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1

Comparative clinical outcomes of insulin degludec and insulin glargine 300 U/mL after switching from other basal insulins in real‐world patients with type 1 and type 2 diabetes

المؤلفون: Yukiko Hasegawa, Tetsuya Babazono, Junko Oya, Aki Katamine, Tomoko Nakagami, Yuichiro Kondo

المصدر: Journal of Diabetes Investigation, Vol 12, Iss 11, Pp 1983-1991 (2021)
Journal of Diabetes Investigation

مصطلحات موضوعية: Insulin degludec, Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Insulins, Insulin Glargine, Type 2 diabetes, 030204 cardiovascular system & hematology, Body Mass Index, chemistry.chemical_compound, 0302 clinical medicine, Japan, Drug Substitution, Insulin glargine 300 U/mL, General Medicine, Articles, Middle Aged, Insulin, Long-Acting, Treatment Outcome, Clinical Science and Care, Female, Original Article, medicine.drug, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Real‐world clinical setting, Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Aged, Retrospective Studies, Glycated Hemoglobin, Type 1 diabetes, Insulin glargine, business.industry, Insulin, medicine.disease, RC648-665, Endocrinology, Diabetes Mellitus, Type 1, Logistic Models, Basal (medicine), chemistry, Diabetes Mellitus, Type 2, Glycated hemoglobin, business

الوصف: Aims/Introduction To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real‐world clinical setting. Materials and Methods A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. Results HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately −0.3% and −0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. Conclusions The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.
Insulin degludec and insulin glargine 300 U/mL showed similar values of reduction in glycated hemoglobin with body mass index almost unchanged 6 months after switching from other basal insulins in both type 1 and type 2 diabetes patients. Switching to insulin degludec was significantly associated with a reduction of basal and total insulin doses in both type 1 and type 2 diabetes patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd8e343952d329f98d4b6977a3a8fce5Test
https://doaj.org/article/33e2f17798204034beea375b21f2d506Test

2

With or Without Residual C-Peptide, Patients with Type 2 Diabetes Realize Glycemic Benefits from Real-Time Continuous Glucose Monitoring

المؤلفون: Tomas C. Walker, Peter Calhoun, Ryan R. Bailey, Christy Chao

المصدر: Diabetes Technology & Therapeutics. 24:281-284

مصطلحات موضوعية: Adult, Blood Glucose, medicine.medical_specialty, endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, Gastroenterology, chemistry.chemical_compound, Endocrinology, Diabetes mellitus, Internal medicine, medicine, Humans, Hypoglycemic Agents, Insulin, Glycemic, Glycated Hemoglobin, Blood glucose monitoring, C-Peptide, medicine.diagnostic_test, Continuous glucose monitoring, business.industry, C-peptide, Blood Glucose Self-Monitoring, Basal insulin, nutritional and metabolic diseases, medicine.disease, Medical Laboratory Technology, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, chemistry, Disease Progression, business

الوصف: Real-time continuous glucose monitoring (RT-CGM) is superior to blood glucose monitoring (BGM) for adults with insulin-treated type 2 diabetes (T2D); however, the utility of C-peptide levels for predicting the magnitude of the glycemic benefits is controversial. Data were from a subset of 147 participants in the MOBILE study (NCT03566693) who were treated with basal-only insulin and who had baseline C-peptide levels ≥0.5 ng/mL. Participants were randomized to treatment with either RT-CGM (n=100) or BGM (n=47). Between-group differences in HbA1c and time in range (TIR) changes were assessed. The between-group difference in HbA1c favored the RT-CGM group (by 0.58 percentage points, P=0.004 at 3 months and by 0.42 percentage points, P=0.04 at 8 months). TIR was 16% higher, and time >180 mg/dL was 16% lower, in the RT-CGM group at 8 months (P=0.002 for each). In T2D managed with basal insulin, RT-CGM benefits occur for those with residual insulin secretory capacity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d3a7d9d8a379b06e8dcf3fee33d5f69Test
https://doi.org/10.1089/dia.2021.0384Test

3

Lower versus standard sucrose dose for treating hypoglycemia in patients with type 1 diabetes mellitus in therapy with predictive low glucose suspend (PLGS) augmented insulin pumps: A randomized crossover trial in Santiago, Chile

المؤلفون: Paulina Jofré, María Teresa Onetto, Yazmín Zapata, Bruno Grassi, Guadalupe Echeverría

المصدر: Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 15:695-701

مصطلحات موضوعية: Adult, Blood Glucose, Male, Sucrose, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Hypoglycemia, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, Insulin Infusion Systems, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, Humans, Hypoglycemic Agents, Insulin, Medicine, In patient, 030212 general & internal medicine, Low glucose suspend, Chile, Type 1 diabetes, Cross-Over Studies, business.industry, Blood Glucose Self-Monitoring, General Medicine, Prognosis, medicine.disease, Crossover study, Diabetes Mellitus, Type 1, chemistry, Female, business, Algorithms, Biomarkers, Follow-Up Studies

الوصف: Recommended hypoglycemia treatment in adults with T1D consists of 15 g of rapid absorption carbohydrates. We aimed to evaluate the response to fewer carbohydrates for treating hypoglycemia in patients with T1D on insulin pumps with predictive suspension technology (PLGS).T1D patients on insulin pumps with PLGS were randomized to receive 10 or 15 g of sucrose per hypoglycemia for two weeks (S10 and S15 groups, respectively) when capillary blood glucose (BG) was70 mg/dL, with crossover after two weeks. Evolution of capillary BG, active insulin, and suspension time were assessed.59 hypoglycemic episodes were analyzed, 33 in S10 and 26 in S15. Baseline BG in S10 was 54.3 ± 7.7 mg/dL versus 56.9 ± 8.8 in S15 (p = 0,239). Active insulin, present in 85% of the episodes, and PLGS suspension time were similar between groups. BG at 15 min was 77 mg/dL in S10 and 95 mg/dL in S15 (p = 0.0007). In S10, 21% of the episodes required to repeat the treatment after 15 min compared with none on S15, with a RR of 0,79 (95% CI 0.66, 0.940, p = 0,014) for successfully treating the episode. Sensor glucose was significantly different from BG at the moment of the hypoglycemia and control 15 min after treatment. No severe hypoglycemia and no rebound hyperglycemia occurred in neither group.A hypoglycemia treatment protocol with a lower dose of sucrose might be insufficient despite PLGS technology. Our data suggest that standard doses of sucrose should still be recommended.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::47d6dbe82ceb11a07e1498bb0be74518Test
https://doi.org/10.1016/j.dsx.2021.03.017Test

4

Suppression of serum lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism by intensive insulin therapy in the first year of type 1 diabetes mellitus: Prospective InLipoDiab1 study

المؤلفون: Agata Grzelka-Woźniak, Aleksandra Uruska, Paweł Niedźwiecki, Aleksandra Cieluch, Justyna Flotyńska, Ewa Wysocka, Dorota Zozulińska-Ziółkiewicz, Marcin Nowicki

المصدر: Nutrition, Metabolism and Cardiovascular Diseases. 31:1219-1226

مصطلحات موضوعية: Adult, Blood Glucose, Male, medicine.medical_specialty, Time Factors, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medicine (miscellaneous), Pilot Projects, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Phospholipid transfer protein, Internal medicine, Diabetes mellitus, Cholesterylester transfer protein, Humans, Hypoglycemic Agents, Insulin, Medicine, Prospective Studies, Phospholipid Transfer Proteins, Type 1 diabetes, Nutrition and Dietetics, biology, business.industry, Reverse cholesterol transport, medicine.disease, Cholesterol Ester Transfer Proteins, Diabetes Mellitus, Type 1, Treatment Outcome, Endocrinology, chemistry, biology.protein, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business, Plant lipid transfer proteins, Biomarkers

الوصف: Background and aims Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are crucial proteins in reverse cholesterol transport. There are insufficient data on regulating these proteins by insulin therapy in type 1 diabetes mellitus (T1DM). We aimed to assess prospectively the impact of insulin therapy initiation on transfer proteins serum levels in adults with newly diagnosed T1DM. Methods and results 57 adults with newly diagnosed T1DM were enrolled in the InLipoDiab1 Study. All participants were treated with subcutaneous insulin in the model of intensive insulin therapy since the diagnosis of diabetes. Serum PLTP and CETP concentrations were measured at diagnosis, after three weeks, six months, and after one year of insulin treatment, using the immunoenzymatic method ELISA. A significant decrease in PLTP and CETP concentrations were demonstrated during twelve months of insulin therapy in newly diagnosed T1DM. The dynamics of changes in the level of these proteins varied depending on the occurrence of remission after a year of the disease. In the group without remission, a significant decrease in PLTP and CETP levels appeared after six months of follow-up. The remission group was characterized by a decrease in proteins concentration only after one year of treatment. In the non-remission group, significant negative correlations were found between the daily dose of insulin and levels of PLTP and CETP. Conclusion Exogenous insulin is an inhibitor of lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism in the first year of treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d227254b7b81ce95dcb9f369611a2c09Test
https://doi.org/10.1016/j.numecd.2020.11.006Test

5

Insulin Receptor–Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice

المؤلفون: Mark A. Atkinson, Tasneem Al-Huniti, Nirdesh K Gupta, Tian Chen, Jamie L. Felton, James D Horner, Steven K. Lundy, Michael P. Morran, Douglas Rogers, Emily Esakov, Swapnaa Balaji, Andrea Nestor Kalinoski, Neha Nandedkar-Kulkarni, Brigid Gregg, Kanakadurga Singer, Marcia F. McInerney, James D. Bretz

المصدر: J Immunol

الوصف: Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell–mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR− T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d0b0469b6fd27c7f018eab522859d75Test
https://doi.org/10.4049/jimmunol.1900357Test

6

Glycemic Variability and KIM-1–Induced Inflammation in the Diabetic Kidney

المؤلفون: Katherine R. Tuttle, Radica Z. Alicic

المصدر: Diabetes

الوصف: Diabetes, the “other pandemic,” has progressively increased in magnitude despite advances in knowledge about diabetes prevention over the last two decades (1). Therefore, diabetes will remain a major public health problem for the foreseeable future. More patients with diabetic complications inevitably accompany more people living with diabetes. Diabetic kidney disease (DKD) is one of the most serious, risky, and common, occurring in ∼30% of patients with type 1 diabetes and ∼40% of those with type 2 diabetes (2). Progressive DKD is now the foremost cause of kidney failure worldwide, accounting for half of all cases (3). However, in many regions, treatment for kidney failure by dialysis or transplantation is inaccessible and DKD becomes an unescapable death sentence. Indeed, DKD is now the most common cause of death in Mexico City (4). However, even such sobering observations fail to capture the true magnitude of the impact, as DKD independently increases risks of all-cause and cardiovascular mortality by more than fivefold even before patients develop kidney failure (5). Indeed, the mortality rate outpaces the rate of progression to kidney failure by more than 2:1 once macroalbuminuria develops (6). The need to find better ways to identify and treat DKD has never been more urgent. Recent therapeutic advances with the sodium–glucose cotransporter 2 inhibitors demonstrate clear benefits on top of the standard of care, yet substantial residual risk of kidney failure and death remains (7,8). Uncovering the biological basis of disease is essential to further therapeutic advancement. While hyperglycemia is a well-recognized DKD risk factor, the traditional biomarker of glycated hemoglobin is an average …

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14a39e6bacabe67cc294420e19eaf781Test
https://doi.org/10.2337/dbi21-0021Test

7

Targeting PD-L1 (Programmed death-ligand 1) and inhibiting the expression of IGF2BP2 (Insulin-like growth factor 2 mRNA-binding protein 2) affect the proliferation and apoptosis of hypopharyngeal carcinoma cells

المؤلفون: Jisheng Liu, Xudong Yang

المصدر: Bioengineered
article-version (VoR) Version of Record
Bioengineered, Vol 12, Iss 1, Pp 7755-7764 (2021)

مصطلحات موضوعية: Adult, Male, proliferation, medicine.medical_treatment, Cell, Mice, Nude, Apoptosis, Bioengineering, Applied Microbiology and Biotechnology, B7-H1 Antigen, Hypopharyngeal Carcinoma, Mice, Cell Line, Tumor, PD-L1, medicine, Animals, Humans, Viability assay, programmed cell death 1 ligand 1, Aged, Cell Proliferation, Aged, 80 and over, Gene knockdown, Hypopharyngeal Neoplasms, biology, Chemistry, Growth factor, RNA-Binding Proteins, insulin-like growth factor 2 mRNA-binding protein 2, General Medicine, Middle Aged, Xenograft Model Antitumor Assays, medicine.anatomical_structure, Insulin-like growth factor 2, Cancer research, biology.protein, hypopharyngeal carcinoma, TP248.13-248.65, Research Article, Research Paper, Biotechnology

الوصف: Programmed cell death-ligand 1 (PD-L1) have been attracting increasing attention in cancer diagnosis and treatment. The insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is involved in the progression of multiple types of cancer. So, the role of IGF2BP2 and PD-L1 in hypopharyngeal carcinoma was assessed. Western blotting and immunochemistry were used to evaluate the expression of IGF2BP2 and PD-1/PD-L1. IGF2BP2 expression was knocked down in FaDu cells, and the effects on cell viability, apoptosis and proliferation were measured. A tumor-bearing nude model of hypopharyngeal carcinoma was constructed to evaluate the effect of a PD-L1 inhibitor and IGF2BP2 knockdown on hypopharyngeal carcinoma in vivo. RNA pull-down assays were used to assess the interaction between IGF2BP2 and PD-L1. The results showed that knockdown of IGF2BP2 inhibited FaDu cell proliferation and promoted apoptosis, as evidenced by the lower cell viability, a higher ratio of TUNEL-positive cells, decreased expression of Bcl-2 and cyclins, and increased expression of cleaved-caspase 3. In vivo, the tumor volume and weight were reduced by both the PD-L1 inhibitor and IGF2BP2 knockdown. Additionally, the interaction between PD-L1 and IGF2BP2 was confirmed. In conclusion, the results in the present study revealed that inhibition of IGF2BP2 might be a potentially relevant method for treating hypopharyngeal carcinoma, and the effects might be mediated via inhibition of the PD-1/PD-L1 axis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc5be91fc6698d2c0556a18942a16a3dTest
https://doi.org/10.1080/21655979.2021.1983278Test

8

Efficacy and safety of adding ipragliflozin to insulin in Japanese patients with type 1 diabetes mellitus: a retrospective study

المؤلفون: Yukino Katakura, Shuhei Nakanishi, Akiko Mashiko, Hideaki Kaneto, Fuminori Tatsumi, Atsushi Obata, Masashi Shimoda, Kenji Kohara, Kohei Kaku, Tomohiko Kimura, Yoshiro Fushimi, Junpei Sanada, Tomoatsu Mune

المصدر: Endocrine Journal. 68:1455-1461

الوصف: Advances in insulin preparations and administration methods have produced a gradual improvement in glycemic control in patients with type 1 diabetes mellitus (DM). Nevertheless, glycated hemoglobin (HbA1c) levels in patients with type 1 DM are still poor compared to those in patients with type 2 DM. Here, we sought to assess the efficacy and safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin (IPRA) in patients with type 1 DM. This study was retrospectively conducted with data from type 1 DM patients who had a history of IPRA therapy. The primary endpoint was HbA1c level at 24 weeks. The baseline characteristics of a total of 12 subjects were as follows: age, 50.1 ± 13.2 years; diabetes duration, 17.3 ± 10.5 years; body mass index (BMI), 22.9 ± 2.1 kg/m2; HbA1c, 8.8 ± 1.3%; and daily insulin dose, 0.60 ± 0.21 units/kg. IPRA decreased HbA1c levels to 8.2 ± 1.2% (p < 0.05) and reduced insulin dose to 0.52 ± 0.17 units/kg (p < 0.01) after 24 weeks. HbA1c value was particularly reduced in subjects with preserved C-peptide index. IPRA significantly reduced body weight by -1.4 ± 1.4 kg (p < 0.01) 16 weeks after starting treatment, with no further weight loss after 24 weeks. There were no instances of diabetic ketoacidosis or severe hypoglycemia. IPRA exerted beneficial effects on glycemic control without any severe adverse effects, and should be safe and effective when used in patients with type 1 DM with understanding of correspondence in sick day.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aeb2ae8e08e3ea6a625861dc1439c4b4Test
https://doi.org/10.1507/endocrj.ej21-0161Test

9

miR-23b mediates TNF-α-Inhibited Osteogenic Differentiation of Human Periodontal Ligament Stem Cells by Targeting Runx2

المؤلفون: Mingwei Li, Jinghao Ban, Zhidan Li, Xuefei Sun

المصدر: International Journal of Medical Sciences

الوصف: Periodontitis is the most prevalent oral infection disease, which causes the destruction of periodontal supporting tissues and eventual tooth loss. This study aimed to investigate the molecular mechanism of miRNA-23b (miR-23b) in regulating the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) in an inflammatory environment. Results revealed that tumor necrosis factor-α (TNF-α), a notoriously inflammatory cytokine, remarkably attenuated the osteogenic differentiation of hPDLSCs, which were partially rescued by SKL2001 (Wnt/β-catenin agonist). We further explored the underlying roles of miRNAs involved in TNF-α-inhibited osteogenesis of hPDLSCs. The miR-23b significantly increased with TNF-α stimulation, which was abolished by SKL2001. Similar to the effect of TNF-α, miR-23b agonist (agomir-23b) dramatically reduced the expression of runt-related transcription factor 2 (Runx2) and suppressed the osteogenic differentiation of hPDLSCs. The inhibition of miR-23b significantly increased Runx2, which is the major transcription factor during osteogenesis, thereby indicating that miR-23b was an endogenous regulator of Runx2 in hPDLSCs. Bioinformatic analysis and dual luciferase reporter assays confirmed that Runx2 was a target gene of miR-23b. Furthermore, the gain function assay of Runx2 revealed that the Runx2 overexpression efficiently reversed the suppression of the osteogenic differentiation of hPDLSCs with miR-23b agonist, suggesting that the suppressing effect of miR-23b on osteogenesis was mediated by Runx2 inhibition. Our study clarified that miR-23b mediated the TNF-α-inhibited osteogenic differentiation of hPDLSCs by targeting Runx2. Therefore, the expanded function of miR-23b in the osteogenesis of hPDLSCs under inflammatory conditions. This study might provide new insights and a novel therapeutic target for periodontitis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa5559d0805ab07b69696ec9ab7330c8Test
http://europepmc.org/articles/PMC8579284Test

10

Low C‐peptide together with a high glutamic acid decarboxylase autoantibody level predicts progression to insulin dependence in latent autoimmune diabetes in adults: The HUNT study

المؤلفون: Valdemar Grill, Elin Pettersen Sørgjerd, Bjørn Olav Åsvold

المصدر: Diabetes, obesity and metabolism

الوصف: Aim: To search for risk factors that could predict progression in latent autoimmune diabetes in adults (LADA) and compare them with those for type 2 diabetes. Materials and Methods: This study included 175 participants with LADA (autoanti-body positive, without insulin treatment ≥1 year after diagnosis) and 2331 partici-pants with type 2 diabetes (autoantibody negative, without insulin treatment ≥1 yearafter diagnosis) from the HUNT2 and HUNT3 surveys. We used Cox regressionmodels and receiver operating characteristic curve analysis to identify predictive fac-tors for progression to insulin dependency within 10 years. Results: Low C-peptide levels (

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6b6dc298400dc53ff7d4720c18f5f6c1Test
https://doi.org/10.1111/dom.14501Test

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