Thursday, September 5, 2019

Anchorage in Orthodontics- A Review

Anchorage in Orthodontics- A Review Orthodontics is the branch of dentistry concerned with facial growth, the development of the dentition and occlusion, and the diagnosis, interception and treatment of occlusal anomalies. The goal of orthodontic treatment is to improve the persons life by enhancing dental and jaw function and dentofacial aesthetics. This is achieved by obtaining optimal proximal and occlusal contact of teeth (occlusion) within the framework of normal function and physiologic adaptation, acceptable dentofacial aesthetics and self-image and reasonable stability (Graber and Vanarsdal, 1994). Conventional orthodontic treatment is achieved using fixed and removable appliances to achieve a planned end point of treatment. Orthodontic anchorage is an important concept in orthodontic treatment, and can be reinforced by many types of appliances. Orthodontic headgear has traditionally been considered to be the gold standard appliance for reinforcing anchorage. However, an increasing awareness of the drawbacks of headgear, mainly poor patient compliance and serious eye injuries, has led to the development of appliances in which the evidence base supporting their use is incomplete. In addition, it has been suggested that functional appliances which are traditionally used for growth modification, can be used for   anchorage preparation. In this section, the concept of anchorage in orthodontic treatment is reviewed. The definition of anchorage is presented including its relationship to space requirements, extractions and certain appliances, including the potential of using functional appliances for anchorage. As the effectiveness of some of these appliances has been evaluated by randomized trial methodology (RCT), an account of the bias that can arise in RCTs is given and the potential effect this bias may have on the trial results. Finally, the important aspect of measurement of variables in orthodontic research is reviewed focusing on the reliability and validity of new measurement methods using computer software and digital models. 1.2.1 Definition and importance Anchorage in orthodontics can be defined as the resistance to unwanted tooth movement [1]. When an orthodontist/dentist plans treatment they evaluate the anchorage requirement by estimating the amount of space that is needed to correct the malocclusion. Anchorage   or space may be obtained by extracting teeth, moving teeth into certain position and/or the use of orthodontic appliances. Achieving anchorage can be obtained by one of the following methods: 1.2.2 Maximising the potential of available teeth: In this method a force is applied between two points (tooth or groups of teeth) and tooth movement is controlled by making one point more resistant to movement than the other. This is done by careful planning of the site of force application. Examples include: Active movement of one tooth versus several anchor teeth, for example correcting the centreline by moving one tooth at a time. Teeth of greater resistance to movement are utilized as anchorage for the translation of teeth that have less resistance to movement. A common example of this is closing space by pitting the posterior teeth (greater resistance) against the anterior teeth (less resistance). Increasing the number of teeth in the anchor unit, examples are: Adding the second molar to the fixed appliance. Adding the anterior teeth to reinforce posterior anchorage by bending loops mesial to the first molars. Adding teeth from the opposing arch to the anchor unit by utilizing inter-arch elastics. Making movement of anchor teeth more difficult, for example putting a tip- back bend in first molars. Using ankylosed teeth as anchors. 1.2.3 Providing an additional form of orthodontic appliance: The anchorage gained from the previous methods is limited. As a result, it is necessary to reinforce the anchorage with an additional appliance. The most commonly used orthodontic anchorage devices are: Extra oral anchorage (EOA) with headgear Intraoral anchorage with palatal and lingual arches. 1.2.4 Headgear Headgear is an orthodontic appliance that is used to apply forces to the teeth utilising structures outside the oral cavity. Headgear is usually applied to the first maxillary molar via a tube attached to the molar band. The force necessary to provide extra oral anchorage is 200 to 250 gm applied for 10-12 hours per day [2]. Headgear was first used for anchorage by Kingsley in 1866 to retract upper incisors in an upper premolar extraction case [3]. This was followed by Angle in 1888 and Case in 1907 [3]. In 1953, Kloehn developed the contemporary design of headgear that orthodontists   use today [3]. Since then, headgear has been used conventionally when maximum anchorage is required. As a result, it may be considered the gold standard for anchorage in orthodontic anchorage. 1.2.5 Disadvantages of headgear: The use of headgear has the following disadvantages or risks: Compliance: From the early days of headgear use, it was clear that substantial compliance was required and failure to wear headgear, for the prescribed amount   of time, was recognised [3]. Headgear compliance is measured as the discrepancy between actual hours of wear and reported hours of wear and has been evaluated in several studies. Results of these studies have been discouraging as the actual hours of wearing headgear appear to be much lower than that required [4-6]. For example, Brandao et al in 2006 suggested that patients who had been asked to wear their headgear for 14 hours a day, reported wearing their headgear an average of 13.6 hours a day while the actual hours of wear were only 5.6 hours [4]. Cole [6] and Cureton [5] also found that the reported hours of wear were much less than the actual hours of wearing headgear . Soft tissue injuries: Apart from minor injuries to the surrounding intraoral and   extra oral soft tissues, serious ocular injuries have been reported both in Europe and the United States. In some of these instances blindness has resulted as a final result of the injury. Ten eye injuries have been reported in the literature; 2 in the UK, 3 in France, 2 in Italy, 1 in Germany and 2 in the United States [7, 8]. These injuries resulted from one of several factors including dislodgement during sleep, improper removal of headgear or improperly playing with the headgear. Nickel Allergy: A small portion of the population will exhibit sensitivity to the Nickel alloy in facebows [9-11]. Nickel allergies in response to orthodontic appliances are not considered a major health risk. Exacerbation of pre-existing eczema: there has been a case reported in the literature in which an increase in the severity of a pre-existing atopic eczema was observed after headgear wear [12]. It is evident from the problems mentioned that the most significant drawbacks of headgear use are non-compliance and serious eye injuries. Several measures have been taken to overcome these two problems with varying amounts of success. 1.2.6 Improving headgear compliance: Suggestions have been made in the literature to encourage patients to increase the actual number of hours in which headgear is worn; these include the following: The use of a headgear calendar [13], The use of a headgear timer or electronic monitoring device and informing the patient of its presence [14], The use of conscious hypnosis for patient motivation during headgear wear [15], Treatment by a defined behavioural model which depends on a schedule for wearing headgear, in addition to parental observations and rewards based on patient compliance. This behavioural model is flexible and will evolve according   to the patients response and needs [16], Promoting headgear wear by considering gender differences, making patients more aware of their malocclusions and the effect of treatment [17]. 1.2.7 Headgear safety mechanisms: Several features have been added to headgear in an attempt to prevent elastic   recoil injuries or unintentional detachment of the headgear. These include: Lock mechanisms which prevent release of the facebows from the molar tubes [18], Snap-release headgears which prevent elastic recoil of the facebows when an excessive force is used [7], Plastic safety straps which attempt to limit the movement of the facebows [7], Intraoral elastics to attach the inner bow to the molar tube [7], Blunting and smoothening the ends of the facebows to reduce the potential for injury [7]. It has been recommended that at least two of these mechanisms are used simultaneously in addition to clear verbal and written instructions to the patients and parents [19]. In summary, headgear is considered the gold standard appliance for providing anchorage. However, in order for it to work effectively, it requires a significant amount of patient cooperation and compliance. There have been many attempts to improve headgear compliance, which is a reflection of the failure to overcome this problem. Finally, there   are several safety issues related to headgear, which may discourage patients and orthodontists from its use. The ideal solution would be to use an anchorage device that provides at least the same anchorage potential as headgear, but requires little or no compliance. This has led to the development of surgical anchorage devices. 1.2.3 Surgical anchorage In this thesis I will use the term surgical anchorage to denote all types of anchorage devices which are surgically placed in the maxilla or mandible. The use of implants for orthodontic anchorage is a rapidly developing field and appears to be very promising. It has evolved from using conventional restorative implants in the line of the arch to more specialized palatal implants and mini-plates, to mini-screw implants. Types of surgical anchorage include mini-screw implants, mini-plates and midpalatal implants. The mini-screw implant is a modification of screws used for fixation of maxillofacial fractures. Although they have varying lengths and diameters, they are generally smaller than maxillofacial fixation screws, hence the term mini. It is also important to distinguish mini-screw implants from midpalatal implants which can be used for orthodontic anchorage, as the latter are endosseous implants and a modification of prosthetic implants. Mini-plates are small surgical plates that must be surgically screwed to bone under the soft tissue. Mini-screw implants may provide anchorage reinforcement because of the combination of mechanical retention immediately after insertion (primary stability) and a degree of osseointegration. Mini-plates provide a stable structure fixed to bone for application of forces and midpalatal implants offer stability by osseointegration. Despite the widespread adoption of this type of technology, there is a dearth of high quality clinical research into their effectiveness. The literature concerning their use is referenced in section III as part of the systematic review. 1.2.4 Class II functional appliances Functional appliances are orthodontic appliances that utilize the facial and masticatory musculature to produce orthodontic forces. They are commonly used in the treatment of Class II malocclusions. They can either be removable, for example the Clarks Twin Block appliance, or fixed, for example, the Herbst appliance. In the UK, the most popular functional appliance for treating Class II malocclusions is the Twin Block [20]. Functional appliances were developed to treat malocclusions by growth modification,   by encouraging differential growth of the mandible and maxilla. In Class II malocclusions the objective is to encourage growth of the mandible and/or restrain growth of the maxilla. While this theoretical effect of functional appliances is often quoted, the evidence behind these concepts is lacking.   Recently, there have been a number of randomized clinical   trials evaluating the skeletal effect of functional appliances. These are summarised in a Cochrane systematic review published in 2013 which assessed and analysed outcomes of 17 studies [21]. These studies produce interesting results. When early two-phase treatment with a functional appliance was compared to adolescent one phase treatment (patients who did not receive a functional appliance), there was no difference in the final ANB (MD -0.02 °, 95% CI -0.47 to 0.43. P = 0.92). Similarly, when a comparison was made for early treatment between headgear and functional appliances, there was no difference in the final ANB (MD -0.17 °, 95% CI -0.67 to 0.34, P = 0.52). When functional appliance treatment was performed in adolescents and compared to untreated controls, there was a statistically significant difference in ANB (MD -2.37 °, 95% CI -3.01 to -1.74, P It was concluded from the results of these trials that the amount of skeletal change (growth modification), from the use of functional appliances is small and is unlikely to be   clinically significant. Nevertheless, it is clear that these appliances are very effective in the correction of Class II malocclusion primarily through dentoalveolar movements. The following effects of Twin Block treatment are clinically useful: Enhancing facial appearance [22, 23] Distalising upper molars and molar correction [24, 25] Reducing the overjet [24-30] Proclination of lower incisors [24-26, 28, 30, 31] Retroclination of upper incisors [24-26, 28, 30] A case report using Twin Blocks to treat a Class II division II case suggested that a Twin Block can be used instead of headgear derived anchorage [32]. When we consider the preparation of orthodontic anchorage it is common clinical experience that molar correction and the reduction of the overjet are major factors in reducing the anchorage requirements of a case. As a result, some clinicians use functional appliances in anchorage preparation with the aim of avoiding dental extractions or other forms of anchorage. A common method of achieving this is by utilizing a 2-phase treatment protocol during adolescence [33]. The first phase of treatment is achieved by using only a functional appliance. This phase usually continues until the overjet and/or molar relationship is corrected. The clinician may then choose to retain the correction obtained by the functional appliance by keeping the functional appliance in place or by using a simple removable appliance [34]. This is immediately foll owed by a second phase of active fixed orthodontic treatment. 1.2.5 Extraction As mentioned in the previous section, the anchorage requirements of a case are related to the space available in the upper and lower arches. It is common orthodontic practice to change anchorage requirement by the extraction of teeth [2]. The literature examining factors influencing the extraction decision can be divided into three different methodologies according to the method of study. These are: (i) the studies that directly ask clinicians their stated reasons for extraction, (ii) studies that measured the influence of the presence or absence of a cephalometric radiograph on the decision to extract, and (iii) studies that define some patient characteristic, such as cephalometric variables or orthodontic indices, and attempt to identify a correlation between these characteristics and whether or not extractions had been undertaken. I will discuss these studies in the following section: 1.2.5.1 Clinicians stated reasons influencing the extraction decision Only one study, Baumrind et al, directly asked orthodontists the factors that were related   to their decision to extract teeth as part of a course of treatment [35]. In this study full orthodontic records of 72 patients were given to 5 clinical instructors in a University setting in the USA. They were given a treatment planning form to complete for each patient; included in the form were questions about the extraction decision and the reasons for extraction. The clinicians stated that the most important reasons for extraction were crowding (49%), followed by incisor protrusion in 14% and profile improvement in 8%. Other, less frequent, reasons were Concern over Class II severity and concern for post- treatment stability (5%). No other single reason was stated as the most important reason in more than 2% of the forms. When considering all replies, crowding was cited in 72% of forms, incisor protrusion in 35%, profile improvement in 27% and Class II severity in 15%. No other si ngle reason was stated in more than 9% of forms. This was a simple cross-sectional study, in which the patient records and the participants were a convenience sample. It does, however, provide some relevant information on the reasons for extraction. 1.2.5.2 Cephalometric radiographs influencing the extraction decision: There have been several studies that have evaluated the effect of radiographs on the extraction decision. For example, Devereux et al [36] carried out a study in which a group of orthodontists were sent the orthodontic records of 6 patients on a CD, not containing lateral cephalometric radiographs or tracings, and were asked if they would extract teeth (T1). At this point, the orthodontists did not know that they were to be asked to examine the cases again after a washout period. After a period of 8 weeks (T2), the orthodontists were sent the records of the same 6 patients, but the lateral cephalometric radiographs and tracings were included in the records. They were asked again if they would extract teeth. The decisions made by this group (group A) were compared to another group of orthodontists (group B) who had full patient records, including lateral cephalometric radiographs and tracings, at both T1 and T2. It was found that the orthodontists in group A were 1.7 (95% CI, 1.0-2.8) times more likely to change their extraction decision than those in group B (odds ratio). In a similar investigation, Nijkamp et al investigated the influence of lateral cephalometric radiographs on the treatment planning decision [37]. This was a crossover design in which diagnostic records of 48 patients were given to 10 orthodontic postgraduates and 4 orthodontists. They were asked to formulate a treatment plan based around a dichotomous decision regarding three treatment options; (i) extraction, (ii) the use of a functional appliance and (iii) the use of rapid maxillary expansion. The diagnostic records at T1 included dental casts, but did not include a lateral cephalometric radiograph. T2 was 1 month later, and included both dental casts and lateral cephalometric radiographs and values. This design was repeated so that at T3, which was one month after T2, only dental casts were included; and at T4, which was one month after T3, dental casts and lateral cephalometric radiographs were included in the diagnostic records. Agreement between the treatment planning decision with and without the lateral cephalometric radiograph was assessed. In order for the treatment plans to agree, decisions about all three treatment options had to be the same. There was no statistically significant difference in the treatment plans between the use of only dental casts or with additional cephalometric information (P = 0.74). Another study by Han et al evaluated the effect of the incremental addition of diagnostic records on the extraction decision [38]. Five orthodontists provided a treatment plan for 57 patients. Orthodontic records were given to each of the five orthodontists in the following order: Session 1: study models only Session 2: study models and facial photographs Session 3: study models, facial photographs, and panoramic radiographs Session 4: study models, facial photographs, panoramic and lateral cephalometric radiographs. Session 5: all the previous records in addition to a lateral cephalometric tracing. The time interval between each session was 1 month, and the records were re-numbered between sessions. In each session, the orthodontists were asked to select a treatment pathway from a decision tree. The end point of each of the treatment pathway was a decision on whether or not to extract. The treatment planning decisions for each of the orthodontists in session 5 was considered the gold standard for that clinician. As a   result, the proportion of agreement between the treatment plan in each of the four sessions and the treatment plan in session 5 was obtained. The proportions of agreement between sessions 1, 2, 3, 4 and session 5 were 55%, 55%, 65% and 60% respectively. Therefore,] they concluded that study models alone are adequate for treatment planning, and that the addition of other types of diagnostic records made only a small difference. These three studies were good quality cross-sectional studies. The randomisation and method of washout were clear strengths of the studies. In addition sample size calculations were undertaken in two of these studies; Devereux et al and Nijkamp et al. 1.2.5.3 Patient characteristics influencing the extraction decision: The final type of studies evaluating the extraction decision are studies which attempt to identify a correlation between patient characteristics and whether or not extractions had been undertaken. Two studies, Xie et al and Takada et al, used a mathematical model to construct a decision-making Expert System (ES), which could formulate treatment decisions. [39, 40]. ES is a branch of artificial intelligence in which the computer programme simulates the decision-making and working processes of experts and solves clinical problems. They developed a model in which twenty-five patient characteristics were tested on 180 treated patients [39]. The rate of coincidence between the recommendations given by the optimized model and the actual treatments performed was found to be 100%. The characteristics that influenced the extraction decision were the anterior teeth uncovered by incompetent lips and IMPA (L1-MP). Another similar study was carried   out by Takada et   al whenÂà ‚   they selected   25 patient   characteristics   and 188 treated patients in their model [40]. The rate of coincidence between the recommendations given by the model and the actual treatment performed was 90.4%. The characteristics mostly influencing the extraction decision were incisor overjet and upper and lower arch length discrepancies. Heckmann et al investigated the influence of the angulations between the first and second lower molars on panoramic x-rays, on the extraction decision [41]. They used a sample of 30 patients treated by a premolar extraction approach, and a further matched sample of patients treated with a non-extraction approach. Pre- and post-treatment panoramic x-rays were scanned and computer software used to measure the angulations between lower first and second molars. Comparison between the mean angulation of the molars before treatment in the extraction and non-extraction group was not significant. Li et al compared mean cephalometric parameters and model analysis of Class II division 1 patients who were treated with either an extraction or non-extraction approach [42]. The sample consisted of 81 patients; 42 who had 4 premolar extractions and 39 who had non- extraction treatment. The extraction group had statistically significant greater values for the following parameters; arch length discrepancy, curve of spee, upper incisor tip, Frankfort-mandibular plane angle and lower anterior facial height. Bishara et al compared patient characteristics of Class II division 1 patients who were treated with either an extraction or non-extraction approach [43]. The sample consisted of 91 patients; 44 had first premolar extractions and 47 who had non-extraction treatment. A statistically significant difference was found between the extraction and non-extraction groups with regards to the following parameters; upper and lower arch length discrepancy, upper and lower lip protrusion in relation to the aesthetic plane in male patients, and the protrusion of the lower lip in female subjects. These studies were retrospective in nature. There were variations among the studies in the application of inclusion criteria in an attempt to control the characteristics of patients included in the study. Nevertheless, selection bias was inevitably present in these studies. Bias due to periodical changes may also be present due to the retrospective nature of the studies. In summary, studies evaluating the factors influencing the extraction decision are few in number. They have been carried out by gathering the opinion of clinicians in cross sectional studies or by conducting retrospective investigations on a sample of cases in which teeth were extracted as part of orthodontic treatment. The main deficiencies of the studies were due to inadequate selection and number of the study sample; and bias arising from their retrospective nature. References: 1.Roberts-Harry, D. and J. Sandy, Orthodontics. Part 9: Anchorage control and  distal movement. British Dental Journal, 2004. 196(5): p. 255-263.   2. Mitchell, L., An Introduction to Orthodontics. Second Edition ed. 2002, Oxford,  UK: Oxford University Press. 3. Charles T, P., Jr., Cervical headgear usage and thebioprogressive orthodontic  philosophy. Seminars in Orthodontics, 1998. 4(4): p. 219-230. 4. Brandao, M., H.S. Pinho, and D. Urias, Clinical and quantitative assessment of  headgear compliance: a pilot study. American Journal of Orthodontics Dentofacial Orthopedics, 2006. 129(2): p. 239-44. 5. Cureton, S.L., F.J. Regennitter, and J.M. Yancey, Clinical versus quantitative  assessment of headgear compliance. American Journal of Orthodontics   Dentofacial Orthopedics, 1993. 104(3): p. 277-84. 6. Cole, W.A., Accuracy of patient reporting as an indication of headgear  compliance. American Journal of Orthodontics Dentofacial Orthopedics, 2002.  121(4): p. 419-23. 7. Samuels, R.H.A. and N. Brezniak, Orthodontic facebows: safety issues and  current management. Journal of Orthodontics, 2002. 29(2): p. 101-7.   8. Samuels, R.H., A review of orthodontic face-bow injuries and safety equipment.  American Journal of Orthodontics and Dentofacial Orthopedics, 1996. 110(3): p.  269-272. 9. Burden, D.J. and D.J. Eedy, Orthodontic headgear related to allergic contact  dermatitis: a case report. British Dental Journal, 1991. 170(12): p. 447-8.   10. Lowey, M.N., Allergic contact dermatitis associated with the use of an Interlandi  headgear in a patient with a history of atopy. British Dental Journal, 1993. 175(2):  p. 67-72. 11. Kerosuo, H.M. and J.E. Dahl, Adverse patient reactions during orthodontic  treatment with fixed appliances. American Journal of Orthodontics Dentofacial  Orthopedics, 2007. 132(6): p. 789-95. 12. McComb, J.L. and C.M. King, Atopic eczema and orthodontic headgear. Dental  Update, 1992. 19(9): p. 396-7. 13. Cureton, S.L., F.J. Regennitter, and J.M. Yancey, The role of the headgear  calendar in headgear compliance. American Journal of Orthodontics   Dentofacial Orthopedics, 1993. 104(4): p. 387-94. 14. Doruk, C., U. Agar, and H. Babacan, The role of the headgear timer in extraoral  co-operation. European Journal of Orthodontics, 2004. 26(3): p. 289-91.   15. Trakyali, G., et al., Conscious hypnosis as a method for patient motivation in  cervical headgear weara pilot study. European Journal of Orthodontics, 2008.  30(2): p. 147-52. 16. Gross, A.M., G. Samson, and M. Dierkes, Patient cooperation in treatment with  removable appliances: A model of patient noncompliance with treatment implications. American Journal of Orthodontics, 1985. 87(5): p. 392-397.   17. Clemmer, E.J. and E.W. Hayes, Patient cooperation in wearing orthodontic  headgear. American Journal of Orthodontics, 1979. 75(5): p. 517-24.   18. Samuels, R., et al., A clinical evaluation of a locking orthodontic facebow.  American Journal of Orthodontics and Dentofacial Orthopedics, 2000. 117(3): p.  344-350. 19. ADVICE ON THE USE OF HEADGEAR, D.A.S.C. The British Orthodontic  Society (BOS), Editor. 20. Chadwick, S.M., P. Banks, and J.L. Wright, The use of myofunctional appliances  in the UK: a survey of British orthodontists. Dental Update, 1998. 25(7): p. 302-8.   21. Thiruvenkatachari, B., et al., Orthodontic treatment for prominent upper front  teeth (Class II malocclusion) in children. Cochrane Database of Systematic  Reviews 2013, Issue 11. Art. No.: CD003452. DOI:  10.1002/14651858.CD003452.pub3., 2013. 22. OBrien, K., et al., Early treatment for Class II malocclusion and perceived  improvements in facial profile. American Journal of Orthodontics Dentofacial  Orthopedics, 2009. 135(5): p. 580-5. 23. Singh, G.D. and W.J. Clark, Soft tissue changes in patients with Class II Division 1  malocclusions treated using Twin Block appliances: finite-element scaling  analysis. European Journal of Orthodontics, 2003. 25(3): p. 225-30. 24. OBrien, K., et al., Effectiveness of early orthodontic treatment with the Twin-block  appliance: a multicenter, randomized, controlled trial. Part 1: Dental and skeletal  effects. American Journal of Orthodontics Dentofacial Orthopedics, 2003.  124(3): p. 234-43; quiz 339. 25. Keeling, S.D., et al., Anteroposterior skeletal and dental changes after early Class  II treatment with bionators and headgear. American Journal of Orthodontics   Dentofacial Orthopedics, 1998. 113(1): p. 40-50. 26. Illing, H.M., D.O. Morris, and R.T. Lee, A prospective evaluation of Bass,  Bionator and Twin Block appliances. Part IThe hard tissues. European Journal of  Orthodontics, 1998. 20(5): p. 501-16. 27. Thiruvenkatachari, B., et al., Comparison of Twin-block and Dynamax appliances  for the treatment of Class II malocclusion in adolescents: a randomized controlled  trial. American Journal of Orthodontics Dentofacial Orthopedics, 2010. 138(2):  p. 144.e1-9; discussion 144-5. 28. OBrien, K., et al., Effectiveness of treatment for Class II malocclusion with the  Herbst or twin-block appliances: a randomized, controlled trial. American Journal  of Orthodontics Dentofacial Orthopedics, 2003. 124(2): p. 128-37. 29. OBrien, K., et al., Early treatment for Class II Division 1 malocclusion with the  Twin-block appliance: a multi-center, randomized, controlled trial. American  Journal of Orthodontics Dentofacial Orthopedics, 2009. 135(5): p. 573-9.   30. Tulloch, J.F.C., W.R. Proffit, and C. Phillips, Outcomes in a 2-phase randomized  clinical

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