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Biao-Qi Chen,1 Ranjith Kumar Kankala,1,2 Ai-Zheng Chen,1,2 Ding-Zhu Yang,1 Xiao-Xia Cheng,1 Ni-Na Jiang,1,2 Kai Zhu,3,4 Shi-Bin Wang1,2 1Institute of Biomaterials and Tissue Engineering, 2Fujian Provincial Key Laboratory of Biochemical Technology, Huaqiao University, Xiamen, Fujian, 3Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, 4Shanghai Institute of Cardiovascular Disease, Shanghai, People’s Republic of China Abstract: Attempts to reflect the physiology of organs is quite an intricacy during the tissue engineering process. An ideal scaffold and its surface topography can address and manipulate the cell behavior during the regeneration of targeted tissue, affecting the cell growth and differentiation significantly. Herein, silk fibroin (SF) nanoparticles were incorporated into poly(L-lactic acid) (PLLA) to prepare composite scaffolds via phase-inversion technique using supercritical carbon dioxide (SC-CO2). The SF nanoparticle core increased the surface roughness and hydrophilicity of the PLLA scaffolds, leading to a high affinity for albumin attachment. The in vitro cytotoxicity test of SF/PLLA scaffolds in L929 mouse fibroblast cells indicated good biocompatibility. Then, the in vitro interplay between mouse preosteoblast cell (MC3T3-E1) and various topological structures and biochemical cues were evaluated. The cell adhesion, proliferation, osteogenic differentiation and their relationship with the structures as well as SF content were explored. The SF/PLLA weight ratio (2:8) significantly affected the MC3T3-E1 cells by improving the expression of key players in the regulation of bone formation, ie, alkaline phosphatase (ALP), osteocalcin (OC) and collagen 1 (COL-1). These results suggest not only the importance of surface topography and biochemical cues but also the potential of applying SF/PLLA composite scaffolds as biomaterials in bone tissue engineering. Keywords: super critical fluids, surface topography, bone engineering, cellular adhesion, alkaline phosphatase

Background: The biologics derived from human amniotic membranes (AMs) demonstrate potential pain-inhibitory effects in clinical settings. However, the molecular basis underlying this therapeutic effect remains elusive. HC-HA/PTX3 is a unique water-soluble regenerative matrix that is purified from human AMs. We examined whether HC-HA/PTX3 can modulate the gene networks and transcriptional signatures in the dorsal root ganglia (DRG) neurons transmitting peripheral sensory inputs to the spinal cord. Methods: We conducted bulk RNA-sequencing (RNA-seq) of mouse DRG neurons after treating them with HC-HA/PTX3 (15 µg/mL) for 10 min and 24 h in culture. Differential gene expression analysis was performed using the limma package, and Gene Ontology (GO) and protein-protein interaction (PPI) analyses were conducted to identify the networks of pain-related genes. Western blotting and in vitro calcium imaging were used to examine the protein levels and signaling of pro-opiomelanocortin (POMC) in DRG neurons. Results: Compared to the vehicle-treated group, 24 h treatment with HC-HA/PTX3 induced 2047 differentially expressed genes (DEGs), which were centered on the ATPase activity, receptor-ligand activity, and extracellular matrix pathways. Importantly, PPI analysis revealed that over 50 of these DEGs are closely related to pain and analgesia. Notably, HC-HA/PTX3 increased the expression and signaling pathway of POMC, which may affect opioid analgesia. Conclusions: HC-HA/PTX3 induced profound changes in the gene expression in DRG neurons, centered around various neurochemical mechanisms associated with pain modulation. Our findings suggest that HC-HA/PTX3 may be an important biological active component in human AMs that partly underlies its pain inhibitory effect, presenting a new strategy for pain treatment.

Background: In patients with type 2 diabetes mellitus (T2DM), the risk of hypoglycemia also occurs in at a time-in-range (TIR) of > 70%. The hemoglobin glycation index (HGI) is considered the best single factor for predicting hypoglycemia, and offers new perspectives for the individualized treatment of patients with well-controlled blood glucose levels that are easily ignored in clinical settings., Aim: To investigate the relationship between HGI and hypoglycemia and the implications of HGI on hypoglycemia in T2DM with TIR > 70%., Methods: All participants underwent a 7-days continuous glucose monitoring (CGM) using a retrospective CGM system. We obtained glycemic variability indices using the CGM system. We defined HGI as laboratory hemoglobin A1c minus the glucose management indicator. Patients were categorized into low HGI (HGI < 0.5) and high HGI groups (HGI ≥ 0.5) according to HGI median (0.5). Logistic regression and receiver operating characteristic curve analyses were used to determine the risk factors for hypoglycemia., Results: We included 129 subjects with T2DM (54.84 ± 12.56 years, 46% male) in the study. Median TIR score was 90%. The high HGI group exhibited lower TIR and greater time below range with higher hemoglobin A1c than the low HGI group; this suggests more glycemic excursions and an increased incidence of hypoglycemia in the high HGI group. Multivariate analyses revealed that mean blood glucose, standard deviation of blood glucose and HGI were independent risk factors for hypoglycemia. Receiver operating characteristic curve analysis indicated that the HGI was the best predictor of hypoglycemia. In addition, the optimal cut-off points for HGI, mean blood glucose, and standard deviation of blood glucose in predicting hypoglycemia were 0.5%, 7.2 mmol/L and 1.4 mmol/L respectively., Conclusion: High HGI was significantly associated with greater glycemic excursions and increased hypoglycemia in patients with TIR > 70%. Our findings indicate that HGI is a reliable predictor of hypoglycemia in this population., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Opioid overprescribing can lead to nonmedical opioid use. In a previous prospective study (STUDY), we showed that a standardized protocol involving preoperative education and reduced opioid prescription quantity decreased opioid use in idiopathic scoliosis patients following posterior spinal fusion (PSF). A potential limitation was the Hawthorne effect, where participant behavior changes due to observation. At STUDY conclusion, we continued the reduced opioid prescriptions but discontinued the formal preoperative education. This retrospective study (post-STUDY) assessed if opioid refill requests increased outside of a study setting., Methods: Post-STUDY included patients aged 10 to 17 years who underwent PSF for idiopathic scoliosis between January 2022 and December 2023 and were discharged with a prescription of ≤30 oxycodone doses. Patients were excluded if they had previous spine surgery or were discharged with an opioid other than oxycodone. Demographics, perioperative variables, and opioid refill requests were compared with the data from STUDY, in which patients were aware their opioid use would be tracked. Patient-reported outcomes were collected via Scoliosis Research Society-22r (SRS-22r) surveys., Results: The post-STUDY cohort included 67 patients (69% female). The average age at the time of PSF was 13.9 years (range, 11 to 17 y). The mean number of levels fused was slightly higher (10.9 vs. 10.0, P=0.04), and intraoperative estimated blood loss was lower (211 vs. 303 mL, P<0.01) compared with the STUDY cohort. Demographics, preoperative major curve magnitude, surgery duration, and length of hospital stay were similar. The percentage of patients who requested and received opioid refills between the post-STUDY and STUDY cohorts was also similar [6/67 (9%) vs. 3/49 (6%), P=0.30]. SRS-22r showed improvements in self-image, satisfaction, and mean total score from preoperative to postoperative., Conclusions: Reduced opioid prescriptions did not result in increased opioid refill requests in adolescents undergoing PSF for idiopathic scoliosis outside of a study setting. While formal preoperative discussions about postoperative pain control are important, other factors likely influence opioid use. Further research should explore characteristics that predispose patients to require higher amounts of postoperative opioids., Level of Evidence: Level III-therapeutic., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV., Design: Pharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear mixed effects modelling approach. A post hoc analysis of the effect of LEV on seizure burden was conducted., Setting: Neonatal intensive care unit., Patients: Term neonates with electrographically confirmed seizures., Interventions: In NEOLEV1, neonates with seizures persisting following phenobarbital (PHB) received LEV 20 or 40 mg/kg bolus followed by 5 or 10 mg/kg maintenance dose(MD) daily. In NEOLEV2, patients received a 40 mg/kg intravenous LEV load, followed by 10 mg/kg doses 8 hourly. If seizures persisted, a further 20 mg/kg intravenous load was given. If seizures persisted, PHB was given. PK data were collected from 16 NEOLEV1 patients and 33 NEOLEV2 patients. cEEG data from 48 NEOLEV2 patients were analysed to investigate onset of action and seizure burden reduction., Main Outcome Measures: Clearance (CL) and volume of distribution (V d ) were determined. Covariates that significantly affected LEV disposition were identified., Results: Primary outcome: The median initial LEV level was 57 µg/mL (range 19-107) after the first loading dose and at least 12 µg/mL at 48 hours in all infants. CL and V d were estimated to be 0.0538 L/hour and 0.832 L, respectively. A direct relationship between postnatal age and CL was observed. The final population pharmacokinetic(PopPK) model described the observed data well without significant biases. CL and V d were described as CL (L/hour)=0.0538×(weight in kg/3.34)0.75×(postnatal age in days/5.5) 0.402 and V d (L)=0.832×(weight in kg/3.34).Seizure burden reduced within 30 min of LEV administration. 28% of patients were completely seizure free after LEV. In an additional 25% of patients, seizure burden reduced by 50%., Conclusions: LEV pharmacokinetics remained predictable at higher doses. Very high-dose LEV can now be studied in neonates., Trial Registration Number: NCT01720667., Competing Interests: Competing interests: RHH and CS have done consulting work for Sparc pharmaceuticals who are seeking FDA indication for PHB in the treatment of neonatal seizures., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patellofemoral instability (PFI) is a common problem with various anatomic risk factors identified, including patella alta as one of the most powerful predictors. Given that the medial patellofemoral ligament (MPFL) is the primary soft tissue stabilizer of the patella, a common procedure to treat recurrent patellar instability is MPFL reconstruction. The aim of this study is to examine the relationship between MPFL reconstruction and patellar height. We hypothesize that after reconstruction, patellar instability patients would have demonstrable reduction in patella height and patella alta correction., Methods: Patient records were queried for patients who underwent MPFL reconstruction for recurrent patellar instability. Patient and operative demographics were collected. We measured Insall-Salvati ratio (ISR), Caton Deschamps index (CDI), and Blackburne-Peel ratio (BPR) in all patients at various time points. The height indices were compared across the preoperative, immediately postoperative, and 6-month time points in a pairwise fashion using paired-sample t-tests. Further subgroup analysis of patients (n=27) with elevated preoperative Caton Deschamps Index (defined as >1.3) was completed., Results: The final cohort was 103 patients. There was a significant difference between pre- and postoperative ISR (P<0.001) and at 6-month follow up (P<0.001), between preoperative CDI and the 6-month follow-up (P<0.0010), and between the postoperative and preoperative CDI (P<0.001). There was also a difference between preoperative and postoperative BPR (P<0.001), as well as between the preoperative and 6-month follow-up BPR (P=0.002). Twenty-seven patients had an initial CDI greater than 1.3. Differences were observed between pre- and postoperative mean CDI (P=0.001) and at 6-month follow-up (P=0.006), between both postoperative and 6-month ISR (both P<0.001), and preoperative mean BPR and the postoperative (P=0.004) and 6-month mean BPR (P=0.027)., Conclusions: Patients with pre-existing patella alta and recurrent patella dislocations who undergo isolated MPFL reconstruction have decreased patella alta at their 6-month follow-up as measured by ISR, CDI, and BPR. Patients without patella alta do not demonstrate statistically significant differences after their MPFL reconstruction., Level of Evidence: III (retrospective comparative study)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with diabetes have an increased risk of developing heart failure with preserved ejection fraction (HFpEF). This study aimed to compare indices of myocardial deformation and perfusion between patients with type 2 diabetes mellitus (T2DM) with and without HFpEF and to investigate the relationship between myocardial strain and perfusion reserve., Methods: This study included 156 patients with T2DM without obstructive coronary artery disease (CAD) and 50 healthy volunteers who underwent cardiac magnetic resonance (CMR) examination at our center. Patients with T2DM were subdivided into the T2DM-HFpEF (n = 74) and the T2DM-non-HFpEF (n = 82) groups. The parameters of left ventricular (LV) and left atrial (LA) strain as well as stress myocardial perfusion were compared. The correlation between myocardial deformation and perfusion parameters was also assessed. Mediation analyses were used to evaluate the direct and indirect effects of T2DM on LA strain., Results: Patients with T2DM and HFpEF had reduced LV radial peak systolic strain rate (PSSR), LV circumferential peak diastolic strain rate (PDSR), LA reservoir strain, global myocardial perfusion reserve index (MPRI), and increased LA booster strain compared to patients with T2DM without HFpEF (all P < 0.05). Furthermore, LV longitudinal PSSR, LA reservoir, and LA conduit strain were notably impaired in patients with T2DM without HFpEF compared to controls (all P < 0.05), but LV torsion, LV radial PSSR, and LA booster strain compensated for these alterations (all P < 0.05). Multivariate linear regression analysis demonstrated that LA reservoir and LA booster strain were independently associated with global MPRI (β = 0.259, P < 0.001; β =  - 0.326, P < 0.001, respectively). Further, the difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI. Global stress PI, LA booster, global rest PI, and global MPRI showed high accuracy in diagnosing HFpEF among patients with T2DM (areas under the curve [AUC]: 0.803, 0.790, 0.740, 0.740, respectively)., Conclusions: Patients with T2DM and HFpEF exhibited significant LV systolic and diastolic deformation, decreased LA reservoir strain, severe impairment of myocardial perfusion, and elevated LA booster strain that is a compensatory response in HFpEF. Global MPRI was identified as an independent influencing factor on LA reservoir and LA booster strain. The difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI, suggesting a possible mechanistic link between microcirculation impairment and cardiac dysfunction in diabetes. Myocardial perfusion and LA strain may prove valuable for diagnosing and managing HFpEF in the future., (© 2024. The Author(s).)

The Mongolian medical silver needles often encounter issues of bending, fracturing, and blunting in clinical applications. Similarly, Mongolian warm needles can cause burns on patients due to inaccurate temperature control. In this study, we developed an Ag85Cu15 alloy specifically for acupuncture needles based on material preparation. By incorporating appropriate amounts of Mn and Ti elements, we were able to enhance the mechanical properties and biocompatibility of the acupuncture needles. Compared to commercially available silver needles, this alloy exhibited a significant increase in microhardness up to 210.2 Hv 0.2 and an improved tensile strength of 880.2 MPa. Furthermore, we designed a thermoelectric effect-based temperature measurement model for precise control of the warm needle's temperature, enhancing the therapeutic effectiveness of the treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Artemisia species are widely spread in north hemisphere. Artemisia sieversiana pollen is one of the common pollen allergens in the north of China. At present, seven allergens were identified and had been listed officially from A. sieversiana pollen, but the remaining allergens are still insufficiently studied, which need to be found., Methods: Pectate lyase was purified from the extracts of A. sieversiana pollen by anion exchange, size exclusion, and HPLC-hydrophobic interaction chromatography. The gene of A. sieversiana pectate lyase (Art si pectate lyase) was cloned and expressed in Escherichia coli. The enzyme activity and circular dichroism (CD) spectrum of natural and recombinant proteins were analyzed. The allergenicity of Art si pectate lyase was characterized by enzyme-linked immunosorbent assay (ELISA), Western blot, inhibition ELISA, and basophil activation test. The allergen's physicochemical properties, three-dimensional structure, sequence profiles with homologous allergens and phylogenetic tree were analyzed by in silico methods., Results: Natural Art si pectate lyase (nArt si pectate lyase) was purified from A. sieversiana pollen extracts by three chromatographic strategies. The cDNA sequence of Art si pectate lyase had a 1191-bp open reading frame encoding 396 amino acids. Both natural and recombinant pectate lyase (rArt si pectate lyase) exhibited similar CD spectrum, and nArt si pectate lyase had higher enzymatic activity. Moreover, the specific immunoglobulin E (IgE) binding rate against nArt si pectate lyase and rArt si pectate lyase was determined as 40% (6/15) in patients' serum with Artemisia species pollen allergy by ELISA. The nArt si pectate lyase and rArt si pectate lyase could inhibit 76.11% and 47.26% of IgE binding activities to the pollen extracts, respectively. Art si pectate lyase was also confirmed to activate patients' basophils. Its structure contains a predominant motif of classic parallel helical core, consisting of three parallel β-sheets, and two highly conserved features (vWiDH, RxPxxR) which may contribute to pectate lyase activity. Moreover, Art si pectate lyase shared the highest sequence identity of 73.0% with Art v 6 among currently recognized pectate lyase allergen, both were clustered into the same branch in the phylogenetic tree., Conclusion: In this study, pectate lyase was identified and comprehensively characterized as a novel allergen in A. sieversiana pollen. The findings enriched the allergen information for this pollen and promoted the development of component-resolved diagnosis and molecular therapy of A. sieversiana pollen allergy., (© 2024 S. Karger AG, Basel.)

Introduction: Recombinant allergens produced by Escherichia coli (E. coli) system play an important role in the component-resolved diagnostics of allergy and vaccine development. However, incorrect folding of recombinant allergens may affect their application. Therefore, it is very important to monitor the correct folding of recombinant allergens. Currently, there is still a lack of a quality control strategy to solve this problem. In this study, a mite allergen, Der f 2, was taken as an example to establish a novel quality control strategy, which was based on chromatography to isolate the allergen, and on enzyme-linked immunosorbent assay to verify the IgE reactivity of the isolated allergen., Methods: The nucleotide sequence encoding Der f 2 was codon-optimized and cloned into pET-28a (+) plasmid. Best conditions for the expression of Der f 2 in E. coli were sought. The inclusion body of Der f 2 was denatured and purified by nickel affinity chromatography. Refolding processes were compared using glutathione redox system. The fully and partially folded proteins were separated by anion exchange chromatography, and the IgE reactivity of the isolated proteins was verified by indirect enzyme-linked immunosorbent assay., Results: An optimized 387 bp segment of the Der f 2 coding gene was successfully expressed in E. coli. Best induction conditions included preinduction bacterial density with absorbance value at 600 nm was 0.6, 1 mM isopropyl beta-d-thiogalactopyranoside at 28°C for 4 h. The Der f 2 protein after refolding was separated by chromatography and two fractions were obtained. The first fraction was identified as monomer protein and the second as aggregate by size-exclusion chromatography. Indirect enzyme-linked immunosorbent assay also confirmed that the first fraction showed higher IgE reactivity., Conclusion: In this study, a novel quality control strategy based on chromatographic separation and IgE reactivity monitoring was established in the case of mite Der f 2, which systematically evaluated the effectiveness of multiple preparation methods for the first time. It is faster and more convenient when compared with the existing methods such as size-exclusion chromatography. This strategy laid a foundation for the stable application of recombinant allergens produced by E. coli in component-resolved diagnostics and the development of molecular vaccines in the future., (© 2024 S. Karger AG, Basel.)

Rice blast, caused by Magnaporthe oryzae , is a major threat to global rice production causing significant crop losses and impacting grain quality. The annual loss of rice production due to this disease ranges from 10% to 30%. The use of biologically controlled strains, instead of chemical pesticides, to control plant diseases has become a research hotspot. In this study, an antagonistic endophytic bacterial strain was isolated from the roots of Oryza officinalis using the traditional isolation and culture methods. A phylogenetic tree based on 16S RNA and whole-genome sequencing identified isolate G5 as a strain of Bacillus subtilis . This isolate displayed strong antagonistic effects against different physiological strains of M. oryzae . After co-culture in LB medium for 7 days, the inhibition rates of the mycelial growth of four strains of M. oryzae , ZB15, WH97, Guy11, and T-39800E were 98.07 ± 0.0034%, 98.59 ± 0.0051%, 99.16 ± 0.0012%, and 98.69 ± 0.0065%, respectively. Isolate G5 significantly inhibited the formation of conidia of M. oryzae , with an inhibition rate of 97% at an OD 600 of 2. Isolate G5 was able to provide 66.81% protection against rice blast under potted conditions. Whole-genome sequencing revealed that the genome size of isolate G5 was 4,065,878 bp, including 4,182 coding genes. Using the anti-SMASH software, 14 secondary metabolite synthesis gene clusters were predicted to encode antifungal substances, such as fengycin, surfactin, and bacilysin. The G5 isolate also contained genes related to plant growth promotion. These findings provide a theoretical basis for expounding the biocontrol mechanisms of this strain and suggest further development of biogenic agents that could effectively inhibit rice blast pathogen growth and reduce crop damage, while being environmentally friendly, conducive to ecological development, and a sustainable alternative to chemical pesticides. This study also enriches the relevant research on endophytes of wild rice, which proves that wild rice is a valuable microbial resource bank., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lei, Xiong, Li, Yang, Li, Chen, Zhong, Yin, Li, Cheng and Xiao.)

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3 mg·kg -1 ·d -1 ) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background: Polycystic ovary syndrome (PCOS) is currently considered to have a peri-adolescence onset and continuously influence the reproductive and metabolic health of the patients, while the diagnostic criteria among adolescent population haven't been universally unified till now. This survey seeks to preliminarily evaluate the prevalence of PCOS in the tenth grade schoolgirls in Guangzhou area under NIH criteria and analyze the clinical features of adolescents with PCOS., Methods: The cross-sectional epidemiological survey was carried out among the tenth grade schoolgirls in Guangzhou area by the method of cluster sampling. The contents of this survey included the questionnaire, physical exams and serum measurements. Until now, totally 1294 girls underwent this survey and 1095 serum samples were restored. 235 non-hirsute (mFG < 6), postmenarcheally 2-year girls were randomly selected as the control group, among which the cut-off value of biochemical hyperandrogenemia was set accordingly. The prevalence of PCOS among this population was preliminarily evaluated according to the NIH criteria., Results: Along with the increase of gynecological age, the menstruations of girls was becoming more regular and the incidence of oligomenorrhea or amenorrhea was declining. Even among those who were less than 2 years after menarche, those whose menstrual cycle were longer than 90 days accounted for lower than 5%. The 95th percentile of mFG score was 6 among the girls who were < 2 years after menarche, and 5 among the girls who were > 2 years after menarche. Among the 235 healthy girls, the 95th percentile values of Testosterone (T), Free androgen index (FAI) and Androstenedione (A2) were 2.28 nmol/mL, 4.37, and 5.20 nmol/mL respectively. Based on the NIH criteria, the prevalence of PCOS in this survey was 3.86%. The prevalence of adolescent PCOS tend to slightly increase with age and gynecological age, but the difference was not statistically significant. The prevalence of PCOS among obese girls was markedly higher than that in lean girls., Conclusion: Based on the NIH criteria, the prevalence of PCOS among the tenth grade schoolgirls in Guangzhou area was 3.86%. The diagnosis of hyperandrogenism among adolescents should also be based on both clinical and biochemical parameters., (© 2023. The Author(s).)

Patients with cancer and advanced hepatic impairment (HI) (i.e., moderate and severe impairment) are often excluded from first-in-patient, phase II, and phase III studies. Thus, dose recommendations for this subgroup of patients are often derived using a combination of dedicated phase I studies conducted in participants without cancer and a population pharmacokinetic (PK) modeling approach. A standardized risk-based approach to guide the evaluation of HI in patients with cancer is needed. In this review, we evaluated available oncology drug approvals by the US Food and Drug Administration (FDA) from 1999 to 2019, identified strategies utilized by sponsors to characterize the effect of HI on the PK of oncology drugs, and assessed regulatory expectations for each strategy. Finally, we constructed a decision tree that complements current FDA guidance to enable efficient evaluation of the effect of HI on PK and provide guidance for dose recommendations., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: There are variabilities in the distance between the tibial tuberosity and the trochlear groove. The knee angle needs to be considered when talking about patellofemoral instability., Methods: This retrospective study analyses the MRI images of knee angles from 0 and 30 degrees in the patella dislocation group (20 cases) and in the control group (20 cases) from Dec 2017 to Dec 2019. Two experienced orthopedic physicians separately measure the study with a blind experiment method., Results: The TT-TG data of the patella dislocation group and control group are 17.88 ± 3.40 mm and 13.31 ± 3.01 mm when the knee angle is 0, which indicates a difference with statistical significance ( P < 0.01). The TT-TG data of the patella dislocation group and control group are 11.51 ± 3.60 mm and 7.40 ± 1.93 mm when the knee angle is at 30 degrees, indicating a statistically significant difference ( P < 0.01). Also, the TT-TG data of both the patella dislocation group and control group have statistically significant differences within different knee angles of the same group ( P < 0.01). The differences of TT-TG are 6.36 ± 2.43 mm and 5.92 ± 1.65 mm when the knee angle changes from 0 to 30, which shows no statistically significant difference ( P > 0.01)., Conclusion: This research initially obtained the relevant MRI data of the TT-TG distance from different knee angles between the Chinese patella dislocation patient group and control group. The study received a new criterion to evaluate the TT-TG of patients with patella dislocations when the knee angle is below 30 degrees. The knee flexion angles need to be considered to measure the TT-TG distance when comprehensively evaluating patellofemoral instability. The TT-TG distance gradually increases when the knee changes from flexion to extension. The difference of the TT-TG distances shows no statistically significant difference., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Fei Zhang et al.)

Background: The Short Physical Performance Battery (SPPB) is a well-established functional assessment tool used for the screening and assessment of frailty and sarcopenia. However, the SPPB requires trained staff experienced in conducting the standardized protocol, which may limit its widespread use in clinical settings. The automated SPPB (eSPPB) was developed to address this potential barrier; however, its validity among frail older adults remains to be established. Therefore, this exploratory study compared the eSPPB and manual SPPB in patients attending a tertiary fall clinic in relation to their construct validity, reliability, and agreement., Methods: We studied 37 community-dwelling older adults (mean age, 78.5±6.8 years; mean FRAIL score, 1.2±1.0; 65% pre-frail) attending a tertiary falls clinic. The participants used the mSPPB and eSPPB simultaneously. We evaluated the convergent validity, discriminatory ability, reliability, and agreement using partial correlation adjusted for age and sex, an SPPB cutoff of ≤8 to denote sarcopenia, intraclass correlation coefficients (ICC), and Bland-Altman plots, respectively., Results: The eSPPB showed strong correlations with the mSPPB (r=0.933, p&lt;0.01) and Berg Balance Scale (r=0.869, p&lt;0.01), good discriminatory ability for frailty and balance, and good to excellent reliability (ICC=0.94; 95% confidence interval, 0.88-0.97). The Bland-Altman plots indicated good agreement with the mSPPB (mean difference, -0.2; 95% confidence interval, -3.2-2.9) without evidence of systematic or proportional biases., Conclusion: The results of our exploratory study corroborated the construct validity, reliability, and agreement of the eSPPB with the mSPPB in a small sample of predominantly pre-frail older adults with increased fall risk. Future studies should examine the scalability and feasibility of the widespread use of the eSPPB for frailty and sarcopenia assessment.

Objective: This study is to investigate the relationship between time in range (TIR) and glucose management indicator (GMI), and the impact of glycemic variability (GV) on their relationship in patients with type 1 diabetes mellitus (T1DM). Methods: The CGM data were collected from a multicenter randomized clinical trial of adults (≥18 years old) with T1DM, including 83 T1DM patients, respectively from the Third Affiliated Hospital of Sun Yat-sen University (72 cases), Drum Tower Hospital Affiliated to Nanjing University School of Medicine (2 cases), and the First Affiliated Hospital of University of Science and Technology of China (9 cases). All subjects wore the iPro TM 2 system for 14 days at baseline (0-2 weeks), 3 months (12-14 weeks), and 6 months (24-26 weeks). Data derived from iPro TM 2 sensor was used to calculate CGM parameters. Correlation between TIR and GMI was explored according to different stratification of glycemic variability assessed by glucose coefficient of variation ( CV ). Predicted TIR in the fixed GMI value was calculated via the linear regression equations performed in the respective interquartile group of CV . Results: From November 2017 to June 2021, a total of 233 CGM data were collected with 83 collected from baseline, 80 from the 3-month follow-up, 70 from the 6-month follow-up. Patients including 27 males had a median ( Q 1 , Q 3 ) age of 30.69 (25.22, 38.43) years, with a diabetes duration of 10.05(4.46, 13.92) years. The median ( Q 1 , Q 3 ) and effective wearing time of available CGM data was 13.92 (13.02, 14.00) days and 91.61% (84.96%, 95.94%), and the value of TIR, GMI and CV was 60.34%±13.03%, 7.14%±0.61% and 41.01%±7.64%, respectively. There was a strong negative correlation between TIR and GMI ( r =-0.822, P <0.001). Multiple linear regression analysis showed that the predictive value of TIR calculated from a given GMI was 8.352% higher when CV was up to standard (36%) than that when CV was down to standard. Based on the multiple linear regression equations generated from quartiles of CV , the predicted TIR value was decreased across the ascending quartiles with 69.98 % in the lowest quartile of CV (≤35.91%), 64.57 % in 25 th -50 th quartile of CV (35.91%< CV ≤40.08%), 60.96% in 50 th -75 th quartile of CV (40.08%< CV ≤45.86%) and 56.44% in the highest quartile of CV (>75 th quartile, CV >45.86%) when GMI was set as 7%. Conclusions: There is a strong correlation between TIR and GMI in adult patients with T1DM in patients with type 1 diabetes mellitus. CV influenced the relationship between TIR and GMI.

The North Yellow Sea (NYS) is a productive marginal sea of the western North Pacific. In summer and autumn, CaCO 3 saturation states beneath the seasonal thermocline in the NYS have frequently fallen below critical levels, indicating that marine calcifying organisms are under threat. To explore the long-term evolution of the acidification of the NYS, we reconstructed seasonal variations in subsurface aragonite saturation state (Ω arag ) and pH during 1976-2017, using wintertime and summertime temperature, salinity, dissolved oxygen and pH data mainly from a quality-controlled oceanographic database. Over the past 40 years, the wintertime warming rate in the NYS was twice the rate of global ocean surface warming. Warming-induced decrease in CO 2 solubility canceled out a part of the wintertime Ω arag decrease caused by atmospheric CO 2 increase, and also had minor effect on pH changes in winter. Although the NYS is a semi-enclosed marginal sea, its interannual variations of wintertime temperature, salinity, pH and Ω arag were correlated to Pacific Decadal Oscillation with a lag of 2-3 years. Due to the eutrophication-induced enhancement of net community respiration beneath the seasonal thermocline, long-term declines of bottom-water Ω arag and pH in summer were substantially faster than the declines of assumed air-equilibrated Ω arag and pH in spring. Over the past 40 years, the amplitudes of seasonal variations of bottom-water Ω arag and pH from spring to summer/autumn have increased by 4-7 times. This amplification has pushed the NYS towards the critical threshold of net community CaCO 3 dissolution at a pace faster than that forecast under scenarios of atmospheric CO 2 increase. In summary, our results provide insights into the combined effects of ocean warming, eutrophication, atmospheric CO 2 rise and climate variability on coastal hydrochemistry, explaining how the environmental stresses on local marine calcifying organisms and the benthic ecosystem increased over the past 40 years., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hafnium(IV) triflate (Hf(OTf) 4 ) has been identified as a potent catalyst for the direct three-component synthesis of β-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.

5-Hydroxymethyl-2'-deoxycytidine (5hmdC) phosphoramidite and triphosphate are important building blocks in 5hmdC-containing DNA synthesis for epigenetic studies. However, efficient and practical methods for the synthesis of these compounds are still limited. The current research provides an intensively improved synthetic method that enables the preparation of commercially available cyanoethyl-protected 5hmdC phosphoramidite with an overall yield of 39% on 5 g scale. On the basis of facile and efficient accesses to cyanoethyl protected-5hmdU and 5hmdC intermediates, two efficient synthetic routes for 5hmdC triphosphate were also developed.

A bisthienylethene-dipyrimido[2,1- b ][1,3]benzothiazole ( BTE-2PBT ) triad has been designed and synthesized based on our recent discovery of PBTs as atypical propeller-shaped novel AIEgens. The triad not only maintains the photochromic properties of BTE moiety in solution, film, and solid state but also exhibits remarkable AIE properties. Moreover, the fluorescence of BTE-2PBT PMMA film could be modulated with high contrast by alternate UV and visible light irradiation. Photoerasing, rewriting, and non-destructive readout of fluorescent images on BTE-2PBT PMMA film well demonstrate its potential application as optical memory media.

Background: The spine is the most common location of metastatic diseases. Treating a metastatic spinal tumor depends on many factors, including patients' overall health and life expectancy. The present study was conducted to investigate prognostic factors and clinical outcomes in patients with vertebral metastases., Aim: To investigate prognostic factors and their predictive value in patients with metastatic spinal cancer., Methods: A retrospective analysis of 109 patients with metastatic spinal cancer was conducted between January 2015 and September 2017. The prognoses and survival were analyzed, and the effects of factors such as clinical features, treatment methods, primary lesions and affected spinal segments on the prognosis of patients with metastatic spinal cancer were discussed. The prognostic value of Frankel spinal cord injury functional classification scale, metastatic spinal cord compression (MSCC), spinal instability neoplastic score (SINS) and the revised Tokuhashi score for prediction of prognosis was explored in patients with metastatic spinal tumors., Results: Age, comorbidity of metastasis from elsewhere, treatment methods, the number of spinal tumors, patient's attitude toward tumors and Karnofsky performance scale score have an effect on the prognosis of patients (all P < 0.05). With respect to classification of spinal cord injury, before operation, the proportion of grade B and grade C was higher in the group of patients who died than in the group of patients who survived, and that of grade D and grade E was lower in the group of patients who died than in the group of patients who survived (all P < 0.05). At 1 mo after operation, the proportion of grade A, B and C was higher in the group of patients who died than in the group of patients who survived, and that of grade E was lower in patients in the group of patients who died than in the group of patients who survived (all P < 0.05). MSCC occurred in four (14.3%) patients in the survival group and 17 (21.0%) patients in the death group ( P < 0.05). All patients suffered from intractable pain, dysfunction in spinal cord and even paralysis. The proportion of SINS score of 1 to 6 points was lower in the death group than in the survival group, and the proportion of SINS score of 7 to 12 points was higher in the death group than in the survival group (all P < 0.05). The proportion of revised Tokuhashi score of 0 to 8 points and 9 to 11 points were higher in the death group than in the survival group, and the proportion of revised Tokuhashi score of 12 to 15 points was lower in the death group than in the survival group (all P < 0.05). Frankel spinal cord injury functional classification scale, MSCC, SINS and revised Tokuhashi score were important factors influencing the surgical treatment of patients with metastatic spinal cancer (all P < 0.05)., Conclusion: Frankel spinal cord injury functional classification scale, MSCC, SINS and revised Tokuhashi score were helpful in predicting the prognosis of patients with metastatic spinal cancer., Competing Interests: Conflict-of-interest statement: This is no conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The association between the phospholipid transfer protein (PLTP) gene rs4810479 single-nucleotide polymorphism (SNP) and serum lipid levels is largely unknown. This investigation aimed to evaluate the relationship between the PLTP rs4810479 SNP, several environmental risk factors, and serum lipid parameters in the Chinese Maonan and Han nationalities. Polymerase chain reaction-restriction fragment length polymorphism, gel electrophoresis, and direct sequencing were employed to determine the PLTP rs4810479 genotypes in 633 Maonan and 646 Han participants. The frequencies of CC, CT, and TT genotypes and the C allele were different between Maonan and Han groups (29.07%, 53.08%, 17.85%, and 55.61% vs. 35.60%, 49.70%, 14.70%, and 60.45%, respectively, P < 0.05). The C allele carriers in the Maonan group had higher high-density lipoprotein cholesterol levels than the C allele noncarriers, but this finding was only found in Maonan males but not in females. The C allele carriers in Han males had lower total cholesterol and low-density lipoprotein cholesterol levels than the C allele noncarriers. Serum lipid profiles were also affected by several traditional cardiovascular risk factors in both populations. There might be an ethnic- and/or sex-specific association between the PLTP rs4810479 SNP and serum lipid traits., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Fen-Han Zhang et al.)

Objective: To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery., Design: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States., Methods: Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons., Results: A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited., Conclusion: Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To investigate the clinical features of infertile women with non-classic 21-hydroxylase deficiency (21-OHD). Methods: The study enrolled 21 infertile women with non-classic 21-OHD in Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2009 to December 2018. The clinical presentation, endocrine hormone, glucolipid metabolism and treatment outcome were retrospectively analyzed. The diagnosis of non-classic 21-OHD was comprehensively based on clinical and hormonal characteristics. Results: Among 21 cases, the age was (29.9±2.9) years, the mean age at menarche was (13.6±2.0) years, body mass index was (22.1±2.9) kg/m 2 , and 38% (8/21) had oligomenorrhea. Hirsutism was diagnosed in 3 cases (14%, 3/21). Clitoromegaly was seen in 14% (3/21) and polycystic ovarian morphology was found in 33% (7/21) of the patients. The mean serum level of basal progesterone was (11.3±21.0) nmol/L, with 48% (10/21) having high basal progesterone level; after therapy by glucocorticoid, the level of progesterone was (1.9±2.0) nmol/L. Serum 17-hydroxyprogesterone concentration was (66.4±123.6) nmol/L; after therapy by glucocorticoid, it was (2.4±1.8) nmol/L. In the study increased testosterone, androstenedione and dehydroepiandrosterone sulfate were present in 62% (13/21), 52% (11/21) and 43% (9/21), respectively; and 52% (11/21) of patients manifested androgen excess and basal progesterone elevation; androgen levels decreased after therapy by glucocorticoid. The pregnancy rate was 76% (16/21). Out of 19 pregnancies, 6/19 ended in spontaneous miscarriages. Conclusions: Infertile women with non-classic 21-OHD are characterized by hyperandrogenism and basal progesterone elevation, whereas gonad axis disorder is not apparent. After no response to conventional therapy, adult infertile women with non-classic 21-OHD could achieve a desirable pregnancy outcome with proper treatment of glucocorticoid.

Humic acid (HA) removal research focuses on the global water treatment industry. In this work, efficient HA degradation with an ultra-high synergetic intensity is achieved by combined bubble discharge with activated carbon (AC). Adding AC to the discharge greatly improves HA removal efficiency and degradation speed; the synergetic intensity reaches 651.52% in the combined system, and the adsorption residual on AC is 4.52%. After 90 min of treatment, the HA removal efficiency reaches 98.90%, 31.29%, and 7.61% in the plasma-AC combined, solo bubble discharge, and solo AC adsorption systems, respectively. During the plasma process, the number of pore structures and active sites and the amount of oxygen-containing functional groups on the AC surface increase, resulting in a higher adsorption capacity to reactive species (H 2 O 2 and O 3 ) and HA and promoting interactions on the AC surface. For HA mineralization, the presence of AC greatly promotes the destruction of aromatic structures and chromophoric HA functional groups., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The persulfate activation by nanosecond pulsed gas-liquid discharge (NPG-LD) is employed to degrade the trimethoprim (TMP) in water. The results show that persulfate addition enhances the degradation of TMP by NPG-LD through an obvious synergetic effect. With treatment time of 50 min, the high removal efficiency and energy yield reach 94.6% and 0.57 gkWh -1 in air NPG-LD with the addition of persulfate, respectively, which is 13.5% and 0.09 gkWh -1 higher than that in solo air NPG-LD, respectively. Correspondingly, the calculated synergetic factor achieves 1.62, indicating the synergetic effect is established. The activation mechanism of persulfate by NPG-LD is analyzed by the measurement of reactive species and the effects of radical scavenger addition on TMP removal. It is found that the synergetic effect between NPG-LD and persulfate is attributed to the increased production of OH, H 2 O 2 , and . Besides, the TMP degradation by NPG-LD and persulfate synergetic system is influenced by discharge working gas, pulse voltage, addition dosage of persulfate, initial TMP concentration, and initial pH value. Subsequently, the degradation pathway of TMP is analyzed using LC-MS/MS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions., (© 2020 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Betulin (BE) can be obtained from many plants, such as those belonging Betulaceae family, and pharmacological investigations showed its notable biological properties and good potential for food and pharmaceutical development. We investigated the homogeneity, stability, purity, and uncertainty of a newly certified reference material (CRM) of BE. The certified purity value for the CRM of BE was 99.56% with an extended uncertainty of 0.07% (k = 2, P = 0.95), as determined by differential scanning calorimetry (DSC). In this study, DSC was used for the first time for purity determination of BE. Given its high accuracy, precision, and reproducibility, DSC can be used as an alternative technique for purity determination of CRMs in the pharmaceutical and food industry.

Betulin (BE) has exceedingly become a potential natural product, providing multiple pharmacological and biological activities, including anti-cancer, anti-viral, and anti-inflammatory benefits. Previous research indicated that the solvatomorphism of BE can easily occur through crystallization with different organic solvents. This property of BE can directly affect its extraction, isolation, and preparation process. In this study, a system of thermogravimetry (TG)-differential thermal analysis (DTA) coupled with mass spectrometry (MS) with electron ionization (EI) and photoionization (PI) capability, equipped with the skimmer-type interface (i.e., skimmer-type interfaced TG-DTA-EI/PI-MS system), as a real-time and onsite analysis technique, was employed. Then, four solvatomorphs of BE, namely, with pyridine and water (A), sec-butanol (B), n,n-dimethylformamide (DMF) (C), and isopropanol (V), were analyzed for the first time. Finally, five kinds of the main volatile gaseous species, including H 2 O, pyridine, sec-butanol, DMF, and isopropanol, were identified clearly. Furthermore, the multi-step desolvation processes of the four solvatomorphs of BE were revealed by this system for the first time. This system showed great potential for the rapid and accurate analysis of various solvatomorphs of natural products.

Formononetin (FN), a methoxy isoflavone abundant in many plants and herbs, has been evidently proven to possess multiple medicinal properties. Our study aimed to clarify the impact of FN on myocardial ischemia/reperfusion (I/R) injury (MIRI) and the involved mechanism. A rat model of MIRI was produced by ligation and loosening of the left anterior descending (LAD) branch of the coronary artery. Rats received 10 and 30 mg/kg of FN when the reperfusion started. At 24 h after surgery, cardiac function, infarct size, and sera levels of the cardiac markers and inflammatory mediators were measured. To mimic the inflammasome activation in cardiomyocytes, neonatal rat cardiomyocytes (NRCMs) were cultured and treated with lipopolysaccharide (LPS) plus nigericin. Cell death and reactive oxygen species (ROS) were determined. Myocardial expression and activation of the nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome in rats were examined by western blotting. The level of thioredoxin interacting protein (TXNIP)-NLRP3 interaction was assessed. FN notably attenuated cardiac dysfunction, infarct size, release of cardiac markers, and elevation of TNF-α, IL-1β, and IL-6. FN alleviated LPS plus nigericin-induced injury and ROS increase in NRCMs. Western blotting revealed that FN suppressed the activation of NLRP3 inflammasome and TXNIP-NLRP3 interaction in rats. These findings indicate that FN ameliorated MIRI in rats and inhibited the activation of the NLRP3 inflammasome, at least partially, attributable to suppression of the ROS-TXNIP-NLRP3 pathway., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To investigate related factors for microalbuminuria in adult type 1 diabetes (T1D) patients of short disease duration (less than 5 years), and provide evidence for prevention of early diabetic kidney disease in this population. Methods: All adult patients enrolled in the Guangdong T1D translational medicine study between 2011 and 2017 with a disease duration of less than 5 years were included in this analysis. At enrollment, patients' demographic and clinical data were documented, and blood and urine samples were collected for the measurements of blood lipids, glycated hemoglobin A1c and urine albuminuria. Insulin resistance was evaluated by estimated glucose disposal rate (eGDR). Patients were categorized into groups based on urine albumin creatitine ratio (UACR): normoalbuminuric group (UACR<30 mg/g) and microalbuminuric group (UACR≥30 mg/g). Stepwise multivariate linear regression analysis was used to analyze risk factors for microalbuminuria in adult T1D patients of short disease duration. Results: A total of 384 patients were included in this analysis, and 51.3% (197/384) of which was female. The onset age of patients was (24.6±12.5) years, with a disease duration of 2.1(0.6, 3.5) years, body mass index of (19.8±3.2) kg/m(2), waist hip ratio of 0.85±0.21, and glycated hemoglobin A1c of (9.8±3.3)% at enrollment. Microalbuminuria occurred in 62 patients (16.1%). Multivariate linear analysis showed that higher glycated hemoglobin A1c, higher systolic blood pressure and more severe insulin resistance were related factors for microalbuminuria ( t= 2.322, 2.868 and -2.373, respectively, all P< 0.05). Conclusions: Microalbuminuria was not rare in adult T1D patients of short disease duration. Inadequate glycemic control and insulin resistance were independent related factors for microalbuminuria in this population.

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population ( n  = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.

Objective: To evaluate the effect of mobile application (APP) based interactive peer support on glycemic control in patients with type 1 diabetes mellitus (T1DM). Methods: The data of the present study were from the largest mobile APP platform for patients with T1DM in China, Tangtangquan. Patients with T1DM who has registered in the APP for at least 1 year and had completed data entry were recruited. According to the monthly interaction index during the first year of APP registration (including four indicators: praise, comment, posting and collection), the eligible patients were divided into the high-interaction group and the low-interaction group. The changes from baseline of self-blood glucose monitoring frequency (SMBG), glycosylated hemoglobin (HbA1c), incidence of hyperglycemia and incidence of hypoglycemia were compared between the two groups after one year of using the APP. Results: A total of 238 patients with T1DM with an age of (27±8) years were included. Among them, 77.3% (184/238) were female. The baseline SMBG [the low-interaction group (1.71±1.14) times/day vs. the high-interaction group (1.82±1.15) times/day] and HbA1c [the low-interaction group (6.72±0.99)% vs. the high-interaction group (6.76±1.04)%] were comparable between the two groups. After one year use of the APP, the frequency of SMBG in the high-interaction group was significantly higher than that in the low-interaction group [ΔSMBG (0.59+2.06) times/d vs. (0.08+1.69) times/d, t= 4.280, P= 0.04), and the reduction of HbA1c was more obvious in the high-interaction group [ΔHbA1c (-0.40+1.10)% vs. (-0.06+1.13)%, t= 5.651, P= 0.018] than in the lower-interaction group. The incidence of hyperglycemia in the high-interaction group was significantly lower than that in the low-interaction group [13.19(6.22,23.19)% vs. 17.69(10.56,30.49)%, Z= 2.850, P= 0.005]. There was no significant difference in the incidence of hypoglycemia between the two groups [4.62(2.14, 8.03)% vs. 4.83(2.06, 8.87)%, Z= 1.276, P= 0.204]. The correlation analysis showed that interaction index was significantly associated with the reduction of HbA1c and incidence of hyperglycemia. Conclusion: Participation in interactive peer education via mobile APP may be beneficent for glycemic control in patients with T1DM.

Objective: To investigate the relationship between insulin resistance (IR) and dyslipidemia in adults with type 1 diabetes (T1DM) and provide more insights on diabetes-related cardiovascular disease management. Methods: A cross-sectional study recruiting patients from Guangdong T1DM Translational Study cohort was conducted between 2011 and 2017. The patients aged ≥18 years, with a diabetes duration of ≥1 year were enrolled in the study. Plasma lipid profile data of eligible patients, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were collected and their relationships with insulin resistance were analyzed. IR in these adults with T1DM was estimated by glucose disposal rate (eGDR) calculated by a model published previously. Patients with eGDR lower than 25 percentiles were grouped as severe IR, otherwise non-severe IR. Results: In total, 499 eligible patients were studied, among which 274 were women (54.9%). The level of eGDR was 8.43 (6.11, 10.63) mg kg(-1) min(-1) and the overall incidence of lipid disorders was 65.3% (326/499) in the study population. The result showed that eGDR was correlated with TC, TG, HDL-C and LDL-C ( r= -0.163, -0.303, 0.170 and -0.150, respectively, all P< 0.05). After adjusting for gender, age and diabetes duration, eGDR was still associated with TG, TC and LDL-C (all P< 0.05). Stepwise multiple linear regression analysis showed that gender (female), elevated TC and declined HDL-C were independent factors associated with the severity of IR ( t= 5.651, 5.823 and 2.908, respectively, all P< 0.05). Conclusions: IR is associated with dyslipidemiain in adults with T1DM. Elevated TC and decreased HDL-C are independent associated factors for insulin resistance.

Objective: To investigate the awareness of preconception care among women of child-bearing age with type 1 diabetes (T1DM) and their self-management status, in order to provide evidence for establishment of management pathway for women with T1DM in pregnancy in China. Methods: This cross-sectional survey recruited female participants of child-bearing age from the cohort of Guangdong Type 1 Diabetes Translational Medicine Study conducted between June 2011 and December 2017. The participants were asked to fill out a questionnaire on the awareness of preconception care, their frequency of self-monitoring of blood glucose (SMBG) and other related variables. Chi-squared test or chi-squared test for trend was used in comparisons of categorical variables, and logistic regression analysis was performed to assess associated factors. Results: Totally, 441 women of child-bearing age with T1DM were investigated. The results show that their awareness of preconception care was poor (15.42%, 68/441). Higher educational level (χ(2trend)=3.990, P= 0.046), experience of post-diabetes education evaluation ( P< 0.001), and better coverage of different modules in diabetes education (survival skills: χ(2)=7.525, P= 0.004; basic knowledge: χ(2)=8.598, P= 0.002; advanced knowledge: P< 0.001) were associated with better awareness of preconception care. The average frequency of SMBG in these participants was 0.29 (0.14, 2.00) times per day, and only 8.5% (37/435) of them reached the frequency (≥4 times per day) recommended by guidelines. Moreover, 21.1% (92/435) of them hardly ever performed SMBG. Conclusion: Child-bearing age women with T1DM in Gunangdong had poor awareness of preconception care, with a much lower SMBG frequency than recommendation.

In this paper, the interactions of pepsin with fluoroquinolones, including norfloxacin (NFX) or ofloxacin (OFX), were investigated using fluorescence spectroscopy. The effects of NFX or OFX on pepsin showed that the molecular conformation of pepsin and the microenvironment of tryptophan residues were changed under mimicked physiological conditions. Static quenching was suggested as a factor. Quenching constants and binding constants were determined and thermodynamic parameters were calculated at three temperatures (25°C, 31°C and 37°C). Molecular interaction distances (binding distance r) were obtained. Binding was enthalpy driven and the process was spontaneous. Synchronous fluorescence, three-dimensional fluorescence spectroscopy and molecular simulation were used for analysis. Interactions were further tested using molecular modelling. Quenching and binding constants of NFX with pepsin were the highest when testing NFX/OFX/fleroxacin/gatifloxacin with pepsin combinations. NFX was the strongest quencher, and affinity of NFX for pepsin was higher than that of OFX/fleroxacin/gatifloxacin., (© 2019 John Wiley & Sons, Ltd.)

Background: Early diagnosis of stroke optimizes reperfusion therapies, but behavioral measures have incomplete accuracy. Electroencephalogram (EEG) has high sensitivity for immediately detecting brain ischemia. This pilot study aimed to evaluate feasibility and utility of EEG for identifying patients with a large acute ischemic stroke during Emergency Department (ED) evaluation, as these data might be useful in the prehospital setting., Methods: A 3-minute resting EEG was recorded using a dense-array (256-lead) system in patients with suspected acute stroke arriving at the ED of a US Comprehensive Stroke Center., Results: An EEG was recorded in 24 subjects, 14 with acute cerebral ischemia (including 5 with large acute ischemic stroke) and 10 without acute cerebral ischemia. Median time from stroke onset to EEG was 6.6 hours; and from ED arrival to EEG, 1.9 hours. Delta band power (P = .004) and the alpha/delta frequency band ratio (P = .0006) each significantly distinguished patients with large acute ischemic stroke (n = 5) from all other patients with suspected stroke (n = 19), with the best diagnostic utility coming from contralesional hemisphere signals. Larger infarct volume correlated with higher EEG power in the alpha/delta frequency band ratio within both the ipsilesional (r = -0.64, P = .013) and the contralesional (r = -0.78, P = .001) hemispheres., Conclusions: Within hours of stroke onset, EEG measures (1) identify patients with large acute ischemic stroke and (2) correlate with infarct volume. These results suggest that EEG measures of brain function may be useful to improve diagnosis of large acute ischemic stroke in the ED, findings that might be useful to pre-hospital applications., (Copyright © 2019 Elsevier Inc. All rights reserved.)