Tag Archive for: Lower urinary tract symptoms

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Article of the week: The effect of the urinary and faecal microbiota on lower urinary tract symptoms measured by the International Prostate Symptom Score: analysis utilising next‐generation sequencing

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

Please use the comment buttons below if you would like to join the conversation.

If you only have time to read one article this week, we recommend this one. 

The effect of the urinary and faecal microbiota on lower urinary tract symptoms measured by the International Prostate Symptom Score: analysis utilising next‐generation sequencing

Bradley Holland*, Mallory Karr*, Kristin Delfino*, Danuta Dynda, Ahmed El-Zawahry, Andrea Braundmeier-Fleming*, Kevin McVary§ and Shaheen Alanee

*Southern Illinois University School of Medicine, Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, USA, Urology, University of Toledo, Toledo, OH, §Loyola University Chicago, Chicago, IL, and Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA

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Abstract

Objective

To examine the correlation between urinary and faecal microbial profiles and the different aspects of lower urinary tract symptoms (LUTS) in men, as there is accumulating evidence that variations in the human microbiota may promote different benign disease conditions.

Patients and Methods

We extracted total DNA from urine and faecal samples of a group of men, under an Institutional Review Board‐approved protocol. At the same time, International Prostate Symptom Score (IPSS) data were collected. We then amplified the extracted DNA and sequenced it using bacterial 16S ribosomal RNA gene high‐throughput next‐generation sequencing platform, and analysed the microbial profiles for taxonomy to examine the correlation between the different operational taxonomy units (OTUs) and LUTS represented by the total IPSS, the different symptom levels of the IPSS (mild, moderate, and severe) and its subcomponents of storage, nocturia, voiding, and bother.

Results

We included 30 patients (60 samples; one urine and one faecal per patient). In all, 48 faecal OTUs showed a significant correlation with one or more of the IPSS components; 27 with nocturia, 19 with bother, 16 with storage symptoms, and nine with voiding symptoms. The most substantial negative (protective) correlation was between Lachnospiraceae Blautia , a bacteria that increases the availability of gut anxiolytic and antidepressant short‐chain fatty acids, and bother (correlation coefficient 0.702; P  = 0.001). The abundance of L. Blautia continued to have a protective correlation against LUTS when looking at the different levels of IPSS severity (moderate and severe vs mild, correlation coefficient 0.6132; P =  0.002). Ten unique urinary OTUs showed significant correlation with LUTS; eight with nocturia, one with bother, three with storage, and one with voiding, but no faecal OUT had more than a low correlation with the outcomes of interest in this study.

Conclusions

Our prospective work finds a plausible correlation between L. Blautia and LUTS. Additional studies are needed to determine if the correlations found in the present research are applicable to the general population of patients affected by LUTS.

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Article of the week: Information on surgical treatment of benign prostatic hyperplasia on YouTube is highly biased and misleading

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to this post, there is an editorial written by a prominent member of the urological community and a visual abstract for a swift overview of the article. Please use the comment buttons below to join the conversation.

If you only have time to read one article this week, we recommend this one. 

Information on surgical treatment of benign prostatic hyperplasia on YouTube is highly biased and misleading

Patrick Betschart*, Manolis Pratsinis*, Gautier Müllhaupt*, Roman Rechner*, Thomas RW Herrmann, Christian Gratzke, Hans–Peter Schmid*, Valentin Zumstein* and Dominik Abt*

*Department of Urology, Cantonal Hospital St Gallen, St Gallen, Urology Clinic, Spital Thurgau AG, Frauenfeld, Switzerland, and Department of Urology, Albert–Ludwigs–University, Freiburg, Germany

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Abstract

Objectives

To assess the quality of videos on the surgical treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) available on YouTube, given that such video‐sharing platforms are frequently used as sources of patient information and the therapeutic landscape of LUTS/BPH has evolved substantially during recent years.

Materials and Methods

A systematic search for videos on YouTube addressing treatment options for LUTS/BPH was performed in May 2019. Measures assessed included basic data (e.g. number of views), grade of misinformation and reporting of conflicts of interest. The quality of content was analysed using the validated DISCERN questionnaire. Data were analysed using descriptive statistics.

Fig. 1. Degree of misinformation compared to currently available evidence on surgical BPH treatment 7 (no: green; very little: light green; moderate: light blue; high: light red; extreme: dark red), rate of commercial bias (yes: red; no: light green) and rate of declaration of conflicts of interests (COI; yes: blue; no: orange) for the analysed videos divided by topics. BipolEP, bipolar enucleation of the prostate; HoLEP, holmium laser enucleation of the prostate; iTIND, temporary implantable Nitinol device; PAE, prostatic artery embolization; ThuLEP, thulium laser enucleation of the prostate

Results

A total of 159 videos with a median (range) of 8570 (648–2 384 391) views were included in the analysis. Only 21 videos (13.2%) were rated as containing no misinformation, 26 (16.4%) were free of commercial bias, and two (1.3%) disclosed potential conflicts of interest. According to DISCERN, the median overall quality of the videos was low (2 out of 5 points for question 16). Only four of the 15 assessed categories (bipolar and holmium laser enucleation of the prostate, transurethral resection of the prostate and patient‐based search terms) were scored as having moderate median overall quality (3 points).

Conclusion

Most videos on the surgical treatment of LUTS/BPH on YouTube had a low quality of content, provided misinformation, were subject to commercial bias and did not report on conflicts of interest. These findings emphasize the importance of thorough doctor–patient communication and active recommendation of unbiased patient education materials.

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Visual abstract: Information on surgical treatment of benign prostatic hyperplasia on YouTube is highly biased and misleading

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Residents’ podcast: NICE Guidance – Transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia

Nikita Bhatt is a Specialist Trainee in Urology in the East of England Deanery and a BURST Committee member @BURSTUrology

NICE Guidance – Transurethral water jet ablation for lower urinary tract symptoms caused by benign prostatic hyperplasia

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Recommendations

  • 1.1 The evidence on transurethral water jet ablation for lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) raises no major safety concerns. The evidence on efficacy is limited in quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.
  • 1.2 Clinicians wishing to do transurethral water jet ablation for LUTS caused by BPH should:
    • Inform the clinical governance leads in their NHS trusts.
    • Ensure that patients understand the uncertainty about the procedure’s efficacy and provide them with clear written information to support shared decision‐making. In addition, the use of the National Institute for Health and Care Excellence (NICE) information for the public is recommended.
    • Audit and review clinical outcomes of all patients having transurethral water jet ablation for LUTS caused by BPH. NICE has identified relevant audit criteria and has developed an audit tool (which is for use at local discretion).
  • 1.3 The procedure should only be done by clinicians who have been trained in the technique.
  • 1.4 NICE encourages further research into transurethral water jet ablation for LUTS caused by BPH and may update the guidance on publication of further evidence. Further research should report long‐term follow‐up and include re‐intervention rates.

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Article of the week: Aquablation for benign prostatic hyperplasia in large prostates: 6‐month results from the WATER II trial

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

We invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Aquablation for benign prostatic hyperplasia in large prostates (80–150 mL): 6‐month results from the WATER II trial

Mihir Desai*, Mo Bidair, Kevin C. Zorn, Andrew Trainer§, Andrew Arther§, Eugene Kramolowsky, Leo Doumanian*, Dean Elterman**, Ronald P. Kaufman Jr.††, James Lingeman‡‡, Amy Krambeck‡‡, Gregg Eure§§, Gopal Badlani¶¶, Mark Plante***, Edward Uchio†††, Greg Gin†††, Larry Goldenberg‡‡‡, Ryan Paterson‡‡‡, Alan So‡‡‡, Mitch Humphreys§§§, Claus Roehrborn¶¶¶, Steven Kaplan****, Jay Motola**** and Naeem Bhojani

*Institute of Urology, University of Southern California, Los Angeles, San Diego Clinical Trials, San Diego, CA, USA, University of Montreal Hospital Center, Université de Montréal, Montréal, QC, Canada, §Adult Pediatric Urology and Urogynecology, P.C., Omaha, NE, Virginia Urology, Richmond, VA, USA, **University of Toronto – University HealthNetwork, Toronto, ON, Canada, ††Albany Medical College, Albany, NY, ‡‡Indiana University Health Physicians, Indianapolis, IN, §§Urology of Virginia, Virginia Beach, VA, ¶¶Wake Forest School of Medicine, Winston-Salem, NC, ***University of Vermont Medical Center, Burlington, VT, †††VA Long Beach Healthcare System, Long Beach, CA, USA, ‡‡‡University of British Columbia, Vancouver, BC, Canada, §§§Mayo Clinic Arizona, Scottsdale, AZ, ¶¶¶UT Southwestern Medical Center, Department of Urology, University of Texas Southwestern, Dallas, TX, and ****Icahn School of Medicine at Mount Sinai, New York, NY, USA

 

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Abstract

Objective

To present 6‐month safety and effectiveness data from a multicentre prospective study of aquablation in men with lower urinary tract symptoms (LUTS) attributable to benign prostatic hyperplasia (BPH) with prostate volumes between 80 and 150 mL.

Methods

Between September and December 2017, 101 men with LUTS attributable to BPH were prospectively enrolled at 16 centers in Canada and the USA.

Results

The mean prostate volume was 107 mL. The mean length of hospital stay after the aquablation procedure was 1.6 days (range: same day to 6 days). The primary safety endpoint (Clavien–Dindo grade 2 or higher or any grade 1 event resulting in persistent disability) at 3 months occurred in 45.5% of men, which met the study design goal of < 65% (P < 0.001). At 6 months, 22% of the patients had experienced a Clavien–Dindo grade 2, 14% a grade 3 and 5% a grade 4 adverse event. Bleeding complications requiring intervention and/or transfusion were recorded in eight patients prior to discharge and in six patients after discharge. The mean International Prostate Symptom Score improved from 23.2 ± 6.3 at baseline to 6.7 ± 5.1 at 3 months, meeting the study’s primary efficacy endpoint goal (P < 0.001). The maximum urinary flow rate increased from 8.7 to 18.8 mL/s (P < 0.001) and post‐void residual urine volume decreased from 131 at baseline to 47 at 6 months (P < 0.0001). At 6 months, prostate‐specific antigen concentration reduced from 7.1 ± 5.9 ng/mL at baseline to 4.0 ± 3.9 ng/mL, a 44% reduction.

Conclusions

Aquablation is safe and effective in treating men with larger prostates (80–150 mL), without significant increase in procedure or resection time.

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Article of the week: Relationship between oxidative stress and lower urinary tract symptoms: results from a community health survey in Japan

Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and the authors have also kindly produced a video describing their work. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

The relationship between oxidative stress and lower urinary tract symptoms: Results from the community health survey in Japan

Teppei Matsumoto*, Shingo Hatakeyama* , Atsushi Imai*, Toshikazu Tanaka*, Kazuhisa Hagiwara*, Sakae Konishi*, Kazutaka Okita*, Hayato Yamamoto*, Yuki Tobisawa*, Tohru Yoneyama, Takahiro Yoneyama*, Yasuhiro Hashimoto, Takuya Koie, Shigeyuki Nakaji§ and Chikara Ohyama*

 

*Department of Urology, Department of Advanced Transplant and Regenerative Medicine, Hirosaki University
Graduate School of Medicine, Hirosaki, Department of Urology, Gifu University Graduate School of Medicine, Gifu
and §Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

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Abstract

Objective

To investigate the relationship between oxidative stress and lower urinary tract symptoms (LUTS) in a community‐dwelling population.

Materials and Methods

The cross‐sectional study included 1 113 people who participated in the Iwaki Health Promotion Project of 2015 in Hirosaki, Japan. LUTS were assessed using structured questionnaires, including the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS). IPSS > 7, OABSS > 5, nocturia score > 1, or urge incontinence score > 1 were defined as moderate to severe symptoms. 8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) and advanced glycation end products (AGEs) were measured by urine analysis and skin autofluorescence, respectively. The relationship between oxidative stress and LUTS was investigated using logistic regression analyses (You can reduce aging under eye masks).

Fig. 1. Association between 8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) and advanced glycation end product (AGE) levels. 8‐OHdG levels were significantly associated with AGE levels (R2 = 0.023, P < 0.001, Spearman’s rank correlation coefficient). However, the R2 value was too small to indicate strong correlation and the significant P value of this correlation does not reflect the strength of the relationship between the two biomarkers.

Results

This study included 431 men and 682 women. AGEs and 8‐OHdG levels were significantly higher in severe forms of LUTS. Multivariate logistic regression analyses showed that AGE levels were significantly associated with a higher frequency of nocturia but were not associated with IPSS, OABSS or urge incontinence. No significant association was observed between LUTS and 8‐OHdG levels.

Conclusions

We observed a significant association between AGE levels and nocturia score > 1. Further research is necessary to clarify a possible causal relationship between oxidative stress and nocturia.

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Editorial: Oxidative stress and lower urinary tract symptoms: cause or consequence?

Oxidative stress has been defined as ‘an imbalance between oxidants and anti-oxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage’ [1]. Reactive oxygen and nitrogen species (ROS/RNS) produced under oxidative stress are known to damage all cellular biomolecules (lipids, sugars, proteins and polynucleotides). ROS/RNS is often used as a generic term but it has been emphasized that all ROS/RNS molecules are not the same [2] and the term encompasses a diverse range of species, including, for example, superoxide, hydrogen peroxide, nitric oxide and peroxynitrite. The biological impacts of ROS/RNS depend critically on the particular molecule(s) involved, and on the microenvironment and physiological or pathological context in which it is being generated [2]. It should be emphasized that ROS are not only harmful agents that cause oxidative damage in pathologies but they also have important roles as regulatory agents in a range of biological phenomena. They are normally generated as by-products of oxygen metabolism; however, environmental stressors (ultraviolet radiation, ionizing radiations, pollutants, heavy metal and xenobiotics) contribute to greatly increase ROS/RNS production.

It is difficult to measure ROS/RNS, therefore, biomarkers are often used as a surrogate; however, many of the biomarkers are insufficiently validated and it is often difficult to draw general conclusions on their significance [3]. 8-OHdG, one of the major products of DNA oxidation, is one of the most commonly used biomarkers of oxidative stress. Advanced glycation end-products (AGEs) are a group of heterogeneous molecules that arise from the non-enzymatic reaction of reducing sugars with amino groups of lipids, DNA and especially long-lived proteins. This process occurs during normal metabolism but is even more pronounced under oxidative stress conditions. AGEs may be harmful and include modified proteins and/or lipids with damaging potential. Using 8-OHdG, AGEs and other biomarkers, several attempts have been made to link oxidative stress, either as a cause or contributor, or both, to a variety of diseases, including LUTS. As pointed out by Ghezzi et al. [4] ‘Today it is a challenge to find a disease for which a role of oxidative stress has not been postulated.’

Matsumoto et al. [5] investigated the possible relationship between some markers of oxidative stress and LUTS in a population of community-living subjects participating in a health promotion project. As markers of oxidative stress, they used 8-OHdG (urine) and AGEs (skin autofluorescence), while structured questionnaires were used to assess LUTS. In their study, despite univariate analyses revealing several significant associations, multivariate analyses showed that the only statistically significant finding was that AGEs were associated with moderate to severe nocturia. This association is thought-provoking but, without functional studies, difficult to evaluate. LUTS are multifactorial and reflect a number of different comorbidities/pathophysiologies. It cannot be excluded that this may contribute to the lack of associations between oxidative stress markers and symptoms.

The finding of an association (or lack of it) between biomarkers of oxidative stress and LUTS does not reveal whether oxidative stress causes or contributes to LUTS. If ROS/RNS were causative/contributing factors to LUTS, it would be predicted that a positive response to antioxidant therapy and a decrease in ROS/RNS levels would not only support an involvement but would also be a promising treatment approach. In a prospective cohort study in the USA of 1670 men aged 65–100 years, Holton et al. [6] examined whether dietary antioxidants were associated with a reduced likelihood of LUTS progression or an increased likelihood of LUTS. They found that there were no significant associations between multiple dietary antioxidants and LUTS progression or remission over 7 years. Many other attempts to validate and exploit chronic antioxidant therapies have provided disappointing results, and still there is no antioxidant with sufficient efficacy to be approved by health authorities [4]. The question of whether antioxidant therapy may be harmful has not yet been answered. If the cause of LUTS is an increase of ROS/RNS in the bladder, it is questionable whether normalization of indicators of oxidative stress is safe, considering that the normal function of ROS/RNS in the rest of the body may be affected.

The clinical relevance of oxidative stress as a pathophysiological factor in lower urinary tract dysfunction or as a treatment target for various lower urinary tract disorders is still unclear. In addition, it has not been established that antioxidant therapy has any beneficial effect on LUTS.

by Karl-Erik Andersson

References

  1. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox Biol 2015; 4: 180–3
  2. Murphy MP, Holmgren A, Larsson NG et al. Unraveling the biological roles of reactive oxygen species. Cell Metab 2011; 13: 361–6
  3. Frijhoff J, Winyard PG, Zarkovic N et al. Clinical relevance of biomarkers of oxidative stress. Antioxid Redox Signal 2015; 23: 1144–70
  4. Ghezzi P, Jaquet V, Marcucci F, Schmidt HHHW. The oxidative stress theory of disease: levels of evidence and epistemological aspects. Br J Pharmacol 2017; 174: 1784–96
  5. Matsumoto T, Hatakeyama S, Imai A et al. Relationship between oxidative stress and lower urinary tract symptoms: results from a community health survey in Japan. BJU Int 2019; 123 877-84
  6. Holton KF, Marshall LM, Shannon J et al. Osteoporotic fractures in men study group. Dietary antioxidants and longitudinal changes in lower urinary tract symptoms in elderly men: the Osteoporotic Fractures in Men study. Eur Urol Focus 2016; 2: 310–8

 

Video: The relationship between oxidative stress and lower urinary tract symptoms: Results from the community health survey in Japan

The relationship between oxidative stress and lower urinary tract symptoms: Results from the community health survey in Japan

 

Abstract

Objective

To investigate the relationship between oxidative stress and lower urinary tract symptoms (LUTS) in a community‐dwelling population.

Materials and Methods

The cross‐sectional study included 1 113 people who participated in the Iwaki Health Promotion Project of 2015 in Hirosaki, Japan. LUTS were assessed using structured questionnaires, including the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS). IPSS > 7, OABSS > 5, nocturia score > 1, or urge incontinence score > 1 were defined as moderate to severe symptoms. 8‐Hydroxy‐2′‐deoxyguanosine (8‐OHdG) and advanced glycation end products (AGEs) were measured by urine analysis and skin autofluorescence, respectively. The relationship between oxidative stress and LUTS was investigated using logistic regression analyses.

Results

This study included 431 men and 682 women. AGEs and 8‐OHdG levels were significantly higher in severe forms of LUTS. Multivariate logistic regression analyses showed that AGE levels were significantly associated with a higher frequency of nocturia but were not associated with IPSS, OABSS or urge incontinence. No significant association was observed between LUTS and 8‐OHdG levels.

Conclusions

We observed a significant association between AGE levels and nocturia score > 1. Further research is necessary to clarify a possible causal relationship between oxidative stress and nocturia.

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Editorial: Exercise to prevent LUTS – myth and reality

The pathophysiology of LUTS is one of the most intriguing issues in urology and the conundrum remains unsolved. Their multifactorial origin imposes a differential diagnosis that is often quite straightforward but sometimes complicated and at times the enigma is cracked only ex adiuvantibus. Clinical trials and personal experience have showed us that patients rarely become asymptomatic albeit our therapeutic efforts, suggesting that part of the problem is in the ageing process. So the question comes as to whether we can halt or delay ageing. Clearly some people age without LUTS apart from a physiological decrease in urinary flow. What goes wrong in our patients that stay right in some other subjects? Most of us would like to have a pill that could fix every problem, an easy answer to swallow and remedy our troubles, but this is not always the case.

‘Lifestyle’ is one of the most frequently cited words with 1 330 000 000 on Google today, more than double the ‘hits’ for happiness (a mere 576 000 000). No doubt that behind the lifestyle mantra there is an industry that makes billions on lifestyle issues, but as there is usually ‘no smoke without fire’ there must be something to it. Who has never been advised to change his way of life? Probably none, but who actually takes up the challenge and changes their routine? Clinical trials on the therapeutic effect of lifestyle changes cannot be analysed with an intent‐to‐treat analysis because ‘there’s many a slip ‘twixt cup and lip’ and we need look at those who really undertake the challenge.

There is a growing body of evidence that a healthy lifestyle will not just help to prevent cancer and cardiovascular events or keep you ‘fit’, but will also reduce the risk of developing LUTS [12]. In this issue of the BJUI, a paper from South Korea [3] provides rather convincing evidence that sitting for ≥10 h/day will increase your risk of storage and voiding symptoms, whilst doing exercise will reduce it. But what if you are a manager and your job is to read an endless number of reports each day? You cannot read whilst walking or doing exercise; you work for a living and LUTS may be the price you pay for a wealthier life.

As a surgeon I have an obsession for fixing things and making my patients better. If my patients have a sedentary job can I suggest a change in their lifestyle (not a change of job) that can counterbalance long sitting hours? The answer from the Korean cohort seems to be negative, as multivariate analysis of a subject cohort with long sitting hours suggested an increased risk of developing LUTS notwithstanding some exercise. I never thought that sitting was that bad but ‘est modus in rebus’ as Horace put it and probably sitting for too long is bad. Actually, my watch keeps telling me to stand at regular intervals, although I think I stand for too long in theatre (it also reminds me to breathe properly but that is another story).

This is a long way to say that I would rather be told what I can do right than be told what I am doing wrong. Is my personal risk of a poor outcome reversible? I think we have enough evidence from observational studies that exercise will reduce the risk of developing LUTS, but the time has come to embark on large prospective trials of LUTS treatment with lifestyle changes including exercise.

I have a number of patients who adopted a healthier lifestyle upon retirement (more info here about how they are doing it), lost weight, lowered their arterial pressure and their glucose levels, and their LUTS improved dramatically. What I need to know is whether this is the exception or whether this is the rule. These are not easy studies but I would rather work to answer an important academic question with a difficult and long‐term trial rather than doing an easier study that will not change the way we live and the way we practise.

Andrea Tubaro and Cosimo De Nunzio
Department of Urology, SantAndrea Hospital, Rome, Italy

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References

  1. De Nunzio C, Presicce F, Lombardo R et al. Physical activity as a risk factor for prostate cancer diagnosis: a prospective biopsy cohort analysis. BJU Int 2016117: E29–35
  2. Gacci M, Corona G, Sebastianelli A et al. Male lower urinary tract symptoms and cardiovascular events: a systematic review and meta‐analysis. Eur Urol 201670: 788–96
  3. Park HJ, Park CH, Chang Y, Ryu S. Sitting time, physical activity and the risk of lower urinary tract symptoms: a cohort studyBJU Int 2018122: 293–99
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