Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

Integrated models of population pharmacokinetics and exposure response to optimize dosage regimen for anaprazole sodium in duodenal ulcer.

Anaprazole sodium enteric-coated tablet is a novel proton pump inhibitor which has been approved for the treatment of duodenal ulcer. The aim of this study is to provide reliable information for the design of an optimal dosage regimen. Population pharmacokinetics and exposure-response models were integrated to evaluate the pharmacokinetic parameters and covariates of Anaprazole and its metabolite M21-1, and subsequently provided dosage suggestions based on clinical trials and simulation data. A pharmacokinetic model incorporating two-compartment for the parent drug and one-compartment for the metabolite, with both first-order and zero-order mixed absorption was used to describe the pharmacokinetics of Anaprazole and M21-1. Age emerged as a significant covariate affecting the elimination rate constant of M21-1, with clearance decreasing as age advances. No correlation was observed between the pharmacokinetics of Anaprazole or M21-1 and the adverse reactions under the current dosages. BMI might be the influence factor of the mild gastrointestinal adverse reactions. Meanwhile, Anaprazole had a good healing rate (94.0 %) in duodenal ulcer patients and the exposure-response analysis indicated that the cured results were not influenced by the exposure parameters of parent drug or metabolite. In conclusion, the drug is safe when dosing between 20 and 100 mg once a day.

Effect of osmotic dehydration combined with vacuum freeze-drying treatment on characteristic aroma components of peach slices.

Hot air drying (HD), vacuum freeze drying (FD), and pilot-scale freeze drying (PSFD) are extensively used to prepare peach slices. However, the aroma of hot air drying and vacuum freeze-drying is yet to be addressed. In this study, HS-SPME-GC-MS was used to characterize and quantify the volatile compounds in peach slices. First, 33, 36, and 46 volatile compounds were identified and quantified in the HD, FD, and PSFD groups, respectively. PSFD is preferable to HD and FD in terms of the volatile compound types, content, and aroma profiles. PSFD was selected for subsequent permeation and dehydration experiments. The key aroma compounds with an OAV ≥ 1 were found in the PSFD30 group. GC-O analysis was conducted on the PSFD30 group, leading to the preliminary identification of 2-methylbutanal, pentanal, hexanal, 2-hexenal, phenylacetaldehyde, ethyl acetate, 2-methylbutyl acetate, ethyl lactate, linalool, methyl heptenone, and γ-octalactone as distinctive aromas in dried peach slices.

Precisely Engineering Asymmetric Atomic CoN4 by Electron Donating and Extracting for Oxygen Reduction Reaction.

The development of nonpyrolytic catalysts featuring precisely defined active sites represents an effective strategy for investigating the fundamental relationship between the catalytic activity of oxygen reduction reaction (ORR) catalysts and their local coordination environments. In this study, we have synthesized a series of model electrocatalysts with well-defined CoN4 centers and nonplanar symmetric coordination structures. These catalysts were prepared by a sequential process involving the chelation of cobalt salts and 1,10-phenanthroline-based ligands with various substituent groups (phen(X), where X=OH, CH3, H, Br, Cl) onto covalent triazine frameworks (CTFs). By modulating the electron-donating or electron-withdrawing properties of the substituent groups on the phen-based ligands, the electron density surrounding the CoN4 centers was effectively controlled. Our results demonstrated a direct correlation between the catalytic activity of the CoN4 centers and the electron-donating ability of the substituent group on the phenanthroline ligands. Notably, the catalyst denoted as BCTF-Co-phen(OH), featuring the electron-donating OH group, exhibited the highest ORR catalytic activity. This custom-crafted catalyst achieved a remarkable half-wave potential of up to 0.80 V vs. RHE and an impressive turnover frequency (TOF) value of 47.4×10-3 Hz at 0.80 V vs. RHE in an alkaline environment.

Elaborate Modulating Binding Strength of Intermediates via Three-component Covalent Organic Frameworks for CO2 Reduction Reaction.

The catalytic performance for electrocatalytic CO2 reduction reaction (CO2RR) depends on the binding strength of the reactants and intermediates. Covalent organic frameworks (COFs) have been adopted to catalyze CO2RR, and their binding abilities are tuned via constructing donor-acceptor (DA) systems. However, most DA COFs have single donor and acceptor units, which caused wide-range but lacking accuracy in modulating the binding strength of intermediates. More elaborate regulation of the interactions with intermediates are necessary and challenge to construct high-efficiency catalysts. Herein, the three-component COF with D-A-A units was first constructed by introducing electron-rich diarylamine unit, electron-deficient benzothiazole and Co-porphyrin units. Compared with two-component COFs, the designed COF exhibit elevated electronic conductivity, enhanced reducibility, high efficiency charge transfer, further improving the electrocatalytic CO2RR performance with the faradic efficiency of 97.2 % at -0.8 V and high activity with the partial current density of 27.85 mA cm-2 at -1.0 V which exceed other two-component COFs. Theoretical calculations demonstrate that catalytic sites in three-component COF have suitable binding ability of the intermediates, which are benefit for formation of *COOH and desorption of *CO. This work offers valuable insights for the advancement of multi-component COFs, enabling modulated charge transfer to improve the CO2RR activity.

Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation.

BACKGROUND AND OBJECTIVE: Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. METHODS: The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. RESULT: Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. CONCLUSION: Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.

A model-informed approach to accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 inhibitor.

AIM: To employ a model-informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. METHODS: Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model-based meta-analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP-4 inhibitors. We hypothesized a consistent relationship between PK and DPP-4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP-4 inhibition and HbA1c. Finally, the predicted PK/DPP-4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. RESULTS: The PK/DPP-4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long-term efficacy in T2D patients, based on healthy subjects. CONCLUSIONS: Successful waiver approval for the phase 2b dose-finding study was achieved through model-informed recommendations, facilitating the clinical development of HSK7653 and other DPP-4 inhibitors.

Autonomous and non-cell autonomous role of cilia in structural birth defects in mice.

Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights into the temporospatial requirement for cilia in SBDs arising from deficiency in Ift140, an intraflagellar transport (IFT) protein regulating ciliogenesis. Ift140-deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula (TEF), randomized heart looping, congenital heart defects (CHDs), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducible CAGGCre-ER deletion of a floxed Ift140 allele between E5.5 to 9.5 revealed early requirement for Ift140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD were not observed with 4 Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed with Wnt1-Cre targeting neural crest and Tbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural crest-mediated craniofacial and body wall closure defects, while non-cell autonomous multi-lineage interactions underlie CHD pathogenesis, revealing unexpected developmental complexity for CHD associated with ciliopathies.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

Purpose: This study aimed to explore the clinical efficacy of transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (triple therapy) compared to TACE alone (monotherapy) for advanced hepatocellular carcinoma (HCC). Material and Methods: Data of consecutive advanced HCC patients receiving triple therapy or monotherapy at our center between January 2019 and December 2022 were collected and retrospectively analyzed. Propensity score matching (PSM) and subgroup analyses were performed to reduce the bias between the two groups. The primary outcomes of the study were the overall survival (OS) and progression-free survival (PFS). The secondary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: A total of 104 patients were enrolled in this study: 41 in the triple therapy group and 63 in the monotherapy group. After PSM analysis, each group included 37 patients. The median OS and PFS were significantly longer in the triple therapy group than in the monotherapy group in the whole cohort (median OS, 18.8 vs 11.7 months, P = 0.022; median PFS, 10.5 vs 6.4 months, P = 0.012) and after PSM (median OS, 19.6 vs 12.5 months, P = 0.030; median PFS, 10.5 vs 6.7 months, P = 0.008). Furthermore, the treatment modality was an independent prognostic factor for OS (hazard ratio [HR]: 0.449, 95% confidence interval [CI]: 0.240-0.840, P = 0.012) and PFS (HR: 0.406, 95% CI: 0.231-0.713, P = 0.002) according to the multivariate cox regression analysis. A greater ORR was also observed in the triple therapy group (ORR: 56.7% vs 32.4%, P = 0.035). No significant difference was observed in DCR between the two groups (83.7% vs 72.9%, P = 0.259). Conclusion: The triple therapy was superior to the monotherapy regarding OS, PFS, and ORR of advanced HCC patients.

Anterior direct decompression significantly relieves spinal cord high signal in patients with ossification of the posterior longitudinal ligament: a case-control study.

BACKGROUND: In patients with cervical spondylotic myelopathy caused by ossification of the posterior longitudinal ligament, high cord signal (HCS) is frequently observed. However, limited research has investigated the variations in HCS improvement resulting from different surgical approaches. This study aims to explore the potential relationship between the choice of surgical approach and the postoperative improvement of intramedullary high signal in ossification of the posterior longitudinal ligament (OPLL) patients. METHODS: We extensively reviewed the patients' medical records, based on which demographic information such as gender, age, and body mass index (BMI) were recorded, and assessed the severity of the patients' neurological status preoperatively and postoperatively by using the Japanese Orthopedic Association score (JOAs), focusing on consecutive preoperative and postoperative Magnetic resonance imaging (MRI) T2WI measurements, to study the statistical correlation between the improvement of HCS and the choice of surgical approach. RESULTS: There were no significant differences in demographic, imaging parameters, and clinical symptoms between patients undergoing anterior and posterior surgery (p > 0.05, Table 1). However, both improvement in JOAs (Recovery2) and improvement in HCS (CR2) were significantly better in the anterior surgery group two years after surgery (p < 0.05, Table 1). Multifactorial logistic regression analysis revealed that posterior surgery and higher preoperative signal change ratio (SCR) were identified as risk factors for poor HCS improvement at the two-year postoperative period (p < 0.05, Table 2). Table 1 Differences in demographic, imaging parameters, and clinical symptoms in patients with anterior and posterior approach Anterior approach Posterior approach P-Values Demographic data  Sex (male/female) 10/12 6/17 0.175  Age 58.59 ± 5.68 61.43 ± 9.04 0.215  Hypertension 14/8 14/9 0.848  Diabetes 16/6 19/4 0.425  BMI 25.58 ± 4.72 26.95 ± 4.58 0.331  Smoking history 19/3 16/7 0.175 Preoperative measured imaging parameters  Preoperative SCR 1.615 ± 0.369 1.668 ± 0.356 0.623  CR1 0.106 ± 0.125 0.011 ± 0.246 0.08  CNR 0.33 ± 0.073 0.368 ± 0.096 0.15  C2-7 Cobb angle 8.977 ± 10.818 13.862 ± 13.191 0.182  SVA 15.212 ± 8.024 17.46 ± 8.91 0.38  mK-line INT 3.694 ± 3.291 4.527 ± 2.227 0.323 Imaging follow-up  6 months postoperative SCR 1.45 ± 0.44 1.63 ± 0.397 0.149  2 years postoperative SCR 1.26 ± 0.19 1.65 ± 0.35 0.000**  CR2 0.219 ± 0.14 - 0.012 ± 0.237 0.000** Clinical symptoms  Preoperative JOAs 10.64 ± 1.59 10.83 ± 1.47 0.679  6 months postoperative JOAs 11.82 ± 1.37 11.65 ± 1.4 0.69  2 years postoperative JOAs 14.18 ± 1.01 12.52 ± 2.06 0.001**  Recovery1 0.181 ± 0.109 0.128 ± 0.154 0.189  Recovery2 0.536 ± 0.178 0.278 ± 0.307 0.001** *, statistical significance (p < 0.05). **, statistical significance (p < 0.01) BMI = body mass index. SCR = the signal change ratio between the localized high signal and normal spinal cord signal at the C7-T1 levels. CR1 = the regression of high cord signals at 6 months postoperatively (i.e., CR1 = (Preoperative SCR-SCR at 6 months postoperatively)/ Preoperative SCR). CR2 = the regression of high cord signal at 2 years postoperatively (i.e., CR2 = (Preoperative SCR-SCR at 2 years postoperatively)/ Preoperative SCR). CNR = canal narrowing ratio. SVA = sagittal vertical axis. mK-line INT = modified K-line interval. JOAs = Japanese Orthopedic Association score. Recovery1 = degree of JOAs recovery at 6 months postoperatively (i.e., Recover1 = (JOAs at 6 months postoperatively-Preoperative JOAs)/ (17- Preoperative JOAs)). Recovery2 = degree of JOAs recovery at 2 years postoperatively (i.e., Recover2 = (JOAs at 2 years postoperatively-Preoperative JOAs)/ (17-Preoperative JOAs)) Table 2 Linear regression analyses for lower CR2 values 95% CI P value Uni-variable analyses Demographic data  Sex (male/female) - 0.01 0.221 0.924  Age - 0.015 0.003 0.195  Hypertension - 0.071 0.204 0.334  Diabetes - 0.195 0.135 0.716  BMI - 0.375 0.422 0.905  Smoking history - 0.249 0.077 0.295  Surgical approach - 0.349 - 0.113 0.000# Preoperative measured imaging parameters  C2-7 Cobb angle - 0.009 0.002 0.185  SVA - 0.008 0.008 0.995  mK-line INT - 0.043 0.005 0.122  Preoperative SCR 0.092 0.445 0.004#  CR1 0.156 0.784 0.004#  CNR - 0.76 0.844 0.918 Multi-variable analyses  Surgical approach - 0.321 - 0.118 0.000**  Preoperative SCR 0.127 0.41 0.000**  CR1 - 0.018 0.501 0.067 #, variables that achieved a significance level of p < 0.1 in the univariate analysis *statistical significance (p < 0.05). **statistical significance (p < 0.01) BMI = body mass index. SCR = the signal change ratio between the localized high signal and normal spinal cord signal at the C7-T1 levels. CR1 = the regression of high cord signals at 6 months postoperatively (i.e., CR1 = (Preoperative SCR-SCR at 6 months postoperatively)/ Preoperative SCR). CR2 = the regression of high cord signal at 2 years postoperatively (i.e., CR2 = (Preoperative SCR-SCR at 2 years postoperatively)/ Preoperative SCR). CNR = canal narrowing ratio. SVA = sagittal vertical axis. mK-line INT = modified K-line interval CONCLUSIONS: For patients with OPLL-induced cervical spondylotic myelopathy and intramedullary high signal, anterior removal of the ossified posterior longitudinal ligament and direct decompression offer a greater potential for regression of intramedullary high signal. At the same time, this anterior surgical strategy improves clinical neurologic function better than indirect decompression in the posterior approach.

Tools and techniques for the discovery of therapeutic aptamers: recent advances.

INTRODUCTION: The pursuit of novel therapeutic agents for serious diseases such as cancer has been a global endeavor. Aptamers characteristic of high affinity, programmability, low immunogenicity, and rapid permeability hold great promise for the treatment of diseases. Yet obtaining the approval for therapeutic aptamers remains challenging. Consequently, researchers are increasingly devoted to exploring innovative strategies and technologies to advance the development of these therapeutic aptamers. AREAS COVERED: The authors provide a comprehensive summary of the recent progress of the SELEX (Systematic Evolution of Ligands by EXponential enrichment) technique, and how the integration of modern tools has facilitated the identification of therapeutic aptamers. Additionally, the engineering of aptamers to enhance their functional attributes, such as inhibiting and targeting, is discussed, demonstrating the potential to broaden their scope of utility. EXPERT OPINION: The grand potential of aptamers and the insufficient development of relevant drugs have spurred countless efforts for stimulating their discovery and application in the therapeutic field. While SELEX techniques have undergone significant developments with the aid of advanced analysis instruments and ingeniously updated aptameric engineering strategies, several challenges still impede their clinical translation. A key challenge lies in the insufficient understanding of binding conformation and susceptibility to degradation under physiological conditions. Despite the hurdles, our opinion is optimistic. With continued progress in overcoming these obstacles, the widespread utilization of aptamers for clinical therapy is envisioned to become a reality soon.

PEGylated exenatide injection (PB-119) improves beta-cell function and insulin resistance in treatment-naïve type 2 diabetes mellitus patients.

Objective: PB-119, a PEGylated exenatide injection, is a once-weekly glucagon-like peptide-1 receptor agonist. In the present study, we aimed to evaluate the effects of PB-119 on insulin resistance and beta-cell function in Chinese patients with type 2 diabetes mellitus (T2DM) to uncover its antidiabetic characteristics. Methods: A total of 36 Chinese T2DM patients were randomized to receive 25 µg and 50 µg PB-119 once weekly and exenatide (5-10 µg injected under the skin 2 times a day adjusted by the doctor) for 12 weeks. Oral mixed meal tolerance tests were conducted before the study and on Day 79. The data were fitted to estimate beta-cell function and insulin sensitivity parameters using the SAAM II package integrating the oral minimal model (OMM), which was compared with Homeostatic Model Assessment (HOMA) analysis results. Results: Exenatide or PB-119 treatment, compared with their baseline, was associated with higher beta-cell function parameters (φb, φs and φtot), disposition index, insulin secretion rates, and a lower glucose area under the curve. High-dose PB-119 also has a higher insulin resistance parameter (SI) than the baseline, but HOMA-IR did not. For the homeostatic model assessment parameters, HOMA-IR showed no statistically significant changes within or between treatments. Only high-dose PB-119 improved HOMA-ß after 12 weeks of treatment. Conclusion: After 12 weeks of treatment, PB-119 decreased glycemic levels by improving beta-cell function and insulin resistance.

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies.

OBJECTIVE: Renal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. METHODS: A systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. RESULTS: The overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose-exposure-effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. CONCLUSION: Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.

Unraveling the Possibilities: Recent Progress in DNA Biosensing.

Due to the advantages of its numerous modification sites, predictable structure, high thermal stability, and excellent biocompatibility, DNA is the ideal choice as a key component of biosensors. DNA biosensors offer significant advantages over existing bioanalytical techniques, addressing limitations in sensitivity, selectivity, and limit of detection. Consequently, they have attracted significant attention from researchers worldwide. Here, we exemplify four foundational categories of functional nucleic acids: aptamers, DNAzymes, i-motifs, and G-quadruplexes, from the perspective of the structure-driven functionality in constructing DNA biosensors. Furthermore, we provide a concise overview of the design and detection mechanisms employed in these DNA biosensors. Noteworthy advantages of DNA as a sensor component, including its programmable structure, reaction predictility, exceptional specificity, excellent sensitivity, and thermal stability, are highlighted. These characteristics contribute to the efficacy and reliability of DNA biosensors. Despite their great potential, challenges remain for the successful application of DNA biosensors, spanning storage and detection conditions, as well as associated costs. To overcome these limitations, we propose potential strategies that can be implemented to solve these issues. By offering these insights, we aim to inspire subsequent researchers in related fields.

Model-Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome.

The exposure to ticagrelor (BRILINTA) is higher in the East Asian population compared with the White population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic (PopPK) model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under the concentration-time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning (ML) methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, calcium channel blockers, antidiabetic medications, ß-blockers, peripheral vascular disease, diabetes, transient ischemic attack, sex, and proton pump inhibitor. In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC-AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC-AUC of 0.81. Moreover, the PopPK model and ML algorithm were used to bridge the real-world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.

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Necrotizing enterocolitis (NEC), with the main manifestations of bloody stool, abdominal distension, and vomiting, is one of the leading causes of death in neonates, and early identification and diagnosis are crucial for the prognosis of NEC. The emergence and development of machine learning has provided the potential for early, rapid, and accurate identification of this disease. This article summarizes the algorithms of machine learning recently used in NEC, analyzes the high-risk predictive factors revealed by these algorithms, evaluates the ability and characteristics of machine learning in the etiology, definition, and diagnosis of NEC, and discusses the challenges and prospects for the future application of machine learning in NEC.

Theoretical Study on the Mechanism of Cobalt-Catalyzed C-O Silylation and Stannylation.

Organosilicon and organotin compounds have been widely used in many fields, such as organic synthesis, materials science, and biochemistry, because of their unique physical and electronic properties. Recently, two novel compounds containing C-Si or C-Sn bonds have been synthesized. These compounds can be used for late modification of drug-like molecules such as probenecid, duloxetine, and fluoxetine derivatives. However, the detailed reaction mechanisms and the influencing factors that determine selectivity are still unclear. Moreover, several questions remain that are valuable to investigate further, such as (1) the influence of the solvent and the lithium salt on the reaction of the Si/Sn-Zn reagent, (2) the stereoselective functionalization of C-O bonds, and (3) the differences between silylation and stannylation. In the current study, we have explored the above issues with density functional theory and have found that stereoselectivity was most likely caused by the oxidative addition of cobalt to the C-O bond of alkenyl acetate with chelation assistance and that transmetalation was most likely the rate-determining step. For Sn-Zn reagents, the transmetalation was achieved by anion and cation pairs, whereas for Si-Zn reagents, the process was facilitated by Co-Zn complexes.

Preliminary Study on Retrograde Recanalization of Radial Artery Occlusion Through Distal Radial Artery Access: a Single-Center Experience.

PURPOSE: Radial artery occlusion (RAO) is an unresolved complication after transradial artery (TRA) puncture. The aim of this observational study was to assess the feasibility and safety of retrograde recanalization of RAO through distal transradial access (dTRA). METHODS: From June 2021 to March 2022, 28 consecutive patients with successful puncture and intubation through the dTRA in the anatomical snuffbox and RAO confirmed by angiography were enrolled. RESULTS: Among the 28 patients, 27 (96.4%) patients with RAO were successfully retrogradely recanalized through the dTRA and successfully underwent coronary angiography or coronary intervention. After the procedure, only 1 (3.7%) patient developed a forearm hematoma, and there were no other bleeding complications or nerve disorders. CONCLUSIONS: DTRA is a safe and feasible approach for retrograded recanalization of RAO, with a high procedure success rate and few complications.

Analysis of Altered Flowering Related Genes in a Multi-Silique Rapeseed (Brassica napus L.) Line zws-ms Based on Combination of Genome, Transcriptome and Proteome Data.

Based on previous researches, we further investigated the multi-silique trait in rapeseed (Brassica napus L.) line zws-ms. In this study, we used a relatively comprehensive list of flowering related genes in rapeseed and compared them between zws-ms and its near-isogenic line (NIL) zws-217. Genes were studied on genome, transcriptome and proteome levels and then we focused on genes with non-synonymous single nucleotide polymorphism (SNP) or frame-shift insertion-deletion (InDel), finding some genes on the list which changes their sequences. Then, combined with their annotation and the information of their orthologs, certain genes such as BnaA09g05900D, ortholog of AGAMOUS-LIKE 42 (AGL42), which encodes an MADS-box protein, were assumed as probably responsible for the multi-silique trait. Also, we analyzed the Differentially Accumulated Proteins (DAPs) between zws-ms and zws-217, revealing some genes involved in homologous recombination and mismatch repair pathways. Since the development of flowers/siliques is crucial to crops and it influences the yield of rapeseed, this study paved a way to deeply understand the mechanism of the multi-pistil flower formation, which may facilitate researches on rapeseed production in future.

Rational Design of Vinylene-Linked Covalent Organic Frameworks for Modulating Photocatalytic H2 Evolution.

Vinylene-linked covalent organic frameworks (COFs) have attracted enormous attention for photocatalytic H2 evolution from water because of their fully conjugated structures, high chemical stabilities, and enhanced charge-carrier mobilities. In this work, two novel vinylene-linked COFs with tuned cyano contents were successfully synthesized and then employed as photocatalysts for H2 generation. Notably, the photocatalytic H2 production rate of the COF with the higher cyano content reached 73 µmol h-1 under visible light irradiation, which is 2.4 times higher than that with the lower content (30 µmol h-1 ). Both the experimental and computational results demonstrated that the rational design incorporating cyano groups into COF skeletons could precisely tune the corresponding energy levels, expand the visible-light absorption, and improve the photoinduced charge separation. This work not only provides a simple method for modulating the photocatalytic activities of COFs at the molecular level, but also affords interesting insights into the relationship between their structures and photocatalytic performance.