Dioscorea nipponica Makino (DNM). After Strain 39 co-cultured with ethanol extract of DNM rhizomes for several days, the content of saponins in this culture mixture would be obviously increased. To analyze the mechanism of this microbial transformation, we used the differential display reverse transcription polymerase chain reaction (DDRT-PCR) method to compare the transcriptomes between Strain 39 cultured in normal PD medium and in PD medium which added ethanol extract of DNM rhizomes. We amplified 29 DDRT-PCR bands using 12 primer combinations of three anchored primers and five random primers, and six bands were re-amplified. Analysis of real-time PCR and sequence alignment showed that three clones were up-regulated in sample group: squalene epoxidase, squalene synthase, and catalase, one clone was expressed only in sample group. The possible roles and origins of the above genes were discussed, and the molecular mechanism of Strain 39 biotransformation was speculated. This study is the first report of the molecular biotransformation mechanism of saponins production by endophytic fungus of DNM.

The Yin and Yang of innate immunity in stroke.

Immune system plays an elementary role in the pathophysiological progress of ischemic stroke. It consists of innate and adaptive immune system. Activated within minutes after ischemic onset, innate immunity is responsible for the elimination of necrotic cells and tissue repair, while it is critically involved in the initiation and amplification of poststroke inflammation that amplifies ischemic damage to the brain tissue. Innate immune response requires days to be fully developed, providing a considerable time window for therapeutic intervention, suggesting prospect of novel immunomodulatory therapies against poststroke inflammation-induced brain injury. However, obstacles still exist and a comprehensive understanding of ischemic stroke and innate immune reaction is essential. In this review, we highlighted the current experimental and clinical data depicting the innate immune response following ischemic stroke, mainly focusing on the recognition of damage-associated molecular patterns, activation and recruitment of innate immune cells, and involvement of various cytokines. In addition, clinical trials targeting innate immunity were also documented regardless of the outcome, stressing the requirements for further investigation.