Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

Evaluating the effect of pulse energy on femtosecond laser trabeculotomy (FLT) outflow channels for glaucoma treatment in human cadaver eyes.

BACKGROUND AND OBJECTIVES: Femtosecond laser trabeculotomy (FLT) creates aqueous humor outflow channels through the trabecular meshwork (TM) and is an emerging noninvasive treatment for open-angle glaucoma. The purpose of this study is to investigate the effect of pulse energy on outflow channel creation during FLT. MATERIALS AND METHODS: An FLT laser (ViaLase Inc.) was used to create outflow channels through the TM (500 µm wide by 200 µm high) in human cadaver eyes using pulse energies of 10, 15, and 20 µJ. Following treatment, tissues were fixed in 4% paraformaldehyde. The channels were imaged using optical coherence tomography (OCT) and assessed as full thickness, partial thickness, or not observable. RESULTS: Pulse energies of 15 and 20 µJ had a 100% success rate in creating full-thickness FLT channels as imaged by OCT. A pulse energy of 10 µJ resulted in no channels (n = 6), a partial-thickness channel (n = 2), and a full-thickness FLT channel (n = 2). There was a statistically significant difference in cutting widths between the 10 and 15 µJ groups (p < 0.0001), as well as between the 10 and 20 µJ groups (p < 0.0001). However, there was no statistically significant difference between the 15 and 20 µJ groups (p = 0.416). CONCLUSIONS: Fifteen microjoules is an adequate pulse energy to reliably create aqueous humor outflow channels during FLT in human cadaver eyes. OCT is a valuable tool when evaluating FLT.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Associations of pyrethroid exposure with bone mineral density and osteopenia in adults.

INTRODUCTION: This study was to investigate the correlations between pyrethroid exposure and bone mineral density (BMD) and osteopenia. MATERIALS AND METHODS: This cross-sectional study included 1389 participants over 50 years of age drawn from the 2007-2010 and 2013-2014 National Health and Nutrition Examination Survey (NHANES). Three pyrethroid metabolites, 3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid (trans-DCCA), and 4-fluoro-3-phenoxybenzoic acid (4-F-3PBA) were used as indicators of pyrethroid exposure. Low BMD was defined as T-score < - 1.0, including osteopenia. Weighted multivariable linear regression analysis or logistic regression analysis was utilized to evaluate the correlation between pyrethroid exposure and BMD and low BMD. Bayesian kernel machine regression (BKMR) model was utilized to analyze the correlation between pyrethroids mixed exposure and low BMD. RESULTS: There were 648 (48.41%) patients with low BMD. In individual pyrethroid metabolite analysis, both tertile 2 and tertile 3 of trans-DCCA were negatively related to total femur, femur neck, and total spine BMD [coefficient (ß) = - 0.041 to - 0.028; all P < 0.05]. Both tertile 2 and tertile 3 of 4-F-3PBA were negatively related to total femur BMD (P < 0.05). Only tertile 2 [odds ratio (OR) = 1.63; 95% CI = 1.07, 2.48] and tertile 3 (OR = 1.65; 95% CI = 1.10, 2.50) of trans-DCCA was correlated with an increased risk of low BMD. The BKMR analysis indicated that there was a positive tendency between mixed pyrethroids exposure and low BMD. CONCLUSION: In conclusion, pyrethroids exposure was negatively correlated with BMD levels, and the associations of pyrethroids with BMD and low BMD varied by specific pyrethroids, pyrethroid concentrations, and bone sites.

Small dense low density lipoprotein predominance in patients with type 2 diabetes mellitus using Mendelian randomization.

BACKGROUND: Patients with T2DM often suffer from CVD-related complications, significantly impacting morbidity and mortality rates. The upsurge in CVD prevalence among them is partly linked to sd LDL particles. Understanding the mechanisms behind elevated sd LDL levels is critical for preventing and managing cardiovascular complications in diabetes. METHODS: MR was employed to identify instrumental variables and establish causality, exploring underlying mechanisms. RESULTS: Notably, T2DM itself, insulin resistance, and fasting glucose seemingly do not directly impact sd LDL levels. Instead, the presence of T2DM or insulin resistance, leading to reduced HDL cholesterol or elevated TG levels, directly contributes to subsequent sd LDL increases, indicating a comprehensive mediating effect. While LDL cholesterol levels correlate positively with sd LDL, they appear unaffected by T2DM or insulin resistance. Importantly, hypertension induced by T2DM or insulin resistance exhibits a positive effect on sd LDL reversal. Unlike T2DM or insulin resistance, blood glucose levels show no significant impact on all processes. CONCLUSIONS: It is hoped that these insights might influence the treatment of patients with diabetes and the management of blood parameters in clinical practice. Examining the effect of T2DM or insulin resistance on sd LDL within HDL cholesterol and triglycerides pathways might provide valuable insights for targeted cardiovascular treatments. Additionally, the study's exploration of the potential positive effects of elevated blood pressure on sd LDL reversal may introduce novel considerations for blood pressure management in patients with diabetes.

Genetic analysis and QTL mapping of seed hardness trait in a soybean (Glycine max) recombinant inbred line (RIL) population.

Seed hardness is a critical quality trait impacting both the suitability of soybeans for consumption and their processing. The primary objective of this study was to explore the genetic foundations underlying seed hardness in soybeans. A 234 recombinant inbred line (RIL) population was evaluated for seed hardness across three years (2015 in Gansu, 2016, and 2017 in Hainan). Notably, the parent varieties, Zhonghuang35 and Jindou21, displayed significant differences in seed hardness. Also, the RIL population exhibited a wide range of genetic variation in seed hardness, with coefficients of variation between 70.53 % and 94.94 %. The frequency distribution of this trait conformed to a relatively normal distribution, making it suitable for QTL analysis. Six QTLs associated with seed hardness were identified with three located on chromosome 2 and three on chromosome 16. The major QTL, qHS-2-1, consistently exhibited the highest percentage of PVE and LOD in Gansu 2015, Hainan 2016, and Hainan 2017, suggesting its central role in determining seed hardness. Further investigation revealed four genes within the qHS-2-1 interval potentially related to seed hardness. GO enrichment analysis provided insights into their functions, including factors such as Glyma.02G307000, a pectin lyase-like superfamily protein, which could influence seed hardness through its role in pectin lyase enzyme activity. Expression analysis of these candidate genes demonstrated significant differences between the two parent varieties, further highlighting their potential role in seed coat hardness. This study offers valuable insights into the genetic mechanisms governing soybean seed coat hardness, providing a foundation for future research and crop improvement efforts.

Pharmacokinetics, Pharmacodynamics, and Safety of Single Dose HSK7653 Tablets in Chinese Subjects with Normal or Impaired Renal Function.

OBJECTIVE: HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function. METHODS: This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate. RESULTS: HSK7653 exposure levels including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC0-t), and area under the plasma concentration-time curve from zero to infinity (AUC0-inf) showed no significant differences related to the severity of renal impairment. Renal clearance (CLR) showed a certain downtrend along with the severity of renal impairment. The CLR of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred. CONCLUSIONS: HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05497297.

Quantitative Optical Coherence Elastography of the Optic Nerve Head In Vivo.

OBJECTIVE: Optical coherence elastography (OCE) was used to demonstrate the relationship between the elasticity of the optic nerve head (ONH) and different intraocular pressure (IOP) levels in an in-vivo rabbit model for the first time. METHOD: Both ex-vivo and in-vivo rabbit ONH were imaged using OCE system. A mechanical shaker initiated the propagation of elastic waves, and the elasticity of the ONH was determined by tracking the wave propagation speed. The elasticity of the ONH under varying IOP levels was reconstructed based on the wave speed. Notably, the ONH exhibited increased stiffness with elevated IOP. RESULTS: In the in-vivo rabbit models, the Young's modulus of ONH increased from 14 kPa to 81 kPa with the IOP increased from 15 mmHg to 35 mmHg. This revealed a positive correlation between the Young's modulus of the ONH and intraocular pressure. CONCLUSION: The OCE system proved effective in measuring the mechanical properties of ONH at different IOP levels, with validation in an in-vivo rabbit model. SIGNIFICANCE: Considering ONH plays a critical role in vision and eye diseases, the capability to image and quantify in vivo ONH biomechanical properties has great potential to advance vision science research and improve the clinical management of glaucoma patients.

Adaptive bias-variance trade-off in advantage estimator for actor-critic algorithms.

Actor-critic methods are leading in many challenging continuous control tasks. Advantage estimators, the most common critics in the actor-critic framework, combine state values from bootstrapping value functions and sample returns. Different combinations balance the bias introduced by state values and the variance returned by samples to reduce estimation errors. The bias and variance constantly fluctuate throughout training, leading to different optimal combinations. However, existing advantage estimators usually use fixed combinations that fail to account for the trade-off between minimizing bias and variance to find the optimal estimate. Our previous work on adaptive advantage estimation (AAE) analyzed the sources of bias and variance and offered two indicators. This paper further explores the relationship between the indicators and their optimal combination through typical numerical experiments. These analyses develop a general form of adaptive combinations of state values and sample returns to achieve low estimation errors. Empirical results on simulated robotic locomotion tasks show that our proposed estimators achieve similar or superior performance compared to previous generalized advantage estimators (GAE).

Causal association of physical activity with low back pain, intervertebral disc degeneration and sciatica: a two-sample mendelian randomization analysis study.

Objective: Previous studies are insufficient to confirm a causal association between physical activity (PA) and low back pain (LBP), intervertebral disc degeneration (IDD), and sciatica. The present study used a two-sample Mendelian randomization (MR) analysis method to demonstrate whether or not there was a causal connection. Methods: First, four PA phenotypes were selected [accelerometer-based PA (average acceleration), accelerometer-based PA (acceleration fraction >425 mg), self-reported moderate-to-vigorous PA, and self-reported vigorous PA], setting thresholds for single nucleotide polymorphisms (SNPs) significantly concerned with PA p < 5 × 10-8, linkage disequilibrium (LD) r 2 < 0.01, genetic distance >5,000 kb, and F-value >10. SNPs associated with the outcome and confounding factors were then excluded using the PhenoScanncer database. Finally, after coordinating the genetic instruments from genome-wide association studies (GWAS) effect alleles for exposure and outcomes, multiplicative random effects inverse variance weighting (IVW), MR-Egger, weighted median method (WMM), and weighted mode method were used to assess exposure-outcome causality and perform sensitivity analysis on the estimated results. Results: The current study's IVW findings revealed proof of a causal connection between PA and LBP. While there was a positive causal tie between accelerometer-based PA (acceleration fraction >425 mg) and LBP [OR: 1.818, 95% CI:1.129-2.926, p = 0.012], there was a negative causal link between accelerometer-based PA (average acceleration) and LBP [OR: 0.945, 95% CI: 0.909-0.984, p = 0.005]. However causal relationship between PA and IDD or sciatica was not found. Conclusion: Increasing average PA but needing to avoid high-intensity PA may be an effective means of preventing low back pain. Although PA is not directly causally related to disc degeneration and sciatica, it can act through indirect pathways.

The Chinese version of the brief pain inventory-Facial (BPI-F) among different populations: Factor structure and measurement invariance.

OBJECTIVE: This study aimed to translate and adapt the Brief Pain Inventory-Facial (BPI-F) into Chinese, proposing a validated Chinese version for clinical application. METHODS: To evaluate the applicability of Chinese BPI-F, this study included two groups: clinical sample (406 patients with OFP) and non-clinical sample (514 college students without OFP medical history). Content validity was improved through patient interviews. Cronbach's α was used to evaluate the reliability of BPI-F in both groups. The best-fit factor structure was tested on clinical sample via exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Convergent and discriminant validity of BPI-F was evaluated by Spearman's coefficient. Serial CFA was used to assess measurement invariance between the two groups. RESULTS: Content validity and reliability of BPI-F were verified. EFA results support a two-factor structure, interference with general activities (1-7 items) and face-specific pain interference (8-14 items). CFA results demonstrated this two-factor structure is appropriate for different populations. Spearman results showed that BPI-F had good convergent and discriminant validity. Full measurement invariance is observed across the two groups. CONCLUSION: The Chinese BPI-F, with two-factor structure (interference with general / orofacial functions), enables accurate assessment of functional interference caused by OFP. BPI-F has the same significance in different clinical populations, which expands its application. CLINICAL SIGNIFICANCE: This manuscript proposed the Chinese version of the BPI-F and examined its psychometric characteristics for the first time. This validated scale provides a favorable instrument for aiding individual diagnosis and treatment for OFP patients in China.

Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans.

BACKGROUND AND OBJECTIVE: HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated. METHODS: A single intravenous dose of 2 µg/0.212 µCi/kg [14C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites. RESULTS: The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (Cmax), the half-life (t1/2) and the area under the concentration-time curve (AUC0-t) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the Cmax, t1/2 and the AUC0-t of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [14C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components. CONCLUSIONS: HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT05835934.

Effect of vascular endothelial growth factor 165 on dopamine level in the retinas of guinea pigs with form-deprivation myopia.

Background: Myopia is the most common refractive error because excessive increase in the axial length of a myopic eye leads to the thinning of the posterior scleral pole and can cause serious complications resulting in blindness. Thus, myopia has become a great concern worldwide. Dopamine (DA) plays a role in the development of myopia. Moreover, in Parkinson's disease, it has been proved that vascular endothelial growth factor 165 (VEGF165) can promote the survival and recovery of DA neurons, resulting in increased DA secretion in the striatum, thereby treating neuropathy. Therefore, we speculate that VEGF165 can also promote the release of DA in the retina to inhibit the occurrence and development of myopia. We aimed to investigate the effect of VEGF165 on DA levels in the retinas of guinea pigs with form-deprivation myopia (FDM) and the effects of DA on myopia prevention and control. Methods: Healthy 3-week-old pigmented guinea pigs were randomly divided into blank, FDM, phosphate buffer saline (PBS), 1, 5, and 10 ng groups. The FDM model was established by covering the right eye continuously with a translucent latex balloon pullover for 14 days. The pigs in the PBS, 1, 5, and 10 ng groups were injected with PBS buffer and 1, 5, and 10 ng of VEGF165 recombinant human protein, respectively, in the vitreous of the right eye before masking. The refractive error and axial length were measured before and after modeling. All retinas were used for biomolecular analyses after 14 days. Results: We found that the intravitreal injection of VEGF165 elevated DA levels in the retina and was effective in slowing the progression of myopia, and 1 ng of VEGF165 was the most effective. Moreover, the number of vascular endothelial cell nuclei in the 1 ng group was lower than that in the other VEGF165 groups. Conclusions: Our data suggest that VEGF165 has a promoting effect on DA in the retinas of guinea pigs with FDM, potentially controlling the development of myopia.

Manipulating rhizosphere microorganisms to improve crop yield in saline-alkali soil: a study on soybean growth and development.

Introduction: Rhizosphere microorganisms can effectively promote the stress resistance of plants, and some beneficial rhizosphere microorganisms can significantly promote the growth of crops under salt stress, which has the potential to develop special microbial fertilizers for increasing the yield of saline-alkali land and provides a low-cost and environmentally friendly new strategy for improving the crop yield of saline-alkali cultivated land by using agricultural microbial technology. Methods: In May 2022, a field study in a completely randomized block design was conducted at the Heilongjiang Academy of Agricultural Sciences to explore the correlation between plant rhizosphere microorganisms and soybean growth in saline-alkali soil. Two soybean cultivars (Hening 531, a salt-tolerant variety, and 20_1846, a salt-sensitive variety) were planted at two experimental sites [Daqing (normal condition) and Harbin (saline-alkali conditions)], aiming to investigate the performance of soybean in saline-alkali environments. Results: Soybeans grown in saline-alkali soil showed substantial reductions in key traits: plant height (25%), pod number (26.6%), seed yield (33%), and 100 seed weight (13%). This underscores the unsuitability of this soil type for soybean cultivation. Additionally, microbial analysis revealed 43 depleted and 56 enriched operational taxonomic units (OTUs) in the saline-alkali soil compared to normal soil. Furthermore, an analysis of ion-associated microbes identified 85 mOTUs with significant correlations with various ions. A co-occurrence network analysis revealed strong relationships between specific mOTUs and ions, such as Proteobacteria with multiple ions. In addition, the study investigated the differences in rhizosphere species between salt-tolerant and salt-sensitive soybean varieties under saline-alkali soil conditions. Redundancy analysis (RDA) indicated that mOTUs in saline-alkali soil were associated with pH and ions, while mOTUs in normal soil were correlated with Ca2+ and K+. Comparative analyses identified significant differences in mOTUs between salt-tolerant and salt-sensitive varieties under both saline-alkali and normal soil conditions. Planctomycetes, Proteobacteria, and Actinobacteria were dominant in the bacterial community of saline-alkali soil, with significant enrichment compared to normal soil. The study explored the functioning of the soybean rhizosphere key microbiome by comparing metagenomic data to four databases related to the carbon, nitrogen, phosphorus, and sulfur cycles. A total of 141 KOs (KEGG orthologues) were identified, with 66 KOs related to the carbon cycle, 16 KOs related to the nitrogen cycle, 48 KOs associated with the phosphorus cycle, and 11 KOs linked to the sulfur cycle. Significant correlations were found between specific mOTUs, functional genes, and phenotypic traits, including per mu yield (PMY), grain weight, and effective pod number per plant. Conclusion: Overall, this study provides comprehensive insights into the structure, function, and salt-related species of soil microorganisms in saline-alkali soil and their associations with salt tolerance and soybean phenotype. The identification of key microbial species and functional categories offers valuable information for understanding the mechanisms underlying plant-microbe interactions in challenging soil conditions.

Effect of SGLT2 inhibitors on fractures, BMD, and bone metabolism markers in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

This meta-analysis aims to evaluate the impact of Sodium Glucose Transporter 2 (SGLT2) inhibitors on fractures, bone mineral density (BMD), and bone metabolism markers in type 2 diabetes mellitus (T2DM) patients. Pooled relative risk (RR) with 95% confidence interval (CI) assessed the relationship between SGLT2 inhibitors and fracture risk. Weighted mean difference (WMD) with 95% CI explored the correlation between SGLT2 inhibitors and BMD, as well as bone metabolism markers. A total of 20 randomised controlled trials (RCTs) involving 12,764 patients were analysed. No significant association emerged between SGLT2 inhibitor use and elevated fracture risk (pooled RR = 1.21, 95% CI [0.95, 1.54], I2 = 22%). Furthermore, SGLT2 inhibitors exhibited no substantial effects on BMD changes at the lumbar spine (WMD = -0.02, 95% CI [-0.38, 0.34]), femoral neck (WMD = 0.11, 95% CI [-0.28, 0.50]), total hip (WMD = -0.20, 95% CI [-0.41, 0.01]), and distal forearm (WMD = -0.20, 95% CI [-0.62, 0.22]). Similarly, no notable impact of SGLT2 inhibitors on bone metabolism markers, including CTX (WMD = 0.04, 95% CI [-0.02, 0.09]), P1NP (WMD = 1.06, 95% CI [-0.44, 2.57]), PTH (WMD = 0.34, 95% CI [-0.07, 0.75]), calcium (WMD = 0.01, 95% CI [-0.02, 0.04]), and phosphate (WMD = 2.37, 95% CI [-0.76, 5.49]). The findings suggest that the utilization of SGLT2 inhibitors is not significantly linked to an elevated risk of fractures in individuals with T2DM. However, further clinical investigations and extended follow-up periods are warranted to establish more conclusive determinations.

Tooth ultrastructure changes induced by a nonsense mutation in the FAM83H gene: insights into the diversity of amelogenesis imperfecta.

OBJECTIVES: The current research on single-nucleotide polymorphism (SNP) mutation sites at different positions of the FAM83H gene and their phenotypic changes leading to amelogenesis imperfecta (AI) is inconsistent. We identified a previously reported heterozygous nonsense mutation c.1192C>T (p.Q398*) in the FAM83H gene and conducted a comprehensive analysis of the dental ultrastructure and chemical composition changes induced by this mutation. Additionally, we predicted the protein feature affected by this mutation site. The aim was to further deepen our understanding of the diversity of AI caused by different mutation sites in the FAM83H gene. METHODS: Whole-exome sequencing (WES) and Sanger sequencing were used to confirm the mutation sites. Physical features of the patient's teeth were investigated using various methods including cone beam computer tomography (CBCT), scanning electron microscopy (SEM), contact profilometry (roughness measurement), and a nanomechanical tester (nanoindentation measurement). The protein features of wild-type and mutant FAM83H were predicted using bioinformatics methods. RESULTS: One previously discovered FAM83H heterozygous nonsense mutation c.1192C>T (p.Q398*) was detected in the patient. SEM revealed inconsistent dentinal tubules, and EDS showed that calcium and phosphorus were lower in the patient's dentin but higher in the enamel compared to the control tooth. Roughness measurements showed that AI patients' teeth had rougher occlusal surfaces than those of the control tooth. Nanoindentation measurements showed that the enamel and dentin hardness values of the AI patients' teeth were both significantly reduced compared to those of the control tooth. Compared to the wild-type FAM83H protein, the mutant FAM83H protein shows alterations in stability, hydrophobicity, secondary structure, and tertiary structure. These changes could underlie functional differences and AI phenotype variations caused by this mutation site. CONCLUSIONS: This study expands the understanding of the effects of FAM83H mutations on tooth structure. CLINICAL RELEVANCE: Our study enhances our understanding of the genetic basis of AI and may contribute to improved diagnostics and personalized treatment strategies for patients with FAM83H-related AI.

In situ activation of flexible magnetoelectric membrane enhances bone defect repair.

For bone defect repair under co-morbidity conditions, the use of biomaterials that can be non-invasively regulated is highly desirable to avoid further complications and to promote osteogenesis. However, it remains a formidable challenge in clinical applications to achieve efficient osteogenesis with stimuli-responsive materials. Here, we develop polarized CoFe2O4@BaTiO3/poly(vinylidene fluoridetrifluoroethylene) [P(VDF-TrFE)] core-shell particle-incorporated composite membranes with high magnetoelectric conversion efficiency for activating bone regeneration. An external magnetic field force conduct on the CoFe2O4 core can increase charge density on the BaTiO3 shell and strengthens the ß-phase transition in the P(VDF-TrFE) matrix. This energy conversion increases the membrane surface potential, which hence activates osteogenesis. Skull defect experiments on male rats showed that repeated magnetic field applications on the membranes enhanced bone defect repair, even when osteogenesis repression is elicited by dexamethasone or lipopolysaccharide-induced inflammation. This study provides a strategy of utilizing stimuli-responsive magnetoelectric membranes to efficiently activate osteogenesis in situ.

Immunogenic cell death-related classifications guide prognosis and immunotherapy in osteosarcoma.

Immunogenic cell death (ICD) is a form of cell death that stimulates the immune system to produce an immune response by releasing tumour-associated antigens and tumour-specific antigens and is considered to play an important role in tumour immunotherapy. In the present study, we identified two ICD-related subtypes in osteosarcoma (OS) by consensus clustering. The ICD-low subtype was associated with favourable clinical outcomes, abundant immune cell infiltration, and high activity of immune response signalling. We also established and validated an ICD-related prognostic model, which could not only be used to predict the overall survival of OS patients but was also found to be closely related to the tumour immune microenvironment of OS patients. Overall, we established a new classification system for OS based on ICD-related genes, which can be used to predict the prognosis of OS patients and to select appropriate immunotherapy drugs.

Cultivation model and deficit irrigation strategy for reducing leakage of bundle sheath cells to CO2, improve 13C carbon isotope, photosynthesis and soybean yield in semi-arid areas.

A better understanding of the photosynthesis and soil water storage regulation of soybean production will be helpful to develop a water conservation strategy under a rain-fed farming system. Reducing the leakage of CO2 bundle sheath cells and improving the photosynthesis capacity and gas exchange characteristics of soybean leaves will contribute to increase yield under the dryland agricultural system and provide a scientific basis. Therefore, during 2019 and 2020, soybean exposed to different cultivation modes to analyze the response curves of photosynthesis and CO2 under different deficit irrigation strategies. In this study, we used two cultivation models: RB: ridge covered with biodegradable film and furrow area not covered; CF: conventional flat land planting under four deficit irrigation modes (R: rainwater irrigation; IB: branch stage irrigation (220 mm); IP: Irrigation during podding (220 mm); IBP: branch stage irrigation (110 mm), podding stage irrigation (110 mm). Compared with CF-IBP treatment, RB-IBP had significant effects on rainwater collection, SWS, and soybean yield. Photo-response curve analysis showed that RB-IBP treatment a significant increase in Pn, Gs, Ci, Tr, leaf WUE, and chlorophyll ab content. Under different irrigation strategies, maximum net photosynthetic rate (Pnmax), light saturation point (LSP), and apparent quantum efficiency under RB-IBP treatment (α), Pn under respiration rate and CO2 response curve were significantly higher than that under CF cultivation mode. Compared with RB culture mode under different irrigation strategies, CF cultivation mode significantly increases Δ13C and CO2 sheath cell leakage (Փ); it also led to a significant decline in the ratio of Ci/Ca concentration. This study shows that RB-IBP treatment is the best water-saving strategy because it means reducing the leakage of CO2 from the bundle sheath, thus significantly increasing soil water storage, photosynthetic capacity, and soybean yield.

A submillimeter bundled microtubular flow battery cell with ultrahigh volumetric power density.

Flow batteries are a promising energy storage solution. However, the footprint and capital cost need further reduction for flow batteries to be commercially viable. The flow cell, where electron exchange takes place, is a central component of flow batteries. Improving the volumetric power density of the flow cell (W/Lcell) can reduce the size and cost of flow batteries. While significant progress has been made on flow battery redox, electrode, and membrane materials to improve energy density and durability, conventional flow batteries based on the planar cell configuration exhibit a large cell size with multiple bulky accessories such as flow distributors, resulting in low volumetric power density. Here, we introduce a submillimeter bundled microtubular (SBMT) flow battery cell configuration that significantly improves volumetric power density by reducing the membrane-to-membrane distance by almost 100 times and eliminating the bulky flow distributors completely. Using zinc-iodide chemistry as a demonstration, our SBMT cell shows peak charge and discharge power densities of 1,322 W/Lcell and 306.1 W/Lcell, respectively, compared with average charge and discharge power densities of <60 W/Lcell and 45 W/Lcell, respectively, of conventional planar flow battery cells. The battery cycled for more than 220 h corresponding to >2,500 cycles at off-peak conditions. Furthermore, the SBMT cell has been demonstrated to be compatible with zinc-bromide, quinone-bromide, and all-vanadium chemistries. The SBMT flow cell represents a device-level innovation to enhance the volumetric power of flow batteries and potentially reduce the size and cost of the cells and the entire flow battery.