The products prepared from Foxtail millet were found to have high acceptability with mean score of more than 8.00. These diversified food products showed higher protein content ranging from 10.98 to 16.10 g/100 g, with the highest protein found in Foxtail millet kheer (16.01 g/100 g). The resistant starch content and predicted glycemic index (PGI) of these products ranged between 13.67 to 22.61 g/100 g and 46.12 to 57.55, respectively, with the highest resistant starch (22.61 ± 0.69 g/100 g) and lowest PGI (48.42 ± 0.20) found in millet bar. The high resistant starch and low PGI in foxtail millet products suggest that they could serve as an excellent food source suitable for diabetics. The obtained results suggest that all the Foxtail millet-based value-added products have superior nutrient profile and are highly acceptable than the traditional products. Inclusion of these foods in the diets of the population may help in the prevention of malnutrition and type 2 diabetes.Millets are a rich source of many health-promoting nutrients as well as bioactive compounds such as dietary fibers, antioxidants, macro and micronutrients etc., compared to other staple cereals such as rice, wheat and maize. These nutrients play a central role in the world nutritional security. Despite the inbuilt nutritional benefits, the production of millets has witnessed sharp decline owing to taste preferences, keeping quality and challenges associated with food preparation from millets. To sensitize the consumers about the nutritional benefits of foxtail millet, the present study was planned to formulate and nutritionally evaluate eight diversified foxtail millet-based food products namely rusk,  With 109.52 and 122.27 million tonnes of production in 2021 . TherefoMillets, also known as Nutri-cereals, are a type of grasses with small seeds. These were a staple diet in many countries decades ago, but are now despised as “minor grains.” They are grown all over the world as cereal grains for human and animal nutrition. However, both their production and consumption have experienced a significant fall. Poor wages, a lack of input subsidies and price incentives, and the subsidized supply of fine cereals through the public distribution system are the main causes of the decline. Additionally, a lack of understanding of the nutritional benefits, challenges in food preparation, and a lack of processing technology are some additional significant issues that have contributed to millets becoming more obsolete .Many nutrients, dietary fiber, and antioxidants are deficient in diets based entirely on wheat and rice , 8. CompA study conducted on type 2 diabetic patients by supplementing their diet with millets. The results showed that the supplementary diet improved the levels of antioxidant, vitamins, calcium, magnesium and hemoglobin . The HbASetaria italica) is a minor millet that contains 11% protein, 59.1% starch, 3.9% fat, 19.1% dietary fiber, 7.0% ash and 6.6 mg/100 g of phenolic compounds  lines of Foxtail Millet , which were moderate in yield, were shortlisted for multilocation trials across Punjab in the summer season and were considered for this study. These were namely F1 and F2, respectively, and were procured from the Department of Plant Breeding and Genetics, College of Agriculture, PAU, Ludhiana. The procured seeds were cleaned to remove any impurity and the samples were stored in air-tight containers for nutritional analysis and product development . The cerin vitro starch digestion rate and predicted glycemic index, using the standard operating procedures described below.The cleaned raw grains of the selected germplasm lines were ground to a flour using an electric grinder with 20 mesh size and was stored at ambient conditions for further nutritional analysis. The flour samples were analyzed in triplicates for proximate composition, minerals , resistant starch, dietary fiber, Proximate parameters namely moisture, crude protein, crude fat, crude fiber and ash were analyzed using three replications of each raw germplasm line using the standard method given by . For moiThe powdered flour was digested by the addition of a triple acid combination made up of nitric acid (HNO3), sulfuric acid (H2SO4), and perchloric acid (HClO4), in the ratio of 10:4:1in order to measure iron, zinc and calcium. Following digestion, the samples were diluted and filtered, and the volume was made to 100 ml. Following the initial preparations, the amount of iron, zinc and calcium was measured by comparing with standards for these elements using an atomic absorption spectrophotometer .The soluble, insoluble and total dietary fiber contents of the samples were analyzed in triplicates using Megazyme-K-TDFR-200A. The soluble and insoluble dietary fiber contents were analyzed using the standard protocol given by . The die1 = residue weight 1 from m1, R2 = residue weight 2 from m2, m1 = sample weight 1,R2 = sample weight 2, A = ash weight from R1,m2 andp = protein weight from RB = blank = Where:BR = blank residue,BP = blank protein from BR1, BA = blank ash from BR2.The starch content was analyzed using method given by . MegazymAspergillus niger; 28 U per ml of acetate buffer). The solution was incubated for 4 h, during which time the glucose concentration in the digesta was monitored using an AccuCheck® Performa® glucometer at various intervals.Five hundred mg of the sample was treated for 15–20 s with 1 ml of artificial saliva containing porcine -amylase  before 5 ml of pepsin  was added and incubated at 37°C for 30 min in a shaking water bath. The digesta was neutralized (5 ml of 0.02 M aq. Sodium hydroxide) before the pH was set to 6 (25 ml of 0.2 M sodium acetate buffer) before adding 5 ml of pancreatin  and amyloglucosidase (Sigma A- 7420 from The glucometer reading at 15 min was converted to the percentage of starch digested using the following equationWhere:GG = Reading of the glucometer (mM/L)V = Digest volume (mL),180 = glucose’s molecular weight W = sample weight (g)S = sample’s starch content (g per 100 g dry sample)M = moisture percentage in sample (g per 100 g sample)0.9 = starch stoichiometric constant from glucose concentrations.RDS% = percentage of starch digested at 15 minSDS% = percentage of starch digested at 120 min – percentage of starch digested at 15 min.Predicted glycemic index was calculated using the method given by . For calThen, the estimated glycemic index was calculated by applying the formula defined by : GI = 39Glycemic load was calculated as:rusk, cookies, vegetable dalia and pinni, rice for papad and kheer (refrigerated) and barley for sattu] and was treated as control. Initially, millets were replaced with a traditional cereal  at the level of 10%; however, all the products of Foxtail millet were found to be acceptable even at 100% replacement. Therefore, the recipes prepared after replacing 100% of wheat, rice and barley rice were developed and analyzed. The ingredients and procedure used to develop the value-added products are given in kheer (form of porridge prepared from milk and rice/millet);pinni ; baked products – rusk and cookies;dalia (porridge); and snack foods – sattu , bar and papad.breakfast cereals – vegetable The nutritionally superior germplasm line of Foxtail millet (F2) was used for the preparation of value-added products, which were compared with the recipes prepared using traditional cereal [wheat for The developed products were evaluated by a panel of minimum semi-trained individuals from the Department of Food and Nutrition, Punjab Agricultural University, Ludhiana for their sensory qualities. The panelists scored different products prepared from Foxtail millet based on their appearance, texture, taste, flavor and overall acceptability by using nine-point Hedonic rating scale , where 9in vitro starch digestion rate, predicted glycemic index using the same methods described above.The products prepared from Foxtail millet along with control prepared from traditional cereal (wheat/ rice) were analyzed for moisture, protein, fat, crude fiber, calcium, iron, zinc, starch, resistant starch, dietary fiber, The data was analyzed in a completely randomized design using SPSS software (26 version). Mean and standard deviation for the various parameters were computed. Analysis of Variance (One-way ANOVA) was employed to assess the sensory and nutritional parameters of the raw Foxtail millet and for comparing the value-added products prepared from Foxtail millet.in vitro starch digestion rate of both germplasm lines of Foxtail millet is shown in The nutritional analysis of the two germplasm lines was done to find out the difference between their nutritional profile and to select the best line for the development of value-added products. The nutritional composition showed that germplasm line F2 was better than F1, as it had higher protein (13.59 ± 0.06) g, fat (4.18 ± 0.07) g, iron (4.53 ± 0.07) mg, calcium (54.85 ± 0.04) mg, zinc (3.44 ± 0.03) mg, total dietary fiber (14.06 ± 0.04) g and resistant starch contents (27.01 ± 0.59) g per 100 g on dry weight basis . The gerpapad obtained the highest overall acceptability score of 8.46 ± 0.50 followed by rusk (8.04 ± 0.49), kheer (8.00 ± 0.50), sattu (8.00 ± 0.41), pinni (7.98 ± 0.47), cookies (7.86 ± 0.40), vegetable dalia (7.82 ± 0.43), and millet bar (7.80 ± 0.52). Sattu and papad were found to have higher overall acceptability scores than the traditional products, while other developed products showed a lower range of scores; however, all of them were found to be acceptable, scoring more than 7.5 on the hedonic scale. The sensory variables, including color, appearance, texture, taste and flour of rusk, sattu and papad, were found to be comparable with their control counterparts, while, other products obtained a lower score for these variables. However, the prepared products were still found acceptable by the panel. No differences (p > 0.05) were found among the sensory characteristics  between the Foxtail millet- and cereal-based products.The sensory characteristics of the developed value added-products are presented in p ≤ 0.05) higher than the control products, which can be due to the greater amount of protein found in millets than traditional cereal (wheat/rice). The highest content of crude protein was found in the Foxtail millet Kheer (16.01 g/100 g), which can be attributed to the basic ingredient milk used in the recipe. The increase in crude protein content of the developed products in comparison to control is shown in rusk, in comparison to the refined wheat flour rusk.The crude protein content in the value-added products of Foxtail millet ranged from 10.98 to 16.10 g/100 g on dry weight basis. The protein content of the developed food products was significantly (pinni (30.45 ± 0.17 g/100 g), while the minimum was found in sattu (3.00 ± 0.16 g/100 g). A significant difference (p ≤ 0.05) was observed in the crude fat content of the products between the control and the experimental group. The highest fiber content was found in sattu (3.86 ± 0.15 g/100 g).The fat content of the developed products was found in the range of 3.00 ± 0.16 to 30.45 ± 0.17 g/100 g with maximum content in sattu (4.21 ± 0.04 mg/100 g), whereas the highest zinc and calcium contents were observed in vegetable dalia (3.16 ± 0.07 mg/100 g) and kheer (157.81 ± 0.28 mg/100 g), respectively. On the other hand, kheer was found to have the lowest iron content (3.03 ± 0.04 mg/100 g), while cookies showed the lowest content of zinc (1.37 ± 0.08 mg/100 g) and calcium (53.30 ± 0.16 mg/100 g).All the Foxtail millet products showed a higher amount of minerals  than their control counterparts. The iron, zinc and calcium content of the developed products ranged from 3.03 ± 0.04 to 4.21 ± 0.04, 1.37 ± 0.08 to 3.16 ± 0.07, and 53.30 ± 0.16 to 157.81 ± 0.28 mg/100 g, respectively, with the corresponding values of 0.97 ± 0.07 to 4.07 ± 0.02, 0.5 ± 0.07 to 1.89 ± 0.04 and 10.60 ± 0.18 to 110.57 ± 0.33 mg/100 g, in the traditional cereal based products. The highest iron content was found in p ≤ 0.05) difference was found among the soluble, insoluble and total dietary fiber of Foxtail millet and traditional cereal-based products, with the respective values ranging from 0.41 ± 0.02 to 0.80 ± 0.02, 7.27 ± 0.16 to 12.67 ± 0.25 and 7.72 ± 0.12 to 13.47 ± 0.23 g/100 g in the Foxtail millet-based products, while the corresponding values in the control group were 0.40 ± 0.02 to 0.79 ± 0.02, 3.26 ± 0.06 to 9.62 ± 0.11 and 3.82 ± 0.06 to 10.32 ± 0.06 g/100 g, respectively. The developed products had a higher total dietary fiber content, with the highest amount of all fractions of dietary fiber found in sattu (13.47 ± 0.23 g/100 g), followed by bar (12.83 ± 0.06 g/100 g).The soluble, insoluble and total dietary fiber of the developed products are presented in p ≤ 0.05) higher in the control group than the developed products, among which, the maximum rapidly digestible starch content was observed in papad (32.26%), while the minimum content was found in sattu (19.9%). The maximum amount of slowly digestible starch was seen in kheer (21.12%).Rapidly digestible starch was found to be significantly , kheer (16.91 ± 0.34), papad (15.76 ± 0.46), cookies (15.32 ± 0.90), sattu (14.08 ± 0.34), pinni (13.67 ± 0.29), and rusk (13.97 ± 0.72) g/100 g.The resistant starch content of the developed products ranged from 13.67 ± 0.29 to 22.61 ± 0.69 g/100 g, with the corresponding values of 7.65 ± 0.29 to 16.35 ± 0.41 g/100 g found in the traditional cereal based products. The highest content of resistant starch was found in the bar (22.61 ± 0.69) g/100 g followed by vegetable sattu (49.30 ± 0.19), cookies (53.05 ± 0.44), kheer (53.46 ± 0.30), papad (54.76 ± 0.14), rusk (56.27 ± 0.10), vegetable dalia (57.13 ± 0.19), and pinni (57.55 ± 0.34). The decrease in predicted glycemic index of the Foxtail millet products compared to the cereal based products is shown in pinni (18.28%), papad (16.78%), cookies (14.2%) and rusk (12.99%). Hence, the glycemic index of the products prepared from millets decreased in comparison to control group, in a range of 8–28%, proving that Foxtail millet products had a low GI in comparison to wheat and rice products , followed by products .papad (41.74 ± 0.36). The glycemic load of kheer was low (4.69 ± 0.70), while it was found to have a glycemic index of 53.46 ± 0.30.Also, glycemic load (GL) is directly proportional to glycemic index; hence the products with low glycemic index depicted a low glycemic load, whereas the products in the control group, which had higher glycemic index were found to have a higher glycemic load. The glycemic load of the developed Foxtail millet products ranged from 4.69 ± 0.70 to 41.74 ± 0.36, with the lowest glycemic load observed in millet bar (35.15 ± 0.36), whereas the highest glycemic load was found in in vitro digestion, more amount of the products from the control group were digested than the millet-based products. The slowest in vitro starch digestion rate at the end of 180 min of digestion was seen in bar (51.5%). On the other hand, Foxtail millet kheer was found to have a higher rate to the tune of 87.1%, while 91.2% of the starch in rice-based kheer was found to be hydrolysed at the end of 180 min. Majority of the millet-based products were found to have a digestion rate ranging from 50 to 60%, while their control counterparts had 54.3–91.2% digestion rate at the end of 180 min  with millet using the standardized recipe. Those recipes which are already liked by the population and fit well in the Indian cuisine were selected and replaced with millets. The incorporation of millets was initiated at a level of 10% and all the recipes were found to be acceptable even at 100% replacement., kheer, pinni, sattu, vegetable dalia, papad, cookies and millet bar were developed and compared with the products prepared from traditional cereal , which were considered as control for their organoleptic scores. The products viz., rusk, kheer, pinni, vegetable dalia, cookies and formulated from Foxtail millet in the present study obtained overall acceptability scores comparable to the control dishes. It was in line with the study, where Foxtail millet was used to make food items such as laddu, vegetable biryani, and halwa and received the highest scores for overall acceptability, color, appearance, texture, and flavor than their control counterparts  were prepared and a fat content of 5.55% was reported, which is in line with the present findings  had a calcium content of 149.2 mg/100 g.The highest iron content in orted by . The higorted by . Similar content . The maxorted by  in whichp ≤ 0.05) higher than the Foxtail millet products, which ranged from 50.50 ± 1.09 to 62.92 ± 1.18 g/100 g, with the highest content found in the Foxtail millet kheer. The highest total starch content in kheer was due to the addition of sugar, which increased the total carbohydrate content and hence, the total starch content. The more rapidly digestible starch in papad can be due to frying of papad. Frying affects starch digestibility in terms of structural damage which leads to an increase in rapidly digestible starch  which can be due to pressure cooking that results in maximum gelatinization, that increases the content of rapidly digestible starch and reducing slowly digestible starch  was seen in the resistant starch content of the products prepared from Foxtail millet and the traditional cereal except in the case of kheer. The temperature at which food is kept after cooking affects its resistant starch content (A significant difference ( content . The refResistant starch content of the products is greatly affected by the cooking technique. The cooking methods like pressure cooking, boiling, microwave cooking and baking lead to a decrease in its concentration, while roasting can potentially retain the resistant starch content , which isattu had the lowest glycemic index, which can be due to their higher resistant starch and higher dietary fiber content. In the current investigation, millet-based products showed a lower GI than the wheat/rice-based products. The lower glycemic load of kheer can be due to its high moisture content as high moisture content of the food results in a lower available carbohydrate content of the food product, resulting in a lower glycemic load. It has been reported that watermelon and high-fat ice cream have glycemic index of 72 and 37, respectively, whereas both were found to have same glycemic load of 4, which was attributed to high moisture content of watermelon that led to lesser available carbohydrate leading to a lower glycemic load (The glycemic index of the product depends upon its total available carbohydrate content and the type of starch present in it. Also, the high concentration of polyphenols and other bioactive components lead to reduction in the rate of fat absorption and sugar release resulting in lesser glycemic index . Moreovemic load .burfi prepared by adding 43% millet had a glycemic index of 45 (Similar to the findings of the present study, biscuits were prepared from barnyard millet and refined wheat flour in the combination of 45:55 ratio and their glycemic index was reported as 68 , whereasex of 45 . The GI ex of 45 . The proex of 45 .in vitro starch digestion rate and the in vitro glycemic response was studied and an increase in both due to absence of protein starch complex was reported (in vitro starch digestion rate by forming a lipophilic amylo-lipid inclusion complex, which refrains the entry of amylase (in vitro starch digestion rate, by binding the water and reducing gelatinization (The slow digestion rate of Foxtail millet-based products can be due to the presence of higher amounts of protein and fat than wheat-rice products. It was reported that during processing, starch can interact with proteins, which is thought to affect starch digestibility . Denaturreported . Similar amylase . The hignization .Kheer prepared from Foxtail millet also had high fiber and calcium contents, which can be useful for osteoporosis and can be consumed as a healthy snack. The formulated Foxtail millet products can be helpful in the prevention of non- communicable diseases like diabetes and obesity, owing to its high fiber, resistant starch and lower glycemic index.Foxtail millet-based food products were developed by 100% replacement of wheat/rice/barley. The developed food products obtained acceptable sensory scores and were found to be at par against the traditional products. The foxtail millet-based products contained higher levels of protein, dietary fiber, resistant starch, and had lower glycemic index and starch digestion rate than wheat/ rice/ barley-based products. The developed Foxtail millet products can be categorized as foods with a medium glycemic index and can be used as therapeutic foods for diabetics. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.LA: investigation, methodology, and writing—original draft. RA: supervision and project administration. RA and ID: conceptualization, resources, and final draft. OG and PK: formal analysis and final draft. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To explore the pathologic basis and prognostic value of tumor and liver stiffness measured pre-operatively by two-dimensional shear wave elastography (2D-SWE) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who undergo hepatic resection.A total of 191 HBV-infected patients with solitary resectable HCC were prospectively enrolled. The stiffness of intratumoral tissue, peritumoral tissue, adjacent liver tissue, and distant liver tissue was evaluated by 2D-SWE. The correlations between stiffness and pathological characteristics were analyzed in 114 patients. The predictive value of stiffness for recurrence-free survival (RFS) was evaluated, and Cutoff Finder was used for determining optimal cut-off stiffness values. Cox proportional hazards analysis was used to identify independent predictors of RFS.p < 0.05). Higher peritumoral stiffness (> 49.4 kPa)  and higher adjacent liver stiffness (> 24.1 kPa)  were significant independent predictors of worse RFS, along with tumor size and MVI. The nomogram based on these variables showed a C-index of 0.77 for RFS prediction.Pathologically, intratumoral stiffness was associated with stroma proportion and microvascular invasion (MVI) while peritumoral stiffness was associated with tumor size, capsule, and MVI. Adjacent liver stiffness was correlated with capsule and liver fibrosis stage while distant liver stiffness was correlated with liver fibrosis stage. Peritumoral stiffness, adjacent liver stiffness, and distant liver stiffness were all correlated to RFS (all Stiffness measured by 2D-SWE could be a tumor microenvironment and tumor invasiveness biomarker. Peritumoral stiffness and adjacent liver stiffness showed important values in predicting tumor recurrence after curative resection in HBV-related HCC.Tumor and liver stiffness measured by two-dimensional shear wave elastography serve as imaging biomarkers for predicting hepatocellular carcinoma recurrence, reflecting biological behavior and tumor microenvironment.• Stiffness measured by two-dimensional shear wave elastography is a useful biomarker of tumor microenvironment and invasiveness.• Higher stiffness indicated more aggressive behavior of hepatocellular carcinoma.• The study showed the prognostic value of peritumoral stiffness and adjacent liver stiffness for recurrence-free survival.• The nomogram integrating peritumoral stiffness, adjacent liver stiffness, tumor size, and microvascular invasion showed a C-index of 0.77.The online version contains supplementary material available at 10.1186/s13244-023-01505-7. Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide . SurgicaThe tissue stiffness reflects the mechanical properties and characterizes the complex interactions between tumor cells and extracellular matrix (ECM). The findings from various studies indicate that higher matrix stiffness promotes proliferation and chemotherapeutic resistance , upregulThe two-dimensional shear wave elastography (2D-SWE) technique is an ultrasound-based technique for real-time visualization of soft tissue’s viscoelastic properties by measuring the speed of shear waves generated using acoustic radiation force . The perSeveral studies have also demonstrated the utility of 2D-SWE for the evaluation of tissue stiffness and for diagnosis or prognosis of focal liver lesions (FLLs) –26, and Therefore, the hypothesis of this study is that tumor stiffness and liver stiffness measured by 2D-SWE can reflect the biological behavior and tumor microenvironment, thus serving as an imaging biomarker for predicting the prognosis of HCC. This study aimed to assess the pathological basis of tumor and liver stiffness and to evaluate the potential utility of tissue stiffness measured by 2D-SWE for predicting the recurrence of hepatitis B virus (HBV)-related HCC patients after hepatic resection, with a focus on combining tumor stiffness and liver stiffness for prediction.This prospective study was approved by the ethics committee of the First Affiliated Hospital of Sun Yat-Sen University. Written informed consents were obtained from all patients before enrollment. HBV-infected patients with solitary HCC who underwent surgical resection from February 2019 to February 2021 were consecutively included in this study according to the inclusion and exclusion criteria. The diagnosis of HCC before surgery was based on the American Association for the Study of Liver Diseases (AASLD) guideline [Both conventional ultrasound and 2D-SWE examinations were performed within one week before surgery. All examinations were performed by an Aixplorer Ultrasound system  equipped with an SC6-1 convex probe by a radiologist with more than 10 years of ultrasound experience and more than 3 years of experience in liver 2D-SWE examination (M.X.L.).After overnight fasting for at least 8 hours, the patient was placed in the supine position with the right arm in maximal abduction. 2D-SWE examination was performed for both tumor and liver according to the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guideline . For 2D-The B-mode ultrasound and 2D-SWE images were analyzed by one radiologist (X.Z.) with more than 5 years of experience in ultrasound, who was unaware of the pathological results. Evaluations of B-mode ultrasound images were performed from the PACS system. The 2D-SWE image analysis was performed on the machine using the built-in ROI (Q-box) whose size and position were adjustable.Evaluations of tumor B-mode ultrasound images included tumor size, shape, boundary, and presence of hypoechoic halo. Evaluations of 2D-SWE images included quantitative stiffness of both intratumoral and peritumoral tissue, as well as adjacent liver parenchyma and distant liver parenchyma. An intratumoral Q-box was placed inside the tumor to cover the tumor area as much as possible for intratumoral stiffness . A peritPreoperative patient characteristics and laboratory data were collected within one week ahead of surgery. Due to the unavailability of some pathological specimens, the pathological specimens of 114 patients from February 2019 to January 2020 were reviewed by a pathologist (L.L.C.) with more than 10 years of experience in HCC pathology, without knowing the patient’s clinical data and ultrasound results. The specimens were sampled according to the 7-point baseline sampling protocol . InformaPatients were consistently followed up after liver resection at intervals of 3 to 6 months based on serum alpha-fetoprotein and imaging examination (contrast-enhanced computed tomography or contrast-enhanced magnetic resonance imaging). All patients were under anti-viral treatment after resection. All patients were followed up until September 2021. The mean period of follow-up was 14.2 ± 9.2 months (range 1.5–30.7 months). Recurrence-free survival (RFS) was calculated from the date of surgical resection to the tumor recurrence . RFS was censored at the date of death or of the last follow-up visit for recurrence-free patients.t-test or the Mann-Whitney test, as appropriate, was used to compare continuous variables in recurrence and non-recurrence groups. The χ2 test was used to compare categorical variables. The elasticity values of different pathological manifestations were compared by using the Mann-Whitney test. An online tool Cutoff Finder was used to determine the optimal cut-off elasticity values for predicting RFS [p value less than 0.05 entered multivariate analysis to identify independent predictors for RFS based on stepwise Cox proportional hazards regression. Schoenfeld residuals were used to check the proportional hazards assumption of the Cox proportional hazards model and a stepwise Cox regression was used to prevent multicollinearity. A nomogram was constructed based on independent predictors. The discrimination performance was quantified by concordance index (C-index) and area under the receiver operating characteristic curve (AUC) at 0.5 years, 1 year, and 2 years. The calibration performance was determined by calibration curve analysis. All statistical tests were two-tailed and a p value < 0.05 was considered a statistically significant difference.Statistical analyses were performed by using SPSS, version 20.0, and R4.1.2. The Student’s ting RFS . The elaA total of 191 HBV-infected patients with single HCC who underwent surgical resection were prospectively enrolled in this study, including 173 males and 18 females with a median age of 55.0 (47.0–64.0) years , presence of MVI (p < 0.001), AFP level (p = 0.006), AST level (p = 0.005), GGT level (p = 0.007), and peritumoral stiffness (p = 0.020) between the recurrence group and non-recurrence group.During the follow-up, HCC recurrence was observed in 66 (34.6%) patients. The baseline characteristics of the recurrence group, non-recurrence group, and all patients were summarized in Table p = 0.016) and in tumors with MVI compared with those without MVI (p = 0.015). Peritumoral stiffness was higher in tumors with larger tumor size , presence of tumor capsule (p = 0.004), and presence of MVI (p = 0.021). Adjacent liver stiffness was significantly correlated with the presence of a tumor capsule (p = 0.026) and cirrhosis of the background liver (p = 0.036). While distant liver stiffness was significantly correlated with cirrhosis of background liver (p = 0.002).Comparisons of intratumoral stiffness, peritumoral stiffness, adjacent liver stiffness, and distant liver stiffness between different pathological characteristics in 114 patients were shown in Table p = 0.003), adjacent liver stiffness (p = 0.001), and distant liver stiffness (p = 0.030) compared with lower ones .The optimal cut-off values of intratumoral stiffness, peritumoral stiffness, adjacent liver stiffness, and distant liver stiffness for predicting RFS were 63.5 kPa, 49.4 kPa, 24.1 kPa, and 15.7 kPa, respectively. Based on these cut-off values, patients were dichotomized into two groups and RFS was compared between the two groups. Kaplan–Meier survival analysis showed that RFS was significantly shorter in patients with higher peritumoral stiffness (p = 0.003), adjacent liver stiffness , and distant liver stiffness  were associated with RFS (Table p < 0.001), AFP level , AST level , GGT level , MVI , and Edmondson-Steiner grade  were associated with RFS , MVI , higher peritumoral stiffness (> 49.4 kPa) , and higher adjacent liver stiffness (> 24.1 kPa)  were significant independent predictors of worse RFS  and higher adjacent liver stiffness (> 24.1 kPa) were independent risk factors for recurrence following hepatic resection in HBV-related HCC, along with traditional predictors such as larger tumor size and presence of MVI.In this study, increased intratumor stiffness and peritumoral stiffness were shown to be associated with higher stroma proportion and the presence of tumor capsule, which were consistent with other studies showing that increased stiffness is mainly correlated with ECM remodeling and the deposition of ECM components , 37. Manp = 0.030), but no significant difference was found in cirrhosis presence between patients with and without recurrence. The inconsistency may be due to different cutoff values because liver stiffness ≥11 kPa is considered as cirrhosis in SuperSonic Imaging [The microenvironment in which HCC develops also exerts a major influence on tumor development and growth . This st Imaging . In this Imaging . Evidenc Imaging . Activat Imaging , which mA nomogram integrating tumor size, MVI, peritumoral stiffness, and adjacent liver stiffness was established with a C-index of 0.77 for RFS prediction, showing satisfactory discrimination and calibration performance. The nomogram may help stratify the risk of recurrence and improve individualized treatments and personalized surveillance strategies.There were some limitations in this study. Firstly, there may be heterogeneity in HCC tissue while only the maximum section of the lesion was assessed. Secondly, the maximum detection depth of 2D-SWE is limited , but tumIn conclusion, stiffness measured by 2D-SWE could be a useful imaging biomarker of the tumor microenvironment and tumor invasiveness in HBV-related HCC, with higher stiffness indicating more aggressive behavior. Peritumoral stiffness and adjacent liver stiffness showed important values in predicting tumor recurrence after curative resection in HBV-related HCC.Additional file 1.


In this paper, the external and internal cooperation determinants of the four types of innovation – product, process, organisational and marketing – are studied from the perspective of small and medium-sized enterprises (SMEs). From a theoretical standpoint, taking into account the dual nature of cooperation, cooperation determinants can be divided into two groups: external - comprising triple helix entities: universities, governments and industry, and internal – comprising employee personality traits: decision-making autonomy, creativity, willingness to cooperate, openness to changes, risk-taking and social empathy. Additionally, three control variables were considered: age, size and sector of economic activity. The data examined comes from an empirical study of a randomly selected representative sample of 1286 SMEs in the Kuyavian-Pomeranian voivodeship, a region in central-northern Poland. The empirical research was carried out between June and September 2019 using the CAPI method. The multivariate probit regression model was used to analyse the obtained data. The results indicate that only two factors directly connected with the triple helix are common and significant determinants explaining all SME innovations. These are cooperation with public administration in the field of financial support, and cooperation with clients. In turn, significant variation was observed in terms of personality traits being an essential element of internal cooperation that may influence SME innovations. A positive impact on the probability of implementing three of the four types of innovation was observed for two personality traits, namely creativity and social empathy. In 2020, there were over 21 million SMEs in the European Union, which accounted for 99.8% of all enterprises in the non-financial sector. SMEs created nearly 53% of the total value added and provided work to over 65% of employees . SMEs alWhen integrating problems connected with the issues of innovation and SMEs, it can be seen that despite many years of scientific studies, there are still many research gaps. As Mendoza-Silva suggests, one of the gaps is the study of the relationship between different types of cooperation and their impact on a company's capacity to create innovations . This isThe external perspective focuses on cooperation between organisations. Its foundations can be identified in research on inter-organisational relations initiated by Coase , which lThe internal cooperation perspective also covers several interesting research problems. A significant part of the literature relates to cooperation between separate business functions in the context of product development. It mainly deals with issues at the intersection of R&D and marketing, perceived as key in developing new products ,34. In tIt is also worth emphasising that when researching various aspects of internal cooperation, the main concern is the problem of the individual and their multiple features that can stimulate or inhibit this relationship ,47. MendCombining both indicated research gaps, the article aims to examine the impact of external and internal cooperation on the innovativeness of SMEs. External cooperation is analysed from the perspective of the triple helix, while internal cooperation is analysed in terms of selected employee personality traits. Meanwhile, the innovativeness of SMEs, according to the 3rd edition of the Oslo Manual , is consFor this purpose, the empirical part of the research uses data from a study conducted in 2019 on a randomly selected representative sample of 1286 SMEs from the Kuyavian-Pomeranian Voivodeship, a region in central-northern Poland.The paper is structured as follows: the second section provides a theoretical framework and proposes research hypotheses; the third section discusses the research design, showing the method of obtaining the data, the research sample, variables and multivariate probit regression; the fourth section presents the model estimation results and their discussion; finally, the fifth section provides the main conclusions.2External cooperation is one of the primary sources of building a competitive advantage . TriguerTo analyse them, it is worth focusing on the innovation ecosystem ,21,59,60H1Cooperation with a university positively affects SMEs' innovativeness.In the case of cooperation with universities, research conducted so far shows various results. On the one hand, there is the aforementioned lack of trust and limited cooperation with universities in CEE countries , as wellH2Cooperation with public administration positively affects SMEs' innovativeness.As far as governments are concerned, such cooperation may boost firms' competitiveness by promoting innovation in private firms . ResearcH3Cooperation with clients positively affects SMEs' innovativeness.In turn, in the field of cooperation between firms, e.g., joint R&D ventures, it should be emphasised that this can take different forms: collaboration with suppliers or clients , with competitors , and with other enterprises within the enterprise group . CooperaH4Cooperation with suppliers positively affects SMEs' innovativeness.Cooperation with suppliers can bring a company various benefits, e.g., improving the quality of products and services or reducing costs due to business process innovation ,73. CollH5Cooperation with competitors positively affects SMEs' innovativeness.Cooperation with competitors, in other words co-opetition, as indicated by Hernández-Trasobares and Murillo-Luna, is intended as a positive sum game in which both parties share the risks of developing technological innovations . On the H6Cooperation with other enterprises within the enterprise group positively affects SMEs' innovativeness.Also, cooperation in innovation with other enterprises within the enterprise group can be practical. As suggested by Tether, firms which belong to the enterprise group are better informed of the capabilities of potential partners due to knowledge pooling and the activities of other members of their group . Prokop Seen from the innovation perspective, internal cooperation is based primarily on the resources embedded among individuals (based on the resource-based view) , their nIt is worth agreeing with Mendoza-Silva that such personality traits are often analysed as an element of the inter-organisational characteristics of a firm's innovation capability . Among eH7Decision-making autonomy positively affects SMEs' innovativeness.Martínez-Román et al., examining the innovative capability of Spanish SMEs, suggested that managers' decision-making autonomy is essential for SMEs' innovativeness. In turn, the decision-making autonomy of non-managers had no such impact . SimilarH8Creativity positively affects SMEs' innovativeness.As Runco points out, creativity is an important part of cognitive, social and emotional activity . It alsoH9Willingness to cooperate positively affects SMEs' innovativeness.Also, the willingness to cooperate is perceived as a personality trait that can influence innovation. Aerne argues that network actors work together to gain prestige . BarrosoH10Openness to changes positively affects SMEs' innovativeness.Openness to experience (change) is a trait that refers to the extent to which people prefer novelty over convention. Being part of the Big Five personality traits, openness to experience measures curiosity and a willingness to search for new experiences and explore new ideas . As MatzH11Risk-taking positively affects SMEs' innovativeness.Risk-taking is a trait that implies consciously or unconsciously controlled behaviour with a sense of uncertainty about its outcome. It is also one of the critical characteristics of entrepreneurs who are perceived as more risk-taking than others . Dyer etdescribes the insights one has about other people's lives that allow one to understand the circumstances and realities of other people's living situations” .The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Weibull distribution analysis was also performed. Group ELD showed significantly higher fracture strength than all other groups (p = 0.001), and the highest Weibull modulus. Conclusions: Lithium disilicate endocrowns exhibit higher fracture strength and are more reliable compared to the other types of restorations examined. Endocrowns had more catastrophic failures compared to overlays.To evaluate the fracture strength and the failure mode of endodontically treated molars restored with monolithic lithium disilicate and zirconia endocrowns and overlays. A total of 48 extracted mandibular molars were endodontically treated, decoronated 2 mm above the cementoenamel junction and divided into four 12-specimen groups. Group ELD: lithium disilicate endocrowns. Group EZ: monolithic zirconia endocrowns. Group OLD: lithium disilicate overlays. Group OZ: monolithic zirconia overlays. Overlays did not extend in the pulp chamber and endocrowns extended in the pulp chamber 2 mm. After adhesive bonding of the restorations, the specimens were subjected to thermocycling (×5000 cycles) and then to fracture resistance testing at lateral static loading (1 mm/min) at a universal testing machine. The failure mode of the specimens was qualitatively evaluated. Differences in means were compared using with t-tests for independent samples or Mann–Whitney test ( Restoration of endodontically treated teeth remains a subject of debate in the literature and a potential source of confusion for clinicians when deciding on the most appropriate technique and materials. Full-coverage restorations used to be the traditional approach and had high survival rates; however, their placement requires significant tissue removal . The modWithout the need for mechanical retention, which is mandatory for full-coverage restorations, most of the remaining sound tooth can be preserved and receive an indirect partial- coverage restoration. The restoration is bonded to the remaining tooth tissues, with enamel presence and immediate denting sealing technique being very important factors . MoreoveEndocrowns are conservative, partial coverage restorations, that are bonded to the internal portion of the pulp chamber and on the cavity margins, thereby resulting in both macro- and micro-mechanical retention, provided by the pulpal walls and adhesive cementation, respectively . In vitrIt remains unclear whether the extension into pulp chamber offers any advantages, in other words if endocrowns perform better than overlays. No difference was found in fracture strength between endocrowns and overlays made of reinforced composite resin in molars ,23. HoweSeveral materials have been used for endocrown manufacturing: composite resins, ceramic-reinforced composite resins, feldspathic and lithium disilicate ceramics, zirconia-reinforced ceramics, polymer-matrix ceramics, and monolithic zirconia. Fracture resistance of teeth restored with endocrowns from different materials is quite high with small differences between them ,27,28,29Monolithic zirconia is a very widespread material in dentistry due to its relatively low cost and its very good mechanical, physical and optical properties. It does not require etching; therefore, the bonding process can be less sensitive and faster. Its use as a material for endocrowns is relatively new with very limited clinical data available ,33. EvenThe purpose of this in vitro study was to compare the mechanical behavior of endodontically treated teeth restored with endocrowns or overlays fabricated with either monolithic lithium disilicate or monolithic zirconia. The null hypothesis was that there is no difference in fracture strength and failure type between the two restorations design (endocrowns and overlays), and between the two materials, monolithic lithium disilicate and monolithic zirconia.For the purposes of the present study, 48 extracted, caries-free mandibular human molars with complete root formation were selected. All subjects gave their informed consent for use of their extracted teeth for the purposes the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Research Ethics Committee of the Dental School (393A/29.11.2018). The teeth had similar mesiodistal and buccolingual dimensions and were stored in 0.1% thymol solution at room temperature. All teeth were prepared for endodontic treatment, with diamond burs in high-speed handpiece and tungsten carbide burs in low-speed handpiece. Root canals were mechanically shaped with NiTi instruments  and a low-speed handpiece  with continuous 5% sodium hypochlorite irrigation. Root canal obturation was performed with warm gutta-percha points  and epoxy resin filling  combined with a vertical compaction technique . The gutta-percha was cut 1 mm below the orifices of the root canals. Cusps were cut parallel to the occlusal surface 2 mm above the cementoenamel junction a. Margin2). Teeth were then randomly divided into two groups, half to be restored with endocrowns and half with overlays.Root canal orifices were covered with low viscosity composite resin , after application of bonding agent  and polymerization for 20 s, with a LED lamp .Digital impressions of the prepared teeth were taken with an intraoral scanner  were fabricated from monolithic lithium disilicate  and 24 restorations (12 endocrowns and 12 overlays) from monolithic zirconia . They were designed with exocad software  and manufactured with Roland DWX-52DC cutting machine  using MillBox software . The occlusal restoration thickness was 5 mm.2O3 particles . Enamel was etched with 37% orthophosphoric acid  for 30 s, rinsed and dried. Single-use activator  was applied for 60 s to the composite resin covering part or all the pulp chamber of the tooth. Finally, bonding agent  was applied to the entire surface of the tooth for 20 s, dried and light-cured for 10 s, according to the manufacturer’s instructions.The marginal fit of the final restorations was checked with an explorer. The teeth were air-abraded with 50-μm AlLithium disilicate restorations were cleaned with Ivoclean paste  for 20 s, rinsed and air-dried. They were etched with 4.9% hydrofluoric acid  for 20 s and rinsed with water for 30 s. Afterwards, they were placed in an ultrasonic bath for 1 min and air-dried. Finally, a single-use activator  was applied for 60 s and air-dried.2O3 particles , rinsed, placed in an ultrasonic bath for 1 min and air-dried. Finally, a single-use activator  was applied for 60 s and air-dried.Zirconia restorations were cleaned with Ivoclean paste  for 20 s, rinsed and air-dried. They were air-abraded with 50-μm AlDual-cure luting resin cement  was used for bonding of all the restorations, according to the manufacturer’s instructions. After seating of the restorations, the excess cement was polymerized for 2 s so that it could be easily removed, an oxygen inhibition gel  was applied to the margins and the final photopolymerization was performed for 20 s on each surface with the LED lamp. The gel was rinsed, the excess cement was removed with a No15 scalpel, and the surfaces were finished and polished with 2-step, flame-shaped diamond rubber polishers  under continuous water irrigation. (1)Monolithic lithium disilicate endocrowns (ELD);(2)Monolithic lithium disilicate overlays (OLD);(3)Monolithic zirconia endocrowns (EZ);(4)Monolithic zirconia overlays (OZ).In total, there were 4 groups with 12 specimens each:After bonding, specimens were placed in saline solution for 24 h at room temperature. They were then subjected to 5000 cycles of thermocycling in a water bath at temperature 5 °C to 55 °C, with a dwell time at each temperature of 30 s.Teeth were embedded in self-curing acrylic resin  1 mm below the cementoenamel junction in metallic cylinders with an inner diameter of 1.3 cm and an outer diameter of 1.6 cm, as shown below.Finally, specimens were subjected to fracture strength test using a universal testing machine . A 6 mm diameter stainless-steel ball at crosshead speed of 1 mm/min, applied a compressive force at an angle of 45° to the long axis of the tooth on the buccal cusps of each specimen . Load waTo overcome the limitations of brittle fracture of materials and the associated problems of wide dispersion of shear values, Weibull analysis was used which expresses the probability of failure with the corresponding confidence limits (95%). This method has been shown to be the best for processing fracture test results .Finally, all fractured surfaces were analyzed using an optical microscope  in reflection mode under 75× magnification to identify failure modes. The type of failure was classified as cohesive type in the restoration material (type I), adhesive type between the restoration material and dentin (type II), cohesive in enamel/dentin (above the CEJ) (type III), IV: fracture extending to root (below the CEJ) (type IV). t-tests for independent samples or Mann–Whitney test, respectively. A chi-square statistical test was performed, with criteria the material of the restoration (ELD-EZ and OLD-OZ) and the extension in the pulp chamber (ELD-OLD and EZ-OZ). The fracture strength data were analyzed by Weibull analysis. The shape or modulus parameter-β , the scale or B63.2 parameter-σ0,  and the strength at 10% failure probability (σ0.1) of the Weibull distributions were calculated. t-test, Mann–Whitney test and chi-square test were performed by SigmaStat software . For the Weibull analysis, the OriginLab software  was used and for graph the softoware Develpe . For all cases, a 95% confidence level was selected (α = 0.05).Distributions of the data were tested with the Shapiro–Wilk test. Descriptive statistics were calculated including means and standard deviations for normally distributed data and medians with interquartile ranges for skewed data. Differences between zirconia-lithium disilicate (overlays or endocrowns), and differences between endocrowns-overlays (zirconia or lithium disilicate) were assessed with The mean fracture strength values and standard deviations of the groups ELD, OLD, and ELD, EZ expressed in Newton are presented in p = 1) and OLD-OZR (p = 0.08). For the extension in the pulp chamber, a statistically significant difference was found between groups ELD-OLD, but not between groups EZ-OZ.A chi-square statistical test was performed, with criteria the material of the restoration (ELD-EZ and OLD-OZ) and the pulp chamber extension (ELD-OLD and EZ-OZ) with a confidence level of 95% (α = 0.05). For the material, no statistically significant difference in failure type was found between groups ELD-EZ  and the extension or not in the pulp chamber (endocrown or overlay) of bonded restorations in endodontically treated mandibular molars was evaluated. Lithium disilicate endocrowns (group ELD) had statistically higher fracture strength compared to the other groups. Weibull analysis also indicated that lithium disilicate endocrown was the most reliable and strong restoration. In general, the type of failure of endocrowns was predominately type IV, which was more destructive to the teeth compared to overlays. Therefore, the null hypothesis was partially rejected.In the current research, endocrowns exhibited higher fracture strength compared to overlays when the material of choice was lithium disilicate. Extending the restoration into the pulp chamber increases the bonding surface as well as the macromechanical retention, preventing its debonding under lateral forces. Lateral movements are more detrimental than axial ones for adhesive interfaces . This caWhen monolithic zirconia was examined, there was no difference between endocrowns and overlays concerning the fracture strength. However, there were differences in the failure type. All monolithic zirconia endocrowns exhibited catastrophic failures as they fractured below the cementoenamel junction. On the other hand, half of the monolithic zirconia overlays debonded without tooth fracture, while the other half debonded and teeth fractured below the cementoenamel junction.In clinical practice, the tooth is evaluated after the failure occurs, to see whether the residual structure is repairable or not. Therefore, understanding the fracture pattern and the type of stress distribution are equally crucial to considering the fracture load. While the lithium disilicate overlay group primarily experienced repairable fractures, the zirconia endocrown group had catastrophic failures that might reach 100%. This is consistent with earlier research’ findings that zirconia endocrowns had a high rate of catastrophic failure ,41,42,43Lithium disilicate endocrowns exhibited higher fracture strength than zirconia endocrowns. This agrees with the findings of a previous study . This diIn some earlier studies, monolithic zirconia outperformed other ceramics, notably lithium disilicate, in terms of mechanical performance ,49. The For males and females, respectively, the mean axial masticatory forces in humans range from about 600 to 900 N ,51,52. T2O3 was used, during which surface cleaning, increase in surface roughness, increase in wettability, and micromechanical retention are achieved [In the overlay’s groups, there were no differences in fracture strength between the two restorative materials. Since the fracture strength of overlays relies solely on adhesion, the results of the present study indicate that bonding of monolithic zirconia to dental tissues was comparable to lithium disilicate. Polycrystalline zirconia ceramics are not etchable like glass-ceramics, therefore some method of priming the bond surface is necessary to achieve a satisfactory bond. In the present study, sandblasting with 50 μm Alachieved . Sandblaachieved . Molars, and not premolars, were used for the experiment, as endocrowns were initially suggested for molars. For quite a long-time, premolars were not considered good candidates for endocrowns. Endocrowns on premolar teeth may not be appropriate because of the smaller pulp chamber space’s reduced bonding surface area, according to one study . In 2020Regarding the thickness of the restoration above the cusps, it was chosen to be 5 mm, even though there are no clear guidelines on this topic. It is advisable, however, not to exceed this thickness, as it was found that stresses increase . RestoraAs far as the extension of the endocrown into the pulp chamber is concerned, results are conflicting and range from 2 to 5 mm. In a previous study no significant difference in fracture resistance was observed between endocrowns of 2 or 4-mm . For theFor artificial aging of the samples, the method of thermocycling was used, which represents laboratory hydrothermal aging. Temperatures, residence times and cycles of this process vary in different laboratory studies . HydrothDuring the fracture test, the force was applied at a 45° angle to the buccal cusps  producing shear stresses that are common in the oral environment during mastication and are more destructive to bonding interfaces than stresses applied perpendicular to the occlusal surface. Under the influence of lateral forces, one would expect that the extension of the endocrown in the pulp chamber will enhance the macromechanical retention, as opposed to the flat overlay, as was performed in the lithium disilicate group. In other studies, the force is applied perpendicular to the occlusal surface simulating a state of ideal occlusion in the molar region and is perhaps overestimating the results .As with all in vitro studies, the present one has some limitations in terms of simulating clinical conditions. Although fracture resistance was considered, the biomechanical properties of the periodontium were not included. An artificial periodontal ligament was not used in the present study, because the materials used for this purpose show degradation during the experimental process. During testing, this can cause the tooth to shift as a result. Previous research has demonstrated that periodontal ligament simulation could alter fracture strength outcomes and failure modes favorably by acting as a shock absorber ,68. MoreWithin the limitations of the present study, the following conclusions emerge: Lithium disilicate endocrowns exhibit higher fracture strength and are more reliable compared to the other types of restorations examined. Endocrowns had more catastrophic failures compared to overlays.The results of the present study could be used as a basis for future research. Randomized control clinical trials are needed to further investigate the topic.


Therefore, the main aim was to use subject-specific finite element knee models and investigate the influence of decreasing graft stiffness and/or increasing graft laxity on knee kine(ma)tics and cartilage loading. In this research, 4 subject-specific knee geometries were used, and the material properties of the ACL were altered to either match currently used grafts or mimic in vivo graft remodeling, i.e., decreasing graft stiffness and/or increasing graft laxity. The results confirm that the in vivo graft remodeling process increases the knee range of motion, up to >300 percent, and relocates the cartilage contact pressures, up to 4.3 mm. The effect of remodeling-induced graft mechanical properties on knee stability exceeded that of graft mechanical properties at the time of surgery. This indicates that altered mechanical properties of ACL grafts, caused by in vivo remodeling, can initiate the early onset of osteoarthritis, as observed in many patients clinically.Anterior cruciate ligament (ACL) rupture is a very common knee joint injury. Torn ACLs are currently reconstructed using tendon autografts. However, half of the patients develop osteoarthritis (OA) within 10 to 14 years postoperatively. Proposedly, this is caused by altered knee kine(ma)tics originating from changes in graft mechanical properties during the  Anterior cruciate ligament (ACL) rupture is one of the most common knee joint injuries in young and active individuals . The natAfter ACLR, alterations in knee kinematics are found, indicating changed knee (in)stability. Knee instability is believed to be a contributor to the development and/or progression of OA . PreviouDuring ACLR surgery, the ruptured ACL is replaced with a PT, ST (/GT) graft. These grafts have a higher linear stiffness and a lower transition strain (the strain where the recruitment of crimped collagen fibers starts/the end of the toe region) than the native ACL . After iin vivo studies using minipigs that underwent ACLR, there is presumed to be a negative correlation between graft stiffness and the area and severity of cartilage damage  with one integration point for all soft tissues and, to save computational time, three-node triangular shell elements (TRI3) for all bones.The material behavior of all tissues was described using constitutive models that provide the material properties of the tissues. Bones are defined as rigid bodies since the elastic modulus of bone is orders of magnitude larger than that of soft tissue . Cartilast invariant of the deviatoric right Cauchy Green deformation tensor Where The fiber contribution was described with the following equations:Where research . An overin situ strain in the body, a pre-strain was prescribed to the reference configuration according to the method developed by Maas et al.  grafts were created. To note, in this research the focus was on the effects of graft remodeling after ACLR by altering stiffness and length of the toe region of the existing ACL in the models, excluding the effects of ACL attachment location and changes in morphology or structure. Since graft stiffness and transition strain are not direct parameters of the Neo-Hookean material model, graft remodeling was modeled by tuning the Neo-Hookean constants , Neo-Hookean constant modeling . Supplemin situ stretch of 1.016, similar to the native ACL  grafts, including the PT, ST, and GT, experienced an tive ACL .The contact between rigid bodies and soft tissues was assumed to be rigid, and all contacts between two soft tissues were modeled as a sliding elastic contact to enable frictionless sliding and to prevent penetration . For theKnee motion was described using 6 degrees of freedom (DoF), three translational and three rotational movements using a four-link kinematic chain with three cylindrical joints, as already implemented by the Open Knee project . In shorin vivo loads, assuming a body weight of 75 kg, obtained from the OrthoLoads database . The stance phase was simulated by applying a force, moment, and rotation to the femur . The tibdatabase . For simdatabase .in vivo findings by Gray et al. stability . This teKnee motion of the rigid connectors and tibial cartilage contact pressure on all nodes of the tibial cartilage were recorded during the stance phase of gait. Next to that, the location of the tibial cartilage contact pressure was quantified using the weighted center of mass on grayscale images of the contact pressure on the tibial cartilage objects in ImageJ . Using tin vivo graft remodeling affect knee kinematics by increasing anterior tibial translation and internal rotation of the knee.The effect of graft remodeling on the anterior tibial translation and internal tibial rotation (IR) was evaluated. Results were analyzed at the point of maximum force on the ACL during the stance phase . For thep > 0.99, Tibial cartilage loading during graft remodeling was evaluated. Tibial cartilage loading was visualized and evaluated at the point of maximum force on the ACL during the stance phase. There were no significant differences found in the maximum contact pressure between the different grafts with respect to the native ACL  . It was A valgus test was simulated to verify whether the pre-strain was applied correctly. The pre-strain stretch in the MCL was visualized for a valgus rotation of 3° in a situation where pre-strain was applied and one in which no pre-strain was applied . In the Besides, as one of the functions of the ACL is to restrain ATT, grafts with decreased mechanical properties, theoretically, should result in an increased ATT. To verify this, an anterior drawer test was simulated, and the resulting ATT was compared to experimental values obtained from literature. in vivo remodeling process of those grafts. A decreasing graft stiffness and/or an increasing graft laxity increased ATT and IR, both movements the native ACL restricts, indicating altered knee kinematics. Together with a relocation of the tibial cartilage contact pattern, which suggests abnormal loading of the knee, it is clear that graft remodeling after ACLR can result in knee instability. Important to note, these changes were not observed in all models, indicating that this may be a subject-specific risk, in analogy with clinical outcome where not all ACLR patients develop OA. We propose that this instability can be an initiator for the development of OA for a subset of patients.One of the main clinical concerns after ACLR is the early onset of OA which occurs in approximately 50% of the, mostly adolescent, patients . It is ket al.  were relatively small, which is in line with previous research. Halonen et al.  and Nagi . Similar results are reported in a study by Li et al. , who mod , while during the ligamentization phase of graft remodeling, the graft stiffness restores to around 50%–60% of the native ACL . For graInterestingly, one of the subjects (subject 2) did not show altered knee kinematics or tibial cartilage pressure patterns, indicating that not every patient might be at risk for the development of OA, which is in line with clinical outcomes . It is bOf course, this research has limitations. First, only fractions of the forces, moments, and rotations of the stance phase were implemented, and valgus-varus moments were excluded, justified by a discrepancy in the manner of applying the loading conditions in the models compared to the Bergmann data, e.g., the lack of muscle contraction in the models . Next toin vivo graft remodeling response, e.g., decellularized grafts, would be an interesting alternative as well (In summary, as the results obtained in this study point in the direction of subject-specificity, this approach should be tested clinically. A retrospective analysis should be performed to assess if ACLR patients with a high intrinsic knee stability, as assessed using the FE analysis presented in this study, result in a low risk for developing OA. In addition, results of this research show that graft remodeling after ACLR can lead to increased knee instability, which suggests the need for novel grafts with mechanical properties that match the native ACL, i.e., anatomical reconstruction of the ACL using ACL allografts . Alterna as well . Finally as well .


Recurrence of immunoglobulin A nephropathy (IgAN) limits graft survival in kidney transplantation. However, predictors of a worse outcome are poorly understood.n = 67).Among 442 kidney transplant recipients (KTRs) with IgAN, 83 (18.8%) KTRs exhibited biopsy-proven IgAN recurrence between 1994 and 2020 and were enrolled in the derivation cohort. A multivariable Cox model predicting allograft loss based on clinical data at the biopsy and a web-based nomogram were developed. The nomogram was externally validated using an independent cohort , P = .026] and retransplantation status  were identified as independent risk factors for IgAN recurrence. Patient age <43 years , proteinuria >1 g/24 hours  and C4d positivity  were found to be associated with graft loss in patients with IgAN recurrence. A nomogram predicting graft loss was constructed based on clinical and histological variables, with a C statistic of 0.736 for the derivation cohort and 0.807 for the external validation cohort.Patient age <43 years {hazard ratio [HR] 2.20 [95% confidence interval (CI) 1.41–3.43], The established nomogram identified patients with recurrent IgAN at risk for premature graft loss with good predictive performance.  KEY LEARNING POINTSWhat was known:Recurrence of immunoglobulin A nephropathy (IgAN) is associated with an increased risk of allograft loss, but predictors of poor outcomes are poorly understood.This study adds:A prognostic web-based nomogram based on clinical variables at biopsy  accurately predicts premature allograft loss.Potential impact:Future innovative interventions may help to slow down the progression of recurrent IgAN among identified patients at risk.The recurrence of immunoglobulin A nephropathy (IgAN) is a common complication in kidney transplantation, significantly affecting the long-term graft outcomes to a similar extent as chronic antibody-mediated rejection . The repMany clinical factors determine the risk of progression of the original disease, including hypertension, young age, proteinuria, the Oxford MEST-C score, low estimated glomerular filtration rate (eGFR), presence of C4d and crescents in kidney biopsy . SimilarIn this study we aimed to identify risk factors associated with biopsy-proven IgAN recurrence and subsequent graft loss in the well-identified patient cohort and construct a prognostic nomogram identifying patients at risk for premature graft loss.In this retrospective observational cohort study, 442 of 5582 patients had undergone kidney transplantation due to biopsy-proven IgAN from 1994 to 2020  mismatch, panel reactive antibody (PRA), cold ischaemia time, time on dialysis, induction immunosuppression, any proteinuria, erythrocyturia and date of graft loss or patient death.To study risk factors for graft loss, variables obtained at the date of graft biopsy-confirming recurrence were eGFR, proteinuria (>1 g/day), erythrocyturia (>10 erythrocytes/µl), C4d staining in histology, time to recurrence, MEST-C score, antihypertensive therapy, renin–angiotensin–aldosterone system (RAAS) inhibitors, steroid therapy and indication biopsy status.n = 78 (94%); 9 on cyclosporine, 69 on tacrolimus] in combination with mycophenolate mofetil  and steroids [n = 77 (93%)]. Five patients had received CNI-free regimens. Because the vast majority (95%) of patients had received tacrolimus along with MMF for immunosuppression, those variables were not particularly studied. In patients with histologically proven IgAN recurrence, steroid pulses were initiated in cases with present crescents (n = 4), RAAS inhibitors were given to all patients with recurrent IgAN.The maintenance immunosuppression consisted of calcineurin inhibitors , higher peak PRA  and female gender of the recipient . Only recipients <43 years of age , female gender of the recipient  and retransplantation  remained significant variables in multivariable analysis. A Cox proportional hazards model was created including patients after the first transplantation only. Similarly, younger age and female gender remained significant in multivariable analysis after the exclusion of retransplanted patients  , y) Table .P < .001) compared with those without proven recurrence , P = .005], proteinuria >1 g/day , indication biopsy  and C4d-positive staining in the allograft biopsy  were found to be associated with graft loss. From the MEST-C score, the T lesion  and the sum of MEST-C scores  significantly predicted graft loss , A multivariable Cox model was constructed based on variables from univariable analysis. Erythrocyturia was excluded from the model since it is closely correlated with proteinuria, which was a stronger allograft loss predictor. In contrast, although there was no significant association of the antihypertensive therapy with graft failure in the univariable analysis, the multivariable model was adjusted for antihypertensive therapy, as hypertension severity is a well-known predictor of graft loss.P = 0.02], proteinuria >1 g/day at biopsy  and C4d-positive staining  were found to be significant risk factors for allograft loss. The use of three and more antihypertensive drugs implied a moderate protective effect on allograft failure [HR 0.49 (95% CI 0.25–0.94), P = .033; Table In the multivariable model adjusted for renal function and time to recurrence, age <43 years [HR 2.77 (95% CI 1.17–6.56), The multivariable Cox regression model based on six predictors of allograft loss after biopsy-proven IgAN recurrence Table  was usedhttp://research.ikem.cz/hrup/graftsurvivalreigan2021/nomogram.The nomogram showed good accuracy in the prediction of patient outcomes. The C-index of the created nomogram was 0.736 for the derivation cohort and 0.807 for the external cohort. The nomograms were validated internally, which yielded C-indexes of 0.697 and 0.745 for the derivation and external cohorts, respectively. The calibration curves displayed good agreement between the prediction capacity of the nomograms and the actual outcomes in both the derivation and validation cohorts  was higher than in mild and non-progressive cases. Of note, recent data from the DAPA-CKD study (NCT03036150)  suggest In conclusion, we identified a progressive phenotype of biopsy-proven IgAN recurrence. A new prognostic web-based nomogram can be used for the identification of patients at risk to whom innovative interventions should be applied.gfad097_Supplemental_FilesClick here for additional data file.


Korean Journal of Women Health Nursing (KJWHN) has been listed as a MEDLINE journal on the “Journals Recently Accepted for Inclusion in MEDLINE” website (https://www.nlm.nih.gov/medline/medline_new_titles.html) on August 26, 2023. This list of recently accepted journals was published on August 25, 2023 (EST). I was thrilled to see KJWHN on the list, as it is a member journal of both the Korean Council of Science Editors and the Korean Association of Medical Journal Editors, organizations where I have served as president. I extend my congratulations to the editors, society executives, and all society members for their hard work in getting the journal listed in MEDLINE—“the United States National Library of Medicine’s (US NLM) premier bibliographic database that contains more than 29 million references to journal articles in life sciences with a concentration on biomedicine.” Another important partner was the publisher, which provides services such as XML and homepage production, English proofreading, and manuscript editing. It is indeed a significant challenge for an academic society in Korea to have a journal listed in MEDLINE. KJWHN is only the third journal in the nursing category in Korea to receive this honor. This accomplishment is a testament to the tireless efforts of all society members, particularly the expertise of the editor-in-chief, Dr. Sue Kim, who has held this position since January 2020.I discovered that the Why do editors of local nursing society journals strive for inclusion in MEDLINE? In addition to the reasons previously cited for other journals , the priThere are other advantages of becoming a MEDLINE journal, although KJWHN has already attained them. For instance, a third advantage is that a MEDLINE journal is searchable in the Scopus database. “For the majority of MEDLINE titles, Scopus has agreements with the publishers directly and receives the content from them. There are around 125 titles for which Scopus has permission to cover, and MEDLINE supplies directly to Scopus” . The fouIn addition to the five measurable benefits of being a MEDLINE journal, the most significant advantage is the enhanced prestige of the journal brand. This is because the journal’s content undergoes rigorous evaluation by experts from the Literature Selection Technical Review Committee (LSTRC) in the same field, ensuring the scientific quality of the content. This assessment of scientific quality is independent of citation frequencies. The LSTRC evaluates five aspects: scope and coverage, editorial policies and processes, scientific rigor of article content, production and administration, and impact. From my years of observation and analysis of why many Korean biomedical journals fail the MEDLINE evaluation process, I believe that the critical concept of acceptable scientific rigor centers on the following issues:-Is the study design stated and the main text described according to the corresponding reporting guidelines?-Is there a hypothesis statement in an experimental or analytic study?-Is there a sample size estimation for a study with a hypothesis statement?-Is the statistical analysis appropriate?-Is the background for variable selection explained?-Is the interpretation reasonable and not exaggerated?KJWHN passed those evaluation items successfully according to the LSTRC Journal Review Summary Report dispatched to the journal.https://www.nlm.nih.gov/medline/medline_statistics.html), Korean nursing society journals have started with PMC indexing [A list of nursing journals currently indexed in MEDLINE is available in indexing  to ensurChild Health Nursing Research, has also been indexed in PMC [Investigación y educación en enfermerías, published in Colombia; International Journal of Community based Nursing and Midwifery, published in Iran; Korean Journal of Women Health Nursing, published in Korea; Curationis, published in South Africa; and Nursing Open, published in the United States , require a subscription (4), or do not provide full text on the journal’s website (1)  .Numerous information technologies have already been introduced to scholarly journal publishing. Standard journal publishing techniques or requirements include a secure URL address for the journal homepage, Journal Article Tag Suite XML , digitalTo consistently meet the scientific quality standards set by the US NLM, it is crucial that a journal adheres to the industry’s best practices. Being listed in MEDLINE is the initial step towards elevating the journal to an internationally top-tier level. The following recommendations are proposed: first, uphold ethical standards under a distinct “Ethics statement” heading; and second, ensure scientific rigor by clearly defining the study design and corresponding reporting guidelines. Like many other local society journals, KJWHN required assistance and thus hired full-time staff to work for the journal. Since all editorial work is voluntary, editor burnout may occur due to the heavy load of reviewing, editing, and administration. One potential solution to this issue could be to increase the article processing charge on the author’s side, which would make it possible to hire professional staff. It is my hope that editors will be able to continue their work without experiencing burnout and find joy and satisfaction in their voluntary roles.


Limited efficacy of additional immunosuppressants was observed in DSA positive pediatric cases. In conclusion, pediatric cases with a high DSA-MFI and risk factors should undergo a histological examination. The appropriate treatment for post-transplant DSA in pediatric LT needs to be determined.The roles of post-transplant anti-HLA donor specific antibody (DSA) in pediatric liver transplantation (LT), including therapeutic strategies, remain controversial. This study aimed to identify the risks of post-transplant DSA for graft fibrosis progression in pediatric living donor LT (LDLT). We retrospectively evaluated 88 LDLT pediatric cases between December 1995 and November 2019. DSAs were assessed with single antigen bead test. Graft fibrosis was histopathologically scored with METAVIR and the centrilobular sinusoidal fibrosis system. Post-transplant DSAs were detected in 37 (52.9%) cases at 10.8 (1.3–26.9) years post-LDLT. The histopathological examination of 32 pediatric cases with post-transplant DSA revealed that 7 (21.9%) with a high DSA-MFI  showed graft fibrosis progression (≥F2). No graft fibrosis was observed in the subjects with a low DSA-MFI. The risk factors for developing graft fibrosis in pediatric cases with post-transplant DSA were an older graft age (>46.5 years old), lower platelet count (<10.7 × 10 De novo DSA presence was shown to be an independent risk factor of liver graft fibrosis progression in LT recipients for hepatitis C virus (HCV)-related liver cirrhosis (de novo DSAs were reportedly associated with graft fibrosis progression in pediatric LT (The recent development of an assay using single antigen beads (SABs) for anti-HLA antibodies has facilitated clinical studies of organ transplantation , 2. Postirrhosis . In addiatric LT . A protoatric LT .However, liver grafts are considered highly resistant to antibody-mediated injury . Feng etIn the present study, we examined the role of post-transplant DSA in pediatric living donor LT (LDLT). In addition, we described our treatment strategies for subjects with post-transplant DSA.The study protocol followed the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the institutional review board at Hokkaido University Hospital (#017-0104). We retrospectively evaluated 88 pediatric recipients who underwent LDLT between December 1, 1995, and November 31, 2019, and were followed up in Hokkaido University Hospital .n = 2), with preformed DSA (n = 1), with difficulty undergoing an evaluation for non-specific response to an SAB assay (n = 1) and who died within 6 months post-LT (n = 1) were excluded from the study . The patients without donor HLA typing information . All patients have been basically examined to detect donor-specific anti HLA-A, HLA-B, HLA-Cw, HLA-DR, and HLA-DQ antibodies using the LABScreen® SAB assay since 2019. Patients with abnormal findings on liver functional tests or suspected antibody-mediated rejection have been evaluated with an SAB assay since 2011. A normalized mean fluorescence intensity (MFI) greater than 1,000 was considered a positive result. Normalized DSA-MFI was represented as the DSA-MFI value calculated from the negative control beads and negative serum sample, according to the manufacture's protocol. The DSA-MFI cut-off of 1,000 for “positivity” was set according to the manufacturer's instructions and referenced from a previous study . The DSAAs induction therapy, Basiliximab was administered to patients who underwent LDLT from October 2003 to January 2019 in Hokkaido University Hospital, in conjunction with a triple-immunosuppressant regimen of tacrolimus (target trough 10–15 ng/ml for 1 month post-transplantation), mycophenolate mofetil  and methylprednisolone . Tacrolimus-based regimens (with or without MMF or mPSL) were usually administered during the maintenance phase.Histological findings were obtained from liver biopsy specimens using a 16-gauge cutting needle with a Pro-Mag ultra-automatic biopsy instrument . During the study periods, liver biopsy were performed in patients with abnormal liver functional test findings, those suspected of graft rejection, those with DSA positivity confirmed by an SAB assay and those in whom no histological evaluation had been conducted for several years despite receiving no immunosuppressant treatment. The histological data in t-tests were used for evaluating treatment efficacies . The Mann-Whitney U test was used to compare continuous variables. Paired ficacies . The assp-value <0.05 was considered to indicate statistical significance in all cases.Statistical analyses were performed using the JMP Pro software program, version 16  and the GraphPad Prism software program, version 5 . A p = 0.0196) and lower platelet counts at the SAB evaluation (p = 0.047) than the patients without post-transplant DSA positivity (p = 0.067), have rejection episodes within 1 year post-LT (p = 0.065) and have a higher total bilirubin at SAB evaluation (p = 0.077) than those without DSA positivity , DQ  and DR   . Of inte 4, 11%) . Furtherp < 0.03), post-transplant DSAs against DQ7 (p = 0.012), platelet count (p = 0.036), Fib4 index calculated by recipient age (p = 0.042) and Fib4 index by donor age (p < 0.0043) were significantly different between the high-risk group and high-DSA-MFI, low-fibrosis group  and a DSA-MFI of 9,300, as shown in is group . The cutonor age .Although the best practice for post-transplant DSA positivity in LT is unclear, we have applied a treatment algorithm to patients with post-transplant DSA positivity since 2015 . Patient+ lymphocytes from the peripheral blood of these patients. No apparent adverse effects or significant changes in the liver function, histological findings or amount of DSA were observed during the course of additional treatments (n = 11) were treated with additional tacrolimus and MMF for 2.15 ± 1.04 years, usually due to nonsignificant but slight fibrotic changes with a liver graft score of F1 (left column in n = 6) were observed without additional immunosuppressants for 2.58 ± 1.51 years  at 21.8 (5.2–28.5) years old  developed class II DSA. Of these, 37 (47.2%) showed a maximum DSA-MFI > 20,000 , recipient immunological factors  and graft factors   .de novo DSA in pediatric LT was associated with both inflammation and fibrosis as well as a significant increase in the number of CD8+ T cells in the graft  was reported to be a risk factor for allograft fibrosis at 5 years post-pediatric LT . Howeverde novo DSA-positive patients has been applied since 2015 in our institute (de novo DSAs due to immune responses to donor antigens may indicate insufficient immunosuppression. The consensus regarding managing modifiable risks in the transplantation group states that, in cases with a DSA-MFI of ≥5,000 and histopathological chronic antibody-mediated rejection, an increased dose of calcineurin inhibitors and the introduction of MMF and other immunosuppressants are recommended (The treatment protocol for nstitute . Althougommended . When hiommended . In addiommended . A scoreommended .We observed no fibrosis progression in the low-risk group for several years. However, we did encounter a subject with a high DSA-MFI and subtle fibrotic changes who was treated with an increased dosage of calcineurin inhibitor and additional MMF. This patient developed diffuse large B cell lymphoma as a post-transplant lymphoproliferative disease requiring chemotherapy. Thus, careful decision making to ensure optimal immunosuppression and close follow-up are required.Of note, we were unable to conclude the requirements for additional treatment even for the high-risk group in the present study. Further investigations based on accumulating evidence and in-depth analyses, i.e., molecular profiling, may provide useful information to help decide on additional and proper immunosuppression. In addition, our study is limited by its single-institute setting. To precisely determine the cut-off DSA-MFI value for predicting graft fibrosis, validation using multicenter data will be needed.In conclusion, a high DSA-MFI of ≥10,000 predicted graft fibrosis progression in pediatric LT. Patients with additional risk factors for graft fibrosis progression, such as an older graft age, higher Fib4 index and lower platelet count, should be considered for a histological evaluation. The need for additional immunosuppressants in high-risk pediatric LT patients warrants a further examination.