Single pulsed electromagnetic field restores bone mass and microarchitecture in denervation/disuse osteopenic mice.

Pulsed electromagnetic fields (PEMFs) have been proposed to treat bone loss. However, time-consuming is the main complaint. A time-saving and effective treatment is of expectation. Previously, we showed a 3 min daily of single pulsed electromagnetic field (SPEMF) accelerated bone formation of long bone defect in mice. Here we compared the effect of SPEMF with PEMF for treating denervation/disuse osteopenic mice. Healthy mice were divided into 3 groups: intact mice (INT), INT + PEMF, and INT + SPEMF. Induced osteopenic mice were divided to osteopenia (IOP), IOP + PEMF, and IOP + SPEMF groups. The PEMF treated groups were subjected to daily 8 h PEMF(15 Hz, 18 G) exposure, while SPEMF treated groups were daily 3 min SPEMF(0.2 Hz, 1 T) exposure. BMD was evaluated every two weeks during the 12 weeks of treatment. Microarchitecture was evaluated on week 12. SPEMF significantly reversed bone loss in IOP mice as early as 6 weeks post-treatment, while PEMF reversed bone loss after 8 weeks. Bone volume was significantly increased in the IOP + PEMF and IOP + SPEMF group. Besides, bone volume and trabecular number of IOP + SPEMF mice were restored to the levels of INT mice in 12 weeks. Our finding suggests SPEMF increased BMD and restored microarchitecture of disuse osteopenic mice to healthy level.

A single-pulsed electromagnetic field enhances collagen synthesis in tendon cells.

Tendinopathy is a progressive pathology of tendon that is characteristic of imbalance between matrix synthesis and degeneration and is often caused by failure to adapt to mechanical loading. Non-steroidal anti-inflammatory medications (NSAIDS) are used as a conventional treatment to alleviate pain and swelling in the short term, but the ideal treatment for tendinopathy remains unclear. Here, we show a single pulsed electromagnetic field (SPEMF, 0.2 Hz) that up-regulated tenogenic gene expression (Col1a1, Col3a1, Scx, Dcn) and down-regulated inflammatory gene expression (Mmp1) in vitro. After five days of SPEMF stimulation (3 min/day), the collagen type I and total collagen synthesis protein levels were significantly increased. Under pro-inflammatory cytokine (IL-1ß) irritation, the decreased expression of Col1a1/Col3a1 was up-regulated by SPEMF treatment, and the increased expression of Mmp1 was also reversed. From the above, it can be inferred that SPEMF that enhances matrix synthesis and reduces matrix degeneration may counteract the imbalance in tendinopathy. SPEMF application may be developed as a potential future strategy for therapeutic intervention in tendon disorders.

Biomechanical investigation of dynamic hip screw and wire fixation on an unstable intertrochanteric fracture.

BACKGROUND: Although use of a dynamic hip screw (DHS) for stable intertrochanteric hip fracture fixation has been successfully applied in fracture healing for more than 20 years, DHS fixation on unstable intertrochanteric fractures still has a high failure rate, especially in patients with osteoporosis. Although the wire fixation is usually incorporated with orthopedic device to treat fracture, the wiring techniques are developed through experiences. Thus, this study is objective to investigate the biomechanical property of different wire fixation methods incorporated with DHS system to provide the lesser trochanter fragment stable fixation on osteoporotic TypeA2.1 fracture for enhancing stability after bone reduction. RESULTS: Sawbone testing results demonstrated higher maximum load, stiffness, and energy in a DHS with wire fixation compared with DHS fixation only. In static biomechanical testing of a cadaver femur, we compared the stiffness of five fixation models and then tested a fatigue failure model in cycle loading with DHS fixation only. Wiring fixation can enhance stability and the cut-out failure model in the fatigue test was identical to the clinical failure model. CONCLUSIONS: Lesser trochanteric fragment fixation is a crucial concern in the stability of an A2.1 unstable fracture, and the combination of a wiring technique with a DHS seems beneficial for achieving better stability. The addition of an antirotational greater trochanter is likely to enhance stability through wiring of the greater trochanter.

Single-pulsed electromagnetic field therapy increases osteogenic differentiation through Wnt signaling pathway and sclerostin downregulation.

Pulsed electromagnetic field (PEMF) therapy has been used for more than three decades to treat bone diseases. The main complaint about using PEMF is that it is time-consuming. Previously, we showed single-pulsed electromagnetic field (SPEMF) applied for 3 min daily increased osteogenic differentiation of mesenchymal stem cells and accelerated bone growth in a long bone defect model. In the current study, we investigated the mechanism of SPEMF to increase osteogenic differentiation in osteoblastic cells. We found that both short-term (SS) and long-term (SL) SPEMF treatment increased mineralization, while alkaline phosphatase (ALP) activity increased during the first 5 days of SPEMF treatment. SS treatment increased gene expression of Wnt1, Wnt3a, Wnt10b, Fzd9, ALP, and Bmp2. Also, SPEMF inhibited sclerostin after 5 days of treatment, and that inhibition was more significant with SL treatment. SL SPEMF increased expression of parathyroid hormone-related protein (PTHrP) but decreased expression of Sost gene, which encodes sclerostin. Together, the early osteogenic effect of SPEMF utilizes the canonical Wnt signaling pathway while the inhibitory effect of long-term SPEMF on sclerostin may be attributable to PTHrP upregulation. This study enhances our understanding of cellular mechanisms to support the previous finding and may provide new insight for clinical applications.

Kinematic analysis of leg alignment during conventional versus navigated total knee arthroplasty: initial results of a prospective study.

Current kinematic navigation systems provide real-time spatial analyses of leg alignments during total knee arthroplasty (TKA) instead of delayed radiographic verification after surgery. A prospective study was conducted to investigate leg alignments of TKAs that underwent different surgical guidance [intramedullary (IM) jig-based vs. navigation-assisted] using a kinematic navigation system. Since May 2007, patients admitted for primary TKA were considered for inclusion. Within 6 months, 38 sets of intraoperative analyses on the operated legs have been performed. Excluding seven unreliable data sets, 15 conventional IM jig-based TKAs and 16 navigation-assisted TKAs were available. The leg alignments in maximum knee extension were retrieved for comparison. Although similar final coronal alignments were accurately achieved in both groups (0.21 valgus in the IM group vs. 0.17 valgus in the NA group, p=0.993), a more flexed sagittal axis was constructed with conventional IM jigs (1.93 flexion in the IM group vs. 0.58 extension in the NA group, p<0.05). The study suggests that comparable coronal precision could be achieved with conventional IM jigs by trained surgeons, although computer-assisted navigation is a documented method to restore accurate alignment. Different sagittal alignments observed in this study indicate the inherent discrepancy between different surgical guides as well as their according concepts.

Fracture of VerSys fully bead-coated long femoral stems: report on four fractures in 41 hips.

The fracture of uncemented, fully porous, coated femoral stems is a rare complication that develops after primary total hip arthroplasty, and it is even rarer after revision surgery. To the best of our knowledge, cases of only 10 broken fully coated stems have been reported. This is the first report on fracture of the VerSys fully bead-coated femoral stem, which is designed for diaphyseal fixation and for application in revision surgery or when a proximal fixation is not feasible. Between 2000 and 2008, we implanted 41 VerSys fully coated stems in 40 patients. We present four cases of femoral stem fractures at 23, 31, 40, and 86 months after surgery. The common risk factors for these four patients were inadequate support for the implant in the proximal femur due to nonunion in this area, a stem diameter ≤12 mm, and a relatively young age.

An effective method to reduce ischemia time during total knee arthroplasty.

BACKGROUND/PURPOSE: Because of controversy regarding timing of tourniquet release during total knee arthroplasty (TKA), a closed arthrotomy as a tamponade for effective hemostasis was used to save ischemia time. The study was to verify the safety and efficacy on clinical issues. METHODS: A prospective cohort study was conducted on 72 consecutive unilateral primary TKAs. They were divided into two groups according to different timing of tourniquet release. The study group was composed of 36 index procedures with an intra-operative release after a tight arthrotomy closure; while the remaining 36 TKAs with a tourniquet application throughout the procedure comprised the comparative group. In all operations, no drain was used to augment the intra-articular tamponade. RESULTS: In the study group, the tourniquet time was significantly shorter (p<0.001), and thus ischemic duration and perioperative blood loss were reduced. The postoperative course was similar on the basis of analgesics consumption and inpatient stay, but better earlier functional recovery as well as subjective performance was observed at early postoperative follow-ups. CONCLUSIONS: The results suggest that a closed tamponade with arthrotomy closure and drainage avoidance is an effective hemostasis to reduce ischemia time during TKAs.

Cementless large-head metal-on-metal total hip arthroplasty in patients younger than 60 years--a multicenter early result.

Large-head metal-on-metal total hip arthroplasty has the theoretical advantages of less wear and better range of motion than traditional polyethylene bearings and seems to be a better choice for young and active patients. We conducted a retrospective study and reported the early results of using such prostheses in 59 patients (70 hips) with a mean age of 43.1 years (range, 23-59 years) at the time of surgery. Osteonecrosis of the femoral head accounted for most diagnoses. Harris Hip Scores and hip range of motion both significantly improved (p<0.001) at an average follow-up of 32.6 months (range, 24-48 months). Only one intraoperative calcar fissure was encountered, and it was fixated by cerclage wiring; there was no infection, dislocation, or osteolysis around either the cup or the stem at the latest follow-up. A postoperative gap in the acetabular component was noted in 24 hips, with a mean depth of 1.11 mm, but this was not correlated with the functional score (p=0.291). Transient thigh pain, which resolved after 6 months, was observed in six patients but was not related to either the postoperative gap or cup inclination (p=1.000 and p=0.664, respectively). All patients resumed their original jobs and recreational activities with little discomfort. Thus far, large-head metal-on-metal total hip arthroplasty has shown excellent early results. The long-term results and the effects of metal debris and potentially elevated serum metal ion levels require further observation.

Effects of tourniquet use on blood loss and soft-tissue damage in total knee arthroplasty: a randomized controlled trial.

BACKGROUND: Although tourniquets are widely used in total knee arthroplasty, their effectiveness in reducing blood loss and their influence on the postoperative course remain unclear. Tourniquet-related soft-tissue damage is a related concern. We performed a prospective, randomized, controlled trial to clarify the effect of tourniquets in total knee arthroplasty. METHODS: Seventy-two patients undergoing total knee arthroplasty were randomly allocated to a tourniquet or non-tourniquet group. Blood loss and changes in C-reactive protein, creatine phosphokinase, and other indicators of soft-tissue damage were monitored preoperatively and postoperatively on Days 1, 2, and 4. Thigh pain, knee pain, limb swelling, rehabilitation progress, and hospital stays were also recorded for comparison. RESULTS: Patients in the tourniquet group showed smaller decreases in hemoglobin (mean and standard deviation, 2.6 ± 0.9 versus 3.7 ± 1.3 g/dL) and hematocrit (7.6% ± 2.8% versus 10.4% ± 4.0%), less calculated blood loss (303 ± 119 versus 423 ± 197 mL), and smaller increases in C-reactive protein (peak value, 175 ± 55 versus 139 ± 75 mg/dL) and creatine phosphokinase (peak value, 214 ± 89 versus 162 ± 104 U/L) compared with those in the non-tourniquet group. There was slightly less postoperative pain in the non-tourniquet group. There were no significant differences between the groups in terms of swelling, rehabilitation progress, or hospital stays. CONCLUSIONS: The use of a tourniquet during total knee arthroplasty was effective for reducing blood loss and avoiding excessive postoperative inflammation and muscle damage. The use of a tourniquet was related to slightly more postoperative pain but did not affect postoperative recovery.

Alendronate in the prevention of collapse of the femoral head in nontraumatic osteonecrosis: a two-year multicenter, prospective, randomized, double-blind, placebo-controlled study.

OBJECTIVE: Osteonecrosis is one of the major debilitating skeletal disorders. Most patients with osteonecrosis of the femoral head eventually need surgery, usually total hip arthroplasty (THA), within a few years of onset. Previous studies showed that alendronate has a pharmacologic effect in reducing osteoclast activity and that it significantly reduced the incidence of collapse of the femoral head in the osteonecrotic hip. The purpose of this study was to determine the cumulative incidence of THA in patients with osteonecrosis of the femoral head and the time-to-event after treatment with alendronate versus placebo during the study period. METHODS: A 2-year multicenter, prospective, randomized, double-blind study was performed. From June 2005 to December 2006, 64 patients were enrolled and randomly assigned to the alendronate or placebo group. In patients with bilateral hip osteonecrosis who met the inclusion criteria, both hips were counted in the analyses. Five patients were excluded from the analysis because they did not comply with any of the study regimens. Seven patients were ineligible because they were not diagnosed as having stage IIC or stage IIIC disease according to the University of Pennsylvania system. Thus, a total of 52 patients (65 hips) were assessed in this study. Disease progression was evaluated by radiography and magnetic resonance imaging (MRI). The Harris Hip Score and the Short Form 36 health survey were used to rate hip function and quality of life, respectively. RESULTS: There was no significant difference in radiographic and MRI data between the 2 study groups. Four of 32 hips in the alendronate treatment group underwent THA, while 5 of 33 hips in the placebo group had THA (P = 0.837). No differences were noted in disease progression, Harris Hip Scores, or Short Form 36 scores between the 2 groups. CONCLUSION: Alendronate has no obvious effect on preventing the necessity for THA, reducing disease progression, or improving life quality.

Tourniquet use in total knee arthroplasty: a meta-analysis.

PURPOSE: The use of an intraoperative tourniquet for total knee arthroplasty (TKA) is a common practice. However, the effectiveness and safety are still questionable. A systematic review was conducted to examine that whether using a tourniquet in TKA was effective without increasing the risk of complications. METHODS: A comprehensive literature search was done in PubMed Medicine, Embase, and other internet database. The review work and the following meta-analysis were processed to evaluate the role of tourniquet in TKA. RESULTS: Eight randomized controlled trials and three high-quality prospective studies involving 634 knees and comparing TKA with and without the use of a tourniquet were included in this analysis. The results demonstrated that using a tourniquet could decrease the measured blood loss but could not decrease the calculated blood loss, which indicated actual blood loss. Patients managed with a tourniquet might have higher risks of thromboembolic complications. Using the tourniquet with late release after wound closure could shorten the operation time; whereas early release did not show this benefit. CONCLUSIONS: The current evidence suggested that using tourniquet in TKA may save time but may not reduce the blood loss. Due to the higher risks of thromboembolic complications, we should use a tourniquet in TKA with caution.

Non-drainage is better than 4-hour clamping drainage in total knee arthroplasty.

The role of wound drainage in total knee arthroplasty (TKA) is controversial. The use of drainage was believed to be effective in decreasing hematoma formation, but it inevitably increases bleeding because the tamponade effect of a closed and undrained wound is eliminated. Clamping the drain tube in the first 4 hours after TKA can temporarily recreate a tamponade effect for bleeding control. Previous studies compared the clamping drainage with the conventional drainage method but not with non-drainage. Some current studies have shown that drainage in TKA is not necessary. Thus, we conducted a study to compare the outcomes between the patients with temporarily clamping drainage and without drainage.One hundred consecutive patients undergoing primary TKA were included. Change of hemoglobin, blood transfusion, use of narcotics, postoperative wound dressing, length of hospital stay, and range of motion were recorded. The drain-clamping group demonstrated more postoperative hemoglobin loss and a longer hospital stay, and gained no benefit compared with the non-drain group. Therefore, we concluded that despite clamping for 4 hours after TKA, the drain was still of no use. We would not recommend using a draining system routinely after TKA.

Temporary drainage clamping after total knee arthroplasty: a meta-analysis of randomized controlled trials.

Drainage-clamping methods are thought to be effective in reducing blood loss after total knee arthroplasty (TKA). We conducted a systematic review to examine if these methods were effective without increasing the risk of complications. After a comprehensive search, 6 randomized controlled trials involving 603 knees and comparing clamping drainage and the immediate release of the drain after elective TKA were included in this analysis. The results demonstrated that drainage clamping could decrease the volume of drainage, but only clamping for no less than 4 hours could reduce the true blood loss. There was no significant difference between the 2 groups regarding blood transfusion, postoperative range of motion, incidence of thromboembolic events, and wound complications. The current evidence cannot confirm the advantage of clamping drainage after TKA.

Elevated temperature trends after total knee arthroplasty.

Fever after total knee arthroplasty (TKA) is a common phenomenon. However, the pattern of temperature change and its correlation with perioperative factors remain unclear. The purpose of this study was to define the trend of postoperative body temperature in patients undergoing TKA. This study also sought any factors influencing body temperature. We reviewed the charts of 186 clinically uncomplicated patients to record the changes of body temperature in the first 5 postoperative days and to determine the factors affecting it. The temperature trends of patients with acute prosthetic infection were also reviewed for comparison. In uncomplicated patients, the average peak temperature was 37.9 degrees C, a 3.3% increase from the preoperative baseline, 36.7 degrees C. The temperature elevation was most remarkable on postoperative days 1 and 2, but only 4 patients experienced fever up to 39 degrees C. Patients with lower hemoglobin loss showed higher peak temperature. Patients with postoperative infection tended to have prolonged fever and delayed presentation of peak temperature. Our study illustrated the elevated pattern of body temperature after uncomplicated TKA and determined the loss of hemoglobin might be the affecting factor. Fever up to 39 degrees C, prolonged fever, and delayed presentation of peak temperature were uncommon and should raise the clinical suspicion of infection or other complication.

A nationwide seven-year trend of hip fractures in the elderly population of Taiwan.

To investigate the recent longitudinal trend of hip fractures (including cervical and trochanteric fractures) in Taiwan's elderly population (> or =65 years), a nationwide descriptive epidemiological study was conducted using the database of the Bureau of National Health Insurance from 1996 through 2002. Frequencies and incidences of hip fracture by gender, fracture site, and age group were estimated, and the 7-year incidence trend was further evaluated. The results showed that a total of 75,482 hip fractures occurred during the study period with an incidence rate of 57.54 per 10,000 per year. Overall incidence significantly increased by 30% (p<0.0001), from 49.56 to 64.37 per 10,000 per year during the 7-year study period. The increase in rates was greater in males (36%) than in females (22%). The average female-to-male ratio was 1.76, lower than those in many countries. In females, the annual incidence of cervical fracture was higher than that of trochanteric fractures throughout the 7 years, while the incidence of trochanteric fractures was higher than cervical fractures each year in males (p<0.0001). The average annual incidence of patients older than 85 years was 9.9 times higher than that of aged 65 to 69 years in females and 7.9 times in males. Development and implementation of public health strategies for hip fractures should more focus on these subgroups in Taiwan's rapidly aging society.

Mini-open anterior spine surgery for anterior lumbar diseases.

Minimally invasive surgeries including endoscopic surgery and mini-open surgery are current trend of spine surgery, and its main advantages are shorter recovery time and cosmetic benefits, etc. However, mini-open surgery is easier and less technique demanding than endoscopic surgery. Besides, anterior spinal fusion is better than posterior spinal fusion while considering the physiological loading, back muscle function, etc. Therefore, we aimed to introduce the modified "mini-open anterior spine surgery" (MOASS) and to evaluate the feasibility, effectiveness and safety in the treatment of various anterior lumbar diseases with this technique. A total of 61 consecutive patients (46 female, 15 male; mean age 58.2 years) from 1997 to 2004 were included in this study, with an average follow-up of 24-52 (mean 43) months. The disease entities included vertebral fracture (20), failed back surgery (13), segmental instability or spondylolisthesis (10), infection (8), herniated disc (5), undetermined lesion for biopsy (4), and hemivertebra (1). Lesions involved 13 cases at T12-L1, 18 at L1-L2, 18 at L2-L3, 22 at L3-L4 and 11 at L4-L5 levels. All patients received a single stage anterior-only procedure for their anterior lumbar disease. We used the subjective clinical results, Oswestry disability index, fusion rate, and complications to evaluate our clinical outcome. Most patients (91.8%) were subjectively satisfied with the surgery and had good-to-excellent outcomes. Mean operation time was 85 (62-124) minutes, and mean blood loss was 136 (minimal-250) ml in the past 6 years. Hospital stay ranged from 4-26 (mean 10.6) days. Nearly all cases had improved back pain (87%), physical function (90%) and life quality (85%). Most cases (95%) achieved solid or probable solid bony fusion. There were no major complications. Therefore, MOASS is feasible, effective and safe for patients with various anterior lumbar diseases.

Effects of screw eccentricity on the initial stability of the acetabular cup.

One of the major failure modes of cementless acetabular components is the loosening of the acetabular cup, which is mostly attributable to insufficient initial stability. A hemispherical cup with a porous coating which is inserted with press-fit fixation and secured with several screws is one of the most widely used approaches. Many studies have found that bone screws are very helpful aids for cup fixation, but the optimal surgical technique for inserting screws has not been clearly reported. In this study, hemispherical cups were fixed into blocks of foam bone with zero to three screws. The effects of three types of screw eccentricity (a 1-mm offset and angular eccentricities of 15 degrees and 25 degrees ) on the initial stability of the acetabular cup were evaluated. The experimental results indicate that increasing the number of screws enhances the cup stability in the case of ideal screwing (i.e., with no eccentricity). An angular eccentricity of 15 degrees did not affect the cup stability for fixation with one or two screws. However, the presence of 25 degrees of angular eccentricity significantly reduced the stability of the cup, while 1 mm of offset eccentricity produced an even greater impact.

The number of screws, bone quality, and friction coefficient affect acetabular cup stability.

One of the major causes of loosening of cementless acetabular cup implants is insufficient initial stability. This study used three-dimensional finite element models of the pelvis and acetabular components to investigate the effects of the number of screws, bone quality, and friction coefficient of the acetabular cup on the initial stability under normal walking. A commercially available hemispherical acetabular cup with five screw holes was used as the default model. The stiffness of the pelvis and the friction coefficient of the cup were systematically varied, within a realistic range, to assess the initial stability of the acetabular cup. The simulations showed that the inserted screws provide only a localized reduction in the relative micromotion between the cup and pelvis therefore inserting several screw closed together might not be useful. Changes in the pelvic stiffness have a non-linear effect on the initial stability of acetabular cup and the subchondral bone provides good support for fixation of the cementless cup. The friction coefficient of the acetabular cup plays a limited role, comparing with the factor of bone quality, in resisting relative micromotion in the cup-pelvis interface.

The relation between micromotion and screw fixation in acetabular cup.

One of the major causes inducing loosening in the cementless acetabular cup implanting is its insufficient initial stability. In this study, three-dimensional finite element models of the pelvis and acetabular components were developed to investigate the relationship between relative micromotion, initial stability, and screw fixation under six daily activity loadings. A commercial available hemispheric cup with five screw holes was used as the target acetabular cup. The simulation results showed that if screws were placed closed together, when the screw number increased from 1 to 5, the peak micromotion decreased less than 14%, from 126.5 to 108.8 microm, while the stable region, micromotion less than 28 microm, enlarged only by 40%, from 46.1% to 64.7%. However, if the screw could be placed near the cup rim, a single rim screw, 202.1 microm micromotion, could provide better stability than that of four dome screws, 209.6 microm micromotion, placed closed together. To conclude, multiple cup screws should be placed near cup rim and as separate as possible to enlarge the stable region and reduce the peak micromotion between cup and acetabulum.

The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study.

BACKGROUND: Osteonecrosis of the femoral head is the most common diagnosis leading to total hip arthroplasty in young adults. Joint-preserving treatment options have been mainly surgical, with inconsistent results. Alendronate (a bisphosphonate agent) has been shown to lower the prevalence of vertebral compression fractures and could potentially retard the collapse of an osteonecrotic femoral head. The purpose of this study was to test the effect of alendronate in preventing early collapse of the femoral head in patients with nontraumatic osteonecrosis. METHODS: Forty patients with Steinberg stage-II or III nontraumatic osteonecrosis of the femoral head and a necrotic area of >30% (class C) were randomly divided into alendronate and control groups of twenty patients each. Patients in the alendronate group took 70 mg of alendronate orally per week for twenty-five weeks, while the patients in the control group did not receive this medication or a placebo. The patients were observed for a minimum of twenty-four months. Harris hip scores, plain radiographs, and magnetic resonance imaging scans were obtained. RESULTS: During the study period, only two of twenty-nine femoral heads in the alendronate group collapsed, whereas nineteen of twenty-five femoral heads in the control group collapsed (p < 0.001). One hip in the alendronate group underwent total hip arthroplasty, whereas sixteen hips in the control group underwent total hip arthroplasty (p < 0.001). CONCLUSIONS: Alendronate appeared to prevent early collapse of the femoral head in the hips with Steinberg stage-II or IIIC nontraumatic osteonecrosis. A longer duration of follow-up is needed to confirm whether alendronate prevents or only retards collapse. LEVEL OF EVIDENCE: Therapeutic Level I.