➢ Patients with multiple sclerosis have increased rates of osteoporosis.
➢ Patients with multiple sclerosis are at increased risk for falls and fractures.
➢ Osteoporotic fractures require special considerations for prevention and treatment.
➢ Patients with multiple sclerosis are prone to complications after fracture and often have incomplete recovery after fracture.
Multiple sclerosis is an inflammatory disorder that primarily affects the central nervous system and ultimately causes widespread neurodegeneration and axonal injury, leading to motor and sensory disability1,2. Multiple sclerosis has secondary effects on the musculoskeletal system that present challenges to the orthopaedic surgeon. Understanding multiple sclerosis will assist the surgeon in caring for these patients. The pathophysiology of the disease is not fully understood; however, research recently has focused on T-cell-mediated autoimmune mechanisms2. The disease primarily damages the myelin sheath of nerves in the brain and central nervous system and manifests clinically by affecting vision, balance, muscle strength and endurance, and mobility3. Multiple sclerosis is highly variable and may follow three distinct courses: relapse and remission (acute exacerbations followed by remissions), primary progression (gradual worsening over time), and secondary progression (relapse and remission followed by gradual progression)1. All patients with multiple sclerosis have worsening of the symptoms; approximately 20% of patients have a primarily progressive course whereas 65% have a relapse-and-remission course or a secondarily progressive course1. Among those who have a relapse-and-remission course, 50% develop a secondarily progressive course within ten years after diagnosis; virtually all will eventually have progression2.
More than 400,000 individuals in the United States and >2,000,000 individuals worldwide have multiple sclerosis, and three to seven individuals per 100,000 are newly diagnosed each year1,2. Multiple sclerosis tends to occur in patients between the ages of twenty and forty years and is the most common cause of nontraumatic neurological disability in young adults1,4. Multiple sclerosis affects women twice as frequently as men and tends to appear more frequently in individuals born in far northern or southern latitudes2,3. The disease has a limited impact on mortality; however, it greatly contributes to disability among those affected4.
Multiple sclerosis is typically diagnosed on the basis of a history and physical examination in patients demonstrating neurological deficits. Examination findings that are suggestive of multiple sclerosis include weakness, gait and balance disturbances, an abnormal Babinski reflex, hyperreflexia, and vision changes5. The diagnosis may be confirmed with additional testing. Evoked potentials may be used to measure neural conduction delays6. Spinal fluid also can be evaluated for the presence of oligoclonal IgG (immunoglobulin G) bands and to calculate the IgG index6,7. Magnetic resonance imaging (MRI) is considered to be a sensitive, noninvasive test for the detection of demyelination in the white matter of the central nervous system, a finding that is associated with multiple sclerosis6.
Multiple sclerosis can affect any part of the central nervous system, causing a wide variety of clinical manifestations. Patients commonly present with weakness, numbness, and paresthesias in the limbs; vertigo; and visual impairment, including double vision or blindness5. The disease has a predilection for affecting the spinal cord, cerebellum, and optic nerves, explaining these symptoms5. Patients with multiple sclerosis also commonly have bowel and bladder incontinence, which is usually progressive5. Multiple sclerosis has been implicated in cognitive dysfunction and may cause an overwhelming and disabling sense of fatigue that is not explained by muscle weakness5. The course of the disease is highly variable; however, a majority of patients with multiple sclerosis have a relapse-and-remission course, with 0.8 to 1 relapse per year5. Early in the disease, patients may have a complete recovery from symptoms a few months after a relapse; later in the disease, complete recovery does not occur, leading to progression of disability5.
The treatment of multiple sclerosis has greatly evolved over the past twenty years. Previously, treatment was limited to pulsed corticosteroid treatment for flares coupled with symptomatic treatment of pain, spasticity, and bladder dysfunction1. Today, treatment is focused on disease-modifying options designed to change the natural history of the disease. In addition to the use of glucocorticoids for the treatment of acute episodes, patients are managed with a variety of immune-modulating drugs, including interferon beta, glatiramer acetate, natalizumab, fingolimod, mitoxantrone, and teriflunomide2,3 These treatments reduce the frequency and severity of exacerbations and reduce disability. However, they do not reverse or completely arrest manifestations of multiple sclerosis.
Multiple Sclerosis and Bone Health
Multiple studies have demonstrated lower bone mineral density in patients with multiple sclerosis compared with healthy controls, particularly in the femoral neck and lumbar spine1,8-10. Osteoporosis represents an important risk factor for fragility fractures11. Patients with multiple sclerosis have been shown to have a 25% overall prevalence of low bone mineral density, with a 3% to 28% reduction of bone mineral density in the hip and a 6% to 23% reduction in the spine1,12. Furthermore, the annual rate of bone loss in the femoral neck in both men and women is three to six times greater in patients with multiple sclerosis compared with healthy controls1. Even patients without disability (i.e., patients who are able to walk) have been shown to have reduced bone mineral density compared with healthy controls, although there is a strong negative correlation between the level of disability and bone mineral density in patients with multiple sclerosis1,10,11.
Immobility and disability play a major role in the development of osteoporosis in patients with multiple sclerosis. As many as 76% of patients with multiple sclerosis report at least moderate disability12. Mechanical loading is important for the maintenance of bone mass; reduced mechanical stress on bone increases bone resorption and decreases bone formation3,4,13. The pattern of bone loss in patients with multiple sclerosis, with bone loss in the femoral neck being greater than that in the spine, is similar to the findings in patients with severe spinal cord injury1,11,14. This finding may be explained by decreased weight-bearing in the lower extremities of patients with severe disability and continued weight-bearing through the lumbar spine in patients who are able to sit but not stand. Furthermore, the risk for osteoporotic fractures in patients with multiple sclerosis has been shown to increase with increasing disability with use of the Expanded Disability Status Scale (EDSS)4,15. This finding suggests that osteoporosis in patients with multiple sclerosis is primarily driven by disuse, with profound effects4.
Patients with multiple sclerosis are often managed with corticosteroids during acute exacerbations, which may also explain bone loss. Corticosteroid therapy has been shown to increase the risk for fracture in a dose and duration-dependent fashion3,4. Proposed mechanisms include reduced osteoblast formation, increased osteoblast apoptosis, and increased osteoclast stimulation13. Such treatments may have suppressive effects on bone formation and may increase bone resorption1,3. However, when used in a pulsed fashion, as for patients with multiple sclerosis, corticosteroids have not been implicated in reductions in bone mineral density1,3. In fact, the transient negative effect of pulsed corticosteroid use may be offset by the tendency for treated patients to remain able to walk1.
An additional factor that may affect bone health in patients with multiple sclerosis is vitamin-D deficiency, which can lead to both osteomalacia and osteoporosis. Epidemiological studies have suggested that low vitamin-D levels are a risk factor for the development of multiple sclerosis16. Low vitamin-D levels in patients with multiple sclerosis may be caused by decreased exposure to sunlight (seen in 40% of patients with multiple sclerosis) and decreased intake (seen in 80% of patients with multiple sclerosis)1,3,4,13. Heat intolerance, resulting in fatigue and muscle weakness, is a documented side-effect of multiple sclerosis, which may explain why some patients with multiple sclerosis avoid direct sunlight1,14. The reported prevalence of vitamin-D deficiency in patients with multiple sclerosis has ranged from 17% to 86.7%1. However, studies in which patients with multiple sclerosis have been compared with matched controls have demonstrated conflicting results with regard to whether or not vitamin-D deficiency is an important difference from the general population1.
The use of antiepileptic drugs (phenytoin, sodium valproate, carbamazepine, and phenobarbital) represents an additional risk factor for osteoporosis in patients with multiple sclerosis3,4,10. Patients with multiple sclerosis have been shown to have an increased risk for epilepsy, and the risk for fracture in patients with epilepsy is as much as six times greater than that in the general population10. Antiepileptic treatments as well as antipsychotic and antidepressant medications have been linked to decreased bone mineral density3,4,10. Specifically, drugs with a high affinity for the 5-hydroxytryptamine reuptake transporter (5-HTT), such as selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, are associated with decreased bone mineral density and an increased risk for osteoporotic fractures3,13. 5-HTT is found in osteoblasts, osteoclasts, and osteocytes, and inhibition of 5-HTT with fluoxetine has been shown to reduce bone mineral density in rat models3.
Prevention and Treatment Strategies to Avoid Osteoporosis
Patients with multiple sclerosis should have a dual x-ray absorptiometry scan every two to five years to rule out low bone mineral density4,11. Dual x-ray absorptiometry scanning may be most useful for certain groups of patients, such as postmenopausal women, patients with an EDSS score of ≥6.0 (indicating loss of the ability to walk independently), patients using antiepileptic medication, and patients using glucocorticoids for longer than three months4.
Numerous options for treating and preventing osteoporosis are available for patients with multiple sclerosis. As activity and weight-bearing positively affect bone density, patients with multiple sclerosis should be encouraged to engage in load-bearing exercise11. Furthermore, smoking cessation, calcium and vitamin-D supplementation, bisphosphonates, raloxifene, and denosumab (a RANKL [receptor activator of nuclear factor kappa-B ligand] inhibitor) represent viable treatments4,11. For patients who are calcium and/or vitamin-D deficient, supplementation has been shown to be safe and represents a mainstay of osteoporosis treatment and prevention4,11.
Bisphosphonates (e.g., alendronate, risedronate, etc.) are indicated for postmenopausal women who have osteoporosis and are at risk for fracture4,11. In addition, bisphosphonates also have been shown to be effective for increasing bone mineral density and for reducing fracture risk in men4. Bisphosphonates currently are the most effective drugs that are widely available for reducing the loss of bone mineral density4.
Risk for Fracture in Patients with Multiple Sclerosis
Patients with multiple sclerosis have been shown to have an increased risk for fracture compared with healthy controls. In a large, multinational study of 60,393 postmenopausal women (52,960 of whom had follow-up data), multiple sclerosis was shown to be a significant risk factor for fracture, with a hazard ratio (HR) of 1.9 (p < 0.001)17. Ramagopalan et al., in a study in which 175,746 patients with multiple sclerosis were compared with matched controls, also found that patients with multiple sclerosis had an increased rate of fracture9. Patients with multiple sclerosis had a relative risk of 2.79 for femoral neck fractures, 6.69 for femoral fractures, and 2.81 for tibial and ankle fractures.
Bazelier et al., in a study of 2415 patients with multiple sclerosis and 12,641 age and sex-matched controls, reported that patients with multiple sclerosis had a fourfold increased risk for hip fracture and a 1.7-fold increased risk for osteoporotic fracture8. Interestingly, the HR for hip fracture (5.25; 95% confidence interval [CI], 2.67 to 10.31) and that for osteoporotic fracture (2.88; 95% CI, 1.84 to 4.50) in patients with multiple sclerosis were significantly increased only when the patient had sustained the injury as the result of a fall, illustrating the devastating effects of falls in these patients8. Furthermore, the risk for osteoporotic fracture in patients with multiple sclerosis was increased three times over that in controls when the patient had been taking antidepressant drugs or hypnotic or anxiolytic drugs in the previous six months8.
Bazelier et al. reported similar findings in a study involving 2963 patients with multiple sclerosis and 15,436 population-based controls who were included in the Danish National Health Registry15. Patients with multiple sclerosis were shown to have close to twice the risk for femoral and hip fractures compared with controls, and patients with multiple sclerosis and an age of more than fifty years had a significantly greater risk for osteoporotic fractures (HR = 1.47; 95% CI, 1.00 to 2.16) compared with controls15. That study also confirmed that increased disability according to the EDSS score was correlated with an increased risk for osteoporotic fractures in patients with multiple sclerosis15.
Falls Among Patients with Multiple Sclerosis
Dysfunction in cognition, vision, muscle function, coordination, sensation, and balance in patients with multiple sclerosis may increase the rate of falls and fall-related injuries8,12,18. Nilsagård et al., in a prospective study of falls among patients with multiple sclerosis, found that forty-eight (63%) of seventy-six subjects had falls over a three-month period; the total number of falls (270) was surprisingly high, corresponding with more than one fall per patient per month19. In comparison, Cameron et al., in a recent Cochrane review, reported a fall rate in nursing homes of 2.8 falls per person per year for men and of 1.49 falls per person per year for women20. Marrie et al., in a cross-sectional analysis of 9346 patients with multiple sclerosis, found that 1482 (16%) of the responders had sustained a fracture after the age of thirteen years and that 6166 (66%) of the responders reported impaired mobility12. A fracture was reported by 24% of patients with low bone mineral density, compared with 13.1% of those with normal bone mineral density (p < 0.0001)12. Furthermore, a fracture occurred in 29% of patients who reported a fall in the last year and had low bone mineral density, compared with only 10.2% of patients who reported no falls and had normal bone mineral density (p < 0.0001)12. The cause of falls among such patients may be related to impaired balance, visual impairment, reduced ability to walk, use of walking aids, reduced proprioception, and increased spasticity18. Thus, fall-prevention programs that evaluate the home environment may be important for mitigating falls and decreasing the risk for fracture among patients with multiple sclerosis.
Calculating Fracture Risk in Patients with Multiple Sclerosis
Assessing the risk for fracture in patients with multiple sclerosis is an important but challenging task. The World Health Organization has developed the Fracture Risk Assessment Tool (FRAX) to predict fracture risk on the basis of clinical risk factors21,22. FRAX is designed to yield a ten-year probability of osteoporotic fracture and a ten-year probability of hip fracture; however, this tool does not incorporate multiple sclerosis as a risk factor for fracture21,23. Thus, Bazelier et al., on the basis of data for a cohort of 5494 patients with multiple sclerosis as well as 32,669 population-based controls, introduced a simple score for predicting the risk for any osteoporotic fracture as well as the risk for hip fracture in patients with multiple sclerosis (Table I and Fig. 1) and (Table II and Fig. 2)21. The authors used Cox proportional hazards models to calculate the probability of fracture for given characteristics (i.e., sex, age, body mass index [BMI], etc.)21. Their study showed that FRAX underestimates the risk for fracture, particularly hip fracture, in patients with multiple sclerosis21.
Surgeons caring for patients with multiple sclerosis must appreciate the tendency for such patients to have an exacerbation of symptoms in the surgically treated extremity in the form of increased weakness, spasms, and sensory losses24. Such findings may be observed after both fracture care and elective operations. The surgeon should consider these issues during preoperative planning, should select fixation methods appropriate for osteoporotic bone, and should pay careful attention to soft-tissue handling during surgery to optimize healing. Many fractures that occur in patients with multiple sclerosis are osteoporotic fractures. Osteoporotic fractures present a challenge to the orthopaedic surgeon because compromised fixation increases the risk for fixation failure. Implant selection is essential in order to maximize bone purchase, fracture stability, and bone healing. In addition, stable fixation is beneficial for patients with multiple sclerosis because early weight-bearing and mobilization help to avoid further disuse osteopenia and immobility25. However, this consideration must be weighed against the fact that implant cutout and late fracture collapse lead to high failure rates in this patient population26.
The goal of surgical treatment of fractures is to obtain stable fixation that allows for early return of function27. The primary mode of failure in patients with osteoporotic fractures is loss of fixation at the bone-implant junction. Fixation failure is a result of the linear relationship between bone mineral density and the holding power of screws28. In addition, osteoporotic fractures may be associated with severe comminution, further increasing the rate of failure. For these reasons, load-sharing devices such as intramedullary nails, anti-glide and buttress plates, sliding nail-plate devices, and tension bands may be beneficial29. Augments such as polymethylmethacrylate and tricalcium phosphate bone cement also may be used to increase screw purchase in osteoporotic bone28. Maintaining principles of biologic fracture repair, including minimizing trauma to surrounding tissue and limited soft-tissue stripping, can help to improve the rate of fracture-healing. Bracing and casting also may be useful adjuncts to achieve fracture union.
Locking plate technology offers many advantages for the treatment of fractures in patients with multiple sclerosis and osteoporotic bone. These plates act as fixed-angle devices with multiple points of fixation. Because locking plates behave like an external fixator, screw failure occurs as an all-or-nothing event27. For this reason, locking plates have a greater resistance to failure in osteoporotic bone25. However, the inability of locking plates to aid in fracture reduction can be problematic.
Fracture fixation in osteoporotic bone has many challenges. For example, the stiffness that is achieved with different fixation techniques compared with the low stiffness of the osteoporotic bone can predispose the construct to periprosthetic fracture (Fig. 3)28. When using rigid fixation techniques, orthopaedic surgeons caring for patients with multiple sclerosis must be aware of this risk.
The postoperative care of patients with multiple sclerosis should be centered on early weight-bearing and mobilization. Because fracture-healing is partially dependent on mechanical stimulation, early weight-bearing may help to prevent increased disuse osteopenia. Therefore, constructs that allow for early weight-bearing are favored. Patients with multiple sclerosis often have decreased mobility at baseline secondary to a decrease in vision, muscle function, coordination, sensation, balance, and endurance30. A recent study of 354 middle-aged and older adults with multiple sclerosis showed that 93% (329) had problems with balance and mobility and that 88% (311) reported fatigue31. These symptoms are exacerbated following surgery; therefore, it is important to try to return these patients to their premorbid condition in a timely fashion in order to prevent further immobility.
Spasticity and Pressure Sores
Spasticity is a common symptom that affects approximately two-thirds of patients with multiple sclerosis32. Spasticity-related issues include restricted joint motion, abnormal and painful limb postures, activity limitations, decreased mobility, and decreased independence with activities of daily living. Current first-line treatments for spasticity include baclofen and gabapentin, with use of tizanidine, diazepam, clonazepam, cannabinoids, or dantrolene as second-line therapies33. Botulinum toxin injections, phenol injections, and intrathecal baclofen also may be used on a trial basis in cases in which the spasticity does not respond to first and second-line treatments34. Other nonpharmacological therapies for the treatment of spasticity include physiotherapy, magnetic stimulation, electromagnetic therapy, and vibration therapy; however, their role is not well defined35.
Postoperative spasticity in a patient with multiple sclerosis can be an especially difficult problem to treat because pain is often a trigger for spastic events. Therefore, it is essential to adequately treat the pain experienced by these patients. Avoiding other triggers such as constipation and urogenital infections also can be an important adjunct36. Pharmacological treatments may be helpful but have been shown to have unwanted side effects such as drowsiness, cognitive impairment, and weakness, all of which increase the risks for falls and fractures. Thus, cautious use of these agents is necessary35.
Nonpharmacological interventions for spasticity are also commonly used. There is Level-II evidence that physiotherapy after the injection of botulinum toxin may reduce spasticity for as long as twelve weeks. In addition, there is Level-II evidence that physical activity can be beneficial in combination with magnetic stimulation and electromagnetic therapies to decrease spasticity35.
Pressure sores are common in patients with multiple sclerosis. Pressure sores have multiple causes, including immobility, abnormal sensation, fatigue, muscle weakness, malnutrition, and bowel and bladder dysfunction37. The baseline immobility of a patient should be expected to worsen after fracture, and immediate postoperative care should include measures to prevent pressure sores. A survey by Cramp et al. demonstrated that 159 (23%) of 696 patients with multiple sclerosis reported the occurrence of pressure sores37. Although we are not aware of any studies detailing the incidence of pressure sores in patients with multiple sclerosis undergoing fracture care, it is clear that caution must be utilized in order to prevent pressure sores37. Early mobilization and early involvement of physical therapists and nursing staff can be essential for preventing pressure sores and pressure sore-related complications38.
Contractures and Deformity in Patients with Multiple Sclerosis
Maintaining mobility and range of motion in patients with multiple sclerosis is crucial for preserving functional ability. Static positioning of a limb over time leads to intrinsic changes within the muscle, including the replacement of muscle with fibrotic and fatty tissue, that cause contracture34. While not common in patients with multiple sclerosis, recommendations for the prevention of contractures include identifying patients who are at risk, instituting regular passive stretching, ensuring appropriate limb positions at rest, the use of orthotic devices, serial casting, botulinum toxin injections, and surgical intervention if conservative measures fail33.
Lower extremity muscles that are prone to spasticity include the iliopsoas, hamstrings, and gastrocnemius muscles39. As these muscles are crucial to daily function, special attention should be paid to the prevention and treatment of contracture. Contracture of the iliopsoas results in a hip flexion deformity and a functionally shorter limb that can lead to poor push-off during the stance phase of gait39. A contracture of 20° to 30° is associated with a large increase in energy expenditure during walking39. Risk factors include prolonged sitting in chairs and lying in bed with the hips flexed. Early detection can allow for the use of nonoperative treatments, including stretching of the iliopsoas muscle by positioning the patient prone on a hard surface several times a day. Hamstring contractures causing knee flexion deformities often accompany hip flexion contractures.
Patients with multiple sclerosis with spasticity may have cavus and claw-toe foot deformities40. Rivera-Dominguez et al., in a study of twenty patients with multiple sclerosis who had foot spasticity and equinus foot posture, reported that one patient had a cavus foot and one had a cavus foot with claw-toe deformities40. These deformities can lead to poor shoe-fitting and the development of pressure sores40. Treatment of these conditions begins with treatment of the responsible spastic muscles and finding properly fitting shoes. Surgical interventions include plantar fascia release, transfer of the tibialis anterior to a more lateral position in patients with supple deformities, and calcaneal and midtarsal osteotomies for patients with rigid deformities.
Contractures of the upper extremity in patients with multiple sclerosis are uncommon. Spasticity of the shoulder adductors, elbow flexors, wrist and finger flexors, and intrinsic muscles of the hand all may be encountered41. We are not aware of any reports on the surgical treatment of upper extremity contractures in this patient population. However, the importance of nonoperative interventions, including stretching, bracing, and pharmacological therapies, should be emphasized. Treatments for spasticity of the upper extremity also may include oral drug therapies, casts and splints, and blocks with use of phenol or botulinum toxin injections41.
Elective Surgery for Patients with Multiple Sclerosis
Elective extremity surgery in patients with multiple sclerosis must be carefully considered. There is a known risk for exacerbation of disease in the operatively treated extremity, predisposing the patient to increased weakness, spasms, sensory losses, and so on24. Patients with multiple sclerosis have less-predictable muscle tone as well as extreme muscle spasms, especially in the early postoperative period42. There is Level-V evidence that, when applicable, more constrained prostheses may be favored to prevent dislocation42,43.
Orthopaedic surgeons must be aware of the technical challenges to joint replacement in this patient population. In 2003, Rao and Targett reported the case of a patient with multiple sclerosis who had two occurrences of posterior knee dislocation secondary to painful hamstring spasms within the first six weeks after primary total knee arthroplasty43. These spasms occurred despite treatment with the anti-spasmodic agent tizanidine. The patient required a total of four operations, with the final revision and long-leg casting being performed 2.5 months after the initial surgery. Similarly, in 2007, Dawson-Bowling et al. reported the case of a patient with multiple sclerosis who had bilateral knee replacement with posterior cruciate ligament-retaining implants, with the procedures being performed one month apart42. The patient had three dislocations of the left knee and two dislocations of the right knee. One of these dislocations occurred after a fall, two occurred after painful hamstring spasms, and two were spontaneous. The patient required multiple revision procedures and continued to wear a brace on the left knee to prevent additional dislocations. While hamstring releases may have benefited these two patients, evidence regarding routine releases in patients with multiple sclerosis is lacking.
Multiple sclerosis is the most common cause of nontraumatic neurological disability in young adults and may lead to substantial functional impairment. The disability that accompanies multiple sclerosis can be severe, causing patients to have low bone mineral density, a high risk for falls, and high risk for fragility fractures. The key to orthopaedic management of patients with multiple sclerosis involves recognition of these risks so that outcomes can be optimized. Fracture care in patients with multiple sclerosis requires a multidisciplinary approach, with the goal of providing stable fixation in osteoporotic bone that allows the patient to mobilize quickly and safely. These patients are particularly susceptible to worsening of the condition after fracture, and special attention must be paid to preventing and treating spasticity and contracture. Surgery should be approached carefully, with the understanding that disease symptoms are likely to be exacerbated in the surgically treated limb, which may lead to issues with muscle imbalance, weakness, and sensory disturbances. Additional research is needed to develop protocols to mitigate osteoporosis and the risk for falls among patients with multiple sclerosis. For patients who require surgery, strategies to limit spasticity and weakness will limit disability, optimizing outcomes.
Source of Funding: No external funds were received in support of this work.
Investigation performed at the Division of Orthopaedic Trauma, Department of Orthopaedics, Warren Alpert Medical School of Brown University, Providence, Rhode Island
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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