U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details

Interstitial Cystitis

; .

Author Information

Last Update: April 14, 2022.

Continuing Education Activity

Interstitial cystitis is a chronic, non-infectious, inflammatory condition of poorly understood etiology that affects the urinary bladder. It is often a difficult condition to manage, with a variable response. It has a profound impact on the psychological and social wellbeing of the patient if symptoms are inadequately treated. This activity explains the approach, investigation, and management of interstitial cystitis and highlights the role of the interprofessional team in evaluating and treating interstitial cystitis.

Objectives:

  • Describe the etiology of interstitial cystitis.
  • Outline the management of patients with interstitial cystitis.
  • Explain the prognosis of interstitial cystitis.
  • Summarize how an interprofessional team can coordinate the care of interstitial cystitis to provide the best outcomes.
Access free multiple choice questions on this topic.

Introduction

Interstitial cystitis is a condition that affects the urinary bladder, characterized by chronic inflammation. It is not secondary to an infection. In many cases, because it remains a diagnosis of exclusion, the condition is often diagnosed late in the patient's journey. Patients often describe pain in the bladder region (suprapubic), with a strong sensation to want to urinate (urgency). This sensation is worsened by filling the bladder and is often relieved by passing urine more often (frequency). This may be during the daytime and/or during the night (nocturia). There may also be other symptoms such as pain or discomfort on passing urine (dysuria) and pain or discomfort during sexual intercourse, known as dyspareunia. Due to these symptoms, there is a profound impact on the emotional, psychological and social well-being of the patient.[1]

Anatomy

The urinary bladder is a hollow viscus located in the pelvis and is anterior to the rectum in both sexes and the uterus in females. It is partially covered in peritoneum on the superior surface. There are four layers.

  • Mucosa, which contains the transitional epithelium, allows for the stretch of the urinary bladder. When stretched, the surface is smooth, but when relaxed, folds form in the mucosa, known as rugae.
  • Submucosa, which is composed of elastic connective tissue, further assists with the stretch of the bladder.
  • Muscularis layer (detrusor muscle) is composed of multiple layers of smooth muscle in multiple directions, which assists with the voiding of the bladder when contraction occurs. They also form a small band that encircles the area between the opening of the bladder and the urethra. This is known as the internal urinary sphincter. The autonomic nervous system controls this layer. Another band around the internal sphincter controls conscious voiding, called the external sphincter, which is composed of skeletal muscle and is innervated by the somatic nervous system.
  • The fibrous connective tissue layer is the outermost layer of the bladder except for the superior surface, with is covered by the parietal peritoneum.

The bladder is also divided into a triangular area called the trigone. This is formed by the openings to each ureter and the opening to the urethra. This forms three apices. The openings of each ureter are also covered by a small flap of mucosa that acts as a valve to prevent reflux of urine into the kidney. The trigone is located at the base, also known as the fundus of the urinary bladder.[2]

Etiology

The etiology of interstitial cystitis is not well understood, and the current thoughts around its pathogenesis remain multifactorial. Leading concepts include

  • Urothelial dysfunction, especially in the epithelial and glycosaminoglycan (GAG) layer
  • Mast cell dysfunction
  • Vascular malformations, seen as glomerulations on cystoscopy.
  • Neurogenic inflammation/edema
  • Autoimmune or immune-mediated process
  • Increase in sensory afferent fibers by upregulation
  • Fibrosis
  • Increase in grey matter volume leading to increase sensitivity to pain

Current research suggests an inflammatory process. However, the cause for inflammation is not well studied or understood. In a recent study, they describe an organic process behind interstitial cystitis. Through cystoscopy, they observed submucosal inflammation, which is seen as glomerulations, with large groups of mast cells, which in turn stimulates afferent fibers more. They also describe increased urothelial permeability due to diminished GAG levels and ultrastructural abnormalities seen on biopsies that show loss of tight junctions and adhesive junction proteins. This may be the reason why immunoglobulin and immune mediators are detected at higher levels in the urine of affected individuals. Furthermore, fibrosis may result from the inflammatory process, evident by upregulation of extracellular matrix proteins, myofibroblasts, and decreased capillary density, which reduces the bladder capacity and leads to a further stretch of afferent sensory pain fibers.[3]

Another multi-center study has demonstrated a non-organic process behind interstitial cystitis, demonstrating increased grey matter volume in some patients with interstitial cystitis in brain regions that are responsible for pain perception. This was observed using functional magnetic resonance imaging (fMRI).[4][5]

An interesting relationship to discuss is between severe interstitial cystitis-like symptoms to the use of illegally sourced ketamine. With this, the etiology remains unknown as well. The main theories behind this are urothelial damage, microvascular changes, autoimmunity, and infection either by ketamine or through metabolites. The symptoms, cystoscopy, and biopsy findings have a great degree of crossover with interstitial cystitis, and the main difference would be the recreational abuse of ketamine. The risk of developing ketamine cystitis does not appear to be increased with the proper medical use of the drug.[6]

Epidemiology

Due to the nature of interstitial cystitis, it is very difficult to formulate a clear diagnosis easily, and there exists no screening tool for it. Hence, the data surrounding its prevalence remains limited. However, there exist some studies that have looked into the epidemiology of interstitial cystitis. There are two main study designs, one based on physician/urologist-based diagnosis and the other by a questionnaire around symptomatology. Based on a large population, questionnaire-based, prevalence study in the US, 2.7% of women meet the specified criteria, with 1.9% of men meeting the criteria.[7][8] In terms of age groups, women between 50-59 and men between 56 to 74 years of age.

However, a lower prevalence is seen when physician-completed questionnaires and histological samples were employed to establish a diagnosis. A study in the Netherlands quoting as low as between 8-16 out of 100,000 individuals.[9] Investigations have noted a female predisposition, with one study in the US quoting a 5 to 1 ratio.[10]

It is estimated that it affects up to 400,000 patients in the UK, with almost 90% of the patients being women between 50 and 69 years of age.[11]

The data for children affected by Interstitial cystitis is poor, but the expert consensus is that the prevalence is very low in the pediatric population.

History and Physical

A detailed history and careful examination are needed to exclude other causes, as there is considerable overlap between other conditions.[1]

Symptoms

  • Lower urinary tract symptoms
    • Dysuria
    • Frequency/nocturia
    • Incontinence
  • Haematuria
  • Pain, usually suprapubic, and particularly persists after voiding
  • Fever, chills, and rigors
  • Weight loss

Other Important Questions

  • Recurrent urinary tract infections and symptoms related to antibiotic use.
  • Vulvar pain
  • Detailed gynecological history
  • Past medical, social, and family history.
  • Sexual history

Physical Examination

  • Abdominal examination, including per-rectal examination, external genitalia, and hernia orifices.
  • Gynecological examination, paying close attention to vulvar pain, cervical excitation, any prolapses/masses, as well as adnexal palpation.
  • Full neurological examination including tone, reflexes, power, sensation, and cranial nerve examination.

Evaluation

The workup before establishing a diagnosis of interstitial cystitis is dependent on ruling out other potential conditions. It may involve multiple specialists before arriving at a diagnosis.

Investigations

  • Bloods
  • Diabetic tests - glucose, HbA1c
  • Urinalysis - urine dipstick, microscopy, culture, and sensitivity
  • Sexual health screening, such as cervical or urethral swabs for herpes and chlamydia.
  • Urodynamic studies
  • Cystoscopy
    • It is mainly to rule out malignancy. The appearance of lesions is very similar to malignancy, particularly carcinoma in situ.
    • During visualization of the distended bladder, there may be Hunner's ulcers, which are often described as a pale central scar with or without a fibrin clot and surrounded erythematous mucosa, with small vessels radiating towards the center. It is specific in the diagnosis of interstitial cystitis. However, it is not common even in patients suffering from it, with some studies describing only between 5% to 10% being present.[12]
    • Reactive hemorrhages are also a sign of interstitial cystitis. This is when on initial examination under cystoscopy, the mucosa appears normal (distended). Still, when deflated and re-inspected, points of capillary bleeding are noted on a background of normal mucosa.[13]
    • The urologist may carry out further investigations whilst performing cystoscopies such as hydro-distention and lidocaine instillation.

Treatment / Management

Before commencing treatment, The American Urological Association (AUA) recommends the patient should have been explained regarding the complex nature of the disease. For the majority of patients, no single treatment exists to relieve symptoms. A baseline record of the patient's experience would be useful to compare the efficacy of treatment. This may be in the form of a pain scale, e.g., a visual chart, or in the form of a patient-recorded bladder diary.

The treatment options are detailed below,

Conservative

  • Manual physical therapy for pelvic floor tenderness to relieve tender muscle points, contracture lengthening, and/or scars.
  • Bladder re-training
  • Stress management to avoid stress-driven symptoms.
  • Special diets. The recommended route should be individualized, with a diary to record what substances cause a flare of symptoms. However, generally, some common foods have been reported to cause symptoms. These are tomatoes, spice, chocolate, and citrus fruits, as well as alcohol and caffeine. The main theory behind this is due to the acidic nature of the substances contributes to bladder irritation.
  • Transcutaneous electrical nerve stimulation (TENS)
  • Support groups
  • Cognitive-behavioral therapy

Pharmacological

Most patients do not respond to a single agent, and a complex multidisciplinary option with expert guidance under a pain specialist or clinic should be sought. However, treatment should be introduced slowly, with the lowest possible dose and a minimal number of drugs used as possible, in line with the WHO pain ladder.

The options are mainly divided further into oral and intra-vesical routes.

Oral

  • Analgesics, e.g.: paracetamol and ibuprofen.
  • Antihistamines (cimetidine)
  • Antidepressants (amitriptyline)
  • Pentosan-polysulfate
  • Oxybutynin and gabapentin

Intravesical Instillation

  • Lidocaine and sodium bicarbonate
  • Pentosan-polysulfate
  • Heparin
  • Dimethyl sulfoxide (DMSO): It acts as a topical analgesic, and a 50% DMSO solution is approved for use by the FDA.
  • Hyaluronic acid and chondroitin sulfate.
  • Trials are looking at improved efficacy of intravesical preparations when a low voltage is applied to drive the preparations into the bladder tissue. This is achieved by using probes in the bladder and abdomen to create a voltage gradient known as electromotive drug administration (EMDA). A randomized prospective trial demonstrated improved short-term efficacy. The main issue with the study is the low sample size (n=31).[14]

Cystoscopy Guided Treatment

  • The AUA recommends low-pressure hydrodistention for a short period, or
  • If Hunner lesions are present, treat using direct fulguration through diathermy or laser, and/or injection of steroid, e.g., triamcinolone.

Intra-detrusor Injection (with Botulinum toxin type A)

  • This is quoted as a 4th line treatment option by the AUA, and current recommendations are that the patient should be warned that there may be a need for intermittent self-catheterization in the future.

Systemic Immunosuppression

  • Currently, only ciclosporin is recommended for use. A mutual decision between the doctor and patient is needed. The patient needs to be made aware of the risks of systemic immunosuppression, such as vulnerability to infection and the development of malignancies. This is the last non-surgical option available currently.

A recent meta-analysis done in July 2020 looked at 81 randomized, controlled trials and compared the effectiveness of treatment of all the options, but focused on 3 main groups, namely antidepressants, pentosan polysulfate, and neuromuscular blockade which is achieved by Botulinum injections. They found improved outcomes compared to control for antidepressants and the neuromuscular blockade. However, the former is of very low certainty. There was no difference in pain relief, daytime frequency, or nocturia. Pentosan polysulfate did not show any improvement compared to control in all domains. However, the authors did not have a separate analysis for the mode of delivery.[15]

Surgical Treatment

This has seen a fall in popularity in recent times, especially after introducing intra-detrusor injections of Botulinum toxin A. However, it remains the last resort option for patients with the intractable disease at a resolution of symptoms. A summary of possible options are.[16]

  • Cystoplasty only
  • Cystoplasty with supra-trigonal resection
  • Cystoplasty with sub-trigonal resection
  • Urinary diversion, with or without cystectomy and urethral resection. This may be in the form of a urostomy.

Furthermore, multiple sources in addition to the American Urological Association, such as the National Institute for Clinical Excellence (NICE) and the European Association of Urology (EAU), do not currently recommend prolonged oral antibiotics, prolonged oral steroids, intravesical BCG, intravesical clorpactin, and prolonged high-pressure hydrodistention as treatment options.

Differential Diagnosis

The possible list of differential diagnoses is extensive, and this list is not exhaustive, but the causes can be broken down into:[17]

Infection

  • Urinary tract infection
  • Sexually transmitted infections such as Chlamydia and Gonorrhoea
  • Tuberculous infections of the bladder

Other Urological/Urogynaecological Conditions

  • Urge incontinence/detrusor instability
  • Stress incontinence
  • Chronic urethral syndrome
  • Prolapses
  • Prostate pathology, including but not limited to prostate hyperplasia, prostate cancer, and prostatitis.
  • Neoplasms of the urinary bladder

Gynecological Conditions

  • Pelvic inflammatory disease
  • Endometriosis
  • Pregnancy

Diabetes

Neurological

  • Diabetic neuropathy
  • Cauda equina/cord compression
  • Demyelinating diseases
  • Stroke

Other Causes

  • Trauma
  • Radiation-induced
  • Inflammatory bowel disease
  • Diverticular disease
  • Urinary diverticulum/congenital malformations

Prognosis

The majority of patients suffer from chronic symptoms, but there is a wide variation in prognosis and resolution. Patterns of the disease have been observed and described. These are

  • Complete resolution
  • Relapsing-remitting
  • Intermittent disease flares
  • Chronic progression.

The patient may also experience spontaneous resolution on, or off-treatment, with or without recurrence.[18]

Complications

If left untreated and without spontaneous resolution, the bladder may undergo further fibrosis, further reducing the bladder volume and further compounding the symptoms experienced. The patient would experience deterioration in their psychological and social health through sleep disturbance, sexual dysfunction, anxiety, depression, and social embarrassment.

Complications of treatment depend on various factors, such as the pharmacological agent used, cystoscopy or surgical complications, and proper counseling and consent before treatment are paramount.[19] It can be broadly categorized as:

  • Infection (introduced through intra-vesical routes or surgery)
  • Bleeding
  • Trauma 
  • Perforation of the bladder during high-pressure hydrodistention
  • Death (from procedure or anesthesia)
  • Anesthetic complications include respiratory depression, pulmonary aspiration, cardiovascular collapse, postoperative nausea and vomiting, anaphylaxis, medication error, and death.[20] The majority of these are due to human factors and patient status, which in the healthiest group has an estimated mortality of 0.4 per 100,000 patients.[21]
  • At the time of writing this article, the risk of potentially contracting COVID-19.[22]

There is also a theoretical risk of urinary tract infections. The symptoms may change and worsen during this time, and tests for infection should always be checked in those circumstances. This is due to the damage and breach of the urothelium, which increases the probability of bacterial invasion, harm, and symptoms. In selected cases like these, a short course of antibiotics could be started. However, prolonged courses for prophylaxis or treatment are not recommended.

Deterrence and Patient Education

Once the diagnosis is made, the patient should be counseled on what that means, why they experience the symptoms, and that the etiology is not well-understood at present.

The patient should be directed and encouraged to engage with self-help and the local support groups, such as those offered by the Interstitial Cystitis Association in the United States, as well as Bladder Health UK, or PainUK in the United Kingdom. Some patients that have used self-help found that it is the most effective out of the treatment options.[23]

There are many treatments for the condition, with variable results. It can take up to months before the patient notices an improvement, and the effects may be only marginal. They need to be explained that the condition may not be cured, and symptoms may return at any time. However, with the right treatment, there can be significant improvements in their symptoms and quality of life for the right patient.

Enhancing Healthcare Team Outcomes

Due to the nature of interstitial cystitis to follow a chronic path, it can lead to significant disturbance in a patient's quality of life and therefore have a profound negative impact on their psychological and social health. The condition is often not easily managed by one intervention alone, and there are often many physical and psychological co-morbidities. Therefore, an interprofessional approach involving different specialties is best suited to offer the best care to the patient. This would likely include a urologist, pain specialist/team, specialist nurses, mental health specialists, and their family doctor.[15][24]

Review Questions

Normal mucosa of the bladder wall, characterised by pale/pink appearance, lack of erythema, swellings, and relatively straight capillaries

Figure

Normal mucosa of the bladder wall, characterised by pale/pink appearance, lack of erythema, swellings, and relatively straight capillaries. Contributed by Mr O'Rourke, FRCS

Abnormal mucosa wall, this image shows capillary glomerulations

Figure

Abnormal mucosa wall, this image shows capillary glomerulations. Contributed by Mr O'Rourke, FRCS

Abnormal bladder mucosa, showing a Hunner's ulcer

Figure

Abnormal bladder mucosa, showing a Hunner's ulcer. The erythematous mucosa, with radiating capillaries towards a pale central ulcer is visualised here. Contributed by Mr O'Rourke, FRCS

Illustration of the bladder anatomy, with an illustration of a classic Hunner's ulcer located at the posterior bladder mucosa, where it is most commonly found

Figure

Illustration of the bladder anatomy, with an illustration of a classic Hunner's ulcer located at the posterior bladder mucosa, where it is most commonly found. Contributed and Illustrated by Dr Ramiz Ahmed-Man, MBBS

References

1.
Bogart LM, Berry SH, Clemens JQ. Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systematic review. J Urol. 2007 Feb;177(2):450-6. [PubMed: 17222607]
2.
Shermadou ES, Rahman S, Leslie SW. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 31, 2021. Anatomy, Abdomen and Pelvis, Bladder. [PubMed: 30285360]
3.
Tyagi P, Moon CH, Janicki J, Kaufman J, Chancellor M, Yoshimura N, Chermansky C. Recent advances in imaging and understanding interstitial cystitis. F1000Res. 2018;7 [PMC free article: PMC6234747] [PubMed: 30473772]
4.
Kairys AE, Schmidt-Wilcke T, Puiu T, Ichesco E, Labus JS, Martucci K, Farmer MA, Ness TJ, Deutsch G, Mayer EA, Mackey S, Apkarian AV, Maravilla K, Clauw DJ, Harris RE. Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome. J Urol. 2015 Jan;193(1):131-7. [PMC free article: PMC4435781] [PubMed: 25132239]
5.
Kilpatrick LA, Kutch JJ, Tillisch K, Naliboff BD, Labus JS, Jiang Z, Farmer MA, Apkarian AV, Mackey S, Martucci KT, Clauw DJ, Harris RE, Deutsch G, Ness TJ, Yang CC, Maravilla K, Mullins C, Mayer EA. Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome. J Urol. 2014 Sep;192(3):947-55. [PMC free article: PMC4432915] [PubMed: 24681331]
6.
Misra S, Chetwood A, Coker C, Thomas P. Ketamine cystitis: practical considerations in management. Scand J Urol. 2014 Oct;48(5):482-8. [PubMed: 24779452]
7.
Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, Nyberg L, Clemens JQ. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011 Aug;186(2):540-4. [PMC free article: PMC3513327] [PubMed: 21683389]
8.
Suskind AM, Berry SH, Ewing BA, Elliott MN, Suttorp MJ, Clemens JQ. The prevalence and overlap of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome in men: results of the RAND Interstitial Cystitis Epidemiology male study. J Urol. 2013 Jan;189(1):141-5. [PMC free article: PMC3894747] [PubMed: 23164386]
9.
Bade JJ, Rijcken B, Mensink HJ. Interstitial cystitis in The Netherlands: prevalence, diagnostic criteria and therapeutic preferences. J Urol. 1995 Dec;154(6):2035-7; discussion 2037-8. [PubMed: 7500452]
10.
Clemens JQ, Meenan RT, O'Keeffe Rosetti MC, Brown SO, Gao SY, Calhoun EA. Prevalence of interstitial cystitis symptoms in a managed care population. J Urol. 2005 Aug;174(2):576-80. [PubMed: 16006901]
11.
Chung KJ, Han AN, Kim KH. Recommendations to the primary care practitioners and the patients for managing pelvic pain, especially in painful bladder syndrome for early and better prognosis. J Exerc Rehabil. 2015 Oct;11(5):251-4. [PMC free article: PMC4625652] [PubMed: 26535214]
12.
Sholan R. Clinical manifestations and results of cystoscopy in women with interstitial cystitis/bladder pain syndrome. North Clin Istanb. 2020;7(5):417-424. [PMC free article: PMC7603858] [PubMed: 33163875]
13.
Grover S, Srivastava A, Lee R, Tewari AK, Te AE. Role of inflammation in bladder function and interstitial cystitis. Ther Adv Urol. 2011 Feb;3(1):19-33. [PMC free article: PMC3126088] [PubMed: 21789096]
14.
Gülpınar O, Haliloğlu AH, Gökce Mİ, Arıkan N. Instillation of Hyaluronic Acid via Electromotive Drug Administration Can Improve the Efficacy of Treatment in Patients With Interstitial Cystitis/Painful Bladder Syndrome: A Randomized Prospective Study. Korean J Urol. 2014 May;55(5):354-9. [PMC free article: PMC4026663] [PubMed: 24868341]
15.
Imamura M, Scott NW, Wallace SA, Ogah JA, Ford AA, Dubos YA, Brazzelli M. Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis. Cochrane Database Syst Rev. 2020 Jul 30;7:CD013325. [PMC free article: PMC8094454] [PubMed: 32734597]
16.
Osman NI, Bratt DG, Downey AP, Esperto F, Inman RD, Chapple CR. A Systematic Review of Surgical interventions for the Treatment of Bladder Pain Syndrome/Interstitial Cystitis. Eur Urol Focus. 2021 Jul;7(4):877-885. [PubMed: 32127327]
17.
Marcu I, Campian EC, Tu FF. Interstitial Cystitis/Bladder Pain Syndrome. Semin Reprod Med. 2018 Mar;36(2):123-135. [PubMed: 30566978]
18.
Cvach K, Rosamilia A. Review of intravesical therapies for bladder pain syndrome/interstitial cystitis. Transl Androl Urol. 2015 Dec;4(6):629-37. [PMC free article: PMC4708535] [PubMed: 26816864]
19.
Engelsgjerd JS, Deibert CM. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 20, 2021. Cystoscopy. [PubMed: 29630232]
20.
Fasting S. [Risk in anaesthesia]. Tidsskr Nor Laegeforen. 2010 Mar 11;130(5):498-502. [PubMed: 20224619]
21.
Gottschalk A, Van Aken H, Zenz M, Standl T. Is anesthesia dangerous? Dtsch Arztebl Int. 2011 Jul;108(27):469-74. [PMC free article: PMC3147285] [PubMed: 21814522]
22.
Axiotakis LG, Youngerman BE, Casals RK, Cooke TS, Winston GM, Chang CL, Boyett DM, Lalwani AK, McKhann GM. Risk of Acquiring Perioperative COVID-19 During the Initial Pandemic Peak: A Retrospective Cohort Study. Ann Surg. 2021 Jan 01;273(1):41-48. [PMC free article: PMC7737880] [PubMed: 33156061]
23.
Breau RH, McGrath PJ, Norman RW. Assessing self-help issues for patients with prostate cancer, interstitial cystitis, erectile dysfunction and urinary diversion. BJU Int. 2003 Nov;92(7):736-40. [PubMed: 14616457]
24.
Gupta P, Gaines N, Sirls LT, Peters KM. A multidisciplinary approach to the evaluation and management of interstitial cystitis/bladder pain syndrome: an ideal model of care. Transl Androl Urol. 2015 Dec;4(6):611-9. [PMC free article: PMC4708537] [PubMed: 26816861]
Copyright © 2022, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK570588PMID: 34033350

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...