The mediation effect of health literacy on social support and health lifestyle of patients with chronic diseases.

BACKGROUND: Previous studies have identified the antecedents of the lifestyle of many patients with chronic diseases. However, the mechanism of social support affecting the lifestyle of patients with chronic diseases is unclear, and the role of health literacy in social support affecting the lifestyle of patients with chronic diseases has not been found. Therefore, this study aims to explore the status quo of social support, health literacy and healthy lifestyle of patients with chronic diseases in China and the relationship among them. METHODS: Through convenient sampling, 356 patients with chronic diseases were surveyed using a health promoting lifestyle scale, a chronic disease patients' health literacy scale and a social support scale. RESULTS: There was a pairwise positive correlation between social support, health lifestyle and health literacy (R = 0.397,0.356,0.556, P < 0.01). After controlling gender, age and education level, it is found that social support has a positive impact on health lifestyle, and health literacy plays an intermediary role between social support and health lifestyle, accounting for 45.78 % of the total effect. CONCLUSION: To promote the healthy lifestyle of patients with chronic diseases and delay the development of the disease, we should strengthen social support for patients with chronic diseases; We should simultaneously take various measures to improve their health literacy.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a novel farnesoid X receptor (FXR) agonist-TQA3526 in healthy Chinese volunteers: a double-blind, randomized, placebo-controlled, dose-escalation, food effect phase I study.

Background: TQA3526 is a novel farnesoid X receptor agonist developed to treat non-alcoholic steatohepatitis (NASH) or primary biliary cholangitis (PBC). This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of TQA3526 in healthy Chinese patients.Methods: Healthy subjects aged 18-55 years were enrolled in this double-blinded, first-in-human, placebo-controlled single ascending dose (1, 2, 5, and 10 mg) comprising food effect investigation (10 mg) and multiple dose study (2 mg and 0.2 + 0.5 + 1 mg). Safety was assessed on the basis of adverse events. The TQA3526 concentrations were analysed in the PK study. Alkaline phosphatase (ALP), fibroblast growth factor-19 (FGF19), bile acid precursor C4 (7α-hydroxy-cholest-4-ene-3-one), cholesterol, and bile acid were selected for PD analysis.Results: TQA3526 was well tolerated, and the primary adverse drug reaction was pruritus, as expected. The exposure to TQA3526 increased in a dose-dependent manner after a single dose of 1-10 mg. The exposure was higher after food intake. A steady state was reached around 5 days, and obvious plasma accumulation of TQA3526 was observed in the multiple dose study. TQA3526 increased circulating FGF-19 and decreased C4 levels in a dose-dependent manner. ALP increased only mildly in the 2 mg multiple dose cohort.Conclusions: TQA3526 (<10 mg/day) was safe and tolerable in healthy Chinese subjects. The safety profile and PK/PD characteristics of TQA3526 support further evaluation of patients with NASH or PBC. This study was registered at https://www.chictr.org.cn/ under the identifier ChiCTR1800019570.

Safety, tolerability and pharmacokinetics of forsythin in healthy subjects: a double-blinded, placebo-controlled single-dose and multiple-dose escalation and food effect study.

BACKGROUND: Forsythin, an active compound from Forsythiae Fructus, has the potential to treat the common cold and influenza through its antipyretic-analgesic, anti-inflammatory and antiviral effects. The safety, tolerability and pharmacokinetic (PK) profile of forsythin were evaluated in healthy Chinese subjects. METHODS: This phase 1a study included three parts: double-blind, randomized, placebo-controlled single-ascending-dose (SAD) (50, 100, 200, 400, 600 or 800 mg), food effect investigation (100 mg) and multiple-ascending-dose (MAD) (50, 100 or 200 mg TID for 5 days). RESULTS: Forsythin is safe and tolerable in healthy Chinese subjects. The rates of adverse events (AEs) in the forsythin cohort were similar to those in the placebo cohort. Forsythin is well-absorbed after single or multiple doses and is extensively metabolized. The primary metabolites were aglycone M1, M1 sulphate (M2) and M1 glucuronide (M7). Exposure to forsythin (100 mg) was higher after food intake by approximately 1.4-fold, whereas M2 and M7 did not change. The steady state was reached around three days in the MAD study. Forsythin, M2 and M7 accumulation on day 5 was 1, 3 and 2, respectively. CONCLUSIONS: The safety and PK profiles of forsythin support further evaluation of its efficacy in individuals with the common cold or influenza.

Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations.

The purpose of this study was to determine the effect of amiodarone (Ami) on hERG-T618I currents in HEK293 cells. A transient transfection method was used to transfer hERG-T618I and hERG wild-type (WT) channel plasmids into HEK293 cells. An extracellular local perfusion method was used for administration. Currents were recorded using the whole-cell patch clamp technique. Ami (10 µM) had a greater retarding effect on the hERG-T618I channel than WT (P < 0.05). The half-inhibitory concentration for the mutant was approximately 1.82 times that of WT (P < 0.05). The WT current inhibition fraction against Ami was significantly greater than T618I in the same cell (P < 0.05). The STEP current of the mutant channel was larger than the WT channel, but the characteristic of inward rectification did not appear. Ami reduced the STEP current of the mutant channel, and the steady-state activation curve indicated that channel activation decreased (P > 0.05). Ami restored partial inactivation of the mutant channel. Ami effectively reduced the current in the phase 2 plateau (P < 0.05), but the phase 3 current did not exhibit the characteristics of a WT current. Ami inhibited hERG-T618I currents on HEK293 cells, but the effect was weaker than WT.

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

Comparison of Pharmacokinetic Similarity, Immunogenicity, and Safety of Ustekinumab and BAT2206 in Healthy Chinese Male Subjects in a Double-Blind, Randomized, Single-Dose, Parallel-Group Phase I Trial.

OBJECTIVE: We aimed to evaluate the similarity of BAT2206 to its originator, ustekinumab, including pharmacokinetic profiles, immunogenicity, and safety in healthy Chinese male subjects. METHODS: This was a double-blinded, randomized, single-dose, parallel-group clinical trial, in which 270 healthy male subjects were enrolled to receive a single subcutaneous injection (45 mg) of either BAT2206 or ustekinumab (European Union or USA) at a 1:1:1 ratio. The pairwise pharmacokinetic similarities and the safety and immunogenicity of both drugs were evaluated and compared. RESULTS: The results showed that the 90% confidence interval of the geometric mean ratio for primary pharmacokinetic parameters (maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity) among BAT2206 and ustekinumab (USA or European Union sourced) groups were all within the predefined equivalent interval of 80-125%. Furthermore, all the groups had similar incidences of treatment-emergent adverse events, in which the majority of cases belonged to Common Terminology Criteria for the Classification of Adverse Events Grade 1 or 2. Anti-drug antibodies were detected in 54 (20.1%) subjects, namely 24 (26.7%), 13 (14.8%), and 17 (18.9%) patients in the BAT2206, ustekinumab (European Union), and ustekinumab (USA) groups, respectively. In contrast, the incidences of positive neutralizing antibodies were similar among the three groups. CONCLUSIONS: Pharmacokinetic similarity between BAT2206 and ustekinumab (USA or European Union sourced) was confirmed. The three groups had similar safety profiles, and the investigational drugs were well tolerated by subjects. CLINICAL TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT04371185).

Distinguishing functional and structural MRI abnormalities between bipolar and unipolar depression.

Background: This study aims to investigate the underlying characteristics of spontaneous brain activity by analyzing the volumes of the hippocampus and parahippocampal gyrus, as well as the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo), in order to differentiate between bipolar disorder (BD) and unipolar depressive disorder. Methods: A total of 46 healthy controls, 58 patients with major depressive disorder (MDD), and 61 patients with BD participated in the study and underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. The researchers calculated the differences in volume, fALFF, and ReHo values among the three groups. Additionally, they conducted correlation analyses to examine the relationships between clinical variables and the aforementioned brain measures. Results: The results showed that the BD group exhibited increased fALFF in the hippocampus compared to the healthy control (HC) and MDD groups. Furthermore, the ReHo values in the hippocampus and parahippocampal gyrus were significantly higher in the BD group compared to the HC group. The findings from the person correlation analysis indicated a positive relationship between ReHo values in the hippocampus and both HAMD and HAMA scores. Moreover, there was no correlation between the volumes, fALFF, and ReHo values in the hippocampus and parahippocampal gyrus, and cognitive function levels (RBANS). Conclusion: Taken together, these aberrant patterns of intrinsic brain activity in the hippocampus and parahippocampal gyrus may serve as quantitative indicators for distinguishing between BD and unipolar depression.

The effect of a single escalating dose of long-acting recombinant human follicle-stimulating hormone Fc fusion protein (KN015) on healthy, pituitary-suppressed women: first-in-human and randomized study on its pharmacokinetics, pharmacodynamics, and tolerability.

OBJECTIVE: KN015 is a long-acting, recombinant human follicle-stimulating hormone Fc fusion protein that induces follicle development. This first-in-human study evaluated the effect of KN015 on healthy, pituitary-suppressed women and examined its pharmacokinetics, pharmacodynamics, and tolerability. METHODS: This phase I study was a double-blind, randomized, and placebo-controlled design with a single ascending dose (20, 40, and 60 µg, respectively). RESULTS: After subcutaneous administration of a single dose, the maximum serum KN015 concentrations reached 1.57, 2.78, and 3.62 ng/mL, respectively, after baseline adjustment. Over this dose range, the median Tmax occurred at 240-312 h, and the half-life (t½) was 752-1160 h. Dose proportionality was shown across the studied dose range. In most subjects, follicular growth was observed, and the number and diameter of the follicles increased with an increasing dose. In the 40-µg and 60-µg groups, the mean numbers of follicles with a diameter of ≥17 mm were 3 and 4, respectively. There was no significant difference in adverse events between the KN015 and placebo groups. KN015 antibody was not detected in any of the dosage groups. CONCLUSION: The administration of a single ascending dose of KN015 was tolerated and able to induce follicular growth. TRIAL REGISTRATION: This trial is registered at the Chinese Clinical Trials website (http://www.chinadrugtrials.org.cn/index.html # CTR20160741) and ClinicalTrials.gov (https://clinicaltrials.gov/ # NCT03192527).

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.

BACKGROUND: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. RESEARCH DESIGN AND METHODS: This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. RESULTS: In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). CONCLUSIONS: Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

MicroRNA-138 Regulates Spinal Cord Development by Activating the Shh in Fetal Rats.

INTRODUCTION: Dysregulation of spinal cord development can lead to serious neuronal damage and dysfunction, causing significant health problems in newborns. MiRNA-138 appears to be crucial for proliferation, differentiation, and apoptosis of cells. However, the regulation of miRNA-138 and downstream molecules in embryonic spinal cord development remain elusive. The aim of this experiment is to determine whether overexpression of miRNA-138 or RNA interference (RNAi) can regulate the development of spinal cord in fetal rats. METHODS: Two plasmid vectors including pLenti-III-mico-GFP (miRNA-138 open reading frame [ORF]) and pLenti-III-miR-Off (miRNA-138 short hairpin) were constructed and injected into the tail vein of rats on the 14th day of pregnancy. Hematoxylin-eosin (HE) staining was used to observe the cell morphology. QRT-PCR, Western blot, and immunostaining confirmed the regulatory relationship between miRNA-138 and downstream molecules sonic hedgehog (Shh). RESULTS: Overexpression of miRNA-138 increased neuron regeneration significantly and decreased neuronal apoptosis when compared with the control. Silencing of miRNA-138 increased neuronal apoptosis and spinal cord atrophy significantly. Furthermore, miRNA-138 ORF treatment effectively increased the expression level of miRNA-138 and also upregulated the level of Shh. Comparatively, knockdown of miRNA-138 downregulated Shh levels in myelodysplastic regions. CONCLUSION: These findings indicated that miRNA-138 overexpression could protect the spinal cord development of fetal rats, and the underlying mechanisms were associated with Shh expression. The present study provides a novel strategy to promote the molecular mechanism of embryonic spinal cord development.

Neurodevelopmental disorders and anti-epileptic treatment in a patient with a SATB1 mutation: A case report.

SATB1 variants causing developmental delay with dysmorphic facies and dental anomalies have been reported in a small cohort. Most patients present epilepsy as a main clinical feature in neurodevelopmental disorders; however, its treatment is unknown. Here, we present a Chinese patient with a de novo truncating variation in SATB1 who presented with mild developmental delay. We disclose the detailed anti-epileptic pharmacological treatment that enabled a favorable outcome. Our study provides important information that may aid clinicians in the prognosis and treatment of rare neurological developmental disorders caused by gene mutations.

Molecular Spectrum, Ethnic and Geographical Distribution of Thalassemia in the Southern Area of Hainan, China.

Background: Thalassemia is one of the most common genetic diseases in southern China. Accurate population frequency data regarding the occurrence and distribution of thalassemia are important for designing appropriate prevention strategies for thalassemia. This study aims to reveal the molecular spectrum, ethnic and geographical distribution of thalassemia in the southern area of Hainan Province, China. Methods: A total of 9813 suspected carriers of thalassemia were screened for genetic analysis by using the PCR-reverse dot blot hybridization method targeting three known deletions of α-thalassemias (--SEA, -α3.7, and -α4.2), three nondeletional mutations of α-thalassaemias (αCS, αQS, and αWS) and the 17 most common mutations of ß-thalassaemias in the Chinese population. Results: Approximately 6,924 subjects were genetically diagnosed as thalassemia carriers or patients, including 5812 cases of α-thalassemia (83.9%), 369 cases of ß-thalassemia (5.3%), and 743 cases of α-composite ß-thalassemia (10.7%). A total of 21 distinct genotypes were identified among the 5,812 α-thalassemia carriers, -α4.2/αα, -α3.7/αα, and -α3.7/-α4.2 were the most common α-thalassemia genotypes. The most frequent ß-thalassemia genotype was ßCD41-42/ßN, with a notable proportion of 69.6%, followed by the ß-28M /ßN, ßIVS-II-654/ßN, ßCD71-72/ßN, ßE/ßN, and ßCD17/ßN genotypes. In addition, 37 genotypes were detected among the 743 cases of both α- and ß-thalassemia mutations. The α-thalassemia genotypes were most commonly found in the Li people, who accounted for 73.5% of α-thalassemia carriers. The ß-thalassemia genotypes were most commonly identified in the Han people, who accounted for 59.4% of ß-thalassemia carriers. Among the subjects carrying both α- and ß-thalassemia variations, only three ethnic minorities were identified, including the Li, Han, and Miao people, accounting for 82.0, 17.4, and 0.7%, respectively. Conclusions: Our study indicates that there is high genetic heterogeneity, geographical and ethnic differences in thalassemia in populations in the southern area of Hainan Province. These findings will be helpful in guiding genetic counseling and prenatal diagnosis of thalassemia in Hainan Province.

Dual functional amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles for the monitoring and inhibition of insulin amyloid fibrillation based on carbohydrate-protein interactions.

Amyloid-related diseases, such as Alzheimer's disease, are all considered to be related to the deposition of amyloid fibrils in the body. Insulin is a protein hormone that easily undergoes aggregation and fibrillation to form more toxic amyloid-like fibrils. So far, it is still challenging to develop a new protocol to study the ex situ detection and in situ inhibition of amyloid fibrillation. Here, we reported a modular synthetic strategy to construct nine amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles (FONs, TPE2/3/4X, X = G, M or S) with glucosamine (G), mannose (M) or sialic acid (S) as a hydrophilic moiety and tetraphenylethylene (TPE) as a hydrophobic AIE core. The carbohydrate-protein interactions between insulin and TPE2/3/4X were investigated by fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy. Among the nine FON AIEgens, TPE2G was screened out as the best dual functional FON for the ex situ detection and in situ inhibition of the insulin fibrillation process, indicating that the glycosyl moiety exhibited a crucial effect on the detection/inhibition of insulin fibrillation. The molecular dynamics simulation results showed that the binding mechanism between TPE2G and native insulin was through weak interactions dominated by van der Waals interactions and supplemented by hydrogen bonding interactions to stabilize an α-helix of the insulin A chain, thereby inhibiting the insulin fibrillation process. This work provides a powerful protocol for the further research of amyloid-related diseases based on carbohydrate-protein interactions.

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects.

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects. Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25-200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions. Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33-0.50 h and 0.62-0.75 h, respectively, and their mean half-life was 2.5-12.3 h and 49.7-53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC). Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients. Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

A Reference-Scaled Average Bioequivalence Study of Azithromycin Tablets Manufactured in China and the United States: An Open-Label, Randomized, Single-Dose, 3-Way Crossover Study in Healthy Chinese Subjects Under Fasted and Fed Conditions.

Azithromycin (Zithromax) is an azalide antibiotic that binds to the 50S ribosomal subunit of the susceptible organism and thereby interferes with its protein synthesis. An open-label, randomized, single-dose, 3-way crossover bioequivalence study was conducted to compare the rate and extent of absorption of the azithromycin 250-mg tablet manufactured at Pfizer Dalian (China) and that at Pfizer Barceloneta (United States) under fasted and fed conditions in healthy Chinese subjects. This study aimed to support a generic consistency evaluation program, initiated by the National Medical Products Administration, for evaluating the quality and efficacy of the products manufactured in China. In the study, the within-subject standard deviation for area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fasted condition was <0.294, and the 90%CI for the ratio was within 80% to 125%; the within-subject SDs for serum peak concentration in the fasted condition, area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fed condition, and serum peak concentration in the fed condition, were all >0.294, with the upper confidence bounds being <0.00, and the point estimates of the ratios being within 80% to 125%. The results support the bioequivalence between azithromycin tablets manufactured in China and the United States in fasted and fed conditions, with both tablets showing an acceptable safety/tolerability profile in the studied population.

Effects of Kangdaxin on myocardial fibrosis in heart failure with preserved ejection fraction rats.

Background: This study aimed to explore the effects of Kangdaxin oral liquid on myocardial fibrosis in heart failure with preserved ejection fraction (HFpEF) rats. Methods: A total of 30 Sprague Dawley (SD) rats were randomly divided into 3 groups Sham operation group (Sham), HFpEF group (HFpEF), and HFpEF with drug intervention group (HFpEF + I). Rats in HFpEF + I group were given Kangdaxin oral liquid at a dose of 2.7 mL/(kg·d). After modeling or treatment, the value of E/A and E/e' in each group of rats were measured by echocardiography. The N-terminal pro b-type natriuretic peptide (NT-proBNP) level was determined by enzyme-linked immunosorbent assay (ELISA). Heart weight/body mass index (Hw/W) and left ventricular weight/body mass index (LVw/W) were calculated after the rats were sacrificed; the transforming growth factor-ß1 (TGF-ß1) protein expression level in cardiac tissue was detected by western blot. Results: Compared with sham group, the values of diastolic function item (E/A) and mitral annular early diastolic velocity (E/e') in HFpEF group were significantly decreased, and the level of NT-proBNP was significantly increased (P<0.05). Compared with HFpEF group, the value of E/A and E/e' in HF + I group were significantly increased, and the level of NT-proBNP was significantly decreased (P<0.05). Compared with sham group, the expression of TGF-ß1 protein in heart tissue of HFpEF group were significantly increased (P<0.05). Compared with HFpEF group, the expression of TGF-ß1 protein in HFpEF + I group were significantly decreased (P<0.05). Conclusions: Kangdaxin oral liquid has protective effect on heart in HFpEF rats, which can reduce the protein expression of TGF-ß1 in the heart tissue of HFpEF rats. This may be a possible mechanism to inhibit myocardial fibrosis and improve cardiac diastolic function.

A Class of Shark-Derived Single-Domain Antibodies can Broadly Neutralize SARS-Related Coronaviruses and the Structural Basis of Neutralization and Omicron Escape.

The identification of a novel class of shark-derived single domain antibodies, named vnarbodies that show picomolar affinities binding to the receptor binding domain (RBD) of Wuhan and Alpha, Beta, Kappa, Delta, Delta-plus, and Lambda variants, is reported. Vnarbody 20G6 and 17F6 have broad neutralizing activities against all these SARS-CoV-2 viruses as well as other sarbecoviruses, including Pangolin coronavirus and Bat coronavirus. Intranasal administration of 20G6 effectively protects mice from the challenges of SARS-CoV-2 Wuhan and Beta variants. 20G6 and 17F6 contain a unique "WXGY" motif in the complementary determining region 3 that binds to a hidden epitope on RBD, which is highly conserved in sarbecoviruses through a novel ß-sheet interaction. It is found that the S375F mutation on Omicron RBD disrupts the structure of ß-strand, thus impair the binding with 20G6. The study demonstrates that shark-derived vnarbodies offer a prophylactic and therapeutic option against most SARS-CoV-2 variants and provide insights into antibody evasion by the Omicron variant.

Regulatory emotional self-efficacy and psychological distress among medical students: multiple mediating roles of interpersonal adaptation and self-acceptance.

BACKGROUND: Psychological distress (depression, anxiety and stress) is more common among medical students than in the general population, and is an important cause of insomnia, internet addiction, substance abuse, decreased academic performance and increased suicidality in medical students. METHODS: To examine the mechanism by which regulatory emotional self-efficacy affects medical students' psychological distress, a questionnaire of 539 medical students using an interpersonal adaptability scale, regulatory emotional self-efficacy scale, self-acceptance scale and depression-anxiety-stress scale was conducted. RESULTS: ① Regulatory emotional self-efficacy, interpersonal adaptability and self-acceptance are positively correlated, but they are negatively correlated with psychological distress. ② The mediation model shows that interpersonal adaptation and self-acceptance are the mediation variables of the effect of regulatory emotional self-efficacy on psychological distress, and the total mediation effect value is -0.37, accounting for 86.05% of the total effect (-0.43). Specifically, the effect involves three paths: first, regulatory emotional self-efficacy indirectly affects psychological distress through interpersonal adaptation (effect value-0.24); second, regulatory emotional self-efficacy indirectly affects psychological distress through interpersonal adaptation and self-acceptance (effect value-0.08); and third, regulatory emotional self-efficacy indirectly affects psychological distress through self-acceptance (effect value -0.05). CONCLUSIONS: Interpersonal adaptation and self-acceptance have a significant mediating effect between regulatory emotional self-efficacy and psychological distress, and the chain mediating effect of interpersonal adaptation and self-acceptance is also significant.

Safety and pharmacokinetics of a new biosimilar trastuzumab (HL02): a Phase I bioequivalence study in healthy Chinese men.

OBJECTIVES: The study aimed to explore the bioequivalence of a proposed biosimilar HL02 vs. its reference products (US-trastuzumab) among healthy Chinese men. METHODS: In this study, nine healthy male subjects received single ascending doses of trastuzumab biosimilar (HL02, 2-8 mg/kg), and then a randomized, double-blind, two-arm, parallel study was conducted to investigate the PK similarity of HL02 (6 mg/kg) with that of US-trastuzumab as a reference drug. RESULTS: PK properties exhibited by HL02 (N = 55) were similar to those of US-trastuzumab (N = 52). The comparison of biosimilarity with US-trastuzumab showed that the 90% confidence intervals (CIs) of the ratios for Cmax, AUC0-t, and AUC0-∞ were within 80-125%. Nineteen subjects were positive for ADA and negative for NAb in both HL02 and US-trastuzumab groups. In total, 81.67% of subjects in HL02 and 78.95% in US-trastuzumab groups showed treatment-related mild or moderate adverse events, mild elevation of transaminase level being the most common adverse events (AE) recorded. CONCLUSIONS: The PK characteristics and immunogenicity exhibited by HL02 were similar to that of the reference product, US-trastuzumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

Safety, tolerability, pharmacodynamics, and pharmacokinetics of CJC-1134-PC in healthy Chinese subjects and type-2 diabetic subjects.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) mimetics are widely used for treating type 2 diabetes (T2D) with pleiotropic effects on heart and kidneys. The safety/tolerability and pharmacokinetics/pharmacodynamics ((PK/PD) of CJC-1134-PC (a long-acting GLP-1) were investigated in Chinese. METHOD: Two randomized, double-blind, placebo-controlled phase I studies were conducted. Study A: 30 healthy subjects received (subcutaneously injected) a single dose (2 mg) or titrate doses (2 + 3 and 2 + 3 + 4 mg at weekly intervals) of CJC-1134-PC. Study B: 49 T2D subjects received 10 weekly doses (1, 2, 3, and 4 mg). RESULT: CJC-1134-PC was well tolerated with gastrointestinal (GI) side effects. Higher doses increased the adverse events risk. CJC-1134-PC was steadily absorbed, with maximum plasma concentrations(Cmax) occurring at 36-72 h and 48 h after administration in healthy and T2D subjects, respectively. The steady-state exposures in T2D subjects increased more than the dose-proportionality(1-3 mg). The mean t1/2 ranged from 111.6 to 127.6 h. After four- five weeks of targeting doses, steady state was reached in T2D subjects with apparent accumulation effect. At week 11 for T2D subjects, HbA1c mean baseline change was significantly different than that of the placebo, and the fasting plasma glucose (FPG) was not significantly altered. CONCLUSION: The safety and PK/PD profiles of weekly CJC-1134-PC doses support Phase II studies with guidance on optimal-dose selection. Clinical trial registration: ChiCTR-IPC-15007190.