Osteopathic Manipulative Treatment: Lymphatic Procedures

Earn CME/CE in your profession:


Continuing Education Activity

The lymphatic system intimately connects to all body parts, yet its clinical significance is poorly understood. Besides playing a role in the immune system, it has many other functions. This mesh of tissues and organs exports toxins, waste, and unnecessary materials out of the body via lymph fluid. Modern medical education today does not do full justice to the lymphatic system. Understanding the lymphatic formation and removal process from the interstitium is a crucial physiologic principle to treat osteopathically. Osteopathic manipulative treatment (OMT) may be used to affect and improve lymphatic flow. This activity outlines lymphatic osteopathic manipulation treatment and explains the role of the interprofessional team in improving care for patients who undergo lymphatic OMT.

Objectives:

  • Identify patients with conditions or symptoms suggestive of lymphatic system involvement where lymphatic OMT may be beneficial.

  • Screen patients for any medical conditions or factors that may affect the suitability of lymphatic OMT as a treatment option.

  • Select appropriate lymphatic OMT techniques based on the patient's specific lymphatic system dysfunction and clinical presentation.

  • Collaborate with other healthcare professionals, such as physical therapists and lymphedema specialists, to optimize patient outcomes through an interprofessional approach.

Introduction

The lymphatic system can easily be overlooked but drastically impacts the immune system. This mesh of tissues and organs exports toxins, waste, and unnecessary materials out of the body via lymph fluid. Modern medical education today does not do full justice to the lymphatic system. This system removes fluids and protein from the extracellular space and interstitium to maintain proper osmotic balance. In acute inflammation, changes occur in the lymphatic system, so our body will try to maintain appropriate homeostasis.[1]

Osteopathic manipulative treatment (OMT) is used to treat somatic dysfunctions. OMT focuses on enhancing the neuromuscular connection, improving biomechanical balance, decreasing pain, and increasing the range of motion.[2] In the historical context of osteopathy, Dr. Andrew Taylor Still placed a lot of importance on the lymphatic system during his development of the tenets of osteopathy. In the book The Philosophy and Mechanical Principles of Osteopathy by Andrew Taylor Still, he mentions that "We suffer from two causes: want of supply and the burdens of dead deposits." Dr. Still understood the importance of the lymphatic system's role in clearing the "debris" that may cause disease. In modern medicine, we know more about the lymphatic vessels and how they may contribute to certain chronic conditions.[3][4]

Inflammation is a normal homeostatic response to injury or infection; it is the body's response to try to heal. During the process, significant amounts of different cytokines and other inflammatory mediators are released to signal the appropriate immune cells. Removing these markers through lymphatic drainage flow is essential to help resolve the inflammation.[5][6] 

Understanding the lymphatic formation and removal process from the interstitium is a crucial physiologic principle to treat osteopathically. Osteopaths believe that lymphatic drainage plays a significant role in rheumatoid arthritis; immune complexes are formed in the disease, which cause substantial inflammatory exudates. These exudates cause pain and destroy joint tissue, and it has been shown that there is increased lymph production and drainage from these patients.[7]

Some osteopathic techniques are similar to those implemented by chiropractors, physical therapists, and massage therapists, and other methods are solely used by osteopathic physicians. However, one main difference is that these physicians are trained to apply these techniques with their extensive knowledge of physiology and anatomy. This allows osteopathic physicians to tailor their treatment to each patient.[8] This will enable OMT to be applied to more than just spinal alignment to treat many physiologic conditions.[8] 

Some techniques were designed to be used to help increase lymphatic flow. Some other techniques were not designed to be lymphatic, but they can be used in its treatment by understanding the complexity of the human anatomy. When treating lymphatic techniques, it is essential to be mindful of structures that may impinge the lymphatic vessels, such as fascia, muscles, ligaments, and other somatic dysfunctions. Many techniques comprise OMT, which can treat many ailments, including the lymphatic system. Problems within this system lead to the accumulation of lymph, decreased immune responses, fat build-up, tissue swelling, and connective tissue accumulation.[9]

Anatomy and Physiology

Lymphatic vessels can be found all over the body. They are very closely located in arterial and venous blood vessels. The lymphatic system begins in the interstitium of tissues with lymph capillaries, and they drain into larger collecting channels, which further drain into lymph nodes. The lymphatic vessels from the lower extremity left thorax, left upper extremity, and left head and neck drain into the thoracic duct. Meanwhile, the right thorax, right upper extremity, right head, neck, and heart drain into the right lymphatic duct.[10]

The lymphatic capillaries are single-layered endothelial cells without any tight junctions anchoring filaments from the basal side of the cell to the interstitial matrix. These filaments change the shape of the vessels depending on the motion of the tissues.[11][12][13] Due to the lack of adhesion molecules at the endothelial cells, the basement membrane acts as a one-way flow valve for the lymphatic fluids[14][15][6]

The presence of a bicuspid valve is the start of the lymph-collecting vessels, which are comprised of smooth muscles near the valves, which thicken as they become more proximal. The segments between the valves are called lymphangions. The smooth muscles around the vessels contain sympathetic innervation.[16] There is a hypothesis that the role of sympathetic innervation is to modify the immune response rather than to increase flow through the vessels.[17] The collecting vessels near skeletal muscles have fewer smooth muscles; this finding suggests that skeletal muscle contraction is essential in moving lymphatic fluids along the vessels.[18]

When lymphatic fluid from the lower extremity flow towards the thoracic duct, intrathoracic pressure is essential. A change in the intrathoracic pressure during respiration may increase lymphatic flow up the thoracic duct.[19]

The lymphatic system comprises the spleen, lymph nodes, thymus, lymph channels, adenoids, tonsils, and thymus.

  • Lymph nodes – The average adult has roughly 700 lymph nodes. These nodules produce and store white blood cells and function to filter lymph fluid.
  • Tonsils and adenoids – Closely packed lymphatic cells in the posterior of the oropharynx and posterior to the soft palate, respectively
  • Thymus – The site of T-cell maturation sits just posterior to the manubrium. This organ is most active in the early stages of life.
  • Spleen – Largest of the organs involved in the lymphatic system, the spleen holds white blood cells to fight infection and filters the blood.

A few areas in the body where lymphatic vessels may be hindered due to somatic dysfunctions are the thoracic outlet, thoracic diaphragm, femoral triangle, and the popliteal fossa. When treating the thoracic diaphragm, it is essential to be aware of the thoracic duct, which crosses the diaphragm at the level of T12 and is between the vertebral body and the aorta. Underneath the diaphragm and slightly to the right of the vertebral column is the cisterna chili, where most lymph from below the diaphragm drains before ascending towards the thoracic duct.

Indications

A foundational principle in osteopathic medicine is to help remove obstructions to circulatory flow. Lymphatic vessels are included in Dr. Still's concept of circulation. As mentioned in the introduction of this activity, Dr. Still emphasized the lymphatic system as a way for the body to remove "debris." Modern medicine understands the role of inflammation, injury, and disease; therefore, osteopathic physicians should understand its implications for the lymphatic system. Lymphatic congestion can lead to significant worsening of conditions based on being unable to remove the inflammatory mediators from the body. Therefore, proper lymphatic flow is essential in many chronic, autoimmune, and inflammatory diseases. 

Examples of common conditions treated with lymphatic techniques can be autoimmune, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. In addition, inflammatory conditions such as pharyngitis, pericarditis, myocarditis, mastitis, colitis, and pancreatitis are a few conditions that can benefit from lymphatic treatments. Lymphatic treatment may also be an adjunct to antibiotic use in an infectious process by helping the flow of immune cells to the area of infection.[20][21] However, osteopathic practitioners must not only rely on lymphatic techniques but also understand the physiology and anatomy of the patient to apply effective treatments.

Lymphatic treatment is a great adjunctive approach for treating infectious diseases like pneumonia. The MOPSE trial even showed that it could reduce hospital length stays.[22] Osteopathic treatment for infection can increase immune cells' flow and efficient delivery of antibiotics to the source of infection.

Contraindications

There are relative contraindications (eg, pain) and absolute contraindications (no consent from the patient). However, these can be more difficult to discern with lymphatic techniques as any technique can become lymphatic treatment with the right intention. 

There are a few absolute contraindications to lymphatic treatments. Any lymphatic pumping techniques should be avoided in areas with acute injuries, such as bone fractures. Leukemia or lymphoma may be a relative contraindication as there is a hypothetical risk that lymphatic techniques may spread the condition further. Another contraindication to lymphatic techniques, commonly taught in school, is that they should be avoided in patients with metastatic cancer due to the hypothetical risk of further metastasis. However, even in the osteopathic community, there is some movement away from avoiding lymphatic techniques in patients with metastases. There are questions regarding the validity of the hypothesis that metastases can be spread using lymphatic techniques.[23] One argument is that even walking is a form of lymphatic treatment.

The practitioner should also be mindful when doing lymphatic treatments during certain infections. For example, there is a hypothetical risk that lymphatic treatments may further disseminate diseases in the case of bacteremia or an abscess about to burst.

Another contraindication is lymphatic techniques in acute heart failure exacerbation. Many physicians may want to apply lymphatic pump techniques when seeing lymphedema in the legs. However, in acute heart failure, lymphatic pumping techniques may hypothetically increase the heart's afterload by pushing more fluid into the circulatory system. Therefore, treating any somatic dysfunctions obstructing lymphatic flow will be more advisable than pumping techniques. However, lymphatic techniques are beneficial overall in cardiac conditions.[24][25]

Lymphatic pumping techniques in the lower extremities should be avoided if there are any concerns of possible deep vein thrombosis. Likewise, lymphatic pumping techniques such as the liver pump and the splenic pump should be avoided if there are concerns of acute liver injury or splenomegaly. 

Equipment

A comfortable place for the patient to sit and lay, typically an exam table, OMT table, or massage table. A pillow for patient comfort.

Preparation

Consent is necessary before any procedure, including OMT. The patient must understand the risks, benefits, and alternative options to provide informed consent. Patients also appreciate the provider warming their hands before the treatment begins. 

Technique or Treatment

Chapman Reflexes

  • There are roughly 100 documented Chapman points. These are areas of gangliform contraction, which, when in certain areas, are associated with specific organs that have dysfunctions. Treating these points will decrease sympathetic tone, increase myofascial motion, and improve lymphatic return to visceral dysfunction.[26]
  • Chapman points have been documented in chronic hepatitis patients on physical exams. They can help physicians narrow their differential, validate a diagnosis, and increase treatment options.[27]

Thoracic (Miller) Pump

  • Increases mobilization of all lymphatic fluid movement and increases rib case mobility.
  • The patient is supine on the table, and the physician is at the head of the table facing the patient. 
  • The physician's hands are placed on either side of the chest, and the patient is asked to take deep breaths.
  • The physician will follow the ribs' motion while applying a gentle oscillatory force during exhalation.

Pedal (Dalrymple) Pump

  • Increases mobilization of all lymphatic fluid movement. This technique is beneficial in pediatric patients or lymphedema.
  • The patient is supine on the table, and the physician is at the feet of the table facing the patient.
  • The physician gently dorsiflexes the feet to "pick up the slack" in the tissue.
  • Gentle oscillatory force is applied cephalad while maintaining dorsiflexion.
  • Amplitude should be enough to visualize the motion of the oscillation in the nose.[28]

Thoracic Inlet Release

  • Sibson's fascia mentioned above is the fascial layer comprised of the connective tissues of the longus coli and scalene muscles and attaches to the transverse process of C7. The right and left thoracic ducts travel through this fascia once and twice. Using techniques to release Sibson's fascia will better allow all lymph to return to the circulatory system. This treatment should be done before most lymphatic treatments.
  • The patient starts supine. The physician is stated at the head of the table facing the patient. The physician places their hands on the shoulder.
  • Motion test the shoulders in flexion/extension, side bending, rotations, and compression.
  • If treating indirectly, stack up the tissue in the direction of ease. If treating directly, stack up the tissue toward the barrier.
  • Hold the fascia until a release can be palpated.

Rib Raising

  • Rib raising is not a strict lymphatic technique, but it can be used to increase compliance with costal motion, allowing for deeper intrathoracic pressure changes to increase lymphatic flow.
  • The patient is supine on the table, and the physician is on the ipsilateral side, facing the patient.
  • The physician's hands slide underneath that patient and contact the rib angle.
  • Gentle, rhythmic motion to translate the ribs anteriorly to articulate the costovertebral joints.[29]

Splenic/Liver Pump

  • This procedure facilitates the flow of lymph to the liver and spleen. In the liver, this increases the ability of the Kupffer cells to interact with antigens and toxins in the lymph. The spleen's ability to screen and remove damaged cells from the system is also enhanced.
  • Rhythmic external compression of the costal margin on either side to "pump" the spleen or liver

Facial Sinus Pressure Techniques (Facial Effleurage)

It improves sinus congestion and otitis media; it involves direct strokes applied to the sinuses, zygomatic bones, and the temporal mandibular joints bilaterally to enhance lymph movement towards the right and left lymphatic ducts.

There are multiple ways and different sequences of doing facial effleurage.[30] The following are some examples:

  • Over the eyebrows for frontal sinus
  • Under the maxillary protuberance for the maxillary sinus
  • On the anterior surface of the mandible
  • Under the mandible
  • Sternocleidomastoid 

Galbreath Technique

  • This maneuver facilitates the opening of the eustachian tubes and allows lymph flow distally from the ears.
  • The patient is supine, and the physician stands on the contralateral side.
  • The cephalad hand is placed on the forehead to stabilize the patient.
  • The caudad hand is placed on the angle of the mandible and pulls the jaw inferio-medially.
  • The technique also pulls the medial pterygoid muscle, stimulating the jugulodigastric lymph nodes.[31]

Doming the Diaphragm

  • Increases mobilization of lymphatic fluid from the lower extremities and increases diaphragm motion
  • Somatic dysfunction in the diaphragm can restrict the thoracic duct as it passes the diaphragm at the level of T12 between the vertebral body and the aorta.
  • The patient starts supine, and the physician is on either side of the patient.
  • Both hands are placed on either inferior costal margin.
  • Follow the motion of the ribs with inhalation, and gently resist during exhalation. Repeat three times. This technique may cause some discomfort for patients.[32]

Complications

OMT is relatively safe, and lymphatic treatments are some of the safest. Some transient effects may include headache, tiredness, and fatigue.[8] Adverse effects may be avoided if the patient drinks plenty of fluids. There is a hypothetical risk of causing a transient decrease in ejection fraction if too much aggressive lymphatic technique is done by suddenly increasing the afterload. There is also a risk of damaging the liver or spleen if an aggressive splenic/liver pump is done during organomegaly.

Clinical Significance

Due to the vast relationship of the lymphatic system to all body organs, lymphatic treatment can have substantial clinical significance. During the Spanish flu of 1918, there was a 33% mortality rate for patients who received care. However, patients who also received treatment with OMT had a mortality rate of 10%. The techniques improved lymphatic flow, immune defense, and respiratory function.[20] 

In 2010, a randomized controlled trial of over 400 elderly patients with pneumonia found that OMT as an adjunctive treatment to the standard of care lowered costs, decreased hospital length of stay, duration of intravenous antibiotics, and incidence of respiratory failure or death.[20]

In essence, lymphatic treatment may be a powerful adjunct to conventional medicine when treating many medical conditions.

Enhancing Healthcare Team Outcomes

For the last 130 years, osteopathic physicians have been practicing medicine.[8] Although the understanding of osteopathic medicine has dramatically increased, it is still poorly understood by many healthcare workers and patients. Interprofessional team members, including nursing staff, must understand OMT and what it can provide to patients. Osteopathic practitioners should document all OMT interventions in the patient's permanent medical record so all team members know the overall treatment plan. This will also allow the patients to know what options are available and may receive increased relief for their ailments in addition to allopathic medicine. Outcomes and patient satisfaction will improve. OMT is also very safe; if some issues are treatable with OMT alone, it will also increase patient safety.


Details

Author

Kailey Remien

Author

Min Je Woo

Updated:

1/29/2024 11:14:43 PM

References


[1]

Ozdowski L, Gupta V. Physiology, Lymphatic System. StatPearls. 2024 Jan:():     [PubMed PMID: 32491765]


[2]

Bodine WA. Osteopathic Manipulative Treatment: A Primary Care Approach. American family physician. 2019 Feb 15:99(4):214     [PubMed PMID: 30763051]


[3]

Trivedi A, Reed HO. The lymphatic vasculature in lung function and respiratory disease. Frontiers in medicine. 2023:10():1118583. doi: 10.3389/fmed.2023.1118583. Epub 2023 Mar 14     [PubMed PMID: 36999077]


[4]

Dori Y, Mazurek J, Birati E, Smith C. Ascites in Animals With Right Heart Failure: Correlation With Lymphatic Dysfunction. Journal of the American Heart Association. 2023 Apr 4:12(7):e026984. doi: 10.1161/JAHA.122.026984. Epub 2023 Mar 28     [PubMed PMID: 36974748]

Level 3 (low-level) evidence

[5]

Roe K. An inflammation classification system using cytokine parameters. Scandinavian journal of immunology. 2021 Feb:93(2):e12970. doi: 10.1111/sji.12970. Epub 2020 Sep 18     [PubMed PMID: 32892387]


[6]

Swartz MA. The physiology of the lymphatic system. Advanced drug delivery reviews. 2001 Aug 23:50(1-2):3-20     [PubMed PMID: 11489331]


[7]

Olszewski WL, Pazdur J, Kubasiewicz E, Zaleska M, Cooke CJ, Miller NE. Lymph draining from foot joints in rheumatoid arthritis provides insight into local cytokine and chemokine production and transport to lymph nodes. Arthritis and rheumatism. 2001 Mar:44(3):541-9     [PubMed PMID: 11263768]


[8]

Earley BE, Luce H. An introduction to clinical research in osteopathic medicine. Primary care. 2010 Mar:37(1):49-64. doi: 10.1016/j.pop.2009.09.001. Epub     [PubMed PMID: 20188997]


[9]

Alitalo K. The lymphatic vasculature in disease. Nature medicine. 2011 Nov 7:17(11):1371-80. doi: 10.1038/nm.2545. Epub 2011 Nov 7     [PubMed PMID: 22064427]


[10]

Goswami AK, Khaja MS, Downing T, Kokabi N, Saad WE, Majdalany BS. Lymphatic Anatomy and Physiology. Seminars in interventional radiology. 2020 Aug:37(3):227-236. doi: 10.1055/s-0040-1713440. Epub 2020 Jul 31     [PubMed PMID: 32773948]


[11]

Leak LV. The structure of lymphatic capillaries in lymph formation. Federation proceedings. 1976 Jun:35(8):1863-71     [PubMed PMID: 1269772]


[12]

Leak LV. Lymphatic endothelial-interstitial interface. Lymphology. 1987 Dec:20(4):196-204     [PubMed PMID: 2451094]


[13]

Leak LV, Burke JF. Fine structure of the lymphatic capillary and the adjoining connective tissue area. The American journal of anatomy. 1966 May:118(3):785-809     [PubMed PMID: 5956107]


[14]

Azhar SH, Lim HY, Tan BK, Angeli V. The Unresolved Pathophysiology of Lymphedema. Frontiers in physiology. 2020:11():137. doi: 10.3389/fphys.2020.00137. Epub 2020 Mar 17     [PubMed PMID: 32256375]


[15]

Murfee WL, Rappleye JW, Ceballos M, Schmid-Schönbein GW. Discontinuous expression of endothelial cell adhesion molecules along initial lymphatic vessels in mesentery: the primary valve structure. Lymphatic research and biology. 2007:5(2):81-9     [PubMed PMID: 17935476]


[16]

Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain, behavior, and immunity. 2007 Aug:21(6):736-45     [PubMed PMID: 17467231]


[17]

McHale NG, Thornbury KD. Sympathetic stimulation causes increased output of lymphocytes from the popliteal node in anaesthetized sheep. Experimental physiology. 1990 Nov:75(6):847-50     [PubMed PMID: 2271162]


[18]

Schmid-Schönbein GW. Microlymphatics and lymph flow. Physiological reviews. 1990 Oct:70(4):987-1028     [PubMed PMID: 2217560]


[19]

Schad H, Flowaczny H, Brechtelsbauer H, Birkenfeld G. The significance of respiration for thoracic duct flow in relation to other driving forces of lymph flow. Pflugers Archiv : European journal of physiology. 1978 Dec 28:378(2):121-5     [PubMed PMID: 569832]


[20]

Yao S, Hassani J, Gagne M, George G, Gilliar W. Osteopathic manipulative treatment as a useful adjunctive tool for pneumonia. Journal of visualized experiments : JoVE. 2014 May 6:(87):. doi: 10.3791/50687. Epub 2014 May 6     [PubMed PMID: 24836893]


[21]

Noll DR, Degenhardt BF, Johnson JC. Multicenter Osteopathic Pneumonia Study in the Elderly: Subgroup Analysis on Hospital Length of Stay, Ventilator-Dependent Respiratory Failure Rate, and In-hospital Mortality Rate. The Journal of the American Osteopathic Association. 2016 Sep 1:116(9):574-87. doi: 10.7556/jaoa.2016.117. Epub     [PubMed PMID: 27571294]


[22]

Noll DR, Degenhardt BF, Morley TF, Blais FX, Hortos KA, Hensel K, Johnson JC, Pasta DJ, Stoll ST. Efficacy of osteopathic manipulation as an adjunctive treatment for hospitalized patients with pneumonia: a randomized controlled trial. Osteopathic medicine and primary care. 2010 Mar 19:4():2. doi: 10.1186/1750-4732-4-2. Epub 2010 Mar 19     [PubMed PMID: 20302619]

Level 1 (high-level) evidence

[23]

Hruby RJ, Martinez ES. The Lymphatic System: An Osteopathic Review. Cureus. 2021 Jul:13(7):e16448. doi: 10.7759/cureus.16448. Epub 2021 Jul 17     [PubMed PMID: 34422479]


[24]

Huff JB, Schander A, Downey HF, Hodge LM. Lymphatic pump treatment augments lymphatic flux of lymphocytes in rats. Lymphatic research and biology. 2010 Dec:8(4):183-7. doi: 10.1089/lrb.2010.0009. Epub     [PubMed PMID: 21190489]


[25]

Racca V, Bordoni B, Castiglioni P, Modica M, Ferratini M. Osteopathic Manipulative Treatment Improves Heart Surgery Outcomes: A Randomized Controlled Trial. The Annals of thoracic surgery. 2017 Jul:104(1):145-152. doi: 10.1016/j.athoracsur.2016.09.110. Epub 2017 Jan 18     [PubMed PMID: 28109570]

Level 1 (high-level) evidence

[26]

Bath M, Nguyen A, Bordoni B. Physiology, Chapman’s Points. StatPearls. 2024 Jan:():     [PubMed PMID: 32644379]


[27]

Chin J, Francis M, Lavalliere JM, Lomiguen CM. Osteopathic Physical Exam Findings in Chronic Hepatitis C: A Case Study. Cureus. 2019 Jan 22:11(1):e3939. doi: 10.7759/cureus.3939. Epub 2019 Jan 22     [PubMed PMID: 30937237]

Level 3 (low-level) evidence

[28]

Adams JS, Parikh SH, Goodwin BJ, Noll DR. Does the osteopathic pedal pump reduce lower limb volume in healthy subjects? Journal of osteopathic medicine. 2023 Apr 1:123(4):201-206. doi: 10.1515/jom-2022-0127. Epub 2023 Jan 27     [PubMed PMID: 36701752]


[29]

Chin AJ, Fischione AD, Shilian R, Walter LM, Ratay SM, Bejanishvili TY, Wynbrandt JH, Rowane MP. Tolerance of Rib Raising Among Hospitalized Patients: A Pilot Study. The Journal of the American Osteopathic Association. 2019 Jan 1:119(1):19-23. doi: 10.7556/jaoa.2019.003. Epub     [PubMed PMID: 30556829]

Level 3 (low-level) evidence

[30]

Heald A, Perrin R, Walther A, Stedman M, Hann M, Mukherjee A, Riste L. Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention. Cardiovascular endocrinology & metabolism. 2022 Jun:11(2):e0261. doi: 10.1097/XCE.0000000000000261. Epub 2022 Apr 12     [PubMed PMID: 35441129]


[31]

Pratt-Harrington D. Galbreath technique: a manipulative treatment for otitis media revisited. The Journal of the American Osteopathic Association. 2000 Oct:100(10):635-9     [PubMed PMID: 11105452]


[32]

Bordoni B. Doming the Diaphragm in a Patient With Multiple Sclerosis. The Journal of the American Osteopathic Association. 2019 May 1:119(5):282a-283. doi: 10.7556/jaoa.2019.048. Epub     [PubMed PMID: 31034063]