Highly Aligned Ternary Nanofiber Matrices Loaded with MXene Expedite Regeneration of Volumetric Muscle Loss

Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as a promising alternative.In this study,we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone)integrated with collagen and Ti_(3)C_(2)T_(x)MXene nanoparticles(NPs)(PCM matrices),and explored their myogenic potential for skeletal muscle tissue regeneration.The PCM matrices demonstrated favorable physicochemical properties,including structural uniformity,alignment,microporosity,and hydrophilicity.In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts.Moreover,in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury.Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices,leading to elevated intracellular Ca^(2+)levels in myoblasts through the activation of inducible nitric oxide synthase(i NOS)and serum/glucocorticoid regulated kinase 1(SGK1),ultimately promoting myogenic differentiation via the m TOR-AKT pathway.Additionally,upregulated i NOS and increased NO–contributed to myoblast proliferation and fiber fusion,thereby facilitating overall myoblast maturation.These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.

Genomic characterization of peritoneal lavage cytology-positive gastric cancer

Objective: Positive peritoneal lavege cytology(CY1) gastric cancer is featured by dismal prognosis, with high risks of peritoneal metastasis. However, there is a lack of evidence on pathogenic mechanism and signature of CY1and there is a continuous debate on CY1 therapy. Therefore, exploring the mechanism of CY1 is crucial for treatment strategies and targets for CY1 gastric cancer.Methods: In order to figure out specific driver genes and marker genes of CY1 gastric cancer, and ultimately offer clues for potential marker and risk assessment of CY1, 17 cytology-positive gastric cancer patients and 31matched cytology-negative gastric cancer patients were enrolled in this study. The enrollment criteria were based on the results of diagnostic laparoscopy staging and cytology inspection of exfoliated cells. Whole exome sequencing was then performed on tumor samples to evaluate genomic characterization of cytology-positive gastric cancer.Results: Least absolute shrinkage and selection operator(LASSO) algorithm identified 43 cytology-positive marker genes, while Mut Sig CV identified 42 cytology-positive specific driver genes. CD3G and CDKL2 were both driver and marker genes of CY1. Regarding mutational signatures, driver gene mutation and tumor subclone architecture, no significant differences were observed between CY1 and negative peritoneal lavege cytology(CY0).Conclusions: There might not be distinct differences between CY1 and CY0, and CY1 might represent the progression of CY0 gastric cancer rather than constituting an independent subtype. This genomic analysis will thus provide key molecular insights into CY1, which may have a direct effect on treatment recommendations for CY1and CY0 patients, and provides opportunities for genome-guided clinical trials and drug development.

Validity of fatty liver prediction scores for diagnosis of fatty liver by Fibroscan

Background:The Korea National Health and Nutrition Examination Survey nonalcoholic fatty liver disease(K-NAFLD)score was recently developed with the intent to operationally define nonalcoholic fatty liver disease(NAFLD).However,there remained an external validation that confirmed its diagnostic performance,especially in patients with alcohol consumption or hepatitis virus infection.Methods:Diagnostic accuracy of the K-NAFLD score was evaluated in a hospital-based cohort consisting of 1388 participants who received Fibroscan®.Multivariate-adjusted logistic regression models and the contrast estimation of receiver operating characteristic curves were used for validation of the K-NAFLD score,fatty liver index(FLI),and hepatic steatosis index(HSI).Results:K-NAFLD-moderate[adjusted odds ratio(aOR)=2.53,95%confidence interval(CI):1.13-5.65]and K-NAFLD-high(aOR=4.14,95%CI:1.69-10.13)groups showed higher risks of fatty liver compared to the K-NAFLD-low group after adjustments for demographic and clinical characteristics,and FLI-moderate and FLI-high groups revealed aORs of 2.05(95%CI:1.22-3.43)and 1.51(95%CI:0.78-2.90),respectively.In addition,the HSI was less predictive for Fibroscan®-defined fatty liver.Both K-NAFLD and FLI also demonstrated high accuracy in the prediction of fatty liver in patients with alcohol consumption and chronic hepatitis virus infection,and the adjusted area under curve values were comparable between K-NAFLD and FLI.Conclusions:Externally validation of the K-NAFLD and FLI showed that these scores may be a useful,noninvasive,and non-imaging modality for the identification of fatty liver.In addition,these scores also predicted fatty liver in patients with alcohol consumption and chronic hepatitis virus infection.

Measurement of very low-molecular weight metabolites by traveling wave ion mobility and its use in human urine samples

The collision cross-sections(CCS)measurement using ion mobility spectrometry(IMS)in combination with mass spectrometry(MS)offers a great opportunity to increase confidence in metabolite identification.However,owing to the lack of sensitivity and resolution,IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites(VLMs250 Da).Here,we describe an analytical method using ultrahigh-performance liquid chromatography(UPLC)coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples.The experimental CCS values,along with mass spectral properties,were reported for the 174 metabolites.The experimental data included the mass-to-charge ratio(m/z),retention time(RT),tandem MS(MS/MS)spectra,and CCS values.Among the studied metabolites,263 traveling wave ion mobility spectrometry(TWIMS)-derived CCS values(TWCCSN2)were reported for the first time,and more than 70%of these were CCS values of VLMs.The TWCCSN2 values were highly repeatable,with inter-day variations of<1%relative standard deviation(RSD).The developed method revealed excellent TWCCSN2 accuracy with a CCS difference(DCCS)within±2%of the reported drift tube IMS(DTIMS)and TWIMS CCS values.The complexity of the urine matrix did not affect the precision of the method,as evidenced by DCCS within±1.92%.According to the Metabolomics Standards Initiative,55 urinary metabolites were identified with a confidence level of 1.Among these 55 metabolites,53(96%)were VLMs.The larger number of confirmed compounds found in this study was a result of the addition of TWCCSN2 values,which clearly increased metabolite identification confidence.

Treatment and prognosis of hepatic epithelioid hemangioendothelioma based on SEER data analysis from 1973 to 2014

Background: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular origin with an unknown etiology, a low incidence, and a variable natural course. We evaluated the management and prognosis of HEH from the Surveillance, Epidemiology and End Results (SEER) program and changes in treatment modalities of HEH over 30 years. Methods: From 1973 to 2014 in the SEER database, we selected patients diagnosed with HEH. We analyzed the clinical characteristics, patterns of management, and clinical outcomes of patients with HEH. Results: We identi ed 79 patients with HEH (median age: 54.0 years;male to female ratio: 1:2.6). The initial extent of disease was local in 22 (27.8%) patients, regional metastasis in 22 (27.8%), distant metas-tasis in 31 (39.2%) and unknown in 4 (5.1%). The median size of primary tumor was 3.85 cm (interquartile range, 2.50 7.93 cm). Among 74 patients with available management data, the most common manage-ment was no treatment (29/74, 39.2%), followed by chemotherapy only (22/74, 29.7%), liver resection-based (13/74, 17.6%), and transplantation-based therapy (6/74, 8.1%). The 5-year cancer-speci c survival rate was 57.8%. Patients who underwent surgical treatment had signi cantly higher survival than those who underwent non-surgical treatment (5-year survival;88% vs. 49%, P=0.019). Multivariate analysis revealed that surgical therapy was the only independent prognostic factor for survival (hazard ratio: 0.20, P=0.040). Conclusions: Resection or liver transplantation is worth considering for treatment of patients with HEH.

Fluoroquinolone-macrolide combination therapy for chronic bacterial prostatitis： retrospective analysis of pathogen eradication rates, inflammatory findings and sexual dysfunction

We previously demonstrated the safety and efficacy of fluoroquinolone-macrolide combination therapy in category Ⅱ chronic bacterial prostatitis （CBP）. The aim of this study is to retrospectively compare the microbiological and clinical findings of two treatment schemes for CBP based on the combination of azithromycin （500 rag, thrice-weekly） with a once-daily 500- or 750-mg dose of ciprofloxacin （Cipro-500 or Cipro-750 cohort, respectively）. Combined administration of azithromycin （1500 mg week^-1） with ciprofloxacin at the rate of 750 mg day^- 1 for 4 weeks rather than at 500 mg day^- 1 for 6 weeks increased the eradication rates from 62.35% to 77.32% and the total bacteriological success from 71.76% to 85.57%. A significant decrease in pain and voiding signs/symptoms and a significant reduction in inflammatory leukocyte counts and serum prostate-specific antigen （PSA） were sustained throughout an 18-month follow-up period in both groups. Ejaculatory pain, haemospermia and premature ejaculation were significantly attenuated on microbiological eradication in both groups, but the latter subsided more promptly in the Cipro-750 cohort. In total, 59 Cipro-750 patients showed mild-to-severe erectile dysfunction （ED） at baseline, while 22 patients had no ED on microbiological eradication and throughout the follow-up period. In conclusion fluoroquinolone-macrolide therapy resulted in pathogen eradication and CBP symptom attenuation, including pain, voiding disturbances and sexual dysfunction. A once-daily 750-mg dose of ciprofloxacin for 4 weeks showed enhanced eradication rates and lower inflammatory white blood cell counts compared to the 500-mg dose for 6 weeks. Our results are open to further prospective validation.

Long-term outcomes of endoscopic submucosal dissection and surgery for undifferentiated intramucosal gastric cancer regardless of size

BACKGROUND The clinical outcomes of endoscopic submucosal dissection(ESD)for undifferentiated(UD)intramucosal early gastric cancer(EGC)compared with those of surgery,regardless of lesion size,are not well known.Furthermore,there is a concern regarding the treatment plan before and after ESD in cases of UD intramucosal EGC within expanded indications.AIM To evaluate clinical outcomes of ESD compared with those of surgery in UD intramucosal EGC patients regardless of tumor size.METHODS We enrolled patients with UD intramucosal EGC after ESD with complete resection or surgery from January 2005 to August 2020 who met the within or beyond expanded indications with lesion size>2 cm(the only non-curative factor).Overall,123 and 562 patients underwent ESD and surgery,respectively.After propensity-score matching,clinical and long-term outcomes,i.e.,recurrencefree survival(RFS)and overall survival(OS),were analyzed.The multivariable Cox proportional hazard model with treatment modality and ESD indication was used to evaluate the recurrence risk.RESULTS After matching,119 patients each were finally enrolled in the ESD and surgery groups.The median length of hospital stay was shorter in the ESD group than surgery group(4.0 vs 9.0 days,P<0.001).Four cases of recurrence after ESD were local recurrences,all of which occurred within 1 year.Total recurrence was seven(5.9%)and two(1.7%)in the ESD and surgery groups,respectively.No difference was observed between the two groups with respect to OS(P=0.948).However,the ESD group had inferior RFS compared with the surgery group(P=0.031).ESD was associated with the risk of recurrence after initial treatment in all enrolled patients(hazard ratio,5.2;95%confidence interval:1.0-25.8,P=0.045).CONCLUSION Although OS was similar between the two groups,surveillance endoscopy was important for the ESD than for the surgery group because RFS was inferior and local recurrence was an issue.

Liver stiffness as a predictor of hepatocellular carcinoma behavior in patients with hepatitis C related liver cirrhosis

Background: Risk strati cation and prognostication of hepatocellular carcinoma (HCC) help to improve patient outcome. Herein we investigated the role of liver stiffness measurement (LSM) in the prediction of HCC behavior. Methods: Totally 121 na ve patients with HCC were included. HCC radiological evaluation and staging were done. LSM was measured using virtual touch quanti cation. Patients were divided into early to intermediate HCC (BCLC-0, A and B) and late HCC (BCLCC and D). HCC was treated according to the BCLC stage. HCC recurrence-free interval was estimated. Results: The mean LSM inside the tumor was signi cantly lower than the peri-tumoral area and the cirrhotic non-cancerous liver parts (P<0.001). In late HCCs stage, the mean LSM inside the tumor and in the peri-tumoral tissue was lower than the corresponding values in the early to intermediate HCCs stage (P<0.001). LSM inside the tumor and in the peri-tumoral tissue negatively correlated with serum AFP, tumor vascular invasion, and stage (P<0.05). The recurrence-free interval was directly correlated to LSM inside the tumor and inversely to LSM in cirrhotic non tumorous liver part. Kaplan-Meier analysis showed that the recurrence-free interval was signi cantly longer in patients with LSM inside the tumor of ≥1.25m/s compared to those with LSM inside the tumor of<1.25m/s. Conclusions: LSM can serve as a potential non-invasive predictor for HCC clinical behavior and the recurrence-free interval following loco-regional treatments.

Metabolomic Profiling Differences among Asthma,COPD,and Healthy Subjects:A LC-MS-based Metabolomic Analysis

Objective Asthma and chronic obstructive pulmonary disease(COPD)feature different inflammatory and cellular profiles in the airways,indicating that the cellular metabolic pathways regulating these disorders are distinct.Methods We aimed to compare the serum metabolomic profiles among mild persistent asthmatic patients,individuals with stable COPD,and healthy subjects and to explore the potential metabolic biomarkers and pathways.The serum metabolomic profiles of 17 subjects with mild persistent asthma,17 subjects with stable COPD,and 15 healthy subjects were determined by an untargeted metabolomic an alysis utilizi ng liquid chromatography-mass spectrometry.A series of multivariate statistical an a lyses was subsequently used.Results Multivariate analysis indicated a distinct separation between the asthmatic patients and healthy controls in electrospray positive and negative ions modes,respectively.A total of 19 differential metabolites were identified.Similarly,a distinct separation between asthma and COPD subjects was detected in the two ions modes.A total of 16 differential metabolites were identified.Among the identified metabolites,the serum levels of hypoxanthine were markedly higher in asthmatic subjects compared with those in COPD or healthy subjects.Conclusions Patients with asthma present a unique serum metabolome,which can distinguish them from individuals with COPD and healthy subjects.Purine metabolism alteration may be distinct and involved in the pathogenesis of asthma.

Gene expression profile of peripheral blood in colorectal cancer

AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated.

Altered physiology of mesenchymal stem cells in the pathogenesis of adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis is the most common spinal deformity during puberty,especially in females.It is characterized by aberrant skeletal growth and generalized reduced bone density,which is associated with impaired bone mineral metabolism.Despite recent progress in multidisciplinary research to support various hypotheses,the pathogenesis of Adolescent idiopathic scoliosis is still not clearly understood.One of the hypothesis is to study the role of mesenchymal stem cells due to its involvement in the above-mentioned bone metabolic abnormalities.In this review,we will summarize reported literatures on the role of mesenchymal stem cells,particularly in the pathogenesis of Adolescent idiopathic scoliosis.In addition,we will describe the research on mesenchymal stem cells of Adolescent idiopathic scoliosis performed using bioinformatics tools.

Possible Relations of Cosmic Microwave Background with Gravity and Fine-Structure Constant

Gravity is the only force that cannot be explained by the Standard Model (SM), the current best theory describing all the known fundamental particles and their forces. Here we reveal that gravitational force can be precisely given by mass of objects and microwave background (CMB) radiation. Moreover, using the same strategy we reveal a relation by which CMB can also precisely define fine-structure constant α.

On the Possibility of Variable Speed of Light in Vacuum

We previously revealed a quantitative relation by which the fine-structure constant α can be described by the temperature T of cosmic microwave background (CMB) with several other fundamental constants, including the elementary charge e, the Boltzmann constant k, the Planck constant h, and the light of speed in vacuum c. Given that the value of α is quite conserved but T is variable across CMBs, we propose that c changes with T and can be given by T, the present CMB temperature T0 and the present light speed c0. As T is continuously decreasing, c is thus predicted to decrease at a rate of ~2.15 centimeters/second (cm/s) per year. Moreover, we provide a lot of evidence to support this finding. In conclusion, this study suggests a possibility of variable speed of light in vacuum.

Perspectives of Certified Registered Nurse Anesthetists on Endoscopy Room Delays

As hospitals undergo reductions in budget and the demand for endoscopic procedures grows, the need for more efficient endoscopy units has increased. Certified Registered Nurse Anesthetists (CRNAs) play a vital role in Endoscopy Units and because of this, increasing CRNA work efficiency would increase the efficiency of the entire unit. This pilot study aims to explore CRNA workflow and identify workflow barriers present in endoscopy rooms through qualitative interview analysis. Ten semi-structured interviews were conducted at the University of Cincinnati Medical Center. The interview data were analyzed qualitatively to generate workflow diagrams and four themes of workflow barriers and representative quotes. These themes include: 1) physician unavailability, 2) patient delay and variability, 3) suboptimal teamwork and coordination, and 4) issues with supporting tools. The workflow barriers reflect and extend the current literature, and can inform future quality improvement initiatives.

Call for action:Increased healthcare utilization with growing use of percutaneous cholecystectomy tube over initial cholecystectomy in cirrhotics

Background:Acute calculous cholecystitis(ACC)is frequently seen in cirrhotics,with some being poor candidates for initial cholecystectomy.Instead,these patients may undergo percutaneous cholecystostomy tube(PCT)placement.We studied the healthcare utilization and predictors of cholecystectomy and PCT in patients with ACC.Methods:The National Database was queried to study all cirrhotics and non-cirrhotics with ACC between 2010-2014 who underwent initial PCT(with or without follow-up cholecystectomy)or cholecystectomy.Cirrhotic patients were divided into compensated and decompensated cirrhosis.Independent predictors and outcomes of initial PCT and failure to undergo subsequent cholecystectomy were studied.Results:Out of 919189 patients with ACC,13283(1.4%)had cirrhosis.Among cirrhotics,cholecystec-tomy was performed in 12790(96.3%)and PCT in the remaining 493(3.7%).PCT was more frequent in cirrhotics(3.7%)than in non-cirrhotics(1.4%).Multivariate analyses showed increased early readmis-sions[odds ratio(OR)=2.12,95%confidence interval(CI):1.43-3.13,P<0.001],length of stay(effect ratio=1.39,95%CI:1.20-1.61,P<0.001),calendar-year hospital cost(effect ratio=1.34,95%CI:1.28-1.39,P<0.001)and calendar-year mortality(hazard ratio=1.89,95%CI:1.07-3.29,P=0.030)in cir-rhotics undergoing initial PCT compared to cholecystectomy.Decompensated cirrhosis(OR=2.25,95%CI:1.67-3.03,P<0.001)had the highest odds of getting initial PCT.Cirrhosis,regardless of compensated(OR=0.56,95%CI:0.34-0.90,P=0.020)or decompensated(OR=0.28,95%CI:0.14-0.59,P<0.001),reduced the chances of getting a subsequent cholecystectomy.Conclusions:Cirrhotic patients undergo fewer cholecystectomy incurring initial PCT instead.Moreover,the rates of follow-up cholecystectomy are lower in cirrhotics.Increased healthcare utilization is seen with initial PCT amongst cirrhotic patients.This situation reflects suboptimal management of ACC in cirrhotics and a call for action.

Data Hiding in DNA for Authentication of Plant Variety Rights

Hiding data in acid （DNA） can facilitate annotation of important plant the deoxyribose nucleic the authentication and variety rights. A grant of plant variety rights for a new plant variety gives you the exclusive right to produce for sale and sell propagating material of the variety. Digital watermarking techniques have been proposed for a wide range of applications, including ownership protection, copy control, annotation, and authentication. However, existing data hiding methods for DNA change the functionalities of DNA sequences, which induce morphological changes in biological patterns. This paper proposes a high capacity data hiding scheme for DNA without changing the functionalities of DNA sequences. This scheme adaptively varies the embedding process according to the amount of hidden data. Experimental results show that the proposed scheme gives a significantly improved hiding performance than previous schemes. And the robustness and security issues are also analyzed.

State of machine and deep learning in histopathological applications in digestive diseases

Machine learning(ML)-and deep learning(DL)-based imaging modalities have exhibited the capacity to handle extremely high dimensional data for a number of computer vision tasks.While these approaches have been applied to numerous data types,this capacity can be especially leveraged by application on histopathological images,which capture cellular and structural features with their highresolution,microscopic perspectives.Already,these methodologies have demonstrated promising performance in a variety of applications like disease classification,cancer grading,structure and cellular localizations,and prognostic predictions.A wide range of pathologies requiring histopathological evaluation exist in gastroenterology and hepatology,indicating these as disciplines highly targetable for integration of these technologies.Gastroenterologists have also already been primed to consider the impact of these algorithms,as development of real-time endoscopic video analysis software has been an active and popular field of research.This heightened clinical awareness will likely be important for future integration of these methods and to drive interdisciplinary collaborations on emerging studies.To provide an overview on the application of these methodologies for gastrointestinal and hepatological histopathological slides,this review will discuss general ML and DL concepts,introduce recent and emerging literature using these methods,and cover challenges moving forward to further advance the field.

Akt isoforms differentially provide for chemoresistance in prostate cancer

Objective:Early prostate cancer micrometastatic foci undergo a mesenchymal to epithelial reverting transition,not only aiding seeding and colonization,but also rendering the tumor cells generally chemoresistant.We previously found that upregulated E-cadherin in the epithelial micrometastases activated canonical survival pathways,including PI3K-Akt,that protected the tumor cells from death;however,the extent of protection from blocking the pathway in its entirety was modest,because different isoforms may have alternately affected cell functioning.Here,we characterized Akt isoform expressions in primary and metastatic prostate cancers,as well as their individual contributions to chemoresistance.Methods:Akt isoforms and E-cadherin were manipulated with drugs,knocked down,and over expressed.Tumor cell killing was determined in vitro and in vivo.Overall survival was calculated from patient records and specimens.Results:Pan-Akt inhibition sensitized tumor cells to chemotherapy,and specific blockade of Akt1 or/and Akt2 caused cells to be more chemoresponsive.Overexpression of Akt3 induced apoptosis.A low dose of Akt1 or Akt2 inhibitor enabled standard chemotherapies to significantly eradicate metastatic prostate tumors in a mouse model,acting as chemosensitizers.In human specimens,we found Akt1 and Akt2 positively correlated,whereas Akt3 inversely correlated,with the overall survival of prostate cancer patients.Akt1high/Akt2high/Akt3low tumors had the worst outcomes.Conclusions:E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance,whereas Akt3 made cells more fragile.These findings emphasized the need to target Akt1/2,rather than pan-Akt,as a rational therapeutic approach.

Rescue of human corneal epithelial cells after alkaline insult using renalase derived peptide, RP-220

AIM:To study the effect of renalase peptide,RP-220,on cell viability of human corneal epithelial cells after alkali insult.METHODS:A dose-response relationship between cell viability and exposure to NaOH solution were characterized using cultured human corneal epithelial cells.Viability of corneal epithelial cells was determined using commercially available MTT and CyQUANT?assays.RESULTS:At a concentration of 6 mmol/L,insult with NaOH leads to reduced corneal epithelial cell viability by approximately 30%.This reduced viability was prevented by treating the cells after initial insult with the 20-amino acid renalase derived peptide(RP-220).CONCLUSION:RP-220 has a pro-survival role for RP-220 following alkaline insult to corneal epithelial cells.

Reversal of the diabetic bone signature with anabolic therapies in mice

The mechanisms underlying the bone disease induced by diabetes are complex and not fully understood;and antiresorptive agents,the current standard of care,do not restore the weakened bone architecture.Herein,we reveal the diabetic bone signature in mice at the tissue,cell,and transcriptome levels and demonstrate that three FDA-approved bone-anabolic agents correct it.Diabetes decreased bone mineral density(BMD)and bone formation,damaged microarchitecture,increased porosity of cortical bone,and compromised bone strength.Teriparatide(PTH),abaloparatide(ABL),and romosozumab/anti-sclerostin antibody(Scl-Ab)all restored BMD and corrected the deteriorated bone architecture.Mechanistically,PTH and more potently ABL induced similar responses at the tissue and gene signature levels,increasing both formation and resorption with positive balance towards bone gain.In contrast,Scl-Ab increased formation but decreased resorption.All agents restored bone architecture,corrected cortical porosity,and improved mechanical properties of diabetic bone;and ABL and Scl-Ab increased toughness,a fracture resistance index.Remarkably,all agents increased bone strength over the healthy controls even in the presence of severe hyperglycemia.These findings demonstrate the therapeutic value of bone anabolic agents to treat diabetes-induced bone disease and suggest the need for revisiting the approaches for the treatment of bone fragility in diabetes.