Abstract
Objectives
To establish the effect of an educational intervention for general practitioners on the health behaviours and wellbeing of elderly patients.
Design
Randomised controlled trial with 1 year follow up.
Setting
Metropolitan general practices in Melbourne, Australia.
Subjects
42 general practitioners and 267 of their patients aged over 65 years.
Intervention
Educational and clinical practice audit programme for general practitioners on health promotion for elderly people.
Main outcome measures
Patients’ physical activity, functional status, self rated health, immunisation status, social contacts, psychological wellbeing, drug usage, and rate of influenza vaccination. Primary efficacy variables were changes in outcome measures over 1 year period.
Results
Patients in the intervention group had increased (a) walking by an average of 88 minutes per fortnight, (b) frequency of pleasurable activities, and (c) self rated health compared with the control group. No change was seen in drug usage, rate of influenza vaccination, functional status, or psychological wellbeing as a result of the intervention. Extrapolations of the known effect of these changes in behaviour suggest mortality could be reduced by 22% if activity was sustained for 5 years.
Conclusions
Education of the general practitioners had a positive effect on health outcomes of their elderly patients. General practitioners may have considerable public health impact in promotion of health for elderly patients.
Key messages
Few educational interventions for doctors have shown benefit to the health of patients
Elderly people were identified in the UK health initiatives as in need of additional attention, and levels of health protective behaviours were low in community surveys
A multifaceted educational intervention for general practitioners was effective in improving walking behaviour, self rated health status, and the frequency of social contacts in elderly patients
General practitioners are effective in improving health and health behaviours in their elderly patients
Introduction
Threats to the health of elderly people and targets for health promotion include low rates of uptake of influenza vaccination1 and exercise,2 increased drug use,3 and social isolation.4 As elderly people attend general practices frequently, general practitioners are well placed to deliver interventions for such people,5 and trials have shown positive outcomes of interventions on smoking and alcohol use in elderly patients.6,7 If an intervention as part of the usual educational programme for general practitioners were successful, it could be easily disseminated. We assessed the impact of an educational intervention for general practitioners on the health behaviours and wellbeing of elderly non-institutionalised patients.
Participants and methods
General practitioners
Our project received the approval of the University of Melbourne human ethics committee. We assigned a number to 398 general practitioners from a list of a regional grouping in metropolitan Melbourne, Australia, then randomly selected 193 of these to be recruited by telephone. Eligibility criteria were: working more than 12 hours per week, not planning to move or retire in the next 2 years, one general practitioner per practice site, and no computerised recall system for influenza vaccination. We excluded 6 general practitioners (3%) who were uncontactable, 25 (13%) who had either moved practice or died, 28 (15%) whose partners were already enrolled in our trial, 25 (13%) who worked less than 12 hours per week, 7 (4%) who were retiring, 13 (7%) who had either no elderly patients or patients who did not speak English, and 7 (4%) who had computerised recall systems.
Overall, 42 of 82 eligible general practitioners (6 females and 36 males) were enrolled (51% participation rate), of whom 17 (40%) were the sole doctor in their practice. The 40 general practitioners who declined to participate (50% returned a survey) had been at their current practice a shorter time (t=2.03; P<0.05) and were less likely to charge their patients (χ2=4.57, P=0.03) than those who participated.
Patients
After informed consent of the participating general practitioners, all practice records were counted (average 6657, range 938-66 000 records). On the basis of patient eligibility criteria for the trial (⩾65 years, English speaking, community dwelling, attended the practice in the past 18 months, attended the enrolled general practitioner for three of the past five consultations) and a random number table, we selected and viewed an average of 397 (range 50-2000) records per practice, and we identified 10 elderly patients per participating general practitioner. Overall, 267 patients agreed to participate in the trial when invited to do so by post (participation rate 64%). Patient non-participants (60% (92 of 153) contacted by telephone) were more likely to be dependent for transportation (P=0.003) and shopping (P<0.0001) but were otherwise indistinguishable from participants. After 1 year, 34 patients (13%) were not followed up (see website).
Randomisation and blinding
An independent research assistant at a distant site used computer randomisation to allocate general practitioners to intervention or control group and this was concealed until the intervention began. Interviewers evaluating outcomes were blinded to the intervention group of patients and general practitioners at all times, and patient’s were unaware of the group allocation of their general practitioner.
Outcomes
Patient outcomes were evaluated by trained interviewers during home visits at baseline from November 1995 to February 1996, and at 1 year follow up from December 1996 to April 1997. Outcomes were (a) patients’ recall of discussions with their general practitioner; (b) patients’ self reported evaluation of physical activity on the basis of questions used in previous surveys8,9; (c) reports of frequency and duration of activity episodes in the previous fortnight (walking, sports and exercises, gardening, housework and home maintenance), which were multiplied to obtain total minutes per fortnight; (d) extent of walking the day before (walking yesterday) using a previously validated question10; (e) frequency of social contact from asking how often patients did something they really enjoyed; (f) validated measures for psychological wellbeing (psychological subscale of the sickness impact profile)11 and functional status (human activities profile)12; patients’ self rated health by asking if, in general, they rated their health as excellent, very good, good, fair, or poor, and by asking how they would rate their health in general now compared with 12 months earlier; (g) total number of drugs taken: psychotropics, non-steroidal anti-inflammatories, and analgesics (coded by NK) as viewed and recorded by interviewers; and (h) patients’ self report of influenza vaccination status.
Intervention
General practitioners undertook an educational programme, comprising 5 stages, which began within 2 weeks of patient enrolment and spanned 2-3 months (box). All stages covered areas of social and physical activity and prescribing and vaccination practices for elderly patients. Each general practitioner in the intervention group undertook some or all of the five stages. They were expected to incorporate the intervention into their daily practice and to pass on health promotion advice to patients as appropriate.
Five stages of educational programme
Clinical practice audit with feedback
Discussion of exercise and social activity
Review of drugs and vaccination status of 50 elderly patients consulting consecutively over a 2 week period were audited (results not shown); research patients were separate from audit patients
Educational detailing
15 minute visit to each general practitioner by NK who:
Outlined key points
Distributed summary reading material
Trained staff in prompt card use
Card based prompt system
Explanation of prompt card:
Reception staff to attach yellow prompt card to the medical records of all patients over 65 years of age (reception staff trained by NK)
Cards to contain records of discussions of physical and social activity, vaccinations, drug lists, and reviews
Seminar or home based learning
In May 1996, one didactic 3 hour seminar on health issues in elderly people, with presentations on:
Exercise from a physiologist
Social activity from a sociologist
Prescribing from a geriatrician
Discussion of audit feedbackfrom NK (a home learning module was distributed to non-attendants)
Resource directory
Distribution of regionally based:
Directories of health services for elderly patients
Recreational resources for elderly people
Analysis
We used STATA to perform an intention to treat analysis, maintaining patients in their original groups regardless of completion of trial. For those not completing the trial, a gradual decline in outcomes would be expected. We avoided an overestimation of the intervention effect by choosing the more conservative estimate of “no change” for the outcome of participants who had not completed the trial at follow up. We adjusted for the effect of clustered design with a cross sectional time series iterative generalised least squares regression.13 For dichotomous outcomes, follow up status was regressed on status at baseline and intervention group status.14 For continuous measures, we used the change over time as the unit of analysis. The robust option was used to allow for non-normally distributed data where appropriate.15 We adjusted for factors unevenly distributed between the groups. Gains in physical activity were converted to estimated energy expenditure and compared to the Harvard alumni data16 to estimate possible reductions in mortality.
Results
Physical activity
Baseline characteristics of the sample (table 1) were evenly distributed between the groups with the exception of practice billing style (whether the doctor billed the National Health Scheme directly for payment, termed “bulk billing,” or charged the patient). After the trial period, 39 patients (32%) in the intervention group and 21 (19%) in the control group remembered discussing exercise with their general practitioner (P=0.043). Overall, 24 entries for discussion of physical activity appeared in the intervention group records. Nine of these patients recalled the discussion and a further 29 recalled a discussion that had not been noted by the doctor.
Table 1.
Characteristic | Intervention group | Control group |
---|---|---|
General practitioners | n=21 | n=21 |
Men | 19 (90) | 17 (81) |
Women | 2 (9) | 4 (19) |
Age (years): | ||
⩾30 | 4 (19) | 4 (19) |
⩾40 | 8 (38) | 6 (29) |
⩾50 | 5 (24) | 8 (38) |
⩾60 | 4 (19.0) | 3 (14.3) |
Years at clinic (mean SE) | 17.6 (2.82) | 15.3 (1.97) |
Billing style: | ||
Bulk bill all patients | 16 (76) | 6 (29) |
Bulk bill card holders | 4 (19) | 8 (38) |
Discretionary charging | 1 (5) | 7 (33) |
No of doctors in practice: | ||
Solo | 8 (38) | 9 (43) |
2-4 | 9 (43) | 10 (48) |
⩾5 | 4 (19) | 2 (10) |
Average patients seen per week: | ||
<150 | 7 (33) | 12 (57) |
151-200 | 7 (33) | 7 (33) |
>201 | 7 (33) | 2 (10) |
Average patients aged >65 per week: | ||
<30 | 7 (33) | 4 (19) |
31-45 | 4 (19) | 7 (33) |
>45 | 10 (48) | 10 (48) |
Patients at baseline | n=135 | n=132 |
Men | 60 (44) | 63 (48) |
Women | 75 (56) | 69 (52) |
Patients in trial sample | n=121 | n=112 |
Men | 55 (46) | 52 (46) |
Women | 66 (54) | 60 (54) |
Age (years; mean SE) | 72.9 (0.57) | 74.2 (0.62) |
Higher education: | ||
Yes | 38 (31) | 26 (23) |
No | 80 (66) | 85 (76) |
Living arrangements: | ||
Live alone | 38 (31) | 44 (39) |
With spouse | 61 (50) | 54 (48) |
With children, relatives, or friends | 22 (18) | 14 (13) |
Total activity (minutes; mean SE): | ||
Previous fortnight | 562 (66) | 656 (87) |
Walking yesterday | 20 (2) | 23 (3) |
Functional status* (mean SE) | 60 (1.5) | 62 (1.3) |
Influenza vaccination: | ||
Yes | 76 (63) | 78 (70) |
No | 44 (36) | 34 (30) |
Drug total (mean SE) | 3.2 (0.25) | 3.9 (0.22) |
Social interaction (mean SE) | 12.1 (0.42) | 11.7 (0.46) |
Score for human activities profile from <10 (bedbound to >80 (jogging quarter (about 0.4 km) to half (about 0.8 km) a mile non-stop, or equivalent activity).
Intention to treat analysis showed positive effects of the intervention on patient walking, frequency of pleasurable activities, and self rated health (table 2). On average, the amount of weekly walking in the intervention group was 44 minutes more than that in the control group (95% confidence interval 7 to 168; P<0.032). Reanalysis of variables for physical activity on the basis of the number of people who increased their walking by discrete amounts (on the basis of quintiles and tertiles) also showed an intervention effect (table 2). Correlation between self reported walking in the past fortnight and yesterday was high at both baseline (Pearsons coefficient 0.66, P<0.0001) and after change (0.38, P<0.0001). Correlation of walking with functional status was also significant (0.22, P<0.001 and 0.31, P<0.001 for walking in the previous fortnight v walking yesterday respectively).
Table 2.
Outcome variable | Mean effect size (95% CI) | P value |
---|---|---|
Change in | ||
Walking (mins/day) | 8.4 (−0.31 to 17.6) | 0.059 |
Walking (mins/day as a 5 point scale of quintiles) | 0.34 (0.1 to 0.58) | 0.005 |
Walking (minutes in previous fortnight) | 88 (8 to 168) | 0.032 |
Walking (minutes in previous fortnight as a 3 point scale of tertiles) | 0.27 (0.03 to 0.51) | 0.025 |
Total activity (minutes in previous fortnight) | 148 (−146 to 442) | 0.342 |
Total activity (minutes in previous fortnight as a 5 point scale of quintiles) | 0.23 (−0.17 to 0.62) | 0.303 |
Score for human activities profile (1-92)* | 2.10 (−0.94 to 5.1) | 0.175 |
Psychosocial score (1-100)† | 1.28 (−0.54 to 3.1) | 0.168 |
Frequency of interactions with family and friends (6 point scale) | 0.03 (−0.14 to 0.21) | 0.70 |
Frequency of pleasurable activities (5 point scale) | 0.30 (0.16 to 0.43) | <0.001 |
Self rated health (5 point scale) | −0.09 (−0.14 to 0.33 ) | 0.44 |
Self rated health compared with 12 months ago (5 point scale) | 0.28 (0.02 to 0.52) | 0.029 |
Total No of drugs taken | −0.08 (−0.36 to 0.53) | 0.71 |
Drugs taken | ||
Non-steroidal anti-inflammatories | −0.01 (−0.08 to 0.07) | 0.82 |
Psychotropics | 0.63 (−0.25 to 1.51) | 0.16 |
Analgesics | 0.03 (−0.05 to 0.12) | 0.45 |
Influenza vaccination status | −0.63 (−1.45 to 0.20) | 0.14 |
For continuous outcomes change in outcome was dependent variable and intervention group status independent. For dichotomous outcomes follow up status was regressed on baseline status and intervention group status. All analyses were controlled for general practitioner billing status and effect of cluster design.
0 (worst) to 92 (highest function).
Subscale of sickness impact profile: 0 (no disability related to psychosocial health) to 100 (100% disability related to psychosocial health).
At follow up, 12 more patients (10%) in the intervention group had increased their walking and 11 more patients (9%) in the intervention group had not decreased their walking compared with the control group (table 3). The frequency of pleasurable activities and perceived change in self rated health was increased in 20% more of patients in the intervention group than in the control group.
Table 3.
Variable | Intervention group (n=121) | Control group (n=112) |
---|---|---|
Minutes of walking yesterday* | ||
Decreased >20 | 11 (10) | 14 (12) |
Decreased <20 | 20 (18) | 28 (25) |
No change | 36 (32) | 40 (35) |
Increased <20 | 26 (23) | 20 (18) |
Increased >20 | 18 (16) | 12 (11) |
Regression coefficient 0.35; robust SE 0.174; P<0.001 | ||
Doing something enjoyable† | ||
Decreased at follow up | 42 (35) | 58 (52) |
No change | 45 (37) | 34 (30) |
Increased | 34 (28) | 20 (18) |
Regression coefficient 0.63; SE 0.17; P<0.0001 | ||
General health compared with 12 months ago‡ | ||
Improvement in perception | 28 (25) | 16 (15) |
No change since baseline interview | 62 (52) | 60 (54) |
Deterioration in perception | 29 (25) | 36 (32) |
Regression coefficient 0.30; robust SE 0.14; P<0.03 |
All analyses adjusted for clustering and billing style.
The intervention did not affect functional status, psychological wellbeing, immunisation rate, or total number of drugs used (table 2). Overall, immunisation rate increased from 66% at baseline to 73% at follow up. Use of psychotropic drugs including benzodiazepines, antidepressants and major tranquillisers, non-steroidal anti-inflammatories, and analgesics showed no differential changes between the groups. When sedative hypnotic drugs were analysed separately, seven more people in the intervention group started taking sleeping tablets compared with one in the control group (P<0.001). On further inquiry, four of the seven patients in the intervention group initiating sleeping tablets consumed one quarter to one half a tablet fortnightly or weekly, and in two patients an operation and a death in the family had prompted use of sleeping tablets.
The average level of walking at baseline was 1.25 hours per week. Assuming a value of 4.5 for metabolic equivalent of work for brisk walking17 and an average body weight of 70 kg, energy expenditure on walking was 393.75 kcal/week, similar to the baseline rate in the Harvard alumni study.16 The intervention group increased walking by an average of 0.73 hours (44 minutes) per week and expended an estimated additional 300 kcal/week. Paffenberger’s second category of 500-999 kcal/week16 showed a relative risk of 0.78 from all cause mortality when compared with the baseline group. It is said that the Harvard alumni data applies to females,18 therefore there may be a 22% reduction in mortality associated with the increase in walking observed in our study.
Discussion
Our rigorously conducted randomised controlled trial of an educational intervention in general practice showed an increase in physical activity, frequency of pleasurable activities, and self rated health of elderly patients, important independent predictors of wellbeing.16,19,20 The public health implications of a sustained increase in physical activity in elderly people could be considerable, reflected by the estimated reduction in mortality of 22%.
No effect on other outcomes was observed. Influenza vaccination rates increased by almost 10% in both groups, and baseline rates were higher than expected. Drug related outcomes for elderly people have been difficult to impact by educational interventions.21 Functional status and psychological wellbeing were favourably influenced, but did not reach statistical significance.
Limitations
Generalisability of our findings is not assured although response rates were similar to other studies. Participating general practitioners had been at their current practice site longer and were less likely to bill their patients in bulk than non-participants. Participating patients were more functionally able than non-participants. Reproducability of this result awaits further study.
Variability in the change in activity and width of confidence intervals around positive results suggests caution in interpretation. The walking variables, however, showed a consistent intervention effect on quintiles and tertiles and were observed with impacts on recall of discussions of exercise (however unreliable), self rated health, and frequency of social activities. Additionally, the question on walking yesterday that was previously validated against a pedometer10 was highly correlated with other self report walking variables and functional status. This lends some validity to the result.
The estimations of reduction in mortality from this trial may be based on incorrect assumptions. The Harvard alumni group comprised men from a different socioeconomic background than our trial group. Similar reductions in mortality, however, have been associated with similar levels of walking in groups more closely resembling a primary care group.22
General practice intervention
To the authors’ knowledge this trial is unique in that general practitioners and elderly patients were randomly selected, the general practitioner was randomised to receive an educational programme, and outcomes were evaluated at the patient level. One trial reported favourable changes in biochemical variables but not exercise behaviour23 and others have not used primary care as the setting.24,25
In our study, walking but not other activities increased. Success of activity interventions was more likely if exercise was enjoyable, of moderate intensity, and not related to attending a facility.26 This programme may have been less expensive or complex than other interventions tested in all ages.27,28 Strategies to aid dissemination need to improve doctors’ participation rate.
Conclusion
Education and clinical practice audit for general practitioners improved health outcomes in elderly patients. Although modest, the improvements in physical activity had public health significance and resulted from a comparatively inexpensive intervention.
Supplementary Material
Acknowledgments
This project was a collaboration between the Department of General Practice and Public Health, University of Melbourne and the National Ageing Research Institute. We thank Linda LeDoeuff, Kerstin McKay, the patients and the general practitioners and their receptionists.
Footnotes
Funding: A doctoral scholarship for NK from the Public Health Division of the National Health and Medical Research Council, and a grant for completion of the project from the Victorian Health Promotion Foundation.
Competing interests: None declared.
References
- 1.MacIntyre C, Carnie J, Plant A. Influenza vaccination in Victoria, 1992. Med J Aust. 1993;159:257–260. doi: 10.5694/j.1326-5377.1993.tb137827.x. [DOI] [PubMed] [Google Scholar]
- 2.Crespo C, Keteyian S, Heath G, Sempos C. Leisure-time physical activity among US adults. Results from the third national health and nutrition examination survey. Arch Intern Med. 1996;156:93–98. [PubMed] [Google Scholar]
- 3.Atkin P, Shenfield G. Medication-related adverse reactions and the elderly: a literature review. Adverse Drug React Toxicol Rev. 1995;14:175–191. [PubMed] [Google Scholar]
- 4.Blazer D. Social support and mortality in an elderly community population. Am J Epidemiol. 1982;115:684–694. doi: 10.1093/oxfordjournals.aje.a113351. [DOI] [PubMed] [Google Scholar]
- 5.Bridges-Webb C, Britt H, Miles D, Neary S, Charles J, Tragnor V. Morbidity and treatment in general practice in Australia 1990-1991. Med J Aust. 1992;157:1–56S. [PubMed] [Google Scholar]
- 6.Anderson P. Effectiveness of general practice interventions for patients with harmful alcohol consumption. Br J Gen Pract. 1993;43:386–389. [PMC free article] [PubMed] [Google Scholar]
- 7.Vetter N, Ford D. Smoking prevention among people aged 60 and over: a randomized controlled trial. Age Ageing. 1990;19:164–168. doi: 10.1093/ageing/19.3.164. [DOI] [PubMed] [Google Scholar]
- 8.National Heart Foundation of Australia. Risk factor prevalence study. Canberra: NHFA; 1990. [Google Scholar]
- 9.Australian Bureau of Statistics. National health survey. Canberra: ABS; 1989-90. [Google Scholar]
- 10.Dallosso HM, Morgan K, Bassey EJ, Ebrahim SBJ, Fentem PH, Arie THD. Levels of customary physical activity among the old and the very old living at home. J Epidemiol Community Med. 1988;42:121–127. doi: 10.1136/jech.42.2.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bergner M, Bobitt R, Carter W, Gibson B. The sickness impact profile: development and final revision of a health status measure. Med Care. 1981;19:787–805. doi: 10.1097/00005650-198108000-00001. [DOI] [PubMed] [Google Scholar]
- 12.Fix AJ, Daughton DM. Human activities profile: professional manual. Odessa, FL: Psychological Assessment Resources; 1988. p. 25. [Google Scholar]
- 13.Goldstein H. Multilevel mixed linear model analysis using iterative generalized least squares. Biometrika. 1986;73:43–56. [Google Scholar]
- 14.Liang K-Y, Zeger S. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13–22. [Google Scholar]
- 15.White H. A heteroskedasticity-consistent covariance matrix estimator and a direct test for heteroskedasticity. Econometria. 1980;48:817–830. [Google Scholar]
- 16.Paffenbarger RS, Lee IM, Hsieh CC. Exercise intensity and longevity in men. JAMA. 1995;273:1179–1184. [PubMed] [Google Scholar]
- 17.Wilson P, Paffenbarger R, Morris J, Havlik R. Assessment methods for physical activity and physical fitness studies. Am J Heart. 1986;111:1177–1192. doi: 10.1016/0002-8703(86)90022-0. [DOI] [PubMed] [Google Scholar]
- 18.Morgan K, Clarke D. Customary physical activity and survival in later life: a study in Nottingham UK. J Epidemiol Community Health. 1997;51:490–493. doi: 10.1136/jech.51.5.490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Bowling A. Social support and social networks: their relationship to the successful and unsuccessful survival of elderly people in the community. An analysis of concepts and a review of the evidence. Fam Pract. 1991;8:68–83. doi: 10.1093/fampra/8.1.68. [DOI] [PubMed] [Google Scholar]
- 20.Idler EL, Benyamini Y. Self-rated health and mortality: a review of twenty-seven community studies. J Health Soc Behav. 1997;38:21–37. [PubMed] [Google Scholar]
- 21.Atkins P, Ogle S, Finegan T, Shenfield G. Influence of “academic detailing” on prescribing for elderly patients. Health Promotion J Aust. 1996;6:14–20. [Google Scholar]
- 22.LaCroix A, Leveille S, Hecht J, Grothaus L, Wagner EH. Does walking decrease the risk of cardiovascular disease hospitalizations and death in older adults? J Am Geriatr Soc. 1996;44:113–120. doi: 10.1111/j.1532-5415.1996.tb02425.x. [DOI] [PubMed] [Google Scholar]
- 23.Schmidt RM. HEALTH WATCH: health promotion and disease prevention in primary care. Methods Inf Med. 1993;32:245–248. [PubMed] [Google Scholar]
- 24.Williams P, Lord S. Effects of group exercise on cognitive functioning and mood in older women. Aust NZ J Public Health. 1997;21:45–52. doi: 10.1111/j.1467-842x.1997.tb01653.x. [DOI] [PubMed] [Google Scholar]
- 25.Hamdorf PA, Withers RT, Penhall RK, Plummer J. A follow-up study on the effects of training on the fitness and habitual activity patterns of 60 to 70 year old women. Arch Phys Med Rahabil. 1993;74:473–477. doi: 10.1016/0003-9993(93)90108-m. [DOI] [PubMed] [Google Scholar]
- 26.Hillsdon M, Thorogood M, Anstiss T, Morris J. Randomised controlled trials of physical activity promotion in free living populations: a review. J Epidemiol Community Health. 1995;49:448–453. doi: 10.1136/jech.49.5.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Cupples M, McKnight A. Randomised controlled trial of health promotion in general practice for patients at high cardiovascular risk. BMJ. 1994;309:993–996. doi: 10.1136/bmj.309.6960.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Imperial Cancer Research Fund OXCHECK Study Group. Effectiveness of health checks condusted by nurses in primary care: final results of the OXCHECK study. BMJ. 1995;310:1099–1104. [PMC free article] [PubMed] [Google Scholar]
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