Harnessing the power within: engineering the microbiome for enhanced gynecologic health.

Abstract: Although numerous studies have demonstrated the impact of microbiome manipulation on human health, research on the microbiome's influence on female health remains relatively limited despite substantial disease burden. In light of this, we present a selected review of clinical trials and preclinical studies targeting both the vaginal and gut microbiomes for the prevention or treatment of various gynecologic conditions. Specifically, we explore studies that leverage microbiota transplants, probiotics, prebiotics, diet modifications, and engineered microbial strains. A healthy vaginal microbiome for females of reproductive age consists of lactic acid-producing bacteria predominantly of the Lactobacillus genus, which serves as a protective barrier against pathogens and maintains a balanced ecosystem. The gut microbiota's production of short-chain fatty acids, metabolism of primary bile acids, and modulation of sex steroid levels have significant implications for the interplay between host and microbes throughout the body, ultimately impacting reproductive health. By harnessing interventions that modulate both the vaginal and gut microbiomes, it becomes possible to not only maintain homeostasis but also mitigate pathological conditions. While the field is still working toward making broad clinical recommendations, the current studies demonstrate that manipulating the microbiome holds great potential for addressing diverse gynecologic conditions. Lay summary: Manipulating the microbiome has recently entered popular culture, with various diets thought to aid the microbes that live within us. These microbes live in different locations of our body and accordingly help us digest food, modulate our immune system, and influence reproductive health. The role of the microbes living in and influencing the female reproductive tract remains understudied despite known roles in common conditions such as vulvovaginal candidiasis (affecting 75% of females in their lifetime), bacterial vaginosis (25% of females in their lifetime), cervical HPV infection (80% of females in their lifetime), endometriosis (6-10% of females of reproductive age), and polycystic ovary syndrome (10-12% of females of reproductive age). Here, we review four different approaches used to manipulate the female reproductive tract and gastrointestinal system microbiomes: microbiota transplants, probiotics, prebiotics, and dietary interventions, and the use of engineered microbial strains. In doing so, we aim to stimulate discussion on new ways to understand and treat female reproductive health conditions.

Use of the International Consultation on Incontinence Questionnaires Bladder Diary in Men Seeking therapy for Lower Urinary Tract Symptoms.

BACKGROUND: Completion rates and correspondence to other measures need to be established for the International Consultation on Incontinence Questionnaire (ICIQ) bladder diary (ICIQ-BD) in the assessment of male lower urinary tract symptoms (LUTS). OBJECTIVE: To evaluate ICIQ-BD completion rates, frequency, volume, and sensation reporting for men. DESIGN, SETTING, AND PARTICIPANTS: Baseline data from the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) randomised controlled trial evaluating 820 men at 26 UK hospitals, looking at the ICIQ-BD, uroflowmetry, International Prostate Symptom Score, and ICIQ symptom score for male LUTS (ICIQ-MLUTS), were assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The ICIQ-BD, IPSS, ICIQ-MLUTS, and uroflowmetry data at baseline obtained from UPSTREAM were assessed. Correlations were analysed by Pearson's correlation coefficient, and comparison between groups were performed using paired or unpaired t tests or Tukey's test. All statistical tests were two sided and the strength of evidence was presented using p values. RESULTS AND LIMITATIONS: Of the participants, 25.0% (205/820) provided complete voiding and bedtime information for 3 d, 41.2% (338/820) omitted bedtime information, and the remainder omitted some or all voiding information. Median values (minimum - maximum) of 24-h, daytime, and night-time frequencies were 9.7 (3.3-24.0), 7.7 (3.3-22.7), and 1.7 (0.0-5.7), respectively. The mean voided volume per micturition for day and night times were 175.8 ± 74.2 and 264.4 ± 150.7 ml (p < 0.001), respectively. For fully completed diaries, day- and night-time frequency showed a weak-to-moderate correlation with symptom score questionnaires. More severe nocturia was generally reported in symptom scores than in the ICIQ-BD. In patients with high bother for increased daytime frequency (symptom), the mean daytime frequency (ICIQ-BD) was 9.6 ± 3.2 versus 7.6 ± 2.2 for low bother (p < 0.001). High bother for nocturia showed night-time frequency of 2.3 ± 1.2 versus 1.5 ± 1.1 for low bother (p < 0.001). For fully and partially completed diaries, ICIQ-BD sensation scores correlated weakly with symptom scores. Voided volumes from the bladder diary and uroflowmetry correlated weakly. CONCLUSIONS: Two-thirds of men (543/820) fully completed voiding information in the ICIQ-BD, but many omitted bedtime information, limiting the ability to quantify nocturia and diagnose nocturnal polyuria. PATIENT SUMMARY: Most men with urinary symptoms complete a bladder diary fully but may fail to indicate bedtimes. Extra information from a diary helps support symptom questionnaires to explain a patient's urinary habits.

Prostate Surgery for Men with Lower Urinary Tract Symptoms: Do We Need Urodynamics to Find the Right Candidates? Exploratory Findings from the UPSTREAM Trial.

BACKGROUND: Identifying men whose lower urinary tract symptoms (LUTS) may benefit from surgery is challenging. OBJECTIVE: To identify routine diagnostic and urodynamic measures associated with treatment decision-making, and outcome, in exploratory analyses of the UPSTREAM trial. DESIGN, SETTING, AND PARTICIPANTS: A randomised controlled trial was conducted including 820 men, considering surgery for LUTS, across 26 hospitals in England (ISCTRN56164274). INTERVENTION: Men were randomised to a routine care (RC) diagnostic pathway (n = 393) or a pathway that included urodynamics (UDS) in addition to RC (n = 427). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Men underwent uroflowmetry and completed symptom questionnaires, at baseline and 18 mo after randomisation. Regression models identified baseline clinical and symptom measures that predicted recommendation for surgery and/or surgical outcome (measured by the International Prostate Symptom Score [IPSS]). We explored the association between UDS and surgical outcome in subgroups defined by routine measures. RESULTS AND LIMITATIONS: The recommendation for surgery could be predicted successfully in the RC and UDS groups (area under the receiver operating characteristic curve 0.78), with maximum flow rate (Qmax) and age predictors in both groups. Surgery was more beneficial in those with higher symptom scores (eg, IPSS >16), age <74 yr, Qmax <9.8 ml/s, bladder outlet obstruction index >47.6, and bladder contractility index >123.0. In the UDS group, urodynamic measures were more strongly predictive of surgical outcome for those with Qmax >15, although patient-reported outcomes were also more predictive in this subgroup. CONCLUSIONS: Treatment decisions were informed with UDS, when available, but without evidence of change in the decisions reached. Despite the small group sizes, exploratory analyses suggest that selective use of UDS could detect obstructive pathology, missed by routine measures, in certain subgroups. PATIENT SUMMARY: Baseline clinical and symptom measurements were able to predict treatment decisions. The addition of urodynamic test results, while useful, did not generally lead to better surgical decisions and outcomes over routine tests alone.

A mouse model displays host and bacterial strain differences in Aerococcus urinae urinary tract infection.

In recent years, the clinical significance of Aerococcus urinae has been increasingly recognized. A. urinae has been implicated in cases of urinary tract infection (UTI; acute cystitis and pyelonephritis) in both male and female patients, ranging from children to older adults. Aerococcus urinae can also be invasive, causing urosepsis, endocarditis, and musculoskeletal infections. Mechanisms of pathogenesis in A. urinae infections are poorly understood, largely due to the lack of an animal model system. In response to this gap, we developed a model of A. urinae urinary tract infection in mice. We compared A. urinae UTI in female C3H/HeN and C57BL/6 mice and compared four clinical isolates of A. urinae isolated from patients with UTI, urgency urinary incontinence, and overactive bladder. Our data demonstrate that host genetic background modulates A. urinae UTI. Female C57BL/6 female mice rapidly cleared the infection. Female C3H/HeN mice, which have inherent vesicoureteral reflux that flushes urine from the bladder up into the kidneys, were susceptible to prolonged bacteriuria. This result is consistent with the fact that A. urinae infections most frequently occur in patients with underlying urinary tract abnormalities or disorders that make them susceptible to bacterial infection. Unlike uropathogens such as E. coli, which cause infection and inflammation both of the bladder and kidneys in C3H/HeN mice, A. urinae displayed tropism for the kidney, persisting in kidney tissue even after clearance of bacteria from the bladder. Aerococcus urinae strains from different genetic clades displayed varying propensities to cause persistent kidney infection. Aerococcus urinae infected kidneys displayed histological inflammation, neutrophil recruitment and increased pro-inflammatory cytokines. These results set the stage for future research that interrogates host-pathogen interactions between A. urinae and the urinary tract.

Treatment decision-making among men with lower urinary tract symptoms: A qualitative study of men's experiences with recommendations for patient-centred practice.

AIMS: To inform and guide patient-centred care for men with lower urinary tract symptoms (LUTS), by providing in-depth qualitative evidence regarding men's perspectives on treatment decision-making for LUTS. METHODS: An interview study of men recruited from 26 English urology departments. Purposive sampling captured surgical/nonsurgical treatment decisions, and diversity in demographics and symptom burden, in men who had urodynamics and those who did not. After diagnostic assessments, men were interviewed either pre-treatment or after LUTS surgery. Thematic analysis was conducted. Participants' descriptions of how LUTS treatment decisions were made were categorised as patient-led, doctor-led, or shared. RESULTS: A total of 41 men participated (25 pre-treatment, 16 post-surgery), ages 52-89. Twenty out of 41 described the treatment decision as shared with their consultant, 14 as doctor-led, and seven as patient-led. There was no obvious association between treatment decision-making style and patients' satisfaction with either clinicians' role in their decision or their treatment decision. Incomplete or rushed discussions and misperceptions of LUTS and its treatment were reported, indicating a risk of suboptimal decision-making support by clinicians. As well as clinician opinion, men's treatment decision-making was influenced by the results of urological assessments, comparing current symptoms with possible side-effects of surgery, and others' experiences and opinions. CONCLUSIONS: Men with LUTS report and prefer different kinds of decision-making support from their clinicians, who must tailor their input to patients' preferences and needs. Patients' treatment decision-making involves multiple factors and can be challenging, and areas of inadequate clinician support were identified. Recommendations for patient-centred consultations about LUTS treatment are presented.

Urodynamics tests for the diagnosis and management of bladder outlet obstruction in men: the UPSTREAM non-inferiority RCT.

BACKGROUND: Lower urinary tract symptoms (LUTS) in men may indicate bladder outlet obstruction (BOO) or weakness, known as detrusor underactivity (DU). Severe bothersome LUTS are a common indication for surgery. The diagnostic tests may include urodynamics (UDS) to confirm whether BOO or DU is the cause, potentially reducing the number of people receiving (inappropriate) surgery. OBJECTIVES: The primary objective was to determine whether a care pathway including UDS is no worse for symptom outcome than one in which it is omitted, at 18 months after randomisation. Rates of surgery was the key secondary outcome. DESIGN: This was a pragmatic, multicentre, two-arm (unblinded) randomised controlled trial, incorporating a health economic analysis and qualitative research. SETTING: Urology departments of 26 NHS hospitals in England. PARTICIPANTS: Men (aged ≥ 18 years) seeking further treatment, potentially including surgery, for bothersome LUTS. Exclusion criteria were as follows: unable to pass urine without a catheter, having a relevant neurological disease, currently undergoing treatment for prostate or bladder cancer, previously had prostate surgery, not medically fit for surgery and/or unwilling to be randomised. INTERVENTIONS: Men were randomised to a care pathway based on non-invasive routine tests (control) or routine care plus invasive UDS (intervention arm). MAIN OUTCOME MEASURES: The primary outcome was International Prostate Symptom Score (IPSS) at 18 months after randomisation and the key secondary outcome was rates of surgery. Additional secondary outcomes included adverse events (AEs), quality of life, urinary and sexual symptoms, UDS satisfaction, maximum urinary flow rate and cost-effectiveness. RESULTS: A total of 820 men were randomised (UDS, 427; routine care, 393). Sixty-seven men withdrew before 18 months and 11 died (unrelated to trial procedures). UDS was non-inferior to routine care for IPSS 18 months after randomisation, with a confidence interval (CI) within the margin of 1 point (-0.33, 95% CI -1.47 to 0.80). A lower surgery rate in the UDS arm was not found (38% and 36% for UDS and routine care, respectively), with overall rates lower than expected. AEs were similar between the arms at 43-44%. There were more cases of acute urinary retention in the routine care arm. Patient-reported outcomes for LUTS improved in both arms and satisfaction with UDS was high in men who received it. UDS was more expensive than routine care. From a secondary care perspective, UDS cost an additional £216 over an 18-month time horizon. Quality-adjusted life-years (QALYs) were similar, with a QALY difference of 0.006 in favour of UDS over 18 months. It was established that UDS was acceptable to patients, and valued by both patients and clinicians for its perceived additional insight into the cause and probable best treatment of LUTS. LIMITATIONS: The trial met its predefined recruitment target, but surgery rates were lower than anticipated. CONCLUSIONS: Inclusion of UDS in the diagnostic tests results in a symptom outcome that is non-inferior to a routine care pathway, but does not affect surgical rates for treating BOO. Results do not support the routine use of UDS in men undergoing investigation of LUTS. FUTURE WORK: Focus should be placed on indications for selective utilisation of UDS in individual cases and long-term outcomes of diagnosis and therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56164274. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 42. See the NIHR Journals Library website for further project information.

After hospital referral, men with bothersome lower urinary tract symptoms (LUTS) are assessed with standard tests. These include measurement of urine flow rate, bladder diaries and questionnaires, including the International Prostate Symptom Score (IPSS). UPSTREAM (Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods) researched whether or not including an extra test, urodynamics (UDS), helps when considering treatment options. UDS is a more invasive test and measures pressure in the bladder to check whether or not the prostate is causing obstruction. It was presumed that, if there is no obstruction, surgery would not be offered, so that using UDS would reduce the number of prostate operations. Each man participating (820 in total) was assessed with the standard tests. Around half of them had no extra tests (the 'routine care' arm of the trial); the rest had the UDS tests (the 'UDS' arm). Men then went on to have treatment, which they chose having discussed their test results with a urologist. IPSS and other symptom scores were examined for each man 18 months after joining the trial. At 18 months, surgery outcomes were known for 792 men and IPSS was known for 669 men. We investigated if the two trial arms showed similar changes in the IPSS and if there were fewer operations done in the UDS arm. We identified similar reductions in the IPSS in both arms. However, UDS tests did not reduce the number of operations. Analysing all the costs, it was found that a pathway including UDS costs more than routine care. Interviews were conducted that showed that men found UDS acceptable, and that the additional information helped both the men and their doctors consider which treatment would be most appropriate. These results do not support the routine use of UDS in the assessment of every man considering prostate surgery for LUTS. Further exploration of the data may identify circumstances in which UDS could be helpful.

Diagnostic Assessment of Lower Urinary Tract Symptoms in Men Considering Prostate Surgery: A Noninferiority Randomised Controlled Trial of Urodynamics in 26 Hospitals.

BACKGROUND: Prostate surgery can improve lower urinary tract symptoms (LUTS) by relieving bladder outlet obstruction (BOO). However, surgery is less effective without BOO, or if detrusor underactivity is present. Urodynamics (UDS) can identify BOO and measure detrusor activity, but evidence in clinical practice is lacking. OBJECTIVE: Urodynamics for Prostate Surgery Trial: Randomised Evaluation of Assessment Methods (UPSTREAM) aimed to evaluate whether a care pathway including UDS would reduce surgery without increasing urinary symptoms. DESIGN, SETTING, AND PARTICIPANTS: UPSTREAM is a pragmatic, noninferiority, randomised controlled trial in men with bothersome LUTS, in whom surgery was an option, in 26 hospitals in England (ISRCTN56164274). INTERVENTION: Participants were randomised (1:1) to routine care (RC) diagnostic tests, or RC plus UDS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the International Prostate Symptom Score (IPSS; patient-reported outcome scale from 0 to 35 points) 18 mo after randomisation, with a noninferiority margin of 1 point. Urological surgery rates were a key secondary outcome. The primary outcome was compared between the arms using linear regression, analysed on an intention-to-treat basis. RESULTS AND LIMITATIONS: Between October 2014 and December 2016, 820 men (median age 68 yr) were randomised (393 and 427 in the RC and UDS arms, respectively). The UDS arm showed noninferiority of the mean IPSSs (UDS 12.6; RC 13.1; adjusted difference at 18 mo -0.33 [95% confidence interval {CI} -1.47, +0.80]). In the UDS arm, 153/408 (38%) received surgery compared with 138/384 (36%) in the RC arm (adjusted odds ratio 1.05; 95% CI 0.77, 1.43). A total of 428 adverse events (UDS 234; RC 194) were recorded, with related events similar in both arms and 11 unrelated deaths. CONCLUSIONS: In this population, the UDS randomised group was noninferior to RC for the IPSS but did not reduce surgical rates. This study shows that routine use of UDS in the evaluation of uncomplicated LUTS has a limited role and should be used selectively. PATIENT SUMMARY: For men with uncomplicated lower urinary tract symptoms, symptom improvements after treatment and the number of operations performed are similar, irrespective of whether or not urodynamic tests are conducted in addition to routine tests. Accordingly, routine use of urodynamics has a limited role in this population group.

Gardnerella vaginalis as a Cause of Bacterial Vaginosis: Appraisal of the Evidence From in vivo Models.

Koch's postulates dictate the use of experimental models to illustrate features of human disease and provide evidence for a singular organism as the cause. The underlying cause(s) of bacterial vaginosis (BV) has been debated in the literature for over half a century. In 1955, it was first reported that a bacterium now known as Gardnerella vaginalis may be the cause of a condition (BV) resulting in higher vaginal pH, thin discharge, a fishy odor, and the presence of epithelial cells covered in bacteria. Here we review contemporary and historical studies on BV with a focus on reports of experimental infections in human or animal models using Gardnerella vaginalis. We evaluate experimental evidence for the hypothesis that G. vaginalis is sufficient to trigger clinical features of BV or relevant health complications associated with the condition. Additionally, we evaluate in vivo models of co-infection employing G. vaginalis together with other bacterial species to investigate evidence for the hypothesis that G. vaginalis may encourage colonization or virulence of other potential pathogens. Together, these studies paint a complex picture in which G. vaginalis has both direct and indirect roles in the features, health complications, and co-infections associated with BV. We briefly review the current taxonomic landscape and genetic diversity pertinent to Gardnerella and note the limitations of sequence-based studies using different marker genes and priming sites. Although much more study is needed to refine our understanding of how BV develops and persists within the human host, applications of the experimental aspects of Koch's postulates have provided an important glimpse into some of the causal relationships that may govern this condition in vivo.

Grading Severity and Bother Using the International Prostate Symptom Score and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms Score in Men Seeking Lower Urinary Tract Symptoms Therapy.

PURPOSE: We established severity banding ranges, bother assessment and key item content in principal patient reported outcomes measures in men seeking therapy for lower urinary tract symptoms. MATERIALS AND METHODS: Data for International Prostate Symptom Score (I-PSS) and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) were derived from a study evaluating 820 men at 26 United Kingdom hospitals. ROC curves were used to establish severity bandings. RESULTS: Classification tree showed that thresholds between mild-moderate and moderate-severe severity bands were 15 and 27 for I-PSS, 16 and 26 for ICIQ-MLUTS/severity, and 22 and 81 for ICIQ-MLUTS/bother, respectively. Highest area under the ROC curve and lowest Akaike's information criteria of univariate logistic regression indicated that ICIQ-MLUTS/bother was more related to global quality of life than were I-PSS and ICIQ-MLUTS/severity. The symptoms affecting I-PSS-quality of life (QoL) were only fully identified by ICIQ-MLUTS, because 2 key symptoms (urinary incontinence and post-micturition dribble) are not measured by I-PSS. ICIQ-MLUTS demonstrated that bother of some lower urinary tract symptoms is disproportionate to severity, and that persisting high bother levels following surgery are more likely due to storage (18% to 25%) and post-voiding (18% to 28%) lower urinary tract symptoms than voiding lower urinary tract symptoms (5% to 13%). Symptom improvement after surgery was uncertain if baseline I-PSS-QoL score was less than 3. CONCLUSIONS: The severity threshold scores were measured for the 2 key lower urinary tract symptoms patient reported outcomes measures, and the results indicate suitable categories of symptom severity for use in men referred for urological care. The ICIQ-MLUTS measures all the lower urinary tract symptoms affecting quality of life and includes individual symptom bother scores.