|Year : 2011 | Volume
| Issue : 4 | Page : 388-392
A clinical study of the relationship between diabetes mellitus and periodontal disease
Neelima S Rajhans1, Ramesh M Kohad2, Viren G Chaudhari1, Nilkanth H Mhaske1
1 Department of Periodontics, Y.C.M.M. and R.D.F's., Dental College, Vadgaon Gupta, Ahmednagar, India
2 Department of Periodontics, Saraswati - Dhanwantari Dental College & Hospital, Parabhani, Maharashtra, India
|Date of Submission||21-Jan-2011|
|Date of Acceptance||30-Nov-2011|
|Date of Web Publication||2-Feb-2012|
Neelima S Rajhans
"Chhand", Plot No. 8, Samartha Nagar, Behind Sagar Hotel, Pipeline Road, Savedi, Ahmednagar, Maharashtra 414 003
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The relationship between diabetes mellitus and periodontal disease is not clear, even though studied intensively. From the available data, it seemed reasonable to believe that diabetics were more susceptible to periodontal disease than non-diabetics. Aim: The present study was to clinically evaluate the relationship of diabetes mellitus with periodontal disease along with various parameters. Materials and Methods: Fifteen hundred patients with diabetes mellitus were examined. A thorough oral examination was carried out and relevant history was recorded for all the patients. Results: Results indicated that the prevalence of periodontal disease in diabetic patients was 86.8%. Conclusion: It can be concluded that poorer the glycemic control, and longer the duration of diabetes, the greater will be the prevalence and severity of periodontal disease.
Keywords: Glycemic control, prevalence, duration, severity
|How to cite this article:|
Rajhans NS, Kohad RM, Chaudhari VG, Mhaske NH. A clinical study of the relationship between diabetes mellitus and periodontal disease. J Indian Soc Periodontol 2011;15:388-92
|How to cite this URL:|
Rajhans NS, Kohad RM, Chaudhari VG, Mhaske NH. A clinical study of the relationship between diabetes mellitus and periodontal disease. J Indian Soc Periodontol [serial online] 2011 [cited 2021 Dec 4];15:388-92. Available from: https://www.jisponline.com/text.asp?2011/15/4/388/92576
| Introduction|| |
Gingival and periodontal diseases, in their various forms, have afflicted mankind since the dawn of history. Diseases of the periodontium occur in childhood, adolescence, and early adulthood but the prevalence of periodontal disease, tissue destruction and tooth loss increases with age. 
Apart from age, the factors such as immediate environment of the periodontium and systemic factors, resulting from the general condition of the patient are responsible for the periodontal disease. Diabetes mellitus deserves a special consideration in any comprehensive text of periodontal diseases. Diabetes mellitus affects many people, as does periodontitis, and is found with increasing frequency as people get older as is periodontitis. 
Diabetes mellitus is a complicated metabolic disorder characterized by hypofunction or lack of function of the beta cells of the Islets of Langerhans More Details in the pancreas, leading to high blood glucose levels and excretion of sugar in the urine.  Diabetes is the commonest among metabolic disorders and its incidence is on the increase all over the world.  It affects 2 to 10% of the human population. 
Periodontal disease has been labeled as the "Sixth Complication" of diabetes.  However, there is no unanimity about the exact relationship between diabetes mellitus and occurrence of periodontal disease. Opinions still differ regarding the correlation of diabetes and periodontal disease. Regarding the influence of diabetes on periodontium, there are two schools of thought.
One school of thought has reported increased severity of periodontal disease in diabetics not related to increased local irritants. According to them angiopathy, abnormal collagen metabolism, abnormal polymorphonuclear cell (PMN) function, and altered sulcular microbial flora are found in close association with the severity of periodontitis in diabetic patients. These factors reduce the defensive capacity of tissues and may disturb the tissue response to local irritants. ,,,
Another school of thought recognizes no relationship between diabetes and periodontal disease and maintains that, when two conditions exist together, it is a coincidence rather than a specific cause and effect relationship. According to them, the distribution and severity of local irritants affect the severity of periodontal disease in diabetics. ,,
As there is a difference of opinion about the cause and effect relationship between diabetes and periodontal disease, it was thought to study the same to resolve the difference of opinion by carrying out the study on larger patient population and applying various periodontal parameters and diabetic variables.
The study was undertaken in diabetic patients with the following objectives.
- To find out prevalence and severity of periodontal disease.
- To determine age and sex influence on the prevalence and severity of periodontal disease.
- To evaluate the relationship between the diabetes mellitus and periodontal disease in terms of plaque and calculus.
- To evaluate the relationship between duration of diabetes and prevalence and severity of periodontal disease.
- To investigate the association between glycemic status of diabetics and prevalence and severity of periodontal disease.
- To study the effect of glycemic status of diabetics on tooth mobility.
- To find out effect of diabetes mellitus on loss of teeth.
| Materials and Methods|| |
The study was carried out in multiple hospitals. A total of 1500 patients were selected from Out Patient Department of Periodontics, Government Dental College and Hospital, the Diabetic Clinic, Government Medical College and Hospital, and Diabetes Care and Research Center at Aurangabad. These patients were diagnosed as having diabetes mellitus and were under treatment. The patients were selected by the following inclusion criteria:
- Under treatment or had diabetes mellitus diagnosed for at least last one year or more.
- Not having any other systemic diseases.
- Not having any history of diabetic complications like neuropathy, nephropathy, retinopathy etc.
- Not using drugs such as phenytoin, nephidipine etc.
- Not undergone any periodontal treatment since last one year.
- Willingness to participate in the study.
The relevant history was recorded for all the patients. A careful oral examination was carried out with the help of mouth mirror and graduated periodontal probe. Ramfjords periodontal disease index having components for plaque, calculus and disease severity and Miller's mobility index were recorded for each patient.
Determination of blood glucose levels
In all the patients, venous blood was collected under strict aseptic conditions, after an overnight fast and one and half hour after meal. The fasting and postprandial blood glucose levels were determined by autoanalyzer.
| Results|| |
Of the 1500 patients, 3.4% of patients had insulin-dependent diabetes mellitus (IDDM) and 96.6% had non-insulin-dependent diabetes mellitus (NIDDM). The collected data was analyzed statistically. Karl Pearson correlation coefficient analysis was used to investigate the relationship between prevalence and severity of periodontal disease and various other factors such as age, sex, glycemic status, and duration of diabetes mellitus.
Out of 1500 patients, 751 (50.1%) were male and 749 (49.9%) were female. The age range of the patients was 15 years to 76 years with a mean age of 53.24±11.91 years. The patients were classified into five groups as shown in [Table 1].
Prevalence and severity of periodontal disease and the effect of patients' age and sex on it
Analysis of the data showed that the prevalence of periodontal disease in diabetic patients was 86.8% (gingivitis 27.3% and periodontitis 59.5%) and complete edentulousness was 10.7%. Remaining 2.5% of patients' were periodontally healthy
|Figure 1: Pie diagram showing periodontal status of diabetes mellitus patients (%)|
Click here to view
The prevalence of periodontal disease was almost equal in both the sexes, male and female; gingivitis, 28.1% in male and 26.4% in female [Figure 2]; periodontitis, 59.4% in male and 59.5% in female [Figure 3]. Mean periodontal disease index score was 3.52±1.96. It was lowest in group I and highest in group V [Table 2]. Pearson analysis indicated statistically significant (P<0.01) correlation of age, but not the sex, with the prevalence and severity of periodontal disease.
Plaque and calculus index
The mean plaque and calculus index scores were 1.22±0.55 and 1.27±0.60, respectively. There was a statistically significant correlation (P<0.01) of plaque and calculus index with severity, but not with the prevalence of periodontal disease.
Duration of diabetes mellitus
The mean duration of diabetes mellitus was 7.99±4.63 years [Table 3]. It was 3.06±1.81, when periodontal disease index score was 1, and 12.79±3.42, when the maximum score was 6. The duration of diabetes mellitus was statistically correlated (P<0.01) with the prevalence and severity of periodontal disease.
|Table 3: Mean duration (in years) of diabetes mellitus and periodontal status |
Click here to view
Glycemic status of diabetes mellitus
The mean fasting blood glucose level was 122.00±34.56, whereas the mean postprandial blood glucose level was 212.36±61.09. In healthy periodontium group, it was 76.24±3.29 and 117.16±4.22 and was found to be maximum in generalized periodontitis group i.e. 146.73±35.91 and 247.66±56.16, respectively [Figure 4]. It was observed that the blood glucose levels were 98.70±19.63 and 154.01±39.59, when periodontal disease index score was 1, and 173.50±29.30 and 287.04±38.65, when score was maximum of 6 [Table 4]. Thus, the glycemic status was significantly (P<0.01) related to the prevalence and severity of periodontal disease.
Miller's mobility index
Six hundred and fifty six patients' (43.7%) and a total 3800 teeth exhibited pathological tooth mobility. Out of these, 2992 (78.7%), 501 (13.2%), and 307 (8.1%) teeth exhibited grade I, II, and III mobility, respectively. No mobility was found in the age groups, I and II (upto 34 years of age). At the level of significance P<0.01, there was a statistically significant correlation of tooth mobility with glycemic status of diabetics.
Out of the 1500 patients, 624 (41.6%) were complete dentulous, while 785 (47.7%) were partially and 161 (10.7%) were completely edentulous. Hundred and eighty seven patients (12.4%) had lost the teeth before the diagnosis of diabetes mellitus, while 479 patients (32%) lost their teeth after the diagnosis of diabetes mellitus. There was a statistically significant (P<0.01) correlation between the number of missing teeth and age of the patient, duration of diabetes mellitus and prevalence and severity of periodontal disease.
| Discussion|| |
Very often, course of periodontal disease is modified by the systemic disorder of patients. The systemic disorder exerts the effect in a generalized manner and so also affects the occurrence and management of the periodontal conditions. One of such systemic conditions playing an important role in the etiology of periodontal disease is diabetes mellitus.
Cianciola et al.  reported the prevalence of periodontitis to be 39% in individuals aged 19 years and older, while in patients above 35 years of age, Rylander et al.,  reported the prevalence of periodontitis to be 87%; Bacic et al. reported the prevalence to be 50%.  Consistent with these findings, the prevalence of periodontitis and gingivitis was 59.5% and 26.4%, respectively, in the present study. This is inspite of the fact that the present study had very small percentage (3.4%) of IDDM patients and 96.6% NIDDM patients.
Sheridan  found that periodontal disease increases in prevalence and severity with age of the patient. Albert et al.,  Novaes et al.,  and Bridges et al.  compared periodontal status of diabetics with non diabetics and supported these results in relation to severity of periodontal disease. The present study had also demonstrated that as age of the diabetic increases, the prevalence and severity of periodontal disease increases. Collagen is the predominant component of gingival connective tissue accounting for approximately 60% of connective tissue volume and 90% of the organic matrix of alveolar bone. Oliver and Tervonen  had stated that the properties of human collagen are changed during aging and with the metabolic abnormalities of diabetes mellitus. Thus, altered collagen metabolism in diabetics would be expected to contribute to the progression of periodontal disease.
The mean plaque and calculus index values were minimum in patients having healthy periodontium, but increased gradually with the progress of the periodontal disease except for localized periodontitis. This may be on account of the absence of or scanty amount of plaque or calculus on the remaining teeth in localized periodontitis patients.
Cerda et al.  and Firatli et al.  had concluded that the duration of diabetes was a significant factor for the severity of periodontal disease. Emrich et al.  stated that the diabetic status was significantly and strongly related to both prevalence and severity of periodontal disease. From the present study also, it can be speculated that poorer the control and longer the duration of diabetes, the greater will be the prevalence and severity of periodontal disease. Karjalainen and Knuuttila  had suggested that hyperglycemia impairs overall cell function, as insulin is required for glucose to enter cells to provide a source of energy. It also decreases PMN cell chemotaxis, phagocytosis and intracellular killing of bacteria. The ability of glycosylated hemoglobin to carry oxygen would be impaired, thereby decreasing tissue oxygenation. Hyperglycemia induces blood flow abnormalities including increased blood viscosity, reduced erythrocyte deformability, and increased platelet aggregation, which further enhance tissue hypoxia. All these factors result in increased periodontal destruction.
It was also noticed that the mean duration of diabetes and mean blood glucose levels were least when the score was one and then increased gradually with increase in periodontal disease index score. However, in complete edentulous patients, even though the mean duration was highest, the mean blood glucose levels were very less when compared to patients with localized/generalized periodontitis. This may point towards the effect of destructive periodontitis on blood glucose level as observed also by Miller et al.  and Taylor et al.  The mechanisms may be:
- The predominant cultivable organisms at the base of the active periodontal pockets are gram negative and thus produce endotoxin which has been shown to cause hyperglycemia and depletion of liver glycogen (Schluger et al. ).
- The tumor necrosis factor alpha and cytokines found in destructive periodontitis interferes with the action of insulin and lead to metabolic alterations during infection. The relationships between insulin resistance and inflammatory connective tissue diseases have also been reported for severe periodontitis as a risk factor for poor glycemic control. It is, thus, expected that there is an increase in blood glucose levels in diabetics with the increasing severity of periodontal disease.
Three thousand and eight hundred teeth were found to have mobility of different grades and were significantly related to the glycemic status of diabetics. Tervonen and Knuuttila,  found the mineral content of bone to be correlated to the fasting blood glucose levels, as altered collagen metabolism in diabetes can lead to osteopenia and osteoporosis. Epstein  demonstrated that essentially all the aspects of bone growth and mineralization are diminished in the absence of insulin i.e. hyperglycemia. The vascular changes also increase with increase in blood glucose levels (Oliver and Tervonen).  All these mechanisms may partly explain the relationship between glycemic status and tooth mobility upto the age of 34 years. No tooth mobility was observed in this study. It started from the age 35 years and then the number of mobile teeth increased with increase in age of the patient. Bacic et al.  called this 35 th year as a critical age when a faster destruction of periodontium in patients suffering from diabetes begins.
The role that diabetes plays in the initiation and progression of periodontal disease involves multiple factors. Particularly poor metabolic control as well as extended duration of diabetes is a risk factor for periodontitis when extensive local irritants are present on teeth. The dentist can play an important role in diabetic patients overall health care through recognition and treatment of their periodontal needs understanding the "Sixth Complication of diabetes mellitus."
| Conclusion|| |
Following inferences are drawn from the present study:
- The prevalence of periodontal disease in diabetic patients was 86.8% (gingivitis 27.3% and periodontitis 59.5%) and complete edentulousness was 10.7%. Remaining 2.5% was periodontally healthy. The average loss of attachment three to six mm was present in 24.2% of the total 1500 patients', whereas more than six mm were present in 15.4% patients.
- Prevalence as well as severity of the periodontal disease increased with increase in age, but not with the sex.
- Plaque and calculus index were significantly correlated with the severity, but not with the prevalence of periodontal disease.
- Duration of diabetes mellitus was significantly correlated to the prevalence and severity of periodontal disease.
- Glycemic status had a significant effect on the prevalence and severity of periodontal disease.
- There was a statistically significant correlation between glycemic status and tooth mobility.
- The number of missing teeth increased with increase in age of the patient and duration of diabetes mellitus, and had the direct correlation with the severity of periodontal disease.
| References|| |
|1.||Carranza FA, Newman MG. Clinical periodontology. 8 th ed. India: Prism Books Ltd. and Philadelphia: W. B. Saunders Company; 1996. |
|2.||Schluger S, Yuodelis R, Page RC, Johnson RH. Periodontal diseases: Basic phenomena, clinical management and occlusal and restorative interrelationships. 2 nd ed. Philadelphia, London: Lea and Febiger; 1990. |
|3.||Macleod J. Davidson's principles and practice of medicine. 14 th ed. English language book society. Philadelphia (US): Churchill Livingstone; 1984. |
|4.||Shah SN, Tripathy BB. API textbook of medicine. In: Sainani GS, Anand MP, Billimoria AR, Chugh KS, Joshi VR, Mehta PJ, et al. editors. 15 th ed. Bombay: Association of Physicians of India; 1994. |
|5.||Firatli E, Yilmaz O, Onan V. The relationship between clinical attachment loss and the duration of insulin dependent diabetes mellitus (IDDM) in children and adolescents. J Clin Periodontol 1996; 23:362-6. |
|6.||Grossi SG, Skrepanski FB, Caro TD, Zambon JJ, Cummins D, Genco RJ. Response to periodontal therapy in diabetics and smokers. J periodontal 1996; 67:1094-102. |
|7.||Bernick SM, Cohen DW, Baker RL and Laster L. Dental disease in children with diabetes mellitus. J Periodontal 1975; 46:241-5. |
|8.||Cianciola LJ, Park BH, Bruck E, Mosonvich L, Genco RJ. Prevalence of periodontal disease in insulin dependent diabetes mellitus (juvenile diabetes). J Am Dent Asso 1982; 104:653-60. |
|9.||Leeper S, Kalkwarf K, Annstrom E. Oral status of "controlled " adolescent type - I diabetics. J Oral Med 1985; 40:127-33. |
|10.||Sandholm L, Swanlijung O, Rytomaa I, Kaprio EA, Manna. J Periodontal status of Finnish adolescent with insulin dependent diabetes mellitus. J Clin Periodontal 1989; 16:617-20. |
|11.||Barnett ML, Baker RL, Yancey JM, Mac Millan DR, Kotoyan M. Absence of periodontitis in population of insulin dependent diabetes mellitus (IDDM) Patients. J Periodontal 1984; 55:402-5. |
|12.||Ervasti T, Knuuttila M, Pohjamo L and Haukipuro K. Relation between control of diabetes and gingival bleeding. J Periodontal 1985;56:154-7. |
|13.||Hayden P, Buckley LA. Diabetes mellitus and periodontal disease in an Irish population. J Periodont Res 1989;24:298-302. |
|14.||Rylander H, Ramberg P, Blohme G, Lind he J. Prevalence of periodontal disease in young diabetics. J Clin periodontal 1986; 14:38-43. |
|15.||Bacic M, Plancak D, Granic M. CPITN assessment of periodontal disease in diabetic patients. J Periodontal 1988;59:816-22. |
|16.|| Sheridan. Advances in dental research. J Am Dent Asso 1987; 115:741-2. |
|17.||Albert M, Banoczy J, Tamas G Jr. Dental and Oral symptoms of diabetes mellitus. Commu Dent Oral Epidemiol 1988;16:378-80. |
|18.||Novaes AB, Pereira AL, Moraes N. Novaes AB.: Manifestations of insulin dependent diabetes mellitus in the periodontium of young Brazilian patients. J Periodontal 1991;62:116-22. |
|19.||Bridges RB, Anderson JW, Saxe SR, Gregory K, Bridges SR. Periodontal status of diabetic and non - diabetic men: Effects of smoking, glycemic control and socioeconomic factors. J Periodontal 1996;67:1185-92. |
|20.||Oliver RC, Tervonen T. Diabetes - A risk factor for periodontitis in adults? J Periodontal 1994;65:530-8. |
|21.||Cerda JG, Dela Torre CV, Malacara JM, Nova LE. Periodontal disease in non - insulin dependent diabetes mellitus (NIDDM). The effect of age and time since diagnosis. J Periodontal 1994; 65:991-5. |
|22.||Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in non - insulin dependent diabetes mellitus. J Periodontal 1991; 62:123-30. |
|23.||Karjalainen KM, Knuuttila ML. The onset of diabetes and poor metabolic control increases gingival bleeding in children and adolescents with insulin dependent diabetes mellitus. J Clin Periodontal 1996;23:1060-7. |
|24.||Miller LS, Manwell MA, Newbold D, Reding ME, Rasheed A, Blodgett J, et al. The relationship between reduction in periodontal inflammation and diabetes control: A report of 9 cases. J Periodontal 1992;63:843-8. |
|25.||Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M, Knowler WC, et al. Severe periodontitis and risk for poor glycemic control in patients with non-insulin dependent diabetes mellitus. J Periodontal 1996;67:1085-93. |
|26.||Tervonen T, Knuuttila M. Relation of diabetes control to periodontal pocketing and alveolar bone level. Oral Surg Med Oral Path 1986;61:346-9. |
|27.||Epstein S. Diabetes mellitus and abnormalities of bone and collagen metabolism. In: Draznin B, Melmed S, Le Roith D, editors. Complications of diabetes mellitus. New York: Alan R Liss Inc; 1989. p. 115-24. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Association between metabolic syndrome and periodontitis: The role of lipids, inflammatory cytokines, altered host response, and the microbiome
| ||Flavia Q. Pirih, Sepehr Monajemzadeh, Neelima Singh, Rachel Sheridan Sinacola, Jae Min Shin, Tsute Chen, J. Christopher Fenno, Pachiyappan Kamarajan, Alexander H. Rickard, Suncica Travan, Bruce J. Paster, Yvonne Kapila |
| ||Periodontology 2000. 2021; 87(1): 50 |
|[Pubmed] | [DOI]|
||Oral health complications in type 2 diabetes: A hospital-based observational study among beneficiaries of employees state insurance in Puducherry, India
| ||PalashKumar Sanyal, Pramod Srirammohan, Sirshendu Chaudhuri |
| ||Indian Journal of Medical Specialities. 2021; 12(4): 222 |
|[Pubmed] | [DOI]|
||The Assessment of General Health Status in Patients with Odonto-Periodontal Pathology and Diabetes Mellitus
| ||Andreea Dinu, George Maniu |
| ||Acta Medica Transilvanica. 2021; 26(3): 24 |
|[Pubmed] | [DOI]|
||Association between health locus of control and oralhealth status in type 2 diabetics - A cross sectional comparative study
| ||B Santhiya, ManjunathP Puranik, KR Sowmya |
| ||Journal of Indian Association of Public Health Dentistry. 2020; 18(2): 124 |
|[Pubmed] | [DOI]|
||Periodontal disease and treatment needs among patients with diabetes mellitus Type 2 attending Talaga Bodas Community Health Center in Bandung City
| ||Agus Susanto, ArinaSarah Amnani Manurung, Aldilla Miranda, Siti Sopiatin |
| ||Scientific Dental Journal. 2020; 4(1): 1 |
|[Pubmed] | [DOI]|
||Effect of Subantimicrobial Dose Doxycycline Treatment on Gingival Crevicular Fluid Levels of MMP-9 and MMP-13 in Periodontitis Stage 2, Grade B in Subjects with Type 2 Diabetes Mellitus
| ||Mai S. Attia, Jazia A. Alblowi, Francesca Santilli |
| ||Journal of Immunology Research. 2020; 2020: 1 |
|[Pubmed] | [DOI]|
||Periodontal Diseases in Diabetes Melitus - A Two Way Link? A Review of Literature
| ||Ovidiu Boitor, Carmen Natea Sitterli, Mihaila Romeo |
| ||Acta Medica Transilvanica. 2020; 25(4): 77 |
|[Pubmed] | [DOI]|
||Oral diseases in diabetic patients
| ||Hana Poskerová, Petra Borilová Linhartová, Lydie Izakovicová Hollá |
| ||Vnitrní lékarství. 2019; 65(4): 314 |
|[Pubmed] | [DOI]|
||Clinical implications of age and sex in the prevalence of periodontitis in Korean adults with diabetes
| ||Kyungdo Han, Jun-Beom Park |
| ||Experimental and Therapeutic Medicine. 2018; |
|[Pubmed] | [DOI]|
||Influence of Diabetes Mellitus on Dental Condition and Periodontal Status
| ||H. Poskerová, P. Linhartová, M. Cvanová, L. Hollá |
| ||Ceská stomatologie/Praktické zubní lékarství. 2018; 118(1): 3 |
|[Pubmed] | [DOI]|
||Periodontal, metabolic, and cardiovascular disease: Exploring the role of inflammation and mental health
| ||Hina Makkar, Mark A. Reynolds, Abhishek Wadhawan, Aline Dagdag, Anwar T. Merchant, Teodor T. Postolache |
| ||Pteridines. 2018; 29(1): 124 |
|[Pubmed] | [DOI]|
||Diabetes Mellitus and Oral Health
| ||H. Poskerová, P. Linhartová, J. Vokurka, A. Fassmann, L. Hollá |
| ||Ceská stomatologie/Praktické zubní lékarství. 2014; 114(5): 75 |
|[Pubmed] | [DOI]|
||Association between diabetes-related factors and clinical periodontal parameters in type-2 diabetes mellitus
| ||Eun-Kyong Kim,Sang Lee,Youn-Hee Choi,Kyu-Chang Won,Jun Moon,Anwar T Merchant,Hee-Kyung Lee |
| ||BMC Oral Health. 2013; 13(1): 64 |
|[Pubmed] | [DOI]|