Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Jun 1.
Published in final edited form as: Curr Bladder Dysfunct Rep. 2019 May 3;14:90–97. doi: 10.1007/s11884-019-00511-0

New Diagnostics for Male Lower Urinary Tract Symptoms

Natalie R Swavely 1, John E Speich 2, Lynn Stothers 3, Adam P Klausner 1
PMCID: PMC6959483  NIHMSID: NIHMS1528559  PMID: 31938079

Abstract

Purpose of review:

Lower urinary tract symptoms (LUTS) is a common constellation of symptoms that affect the aging male population with an astonishing prevalence. New technology and new uses of established technology are being used to help further evaluate LUTS in the male population and help guide treatment options. This review focuses on the developments and future directions in diagnostic modalities for evaluation of male LUTS, focusing on evaluation of both the filling and voiding phases of micturition.

Recent findings:

New techniques in evaluating the voiding phase include penile cuff test, external pressure sensing condom catheter, ultrasound measurement of detrusor wall thickness, ultrasound measurement of intravesical prostatic protrusion, doppler ultrasound and NIRS technology. Evaluation of the filling phase is still undergoing much development and requires additional validation studies. The techniques undergoing evaluation include sensation meters during UDS, assessing bladder micromotion and wall rhythm, assessing detrusor wall biomechanics, ultrasound measurement of detrusor wall thickness, pelvic doppler ultrasound, as well as functional brain imaging including fNIRS and fMRI.

Summary:

The development of novel, non-invasive, diagnostic tools have the potential for better evaluation of LUTS with earlier and enhanced treatments. This will likely improve the quality of life for men with LUTS.

Keywords: Lower urinary tract symptoms, urodynamics, bladder dysfunction, voiding complaints, diagnosis

Introduction

Lower urinary tract symptoms (LUTS) are a common chief complaint seen by urologists, with prevalence rates of 50% - 75% in men over 50, and increasing to 80% in men over 70. [1] LUTS is a constellation of symptoms and includes disruption of both the filling and voiding phases of the micturition cycle. These symptoms often increase with age and affect patient quality of life, activities, and even occupation. [1] LUTS has an array of etiologies, and treatment is largely dependent on the etiology for a particular patient. Urinary tract symptoms are often difficult for the patient to describe, and the Urologist may rely heavily on objective measures such as uroflow and urodynamics (UDS) for assistance in diagnosis. [2] Research is being performed on new methods to evaluate the lower urinary tract for etiology of these symptoms, particularly non-invasive measures to improve and expand upon the diagnostic tools already in place. Patients may often be hesitant to undergo UDS given its invasive nature; however, successful treatment often revolves around knowledge of the etiology of patient’s symptoms.

The micturition cycle is divided into the filling phase and the voiding phase. Pathology in either phase can lead to LUTS. The current diagnostic adjuncts to UDS include uroflow and post void residual (PVR), but these tools only assess the voiding phase with adjunct evaluation of the filling phase being completed in questionnaires. Unlike other medical specialties where an array of non-invasive, diagnostic tools exist which can be utilized prior to invasive diagnostic testing, evaluation of micturition has little to offer prior to invasive and uncomfortable UDS. Therefore, development of an objective evaluation of male LUTS that is also minimally invasive is critical to continued advancement in diagnosis and treatment. This review will focus on these up-and-coming technologies, divided into separate sections regarding the filling and voiding phases of micturition.

Emerging Technologies and Methods to Evaluate the Voiding Phase

Emerging technology and methods to evaluate the voiding phase are derived from multiple sources. The first is an ongoing randomized trial entitled, “Urodynamics for Prostate Surgery Trial - Randomised Evaluation of Assessment Methods (UPSTREAM).” Other methods include the penile cuff test, a novel pressure sensing external catheter, measurements of detrusor wall thickness, evaluation of intravesical prostatic protrusion, use of pelvic doppler, and bladder Near Infrared Spectroscopy (NIRS) (Table 1). These advancements and their effectiveness will be further discussed in this section.

Table 1.

Voiding Phase Diagnostics

Urodynamics Non-inferiority trial assessing UDS prior to prostate surgery, results pending3 UPSTREAM trial3
Penile cuff test Pediatric blood pressure cuff placed around penis and quickly cycle to interrupt flow during micturition. Nomogram of pressure rise during interruption vs pre-interruption flow rate to determine obstructed versus unobstructed patients.613 Griffiths6, Bianchi7, Harding8, Kazemeyni9, Matulewicz10, Salinas11, Sullivan12, Ko13
External condom catheter Pressure sensing condom catheter to serve as abdominal pressure and external pressure applied to the condom catheter to interrupt flow. Nomogram of pressure vs flow rate to determine obstructed versus unobstructed patients.14 Pel14
Detrusor wall thickness Measured with ultrasound, 2–6 mm diagnostic for BOO1522 Franco15, Abdel-Aal16, Aganovic17, El Saied18, Kessler19, Manieri20, Oelke21, Oelke22
Intravesical prostatic protrusion Measured with ultrasound, 10–12mm diagnostic for BOO1517,2329 Franco15, Abdel-Aal16, Aganovic17 Aganovic23, Chia24, Dicuio25, Keqin26, Lim27, Pascual28, Reis29
Doppler ultrasound RI of detrusor muscle significantly increased in BOO3031
VR of urine significantly increased, greater than 1.6, in BOO3233
Belenky30, Kojima31, Ozawa32, Ding33
NIRS CART assessed patterns in changes in oxygenation. Nomogram of detrusor pressure at maximum flow versus relative concentration of total hemoglobin at maximum flow to classify patients as either obstructed or unobstructed4446 Stothers44, Yurt45, Zhang46

UDS=urodynamics, UPSTREAM = Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods, BOO = bladder outlet obstruction, RI = resistive index, VR= velocity ration, NIRS = near–infrared spectroscopy, CART= classification and regression tree algorithm

For men with LUTS, a main cause of voiding phase symptomatology is bladder outlet obstruction (BOO). This commonly treated pathology, benign prostatic enlargement (BPE), often requires surgical management. BOO must be differentiated from an underactive bladder, for which surgical treatment is not employed. The UPSTREAM trial, recently completed with results expected to be published soon, is assessing the use of UDS prior to surgery in men with suspected BOO. [3] Current standard of care does not require UDS prior to operation for BOO and this non-inferiority trial will assess use of UDS prior to surgery. [3,4]

Beyond UDS, a number of additional modalities to establish a diagnosis of BOO have been studied. Malde et al performed a systematic review of non-invasive tests to diagnose BOO. While the heterogeneity of the 42 included studies made conclusions difficult, the study highlights a number of techniques that offer a promise of non-invasive adjuncts. [5] One of these modalities, the penile cuff test, involves place a small, inflatable cuff or pediatric blood pressure cuff around the penile shaft. This is inflated automatically during voiding until urinary flow is stopped. The cuff is rapidly deflated and urine flow is resumed. This cycle is repeated until the end of micturition, and the pressure required to stop urine flow is considered equal to isovolumetric pressure. A nomogram evaluated pressure rise during interruption with pre-interruption flow rate to determine obstructed versus unobstructed patients. [6] Malde et al evaluated 7 studies of penile cuff test compared to pressure flow studies and found 88.9% sensitivity and 75.5% specificity. [512] Continued research into penile cuff test has continued to show promising results, with high negative predictive value of 94.9% on a recent prospective study of 146 men. [13]

Similarly, Pel et al used an external condom catheter in comparison to a pressure flow study to evaluate for BOO. [14] The external condom catheter was drained into a uroflow device and a pressure transducer was placed inside the condom catheter to measure pressure during voiding. A constricting pressure cuff was placed around the condom, and a nomogram was again used to evaluate pressure with flow rates to determine obstructed versus unobstructed. Seventy-five percent of their participants were correctly diagnosed using this method compared to pressure flow studies. The majority of the failures were seen in patients who strained during urination. [14]

Increased detrusor wall thickness has also been examined as a potential diagnostic measurement of BOO. Wall thickness can be assessed via non-invasive ultrasound technology. Franco et al measured the wall thickness of men with approximately 200 mL of fluid in the bladder and found that detrusor wall thickness of 6mm was highly correlated with bladder outlet obstruction index (BOOI) and bladder prostatic obstruction (BPO). [15] In a systematic review of 8 studies of detrusor wall thickness compared to pressure flow studies, a range of detrusor wall thicknesses of 2 mm – 6 mm were used as diagnostic criteria BOO. Five of the 8 studies used as a 2 mm cutoff. Pooled analysis found 82.7% sensitivity and 92.6% specificity. [5,1522]

Using similar ultrasound methodology, intravesical prostatic protrusion has also been examined. Franco et al measured intravesical prostatic protrusion in addition to detrusor wall thickness and found that intravesical prostatic protrusion of 12mm is also highly correlated with BOOI and BPO. They concluded that using detrusor wall thickness with intravesical prostatic protrusion together best predicted BOO, as performing these 2 measurements in succession lead to a diagnostic accuracy of 87%. [15] Systematic review of 10 studies of intravesical prostatic protrusion, with 5 studies using a 10 mm cutoff showed a sensitivity of 67.8% and a specificity of 74.8%. [5,1517, 2329]

In addition, non-invasive doppler ultrasound of the detrusor has been compared to UDS for the diagnosis of BOO. Using doppler technology, a resistive index (RI) can be calculated using the formula: (velocity max-velocity minimum)/velocity max. Using the RI as diagnostic test for BOO was found to have accuracy of 86% with a positive predictive value of 95%. [30] This statistically significant increased RI seen in BOO is thought to be secondary to detrusor hypertrophy seen in BOO associated with reduced vascular supply. [3031] Doppler technology has also been applied to measure the flow of urine to evaluate for BOO. Ozawa et al calculated a velocity ratio (VR) to diagnose BOO. [32] They found a VR greater than 1.6 in men with BOO and a VR less than 1.1 in men that did not have BOO. The VR was calculated during micturition with the maximum velocity of urine in the prostatic urethra compared to the maximum velocity of urine in the membranous urethra. This ratio reduces inter-subject discrepancies due to microbubbles which can affect doppler signaling. The prostatic and membranous urethra were chosen as location points of analysis due to the prostatic urethra being the location of control of flow of urine and the membranous urethra being an area of low resistance. [32] VR was evaluated for reliability and was found to have good intra-rater and inter-rater agreement. [33]

Near-infrared spectroscopy (NIRS) uses near infrared light to quantify changes in tissue oxygenation and has safely been used in human tissue since late 1970s. [3436] NIRS was first used in urology in the 1990s and has recently been used in evaluation of bladder function. [3743] Using NIRS in the evaluation of BOO, Stothers et al performed NIRS simultaneously with UDS. A NIRS patch was placed on the abdominal skin 2 cm above the pubis in the midline. A classification and regression tree algorithm (CART) was used to assess patterns in the NIRS data and changes in oxygenation throughout the UDS. A nomogram was created using detrusor pressure at maximum flow versus relative concentration of total hemoglobin at maximum flow to classify patients as either obstructed or unobstructed. They found a sensitivity of 100% and a specificity of 87.5%. [44] Systematic review of 3 studies using NIRS to define BOO found a sensitivity of 85.7% and a specificity of 87.5%. [5,4446]

Moving forward, a number of these new non-invasive techniques may be combined in an algorithmic manner to provide diagnostic information on BOO without the invasive measures of UDS. [47]

Emerging Technologies and Methods to Evaluate the Filling Phase

New technologies for the assessment of the filling phase of the micturition cycle are still in development and will require additional study and validation prior to widespread application. New metrics to evaluate the filling phase include: sensation metrics, bladder wall micromotion and rhythmic contraction analysis, detrusor biomechanics, pelvic doppler ultrasound, and functional brain imaging using both MRI and NIRS (Table 2). The creation and future utility of these techniques will be discussed in this section.

Table 2.

Filling Phase Diagnositics

Sensation meter Allows for constant assessment of sensation along a continuum5152,55 Nagle51, Naimi52, Lowenstein55
Oral hydration studies Physiologic filling with oral electrolyte consumption with sensation and volume measurements51,5354, 56 Nagle51, Heeringa5354, De Wachter56
Bladder micromotion and bladder rhythm Increased LARC and micromotion in DO6062 Brading60, Drake61, Cullingsworth62
Detrusor biomechanical properties Increased ultrasound shear wave elastography in non-compliant bladder.63
Increased bladder vibrometry in non-compliant bladder.6465
Increased detrusor wall tension in OAB.6667
Abnormal bladder fill shape in OAB.68
Sturm63, Bayat64, Nenadic65, Nagle66, Habteyes67, Glass68
Ultrasound bladder wall thickness Bladder wall thickness is not predictive of DO6970 Rachaneni69, Latthe70
Pelvic doppler ultrasound Doppler ultrasound diagnosing chronic pelvic ischemia, a proposed mechanism of damage leading to LUTS7174 Pinggera71, Yamaguchi72, Andersson73, Andersson74
Functional brain imaging fMRI reveals activation of SMA75 and prefrontal deactivation in patients with DO76. Development of new therapies for patients with DO that do not respond to anti-muscarinic medication.80
fNIRS is able to demonstrate cerebral region functionality similarly to fMRI in a non-restrictive environment.8185
Tadic75, Khavari76, Clarkson80, Ferrari81, Matsumoto8283, Sakakibara84,85

DO = detrusor overactivity, OAB= overactive bladder, LUTS = lower urinary tract symptoms, SMA = supplementary motor area, fNIRS = functional near–infrared spectroscopy, fMRI = functional magnetic resonance imaging

Currently, sensation during UDS is assessed with patient declaration of first sensation, first desire and strong desire. [48] These regimented and subjective terms may not accurately describe what the patient is feeling and may be influenced by investigator prompting as well as the non-physiologic and artificial nature of testing. [4950] In fact Erdem et al. performed sham UDS studies. [49] In the first sham fill, 83% declared first sensation, 79% had first desire, 64% had normal desire, and 25% had strong desire even in the absence of filling, highlighting the artificial nature of UDS. Nagle et al developed a sensation meter that allows the patient, in real time, to use a touch screen and assess what they are feeling and make changes as their sensations change on a scale of 0 to 100%. [51] This new metric generates a sensation-capacity curve throughout the filling phase which enables comparisons of different pathologies, including overactive bladder (OAB). [5152] In addition, the technology gives more accurate and detailed description of bladder sensation during filling using the phrases, adopting the terminology established by Heeringa et al., as “tense,” “tingling,” “pressure,” and “painful”. [5154] Lowenstein et al55 also developed a similar device to allow for continuous sensation data collection during UDS. These investigators completed a feasibility study with the Urgeometer, a handheld device allowing for reporting of sensation on a continuum from no urge to strongest imaginable urge. The patient was able to move the lever throughout UDS. [55] These sensation meters can be used in standard UDS or during oral hydration studies. [5155] Oral hydration studies of bladder filling have the patient consume a prescribed volume of fluid and measure their sensation on a continuous sensation meter as well as volume voided. [5354,56] This technique has demonstrated feasibility in diagnosis of OAB. [51]

During filling, it is known that the bladder displays spontaneous rhythmic contractions (SRC). [57] It has been suggested that SRC may function to maintain bladder tone, which will allow the detrusor to contract and allow for voiding at a range of bladder volumes. [58] Fast Fourier transforms (FFT) have been used to analyze signals and differentiate true signals from background noise to investigate SRC. [59] SRC have been shown to be elevated in a subset of patients with detrusor overactivity (DO) and have additionally been associated with increased micromotion with bladder filling with accompanying increased urgency. [6061] An FFT algorithm applied to UDS of patients with and without DO showed 100% specificity. [62] This additional analysis of pathology in patients with DO can help individualize treatment strategies.

Ultrasound has also recently been added as an adjunct to UDS in several different methods. Ultrasound shear wave elastography has been shown to be correlated with detrusor pressure throughout the filling phase and was able to be used to determine a non-compliant bladder versus a compliant bladder via a significantly increased shear wave speed seen in the non-compliant bladder, as confirmed on UDS. [63] Ultrasound bladder vibrometry (UBV) has also been studied with concurrent UDS to correlate velocity and elasticity with detrusor pressure, assisting in the evaluation of bladder compliance. [6465] Both of these new uses of ultrasound technology would allow for bladder compliance to be measured without the need for invasive UDS.

Ultrasound has additionally been utilized during UDS to calculate detrusor wall tension, stress, compliance and elastic modulus. Detrusor wall tension can increase due to filling, with little increase in bladder pressure, and may better correlate with the symptom of urinary urgency. [6667] Evaluation of OAB symptomatology without DO seen on UDS could possibly be better evaluated with detrusor wall tension. Three dimensional ultrasound has been performed with concurrent UDS to evaluate bladder shape association with LUTS. Alterations in the ultrasound-measured height-to-width ratios of bladders were associated with OAB, identifying a possible shape-associated OAB subtype. [68] Unfortunately, the use of ultrasound to measure bladder wall thickness has not shown to be an effective method for evaluation of DO. [6970]

In addition to its utility in BOO, doppler ultrasound is currently being evaluated for diagnostic utility of chronic pelvic ischemia leading to DO and potentially detrusor underactivity. Using doppler flow studies, it has been determined that patients with LUTS have significantly decreased pelvic blood flow. [71] Chronic pelvic ischemia, caused by atherosclerosis and imaged by doppler studies is thought to be instrumental in the development of LUTS due to oxidative stress, denervation, and release of tissue damaging molecules. [72] Animal models are currently being used to investigate treatment options for LUTS that could prevent the detrusor damage caused by pelvic ischemia. [7374] Moving forward, pelvic doppler studies may help clinicians diagnose patients at risk for development of LUTS and prevent the conditions that lead to LUTS.

With much of the evaluation and treatment options for LUTS focused on the urinary tract, there has been little study of diagnostics related to upstream central nervous system control of micturition. Recent research has focused on the role of the brain in the symptomatology of LUTS as a network of cerebral regions has been identified as vital in the micturition cycle, called the brain-bladder control network. [7579] In order to further investigate this relationship, functional magnetic resonance imaging (fMRI) and brain functional NIRS (fNIRS) have been used.

fMRI has also been used in the evaluation of voiding dysfunction. In one study, patients underwent urodynamic filling while undergoing simultaneous fMRI. Those patients with DO uniformly had increased activation of the supplementary motor area (SMA) which evokes the sensation of urgency as well as contracts the pelvic floor and urethral sphincter. [75] An additional finding in the neural signaling seen in DO is prefrontal deactivation. [78] Moving forward, fMRI is being used to evaluate the differences in signaling in patients with LUTS who respond to treatment, versus nonresponders to develop novel treatment targets for non-responders. [80]

Brain fNIRS has been developed using NIRS technology as a method to evaluate activation of certain regions of the cerebral cortex. The concept behind how the imaging modality works is that active areas of the brain have a large increase in blood flow due to neurovascular coupling, which leads to an excess of oxygenated blood as the amount of oxygenated blood delivered exceeds that of the neuronal oxygen usage. This increase in oxygenated blood is imaged with the NIRS device. [81] fNIRS has the advantage over fMRI of allowing for a more natural testing environment. The patient is free to move around, be positioned as they are comfortable and is not secured, immobile in a large machine. fNIRs has been used to investigate cortical activation during the micturition cycle. [82] During the filling phase of the micturition cycle in normal, healthy adults, fNIRS demonstrated increased blood flow, and thus activation, of the bilateral frontal cortex, an expected finding based on fMRI data. [83] This technology is specific enough to evaluate Brodmann’s areas, which are activated during micturition. [84] This technology is now being used to evaluate the brain’s response to anti-cholinergic medication in the treatment of OAB. [85] Moving forward, fNIRS will help better elucidate the brain’s role in the pathology of LUTS, the mechanism of treatments, and the development of new treatments.

Conclusion

There are currently few diagnostic strategies, especially with less invasivity than UDS, available for the evaluation and diagnosis of male LUTS. Emerging technology and methods to evaluate the voiding phase are derived from multiple sources including the penile cuff test, a novel pressure sensing external catheter, measurements of detrusor wall thickness, evaluation of intravesical prostatic protrusion, use of pelvic doppler, and bladder Near Infrared Spectroscopy (NIRS). New metrics to evaluate the filling phase are less well-established but include sensation metrics, bladder wall micromotion and rhythmic contraction analysis, detrusor biomechanics, dynamic elasticity, pelvic doppler ultrasound, and functional brain imaging using both MRI and NIRS. The development of these novel, non-invasive, diagnostic tools have the potential for better evaluation of LUTS with earlier and enhanced treatments. This will likely improve the quality of life for men with LUTS.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflict of Interest

Natalie R. Swavely declares that she has no conflict of interest.

John E. Speich declares that he has no conflict of interest.

Lynn Stothers declares that she has no conflict of interest.

Adam P. Klausner declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  • 1.Egan KB. The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms: Prevalence and Incident Rates. Urol Clin North Am. 2016. August;43(3):289–97. doi: 10.1016/j.ucl.2016.04.001. [DOI] [PubMed] [Google Scholar]
  • 2.Gravas S, Kyriazis I, & Klausner AP (2018). Lower Urinary Tract Symptoms Including Bladder Outlet Obstruction: What’s New in Diagnostics? European Urology Focus, 4(1), 14–16. doi: 10.1016/j.euf.2018.04.004. [DOI] [PubMed] [Google Scholar]
  • 3.Bailey K, Abrams P, Blair PS, et al. Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial. Trials 2015;16:567. doi: 10.1186/s13063-015-1087-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Young GJ, Lewis AL, Lane JA, Winton HL, Drake MJ, Blair PS. Statistical analysis plan for the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). Trials. 2017. October 3;18(1):455. doi: 10.1186/s13063-017-2206-y. [DOI] [PMC free article] [PubMed] [Google Scholar]; • This randomized control trial has completed data collection and will soon have results available.
  • 5.Malde S, Nambiar AK, Umbach R, et al. Systematic review of the performance of noninvasive tests in diagnosing bladder outlet obstruction in men with lower urinary tract symptoms. Eur Urol 2017;71:391–402. doi: 10.1016/j.eururo.2016.09.026. [DOI] [PubMed] [Google Scholar]; • This is a meta-analysis, pooling data from many trials to help predict usefulness of many discussed techniques
  • 6.Griffiths CJ, Harding C, Blake C, et al. A nomogram to classify men with lower urinary tract symptoms using urine flow and noninvasive measurement of bladder pressure. J Urol 2005;174:1323–6. doi: 10.1097/01.ju.0000173637.07357.9e. [DOI] [PubMed] [Google Scholar]
  • 7.Penile cuff test: Bianchi D, Di Santo A, Gaziev G, et al. Correlation between penile cuff test and pressure-flow study in patients candidates for trans-urethral resection of prostate. BMC Urol 2014;14:103. doi: 10.1186/1471-2490-14-103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Harding CK, Robson W, Drinnan MJ, Griffiths CJ, Ramsden PD, Pickard RS. An automated penile compression release maneuver as a noninvasive test for diagnosis of bladder outlet obstruction. J Urol 2004;172:2312–5. doi: 10.1097/01.ju.0000144027.75838.60. [DOI] [PubMed] [Google Scholar]
  • 9.Kazemeyni SM,Otro jE,Mehraban D,Naderi GH,Ghadiri A,Jafari M. The role of noninvasive penile cuff test in patients with bladder outlet obstruction. Korean J Urol 2015;56:722–8. doi: 10.4111/kju.2015.56.10.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Matulewicz RS, Hairston JC. The UroCuff test: a non-invasive alternative to pressure flow studies in adult males with lower urinary tract symptoms secondary to bladder outlet obstruction. Can J Urol 2015;22:7896–901. [PubMed] [Google Scholar]
  • 11.Salinas J, Virseda M, Arredondo F. Validity of cuff-uroflow as a diagnostic technique for bladder outlet obstruction in males. Scand J Urol Nephrol 2003;37:316–21. doi: 10.1080/00365590310001610. [DOI] [PubMed] [Google Scholar]
  • 12.Sullivan MP, Yalla SV. Penile urethral compression-release maneuver as a noninvasive screening test for diagnosing prostatic obstruction. Neurourol Urodyn 2000;19:657–69. doi: . [DOI] [PubMed] [Google Scholar]
  • 13.Ko KJ, Suh YS, Kim TH, Sung HH, Ryu GH, Lee KS. Diagnosing bladder outlet obstruction using the penile cuff test in men with lower urinary tract symptoms. Neurourol Urodyn 2017;36:1884–9. doi: 10.1002/nau.23203. [DOI] [PubMed] [Google Scholar]
  • 14.Pel JJ, Bosch JL, Blom JH, Lycklama, Nijeholt A, Van Mastrigt R. Development of a non-invasive strategy to classify bladder outlet obstruction in male patients with LUTS. Neurourol Urodyn 2002;21: 117–25. doi: [DOI] [PubMed] [Google Scholar]
  • 15.Franco G, De Nunzio C, Leonardo C, et al. Ultrasound assessment of intravesical prostatic protrusion and detrusor wall thickness — new standards for noninvasive bladder outlet obstruction diagnosis? J Urol 2010;183:2270–4. doi: 10.1016/j.juro.2010.02.019. [DOI] [PubMed] [Google Scholar]
  • 16.Abdel-Aal A, El-Karamany T, Al-Adl AM, Abdel-Wahab O, Farouk H. Assessment of noninvasive predictors of bladder outlet obstruction and acute urinary retention secondary to benign prostatic enlargement. Arab J Urol 2011;9:209–14. doi: 10.1016/j.aju.2011.09.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Aganovic D,Hasanbegovic M,Prcic A,Kulovac B,Hadziosmanovic O. Which is a better indicator of bladder outlet obstruction in patients with benign prostatic enlargement — intravesical protrusion of prostate or bladder wall thickness? Med Arh 2012;66:324–8. doi: 10.5455/medarh.2012.66.324-328. [DOI] [PubMed] [Google Scholar]
  • 18.El Saied W, Mosharafa A, El Fayoumy H, et al. Detrusor wall thickness compared to other non-invasive methods in diagnosing men with bladder outlet obstruction: a prospective controlled study. Afr J Urol 2013;19:160–4. doi: 10.1016/j.afju.2013.03.003 [DOI] [Google Scholar]
  • 19.Kessler TM, Gerber R, Burkhard FC, Studer UE, Danuser H. Ultrasound assessment of detrusor thickness in men — can it predict bladder outlet obstruction and replace pressure flow study? J Urol 2006;175:2170–3. doi: 10.1016/S0022-5347(06)00316-8. [DOI] [PubMed] [Google Scholar]
  • 20.Manieri C, Carter SSC, Romano G, Trucchi A, Valenti M, Tubaro A. The diagnosis of bladder outlet obstruction in men by ultrasound measurement of bladder wall thickness. J Urol 1998;159:761–5. doi: 10.1016/S0022-5347(01)63723-6. [DOI] [PubMed] [Google Scholar]
  • 21.Oelke M, Hofner K, Jonas U, de la Rosette JJ, Ubbink DT, Wijkstra H. Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume. Eur Urol 2007;52: 827–35. doi: 10.1016/j.eururo.2006.12.023. [DOI] [PubMed] [Google Scholar]
  • 22.Oelke M, Hofner K, Wiese B, Grünewald V, Jonas U. Increase in detrusor wall thickness indicates bladder outlet obstruction (BOO) in men. World J Urol 2002;19:443–52. [DOI] [PubMed] [Google Scholar]
  • 23.Aganovic D, Prcic A, Hadziosmanovic O, Hasanbegovic M. Does the combination of intravesical prostatic protrusion and bladder outlet obstruction number increase test accuracy according to benign prostatic obstruction at the individual level? Acta Informat Med 2012;20:160–6. doi: 10.5455/aim.2012.20.160-166. doi:10.1007/s00345-001-0238-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Chia SJ, Heng CT, Chan SP, Foo KT. Correlation of intravesical prostatic protrusion with bladder outlet obstruction. BJU Int 2003;91:371–4. doi: 10.1046/j.1464410X.2003.04088.x. [DOI] [PubMed] [Google Scholar]
  • 25.Dicuio M, Pomara G, Vesely S, et al. The use of prostatic intravesical protrusion correlated with uroflowmetry: a new method to measure obstruction in patients with LUTS due to BOO without using P/F studies. Arch Ital Urol Androl 2005;77:50–3. [PubMed] [Google Scholar]
  • 26.Keqin Z, Zhishun X, Jing Z, Haixin W, Dongqing Z, Benkang S. Clinical significance of intravesical prostatic protrusion in patients with benign prostatic enlargement. Urology 2007;70:1096–9. doi: 10.1016/j.urology.2007.08.008. [DOI] [PubMed] [Google Scholar]
  • 27.Lim KB, Ho H, Foo KT, Wong MY, Fook-Chong S. Comparison of intravesical prostatic protrusion, prostate volume and serum prostatic-specific antigen in the evaluation of bladder outlet obstruction. Int J Urol 2006;13:1509–13. doi: 10.1111/j.14422042.2006.01611.x. [DOI] [PubMed] [Google Scholar]
  • 28.Pascual EM, Polo A, Morales G, et al. Usefulness of bladder-prostate ultrasound in the diagnosis of obstruction/hyperactivity in males with BPH. Arch Espan Urol 2011;64:897–903. [PubMed] [Google Scholar]
  • 29.Reis LO, Barreiro GC, Baracat J, Prudente A, D’Ancona CA. Intravesical protrusion of the prostate as a predictive method of bladder outlet obstruction. Int Braz J Urol 2008;34:627–33. doi: 10.1590/S1677-55382008000500012. [DOI] [PubMed] [Google Scholar]
  • 30.Belenky A, Abarbanel Y, Cohen M, Yossepowitch O, Livne P, & Bachar G (2003). Detrusor resistive index evaluated by doppler ultrasonography as a potential indicator of bladder outlet obstruction. Urology, 62(4), 647–650. doi: 10.1016/s0090-4295(03)00510-7 [DOI] [PubMed] [Google Scholar]
  • 31.Kojima M, Ochiai A, Naya Y, Okihara K, Ukimura O, & Miki T (2000). Doppler Resistive Index in Benign Prostatic Hyperplasia: Correlation with Ultrasonic Appearance of the Prostate and Infravesical Obstruction. European Urology, 37(4), 436–442. doi: 10.1159/000020165 [DOI] [PubMed] [Google Scholar]
  • 32.Ozawa H (2001). Noninvasive urodynamic evaluation of bladder outlet obstruction using Doppler ultrasonography. Urology, 58(4), 637–638. doi: 10.1016/s0090-4295(01)01295-x [DOI] [PubMed] [Google Scholar]
  • 33.Ding YY, Ozawa H, Yokoyama T, Nasu Y, Chancellor MB, & Kumon H (2000). Reliability of color Doppler ultrasound urodynamics in the evaluation of bladder outlet obstruction. Urology, 56(6), 967–971. doi: 10.1016/s0090-4295(00)00804-9 [DOI] [PubMed] [Google Scholar]
  • 34.Delpy DT, Cope M. Quantification in tissue near–infrared spectroscopy. Philosophical Transactions of the Royal Society of London B: Biological Sciences. 1997;352(1354):649–659. doi: 10.1098/rstb.1997.0046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Hamaoka T, McCully KK, Niwayama M, Chance B. The use of muscle near–infrared spectroscopy in sport, health and medical sciences: recent developments. Philosophical Transactions of the Royal Society 2011;369:4591–4601. doi: 10.1098/rsta.2011.0298 [DOI] [PubMed] [Google Scholar]
  • 36.Wolf M, Ferrari M, Quaresima V. Progress of near–infrared spectroscopy for brain and muscle clinical applications. J Biomed Optics. 2007;12(6):062104. doi: 10.1117/1.2804899. [DOI] [PubMed] [Google Scholar]
  • 37.Macnab AJ. The evolution of near infrared spectroscopy in urology. Biomedical Spectroscopy and Imaging. 2014;3:311–344. doi: 10.3233/BSI-140091. doi:10.3233/BSI–140091. [DOI] [Google Scholar]
  • 38.Macnab AJ, Stothers L. Near–infrared spectroscopy: validation of bladder–outlet obstruction assessment using non–invasive parameters. Can J Urol. 2008;15(5):4241–4248. [PubMed] [Google Scholar]
  • 39.Macnab AJ, Stothers LS, Shadgan B. Monitoring Detrusor Oxygenation and Hemodynamics Noninvasively during Dysfunctional Voiding. Adv Urol. 2012;2012:676303. doi: 10.1155/2012/676303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Stothers L, Shadgan B, Macnab A. Urological applications of near infrared spectroscopy. Can J Urol. 2008;15(6):4399–4409. [PubMed] [Google Scholar]
  • 41.Macnab A, Stothers L, Shadgan B. Dynamic topographic mapping of the human bladder during voiding using functional near–infrared spectroscopy. J Biomed Opt. 2009;14(2):020507. doi: 10.1117/1.3122886. [DOI] [PubMed] [Google Scholar]
  • 42.Macnab AJ, Shadgan B, Stothers L. Monitoring physiologic change in the bladder in health and disease. A new biomedical application of near–infrared spectroscopy. Biomedical Spectroscopy and Imaging. 2013;2(2):289–299. doi: 10.3233/BSI-130049 [DOI] [Google Scholar]
  • 43.Macnab AJ, Shadgan B, Stothers L. Monitoring detrusor oxygenation and hemodynamics non–invasively during dysfunctional voiding. Advances in Urology. 2012. doi: 10.1155/2012/676303 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Stothers L, Guevara R, MacNab A. Classification of male lower urinary tract symptoms using mathematical modelling and a regression tree algorithm of noninvasive near–infrared spectroscopy parameters. Eur Urol 2010;57:327–33. doi: 10.1016/j.eururo.2009.05.004 [DOI] [PubMed] [Google Scholar]
  • 45.Yurt M, Suer E, Gulpnar O, Telli O, Arkan N. Diagnosis of bladder outlet obstruction in men with lower urinary tract symptoms: comparison of near infrared spectroscopy algorithm and pressure flow study in a prospective study. Urology 2012;80:182–6. doi: 10.1016/j.urology.2012.03.022 [DOI] [PubMed] [Google Scholar]
  • 46.Zhang P, Yang Y, Wu ZJ, Zhang CH, Zhang XD. Diagnosis of bladder outlet obstruction in men using a near–infrared spectroscopy instrument as the noninvasive monitor for bladder function. Urology 2013;82:1098–102. doi: 10.1016/j.urology.2013.06.019 [DOI] [PubMed] [Google Scholar]
  • 47.Farag F, Elbadry M, Saber M, Badawy AA, Heesakkers J. A novel algorithm for the non–invasive detection of bladder outlet obstruction in men with lower urinary tract symptoms. Arab J Urol 2017;15:153–8. doi: 10.1016/j.aju.2017.01.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub–committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167–178. doi: 10.1002/nau.10052 [DOI] [PubMed] [Google Scholar]
  • 49.Erdem E, Akbay E, Doruk E, Cayan S, Acar D, Ulusoy E. How reliable are bladder perceptions during cystometry? Neurourol Urodyn. 2004;23(4):306–309; discussion 310. (45). doi: 10.1002/nau.20045. [DOI] [PubMed] [Google Scholar]
  • 50.Erdem E, Tunckiran A, Acar D, Kanik EA, Akbay E, Ulusoy E. Is catheter cause of subjectivity in sensations perceived during filling cystometry? Urology. 2005;66(5):1000–1003; discussion 1003–1004. doi: 10.1016/j.urology.2005.05.056. [DOI] [PubMed] [Google Scholar]
  • 51.Nagle AS, Speich JE, De Wachter SG, et al. Non–invasive characterization of real–time bladder sensation using accelerated hydration and a novel sensation meter: An initial experience. Neurourol Urodyn. 2017;36(5):1417–1426. doi: 10.1002/nau.23137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Naimi HA, Nagle AS, Vinod NN, et al. An innovative, non–invasive sensation meter allows for a more comprehensive understanding of bladder sensation events: A prospective study in participants with normal bladder function. Neurourol Urodyn. 2019;38(1):208–214. doi: 10.1002/nau.23831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Heeringa R, Wachter SG, Kerrebroeck PE, & Koeveringe GA (2011). Normal bladder sensations in healthy volunteers: A focus group investigation. Neurourology and Urodynamics. doi: 10.1002/nau.21052 [DOI] [PubMed] [Google Scholar]
  • 54.Heeringa R, Koeveringe GV, Winkens B, Kerrebroeck PV, & Wachter SD (2012). Do patients with OAB experience bladder sensations in the same way as healthy volunteers? A focus group investigation. Neurourology and Urodynamics, 31(4), 521–525. doi: 10.1002/nau.21232 [DOI] [PubMed] [Google Scholar]
  • 55.Lowenstein L, Fitzgerald MP, Kenton K, Brubaker L, Gruenwald I, Papier I,Vardi Y (2008). Validation of a real–time urodynamic measure of urinary sensation. American Journal of Obstetrics and Gynecology, 198(6). doi: 10.1016/j.ajog.2008.02.023 [DOI] [PubMed] [Google Scholar]
  • 56.De Wachter SG, Heeringa R, Koeveringe GA, Winkens B, Kerrebroeck PE, & Gillespie JI (2013). “Focused introspection” during naturally increased diuresis: Description and repeatability of a method to study bladder sensation non–invasively. Neurourology and Urodynamics, 33(5), 502–506. doi: 10.1002/nau.22440 [DOI] [PubMed] [Google Scholar]
  • 57.Brading AF. Spontaneous activity of lower urinary tract smooth muscles: correlation between ion channels and tissue function. The Journal of physiology. 2006; 570(Pt 1):13–22. DOI: 10.1113/jphysiol.2005.097311. doi:10.1113/jphysiol.2005.097311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Almasri AM, Ratz PH, Bhatia H, Klausner AP, Speich JE. Rhythmic contraction generates adjustable passive stiffness in rabbit detrusor. Journal of applied physiology. 2010; 108(3):544–553. doi: 10.1152/japplphysiol.01079.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Colhoun AF, Speich JE, Cooley LF, et al. Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves. World J Urol. 2017;35(8):1255–1260. doi: 10.1007/s00345-016-1994-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Brading AF. A myogenic basis for the overactive bladder. Urology. 1997; 50(6A Suppl):57–67; discussion 8–73. doi: 0.1016/S0090-4295(97)00591-8. [DOI] [PubMed] [Google Scholar]
  • 61.Drake MJ, Harvey IJ, Gillespie JI, Van Duyl WA. Localized contractions in the normal human bladder and in urinary urgency. BJU Int. 2005; 95(7):1002–5. doi: 10.1111/j.1464410X.2005.05455.x. [DOI] [PubMed] [Google Scholar]
  • 62.Cullingsworth ZE, Kelly BB, Deebel NA, et al. Automated quantification of low amplitude rhythmic contractions (LARC) during real–world urodynamics identifies a potential detrusor overactivity subgroup. PLoS One. 2018;13(8):e0201594. doi: 10.1371/journal.pone.0201594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Sturm RM, Yerkes EB, Nicholas JL, et al. Ultrasound shear wave elastography: a novel method to evaluate bladder pressure. J Urol 2017;198:422–9. doi: 10.1016/j.juro.2017.03.127. [DOI] [PubMed] [Google Scholar]; •• This study provides confirmation of use of adjunctive analysis to evaluate filling phase.
  • 64.Bayat M, Kumar V, Denis M, et al. Correlation of ultrasound bladder vibrometry assessment of bladder compliance with urodynamic study results. PLoS One 2017;12:e0179598. doi: 10.1371/journal.pone.0179598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Nenadic IZ, Qiang B, Urban MW, Vasconcelo LH, Nabavizadeh A, Alizad A, Fatemi M (2013). Ultrasound bladder vibrometry method for measuring viscoelasticity of the bladder wall. Physics in Medicine and Biology, 58(8), 2675–2695. doi: 10.1088/0031-9155/58/8/2675 [DOI] [PubMed] [Google Scholar]
  • 66.Nagle AS, Klausner AP, Varghese J, et al. Quantification of bladder wall biomechanics during urodynamics: A methodologic investigation using ultrasound. J Biomech. 2017;61:232–241. doi: 10.1016/j.jbiomech.2017.07.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Habteyes FG, Komari SO, Nagle AS, et al. Modeling the influence of acute changes in bladder elasticity on pressure and wall tension during filling. J Mech Behav Biomed Mater. 2017;71:192–200. doi: 10.1016/j.jmbbm.2017.02.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Glass Clark S, Nagle AS, Bernardo R, et al. Use of Ultrasound Urodynamics to Identify Differences in Bladder Shape Between Individuals With and Without Overactive Bladder. Female Pelvic Med Reconstr Surg. 2018. doi: 10.1097/SPV.0000000000000638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Rachaneni S, Mccooty S, Middleton LJ, Parker VL, Daniels JP, Coomarasamy A, Latthe P (2016). Bladder ultrasonography for diagnosing detrusor overactivity: Test accuracy study and economic evaluation. Health Technology Assessment, 20(7), 1–150. doi: 10.3310/hta20070 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Latthe P, Middleton L, Rachaneni S, Mccooty S, Daniels J, Coomarasamy A, Deeks J (2017). Ultrasound bladder wall thickness and detrusor overactivity: A multicentre test accuracy study. BJOG: An International Journal of Obstetrics & Gynaecology, 124(9), 1422–1429. doi: 10.1111/1471-0528.14503 [DOI] [PubMed] [Google Scholar]
  • 71.Pinggera GM, Mitterberger M, Steiner E, Pallwein L, Frauscher F, Aigner F, Bartsch G, Strasser H. Association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour Doppler ultrasonography. BJU Int. 2008. Aug;102(4):470–4. doi: 10.1111/j.1464-410X.2008.07587.x. [DOI] [PubMed] [Google Scholar]
  • 72.Yamaguchi O, Nomiya M, & Andersson K (2013). Functional consequences of chronic bladder ischemia. Neurourology and Urodynamics, 33(1), 54–58. doi: 10.1002/nau.22517 [DOI] [PubMed] [Google Scholar]
  • 73.Andersson K, Nomiya M, & Yamaguchi O (2014). Chronic Pelvic Ischemia: Contribution to the Pathogenesis of Lower Urinary Tract Symptoms (LUTS): A New Target for Pharmacological Treatment? LUTS: Lower Urinary Tract Symptoms, 7(1), 1–8. doi: 10.1111/luts.12084 [DOI] [PubMed] [Google Scholar]
  • 74.Andersson K, Boedtkjer DB, & Forman A (2016). The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. Therapeutic Advances in Urology, 9(1), 11–27. doi: 10.1177/1756287216675778 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• This study demonstrates a new etiology in the disease process and possibility for novel diagnostic and therapetuic advances.
  • 75.Tadic SD, Griffiths D, Schaefer W, Murrin A, Clarkson B, Resnick NM. Brain activity underlying impaired continence control in older women with overactive bladder. Neurourol Urodyn 2012;31:652–8. doi: 10.1002/nau.21240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Khavari R, Karmonik C, Shy M, Fletcher S, Boone T. Functional magnetic resonance imaging with concurrent urodynamic testing identifies brain structures involved in micturition cycle in patients with multiple sclerosis. J Urol 2017;197:438–44. doi: 10.1016/j.juro.2016.09.077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Tadic SD, Tannenbaum C, Resnick NM, Griffiths D. Brain responses to bladder filling in older women without urgency incontinence. Neurourol Urodyn. 2013;32(5):435–440. doi: 10.1002/nau.22320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Griffiths D, Tadic SD. Bladder control, urgency, and urge incontinence: evidence from functional brain imaging. Neurourol Urodyn. 2008;27(6):466–474. doi: 10.1002/nau.20549 [DOI] [PubMed] [Google Scholar]
  • 79.Ketai LH, Komesu YM, Dodd AB, Rogers RG, Ling JM, Mayer AR. Urgency urinary incontinence and the interoceptive network: a functional magnetic resonance imaging study. American journal of obstetrics and gynecology. 2016;215(4):449 e441–449 e417. doi: 10.1016/j.ajog.2016.04.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Clarkson BD, Griffiths D, Resnick NM. Do brain structural abnormalities differentiate separate forms of urgency urinary incontinence? Neurourol Urodyn. 2018;37(8):2597–2605. doi: 10.1002/nau.23591. [DOI] [PMC free article] [PubMed] [Google Scholar]; • This study validates a diagnostic strategy that focuses on the brain, a novel concept.
  • 81.Ferrari M, Quaresima V. A brief review on the history of human functional near–infrared spectroscopy (fNIRS) development and fields of application. Neuroimage. 2012;63(2):921–935. doi: 10.1016/j.neuroimage.2012.03.049. [DOI] [PubMed] [Google Scholar]
  • 82.Matsumoto S, Ishikawa A, Kume H, Takeuchi T, Homma Y. Near infrared spectroscopy study of the central nervous activity during artificial changes in bladder sensation in men. Int J Urol. 2009;16(9):760–764. doi: 10.1111/j.1442-2042.2009.02358.x. [DOI] [PubMed] [Google Scholar]
  • 83.Matsumoto S, Ishikawa A, Matsumoto S, Homma Y. Brain response provoked by different bladder volumes: a near infrared spectroscopy study. Neurourol Urodyn. 2011;30(4):529–535. doi: 10.1111/j.1442-2042.2009.02358.x. [DOI] [PubMed] [Google Scholar]
  • 84.Sakakibara R, Tsunoyama K, Takahashi O, Sugiyama M, Kishi M, Ogawa E, Yamaguchi C (2010). Real–time measurement of oxyhemoglobin concentration changes in the frontal micturition area: An fNIRS study. Neurourology and Urodynamics, 29(5), 757–764. doi: 10.1002/nau.20815 [DOI] [PubMed] [Google Scholar]
  • 85.Sakakibara, Tateno F, Yano M, et al. Tolterodine activates the prefrontal cortex during bladder filling in OAB patients: a real–time NIRS–urodynamics study. Neurourol Urodyn. 2014;33(7):1110–1115. doi: 10.1002/nau.22471. [DOI] [PubMed] [Google Scholar]

RESOURCES