Research Review By Dr. Josh Plener©

Audio:

Download MP3

Date Posted:

November 2020

Study Title:

International Framework for Red Flags for Potential Serious Spinal Pathologies

Authors:

Finucane L, Downie A, Mercer C et al.

Author's Affiliations:

Sussex MSK Partnership, Brighton, United Kingdom; Department of Chiropractic, Faculty of Science and Engineering, Macquarie University, North Ryde, Australia; Institute for Musculoskeletal Health, School of Public Health, The University of Sydney, Sydney, Australia.

Publication Information:

Journal of Orthopaedic & Sports Physical Therapy 2020; 50(7): 350-372. doi: 10.2519/jospt.2020.9971. Epub 2020 May 21.

Background Information:

Red flags are used by clinicians in many disciplines to identify if serious pathology may be the underlying cause of the patient’s musculoskeletal presentation. Depending on the practice setting, the prevalence of serious spinal pathology will vary. For example, a spine surgeon will (at least in theory) see a greater number of serious pathologies than a general practitioner. Unfortunately, confusion has persisted amongst clinicians, since recommendations regarding which specific red flags that should be considered are not consistent across guidelines. For spinal pathology specifically, the literature has reported 163 signs and symptoms as red flags (1), consisting of 119 symptoms from the individual’s history and 44 signs from the physical examination – quite a big list!

Despite red flag screening and tests lacking high-quality evidence for their diagnostic accuracy (2, 3), their combination with an in-depth history and physical examination remain the best tools health care practitioners have to raise their suspicion of a serious spinal pathology.

The aim of this clinical position statement/framework is to provide clinicians with a standardized and consistent approach to identify, assess and provide initial management for four key spinal pathologies: Cauda equina syndrome, spinal fracture, spinal malignancy and spinal infection.

This framework assists clinicians in identifying serious spinal pathology via three steps:
  1. Determining your level of concern through consideration of the evidence to support red flags and the individual profile of the patient.
  2. Deciding on your clinical action based on your concern level.
  3. Considering the optimal pathway for emergency/urgent referral.

Summary:

Cauda Equina Syndrome (CES)

CES results from the compression of the cauda equina (2) (nerve roots that originate from the conus medullaris at the spinal cord base). If present, this diagnosis needs to be made quickly to avoid serious lasting effects.

Epidemiology:
The incidence of CES in the United Kingdom has been estimated at 0.002% (4). Overall CES prevalence is estimated to range from 1 in 33 000 to 1 in 100 000 persons (5), with point prevalence of CES as a cause of low back pain estimated at 0.04% in primary care (6) and 0.4% in tertiary care (7). It is thought that approximately 2% of herniated discs result in CES (8).

Risk Factors:
Space occupying lesions, most commonly a disc prolapse/herniation, can cause CES (8). CES should be suspected if neurological symptoms progress with changes in bladder or bowel function or saddle sensory disturbance.

Condition-Specific Risk Factors for Developing CES (with level of evidence) Leading to High Clinical Suspicion:
  1. Herniated intervertebral disc (low): Unilateral or bilateral radicular pain and/or dermatomal reduced sensation and/or myotomal weakness, reduced saddle sensation, bladder disturbance, bowel disturbance, reduced anal tone/absent squeeze, sexual disturbance (4).
  2. Lumbar spinal stenosis (low): Gradual onset of unilateral or bilateral lower limb sensory disturbance and/or motor weakness, incomplete bladder emptying, urinary hesitancy, nocturia, urinary tract infection (UTI), bowel and/or bladder dysfunction.
  3. Spinal surgery (low): Nerve injuries and paralysis can be caused by a number of problems such as bleeding inside the spinal cord (9)
Clinical Picture:
When CES is suspected, a full neurological examination should be carried out to determine dermatomal sensory loss, myotome weakness or reflex changes (10). In any clinical setting, sensation to light touch and pinprick throughout the saddle region, including buttocks, inner thighs and perianal region is necessary. Some tests, for example the digital rectal examination, are required in secondary care settings but not primary care settings in some parts of the world (ex. United Kingdom). Upon suspicion of CES, emergency magnetic resonance imaging (MRI) and surgical opinion should be sought. If CES is not present, but the patient is at a risk of developing CES, appropriate information regarding signs and symptoms and plan of action if CES develops should be discussed with the patient.

Symptoms of CES (with level of evidence):
  • Sensory change – lower limbs (low)
  • Motor weakness – lower limbs (low)
  • Saddle sensory disturbance (low)
  • Change in ability to achieve an erection or ejaculate (low)
  • Loss of sensation in genitals during sexual intercourse (low)
  • Urinary function (ex. frequency) (low)
  • Urinary retention (low)
  • Urinary incontinence (low)
  • Bowel incontinence (low)
  • Constipation (low)
  • Unilateral/bilateral leg pain (low)
  • Low back pain (low)
Signs of CES (level of evidence):
  • Sensory deficit in saddle region to light touch and pinprick (low)
  • Abnormal lower-limb neurology (i.e. progressing neurological deficit) (low)…management is dependent on level of severity
  • Reduced anal tone (low)
Spinal Fracture

Spinal fractures make up the largest number of serious pathologies in the spine.

Epidemiology:
The point prevalence of osteoporotic compression fractures ranges between 0.7% and 4.5% in primary care settings (11-15) and 6.5% in the emergency care setting (16). Vertebral fractures are the most common osteoporotic fracture of the spine. It is important to consider the whole picture, as many of the tests are prone to false-positives (see below) as well as low diagnostic accuracy (17). The majority of spinal fractures occur between T8 and L4, with 70% occurring in the thoracic region, 20% in the lumbar region and 10% in the cervical region (18).

Risk Factors:
Typically, an older age is thought of when thinking about spinal fractures, however younger people are increasingly being affected by insufficiency spinal fractures (normal stresses placed on weakened bone).

Risk factors for Developing Spinal Fracture (with level of evidence) Leading to High Clinical Suspicion:
  1. History of osteoporosis (high)
  2. Corticosteroid use (high): Steroid use > 5 mg over a 3-month period.
  3. Previous history of cancer (low): Particularly a history of breast, prostate, lung, kidney or thyroid.
  4. Severe trauma (high): Immediate spinal pain post injury, focal bony tenderness in the midline of the spine.
  5. Female sex/postmenopausal (high): postmenopausal women; especially early menopause (< 45 yoa) or late menarche (> 16 yoa).
  6. Older age (high): Women over 65 yoa and men over 75 yoa, as 12% of women aged 50-70 have had a spinal fracture, and 20% of women over 70 have had a spinal fracture (of which 70% will not be known to the patient!) (19). Over 80 yoa = very high likelihood of osteoporotic fracture.
  7. Previous spinal fracture (high): Previous fracture leads to a 5.4-fold increased risk of vertebral fracture and a 2.8-fold increased risk of hip fracture within the year (20).
  8. History of falls (low): The risk of falls is elevated if the person has comorbidities such as Parkinson’s disease and dementia.
Clinical Picture:
Typically, patients present with sudden onset of pain after a low-impact trauma, such as a slip or lifting something in a forward-flexed position. The pain is often described as severe (although it can vary) and is also typically localized to the fracture site (21). As a result, weight-bearing and active movements are painful and restricted. An x-ray should be requisitioned if a spinal fracture is suspected and possible differential diagnoses should be considered, such as spinal malignancy and metastasis, as these fractures may look similar to an osteoporotic fracture (i.e. anterior wedge shape).

Symptoms of Spinal Fracture (with level of evidence):
  • Thoracic pain (high): 70% of non-traumatic spinal fractures occur in the thoracic spine and 70% of metastases occur in the thoracic spine. Therefore, history of cancer, myeloma or osteoporosis increases clinical suspicion in the presence of thoracic pain.
  • Severe pain (low): Pain that is unfamiliar and possibly worsening.
  • Neurological symptoms (low): Spinal fracture patients will not usually develop neurological deficits, but we should still assess for bilateral/quadrilateral neurological symptoms (i.e. gait disturbance, coordination issues, bowel and bladder disturbance).
Signs of Spinal Fracture (with level of evidence):
  • Spine tenderness (low): Midline bony tenderness and reproduction of symptoms with palpation, percussion and/or vibration (interpret these caution).
  • Neurological signs (low): Subjective complaint of neurological symptoms such as coordination/gait disturbance and changes to bladder/bowel activity warrant neurological examination.
  • Spinal deformity (low): Sudden change in spinal shape or posture related to trauma in a known osteoporotic patient.
  • Contusion or abrasion (low): May indicate trauma and high clinical suspicion if central spinal bony tenderness is present as well.
Spinal Malignancy

Spinal malignancy refers to metastases that have spread specifically into the spine. Certain cancers (breast, prostate, lung, kidney and thyroid) have a tendency to metastasize to the spine (23).

Epidemiology:
The point prevalence of spinal malignancy as a cause of LBP ranges between 0-0.7% in primary care settings (11, 12, 24-27), 0.1% in the emergency care setting (28) and 1.6% in tertiary care setting (7).

Risk Factors:
Metastatic bone disease (MBD) is the second most common serious pathology to affect the spine. The risk of malignancy increases with age (29).

Risk Factors for Spinal Malignancy (with level of evidence) Leading to High Clinical Suspicion:
  1. Past history of cancer (high): cancers with a predilection to bone metastases and later stage cancer
Clinical Picture:
Approximately 30% of breast, prostate, lung, kidney and thyroid cancers will metastasize to the spine. Other cancers can metastasize, but with a lower incidence (30). In addition, in approximately 25% of cases, metastatic spinal cord compression is the first sign of metastases without a primary diagnosis of cancer (31). Metastasis to the spine affects similar proportions of the spinal regions as spinal fractures (thoracic > lumbar > cervical) (14).
 
Symptoms of Spinal Malignancy (with level of evidence):
  • Severe pain that may become progressive and constant (low): Subjective features of band-like pain and inability to lie flat. Malignant bone disease is more likely to wax and wane and become more constant as the disease progresses.
  • Night pain (low): High suspicion if there is an inability to fall back to sleep due to symptom intensity and the patient experiences minimal relief with walking, sitting in a chair or lying on the floor.
  • Systemically unwell (low): Usually described in later stages and may include fatigue, nausea, stomach pain and fever which are suggestive of hypercalcemia (32).
  • Thoracic pain (low): Metastatic bone disease most commonly affects the thoracic spine and suspicion is raised with a non-mechanical pain presentation.
  • Neurological symptoms (low): Neurological symptoms such as upper motor neuron signs (i.e. gait disturbance, coordination issues/bladder and bowel disturbance) could arise from cord compression.
  • Unexplained weight loss (high): 5% or greater weight loss over a 6-month period is significant and requires further questioning (33).
  • Unfamiliar back pain (low): Pain is unfamiliar and possibly worsening
Signs of Spinal Malignancy (with level of evidence):
  • Altered sensation from trunk down (low): Objective neurological signs with reduced sensation.
  • Neurological signs (low): Subjective complaint of neurological symptoms warrant a full neurological examination.
  • Spinal tenderness (low): Tenderness or reproduction of symptoms can raise suspicion but lack of tenderness doesn’t rule out possible metastases (note: important to percuss the whole spine as painful area may not be the metastatic site).
Spinal Infection

Spinal infection can affect spinal structures including vertebrae, intervertebral discs, and adjacent paraspinal tissues (34).

Epidemiology:
Spinal infections are uncommon, with an incidence of 0.2 to 2.4 cases per 100 000 annually in Western societies (35, 36). The point prevalence in developed countries is 0.0004% (37), 0.01% in primary care settings (41) and 1.2% in tertiary settings (7). Discitis most commonly affects the lumbar spine (58%), followed by thoracic spine (30%) and cervical spine (11%) (36). Often, due to spinal infection not being common in high-income countries, diagnosis is delayed due to a failure to recognize the red flags involved.

Risk Factors for Spinal Infection (with level of evidence) Leading to High Clinical Suspicion:
  1. Immunosuppression (low): Immunosuppression due to uncontrolled morbidities such as diabetes, HIV/AIDS and alcohol abuse with previous evidence of infections.
  2. Invasive Surgery (low): A patient who has undergone surgery of the spine with repeated revisions raises suspicion of spinal infection (38).
  3. Intravenous drug use (low):
  4. Social and environmental factors (low): Factors such as homelessness, imprisonment, alcohol abuse (39) and unkempt appearance raise concerns for poor living and social conditions.
  5. History of tuberculosis (TB)/born in TB endemic country (low): Exposed to TB in an endemic country or known individual with TB
  6. Recent pre-existing infection (low): New and progressively worsening symptoms following an episode of sepsis or infection (40).
Clinical Picture:
Spinal infection presentation typically follows a more linear pattern, first presenting as back pain, followed by progressing neurological symptoms. Patients with spinal infection can remain relatively healthy until the later stages of the disease (41).

Diagnosis:
The classic triad of clinical symptoms consist of back pain, fever, and neurological dysfunction (42). However, only 50% of people report a fever as a symptom (43), therefore fever absence cannot rule out spinal infection.

Symptoms of Spinal Infection (with level of evidence):
  • Spinal pain (low): Limitation in movement due to localized spinal pain and muscle spasm (40).
  • Neurological symptoms (low): Bilateral/quadrilateral neurological symptoms including gait disturbance and coordination issues/bladder and bowel disturbance.
  • Fatigue (low): Abnormal level of fatigue and unable to perform activities they were normally able to (44).
  • Fever (consider sepsis/septic shock) (low): Fever onset within back pain time frame. However, 50% of people with spinal infection may not present with a fever (39).
  • Unexplained weight loss (low): 5% or greater weight loss over a 6-month period is significant and requires further questioning (33)
Signs of Spinal Infection (with level of evidence):
  • Neurological signs (low): Subjective complaint of neurological symptoms warrant a full neurological examination.
  • Radiculopathy (low): Radiating leg pain that is abnormal and progressing. Management depends on severity of neurological deficit.
  • Spinal tenderness on palpation (low): Tenderness or reproduction of symptoms can raise suspicion but lack of tenderness doesn’t rule out possible infection (note: important to percuss the whole spine as painful area may not be the infection site)

Clinical Application & Conclusions:

This article discusses the importance of using a person-centered, collaborative approach when evaluating patients with possible serious pathology. Clinicians should provide reassurance, support, non-judgmental answers, and clear and open communication. Clear communication is particularly important, as patients presenting with spinal pain may not understand the reasoning for a line of questioning, such as how their bladder or bowel function may relate to their spinal pain.

Overall, this framework is an easy to use clinical tool for clinicians to assess if serious spinal pathology is present and determine appropriate next steps to take. Despite high quality evidence lacking for most red flags used in isolation, this framework advocates for examining the entire patient and clinical profile. This is a timely and important paper to help reduce complexity surrounding this challenging topic.<

Study Methods:

Four priority areas were identified in 2016 by the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT): cauda equina syndrome (CES), spinal fracture, malignancy, and spinal infection. This framework followed the Haute Autorité de Santé recommendations for the development of clinical guidelines (45):
  • Phase 1: Systematic reviews and other key papers related to red flags in one or more of the four key spinal pathologies were summarized, leading to the formulation of four international expert consensus questionnaires.
  • Phase 2: The four questionnaires were administered through an online survey to the international expert group (100 experts from 19 countries), who rated red flag statements based on the evidence presented in phase 1 and their own experience. Responses were anonymized and employed a rating scale between 1 (totally inappropriate) and 9 (totally appropriate). The steering committee reviewed all the results. Statements with a median score of 7 or above were classified as appropriate and statements with a median score of 3.5 or less were classified as inappropriate (45).
  • Phase 3: The draft framework was developed by the steering committee based on a synthesis of results from phase 1 and 2.
  • Phase 4: The draft framework was presented to an international group of 70 independent individuals to provide feedback and rate the content based on applicability, acceptability and readability. Once again, scores were provided and scores of 7 or above were classified as appropriate.
  • Phase 5: The final version of the framework was created by the steering committee based on phase 4 feedback.

Study Strengths / Weaknesses:

Strengths:
  • This framework was formed based on the combination of the best available evidence and expert opinion – an appropriate approach for this topic.
  • This framework is the first of its kind in helping clinicians manage these difficult clinical presentations
  • This framework was presented to a large number of individuals to gain feedback, which helps increase its applicability and acceptability in clinical practice.
  • Case examples were provided in the text to provide context of each section.
Weaknesses:
  • The evidence surrounding red flags is limited and requires more high-quality studies.

Additional References:

  1. Greenhalgh S, Selfe J. Red Flags and Blue Lights: Managing Serious Spinal Pathology. 2nd ed. Edinburgh, UK: Elsevier; 2019.
  2. Downie A, Williams CM, Henschke N, et al. Red flags to screen for malignancy and fracture in patients with low back pain: systematic review. BMJ 2013; 347: f7095.
  3. Henschke N, Maher CG, Ostelo RW, de Vet HC, Macaskill P, Irwig L. Red flags to screen for malig¬nancy in patients with low-back pain. Cochrane Database Syst Rev 2013: CD008686.
  4. Greenhalgh S, Finucane L, Mercer C, Selfe J. Assessment and management of cauda equina syndrome. Musculoskelet Sci Pract 2018; 37: 69- 74.
  5. Long B, Koyfman A, Gottlieb M. Evaluation and management of cauda equina syndrome in the emergency department. Am J Emerg Med 2020; 38: 143-148.
  6. Deyo RA, Rainville J, Kent DL. What can the his¬tory and physical examination tell us about low back pain? JAMA 1992; 268: 760-765.
  7. Premkumar A, Godfrey W, Gottschalk MB, Boden SD. Red flags for low back pain are not always really red: a prospective evaluation of the clinical utility of commonly used screening questions for low back pain. J Bone Joint Surg Am 2018; 100: 368-374.
  8. Dionne N, Adefolarin A, Kunzelman D, et al. What is the diagnostic accuracy of red flags related to Cauda Equina Syndrome (CES), when compared to Magnetic Resonance Imaging (MRI)? A systematic review. Musculoskelet Sci Pract 2019; 42: 125-133.
  9. National Health Service. Risks: lumbar decom¬pression surgery. Available at: https://www.nhs. uk/conditions/lumbar-decompression-surgery/ risks/. Accessed April 16, 2020.
  10. Germon T, Ahuja S, Casey ATH, Todd NV, Rai A. British Association of Spine Surgeons standards of care for cauda equina syndrome. Spine J 2015; 15: S2-S4.
  11. Deyo RA, Diehl AK. Lumbar spine films in pri¬mary care: current use and effects of selective ordering criteria. J Gen Intern Med 1986; 1: 20-25.
  12. Henschke N, Maher CG, Refshauge KM, et al. Prevalence of and screening for serious spinal pathology in patients presenting to primary care settings with acute low back pain. Arthritis Rheum 2009; 60: 3072-3080.
  13. Jarvik JG, Deyo RA. Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 2002; 137: 586-597.
  14. Scavone JG, Latshaw RF, Rohrer GV. Use of lumbar spine films. Statistical evalua¬tion at a university teaching hospital. JAMA 1981; 246: 1105-1108.
  15. van den Bosch MA, Hollingworth W, Kinmonth AL, Dixon AK. Evidence against the use of lum¬bar spine radiography for low back pain. Clin Radiol 2004; 59: 69-76.
  16. Gibson M, Zoltie N. Radiography for back pain presenting to accident and emergency depart¬ments. Arch Emerg Med 1992; 9: 28-31.
  17. Williams CM, Henschke N, Maher CG, et al. Red flags to screen for vertebral fracture in patients presenting with low-back pain. Cochrane Database Syst Rev 2013: CD008643.
  18. Patel U, Skingle S, Campbell GA, Crisp AJ, Boyle IT. Clinical profile of acute vertebral compres¬sion fractures in osteoporosis. Br J Rheumatol 1991; 30: 418-421.
  19. Royal Osteoporosis Society. Clinical guidance for the effective identification of vertebral fractures. Available at: https://www.guidelines.co.uk/ musculoskeletal-and-joints-/ros-guideline-iden¬tification-of-vertebral-fractures/454148.article. Accessed April 16, 2020.
  20. Scottish Intercollegiate Guidelines Network. Management of Osteoporosis and the Prevention of Fragility Fractures. Edinburgh, UK: Scottish Intercollegiate Guidelines Network; 2015.
  21. Hippisley-Cox J, Coupland C. Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective deriva¬tion and validation of QFractureScores. BMJ 2009; 339: b4229.
  22. McCarthy J, Davis A. Diagnosis and management of vertebral compression fractures. Am Fam Physician 2016; 94: 44-50.
  23. Sutcliffe P, Connock M, Shyangdan D, Court R, Kandala NB, Clarke A. A systematic review of evi¬dence on malignant spinal metastases: natural history and technologies for identifying patients at high risk of vertebral fracture and spinal cord compression. Health Technol Assess 2013; 17: 1- 274.
  24. Deyo RA, Diehl AK. Cancer as a cause of back pain: frequency, clinical presentation, and diag¬nostic strategies. J Gen Intern Med 1988; 3: 230- 238.
  25. Donner-Banzhoff N, Roth T, Sönnichse AC, et al. Evaluating the accuracy of a simple heuristic to identify serious causes of low back pain. Fam Pract 2006; 23: 682-686.
  26. Frazier LM, Carey TS, Lyles MF, Khayrallah MA, McGaghie WC. Selective criteria may increase lumbosacral spine roentgenogram use in acute low-back pain. Arch Intern Med 1989; 149: 47-50.
  27. Khoo LA, Heron C, Patel U, et al. The diagnostic contribution of the frontal lumbar spine radio¬graph in community referred low back pain—a prospective study of 1030 patients. Clin Radiol 2003; 58: 606-609.
  28. Reinus WR, Strome G, Zwemer FL, Jr. Use of lumbosacral spine radiographs in a level II emergency department. AJR Am J Roentgenol 1998; 170: 443-447.
  29. Harel R, Angelov L. Spine metastases: current treatments and future directions. Eur J Cancer 2010; 46: 2696-2707.
  30. Oliver TB, Bhat R, Kellett CF, Adamson DJ. Diagnosis and management of bone metastases. J R Coll Physicians Edinb 2011; 41: 330-338.
  31. National Institute for Health and Care Excellence. Metastatic Spinal Cord Compression in Adults: Risk Assessment, Diagnosis and Management. Manchester, UK: National Institute for Health and Care Excellence; 2008.
  32. Farrell C. Bone metastases: assessment, management and treatment options. Br J Nurs 2013; 22: S4, S6, S8-S11.
  33. Nicholson BD, Aveyard P, Hamilton W, Hobbs FDR. When should unexpected weight loss war¬rant further investigation to exclude cancer? BMJ 2019; 366: l5271.
  34. Nickerson EK, Sinha R. Vertebral osteomyelitis in adults: an update. Br Med Bull 2016; 117: 121-138.
  35. Cheung WY, Luk KD. Pyogenic spondylitis. Int Orthop 2012; 36: 397-404.
  36. Gouliouris T, Aliyu SH, Brown NM. Spondylodiscitis: update on diagnosis and management. J Antimicrob Chemother 2010; 65 suppl 3: iii11-iii24.
  37. Duarte RM, Vaccaro AR. Spinal infection: state of the art and management algorithm. Eur Spine J 2013; 22: 2787-2799.
  38. Lener S, Hartmann S, Barbagallo GMV, Certo F, Thomé C, Tschugg A. Management of spi¬nal infection: a review of the literature. Acta Neurochir (Wien) 2018; 160: 487-496.
  39. Yusuf M, Finucane L, Selfe J. Red flags for the early detection of spinal infection in back pain patients. BMC Musculoskelet Disord 2019; 20: 606.
  40. Nagashima H. Spinal infections. In: Berhouma M, Krolak-Salmon P, eds. Brain and Spine Surgery in the Elderly. Cham, Switzerland: Springer; 2017: 305-327.
  41. Wainwright A. Spinal infection. In: Bartley R, Coffey P, eds. Management of Low Back Pain in Primary Care. Oxford, UK: Elsevier/Butterworth- Heinemann; 2001:ch 9.
  42. Davis DP, Wold RM, Patel RJ, et al. The clinical presentation and impact of diagnostic delays on emergency department patients with spinal epi¬dural abscess. J Emerg Med 2004; 26: 285-291.
  43. Lener S, Hartmann S, Barbagallo GMV, Certo F, Thomé C, Tschugg A. Management of spi¬nal infection: a review of the literature. Acta Neurochir (Wien) 2018; 160: 487-496.
  44. Howell DA, Hart RI, Smith AG, et al. Myeloma: patient accounts of their pathways to diagno¬sis. PLoS One 2018; 13: e0194788.
  45. André-Vert J, Dhénain M. Development of Good Practice Guidelines: “Formal Consensus” Method. Seine-Saint-Denis, France: Haute Autorité de Santé; 2015.

Contact Tech Support  Contact Dr. Shawn Thistle
 
RRS Education on Facebook Dr. Shawn Thistle on Twitter Dr. Shawn Thistle on LinkedIn Find RRS Education on Instagram RRS Education (Research Review Service)