Genital Pain and the Spectrum of Bladder-Related Symptoms: Findings from the Prevention of Lower Urinary Tract Symptoms Research Consortium RISE FOR HEALTH Study, USA.

INTRODUCTION AND HYPOTHESIS: Women with vulvovaginal or genital pain more commonly experience interstitial cystitis/bladder pain syndrome (IC/BPS) and urinary tract infections. However, the relationship between genital pain and bladder health is lacking. METHODS: Women in the Prevention of Lower Urinary Tract Symptoms Consortium's RISE FOR HEALTH population-based study answered questions about bladder health globally, and across nine bladder health domains of holding, efficacy, social-occupation, physical activity, intimacy, travel, emotion, perception, and freedom. Bladder function was assessed across six indices including urinary frequency, sensation, continence, comfort, emptying, and dysbiosis (e.g., urinary tract infections). Participants were grouped by no pain beyond transitory events (i.e., minor headaches, toothaches, or sprains), nongenital-related pain only, and any genital pain using a validated pain diagram. Mean adjusted scores and indices were compared using general linear modelling. RESULTS: Of 1,973 eligible women, 250 (12.7%) reported genital pain, 609 (30.9%) reported nongenital pain only, and 1,114 (56.5%) reported no pain. Women with any genital pain had lower (worse) adjusted mean scores across all bladder health scales (BHS; BHS global adjusted mean 47.5; 95% CI 40.8-54.1), compared with those with nongenital pain only (53.7; 95% CI 47.6-59.8), and no pain (59.3; 95% CI 53.3-65.4). Similarly, adjusted mean total Bladder Functional Index scores were lower for those with genital pain (63.1; 95% CI 58.4-67.9) compared with nongenital pain (72.1; 95% CI 67.7-76.5) and no pain (77.4; 95% CI 73.0-81.8). CONCLUSIONS: Heightened awareness of the relationship between genital pain and bladder health should prompt clinicians caring for women with genital pain to assess bladder health and function.

Exploring women's bladder self-care practices: A qualitative secondary analysis.

AIMS: To describe women's experiences with a range of bladder self-care practices. DESIGN: We conducted a secondary, directed content analysis of qualitative data from the Study of Habits, Attitudes, Realities and Experiences, a multisite focus group study designed to explore adolescent and adult women's experiences, perceptions, beliefs, knowledge and behaviours related to bladder health. This study was conducted by the National Institute of Diabetes and Digestive and Kidney Diseases' Prevention of Lower Urinary Tract Symptoms Research Consortium. Study methods were informed by the Consortium's conceptual framework, based on a social ecological model adapted from Glass and McAtee's Society-Behavior-Biology Nexus. METHODS: Participants were recruited at seven geographically diverse United States research centres between July 2017 and April 2018. Data for the current analysis were collected using a semi-structured discussion group with 36 focus groups involving 316 community-dwelling adult women aged 18-93 years. Coded text was re-examined according to eight self-care behavioural domains identified through literature review and expert opinion as potentially influencing bladder health. RESULTS: Participants described many self-care practices they had adopted to prevent bladder problems or manage existing symptoms and conditions. Eight themes were identified: 'Choosing fluids, foods and medications'; 'Dressing for bladder health'; 'Promoting bodily cleanliness'; 'Managing toileting environments'; 'Timing when to void'; 'Exercising pelvic floor muscles for bladder control'; 'Limiting physical activities that challenge the bladder' and 'Staying home and navigating when away'. Thirteen subthemes were derived from five of the eight themes. CONCLUSION: Women use a broad array of self-care practices related to their bladder health. Research is needed to examine the efficacy of self-care behaviours for preventing or managing bladder symptoms and conditions, and to discern potential risks. Results have important implications for development of bladder health promotion interventions and public health messaging around women's bladder health. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study provides a comprehensive framework for understanding women's bladder self-care practices, which can be used by clinicians and public health professionals in designing interventions to promote bladder health and function. IMPACT: Women with and without lower urinary tract symptoms use a broad range of self-care practices that may affect their bladder health, including some that may be harmful. Because of the high prevalence of bladder symptoms in women, this study may help patient assessment and counselling regarding self-care practices. REPORTING METHOD: This study was reported according to the Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Validation of bladder health scales and function indices for women's research.

BACKGROUND: Existing bladder-specific measures lack the ability to assess the full range of bladder health, from poor to optimal health. OBJECTIVE: This study aimed to report evidence of validity of the self-administered, multidimensional bladder health scales and function indices for research in adult women. STUDY DESIGN: A cross-sectional population-based validation study with random assignment to paper or electronic administration was conducted using national address-based probability sampling supplemented by purposive sampling of women with lower urinary tract symptoms in 7 clinical research centers. Construct validity of the bladder health scales and function indices was guided by a multitrait-multimethod approach using health and condition-specific questionnaires, bladder diaries, expert ratings of bladder health, and noninvasive bladder function testing. Internal dimensional validity was evaluated using factor analysis; internal reliability was assessed using paired t-tests and 2-way mixed-effects intraclass correlation coefficient models. Chi-square, Fisher exact, or t-tests were used for mode comparisons. Convergent validity was evaluated using Pearson correlations with the external construct measures, and known-group validity was established with comparison of women known and unknown to be symptomatic of urinary conditions. RESULTS: The sample included 1072 participants. Factor analysis identified 10 scales, with Cronbach's alpha ranging from 0.74 to 0.94. Intraclass correlation coefficients of scales ranged from 0.55 to 0.94. Convergent validity of the 10 scales and 6 indices ranged from 0.52 to 0.83. Known-group validity was confirmed for all scales and indices. Item distribution was similar by mode of administration. CONCLUSION: The paper and electronic forms of the bladder health scales and function indices are reliable and valid measures of bladder health for use in women's health research.

Survey of lower urinary tract symptoms in United States women using the new lower urinary tract dysfunction research Network-Symptom Index 29 (LURN-SI-29) and a national research registry.

PURPOSE: An online bladder health survey was administered to national registry volunteers to: (1) determine the feasibility of using ResearchMatch for studying lower urinary tract symptoms (LUTS); (2) pilot the new, comprehensive Lower Urinary Tract Dysfunction Research Network Symptom Index-29 (LURN-SI-29) and determine its ability to detect known associations with LUTS; and (3) explore novel areas of bladder health in community-based women. METHODS: A cross-sectional web-based survey was administered to a random sample of ResearchMatch adult female, transgender and non-binary volunteers. Participant demographics, health characteristics, the LURN-SI-29, and LUTS-related experiences were collected. RESULTS: A total of 1725 ReseachMatch volunteers with a mean age of 44.0 years completed the study and were eligible for the analysis. Participants were primarily white, cisgendered, highly educated, nulliparous, and premenopausal. The median LURN-SI-29 score was 17 (interquartile range: 11-26). More than half the sample reported urinary urgency (71.0%), nocturia (65.7%), and stress incontinence (52.3%) a "few times" or more in the last 7 days. Approximately half reported sensation of incomplete bladder emptying (49.6%) with one-third reporting urgency incontinence (37.6%); notably, 52.6% of respondents reported being at least "somewhat" bothered by LUTS. LURN-SI-29 scores increased with age, body mass index, decrements in self-reported health, medical comorbidity, parity, menopausal status, and urinary symptom bother, providing evidence of convergent validity. LURN-SI-29 scores varied by race and education, with the lowest scores in Asian and highly educated women. CONCLUSION: Overall, the prevalence and spectrum of LUTS in an online research registry of women volunteers were high and comparable to other population-based samples. The new LURN-SI-29 demonstrated its ability to detect expected associations with demographic and health characteristics in a nonclinical population.

Necrotizing leg gangrene from invasive cutaneous Kaposi sarcoma, reversed by pegylated liposomal doxorubicin.

INTRODUCTION: Although rare, Kaposi sarcoma is the most common malignant neoplasm associated with human immunodeficiency virus (HIV) infection. Several agents have now been approved in the treatment of this malignancy and are used with varying degrees of success. CASE REPORT: We present a unique case of a 64-year-old man with well-controlled HIV infection who developed necrotizing leg gangrene from invasive cutaneous Kaposi sarcoma. He responded very well to systemic chemotherapy, thereby avoiding limb amputation. MANAGEMENT AND OUTCOME: Pegylated liposomal doxorubicin (PLD) at a dose of 20 mg/m2 every 3 weeks was utilized, with a near-complete response after six cycles of therapy. The patient continues to receive maintenance treatment with PLD. His HIV infection remains in excellent control, with a high-normal CD4 T-cell count. Periodic echocardiogram evaluations have not shown any decline in left ventricular ejection fraction (LVEF) over time. CONCLUSION: Most patients with Kaposi sarcoma achieve partial responses to treatment with PLD. Our case illustrates that near complete and complete responses are possible with this agent, leading to potential limb salvage in necrotizing gangrene.

A fatal disseminated cryptococcal infection in a patient treated with zanubrutinib for Waldenström's macroglobulinemia.

INTRODUCTION: Zanubrutinib is a second generation, irreversible small-molecule Bruton tyrosine kinase inhibitor (BTK) approved for the treatment of Waldenström's macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. As a class, BTKs have been linked with an increased risk of respiratory infections in clinical trials. CASE REPORT: We describe a 75-year-old patient who presented with generalized weakness, fevers, dyspnea, and dry cough four months after starting zanubrutinib therapy for Waldenström's macroglobulinemia. He was subsequently diagnosed with pneumonia. Septic work-up led to diagnosis of disseminated cryptococcal infection, complicated by fungal pneumonia and meningitis. MANAGEMENT AND OUTCOME: Zanubrutinib was held on admission, and the patient was started on combination oral and intravenous antifungal therapy. Despite clearance of fungemia, aggressive resuscitation, and appropriate antimicrobial therapy, respiratory status deteriorated requiring intubation. His condition progressed to septic shock, multiorgan failure, and demise. DISCUSSION/CONCLUSION: We report herein a case of fatal disseminated cryptococcosis in the setting of zanubrutinib use for Waldenström's macroglobulinemia. At the time of diagnosis, his Waldenström's macroglobulinemia was in a partial response. The mechanism by which Bruton tyrosine kinase inhibitors (BTKs) lead to invasive fungal infections in these patients remains to be explored. T- and B-cell immune defects accompanying low-grade B-cell lymphomas may contribute to the severity of these infections.

Asymptomatic Bacteriuria and Pyuria in Premenopausal Women.

BACKGROUND: Asymptomatic bacteriuria and pyuria in healthy women often trigger inappropriate antimicrobial treatment, but there is a paucity of data on their prevalence and persistence. METHODS: To evaluate the prevalence and persistence of asymptomatic bacteriuria and pyuria in women at high risk of recurrent urinary tract infection, we conducted an observational cohort study in 104 healthy premenopausal women with a history of recurrent urinary tract infection with daily assessments of bacteriuria, pyuria, and urinary symptoms over a 3-month period. RESULTS: The mean age of participants was 22 years, and 74% were white. Asymptomatic bacteriuria events (urine cultures with colony count ≥105 CFU/mL of a uropathogen on days with no symptomatic urinary tract infection diagnosed) occurred in 45 (45%) women on 159 (2.5%) of 6283 days. Asymptomatic bacteriuria events were most commonly caused by Escherichia coli, which was present on 1.4% of days, with a median duration of 1 day (range, 1-10). Pyuria occurred in 70 (78%) of 90 evaluable participants on at least 1 day and 25% of all days on which no symptomatic urinary tract infection was diagnosed. The positive predictive value of pyuria for E. coli asymptomatic bacteriuria was 4%. CONCLUSIONS: In this population of healthy women at high risk of recurrent urinary tract infection, asymptomatic bacteriuria is uncommon and, when present, rarely lasts more than 2 days. Pyuria, on the other hand, is common but infrequently associated with bacteriuria or symptoms. These data strongly support recommendations not to screen for or treat asymptomatic bacteriuria or pyuria in healthy, nonpregnant women.

Response to Persistent ER Stress in Plants: A Multiphasic Process That Transitions Cells from Prosurvival Activities to Cell Death.

The unfolded protein response (UPR) is a highly conserved response that protects plants from adverse environmental conditions. The UPR is elicited by endoplasmic reticulum (ER) stress, in which unfolded and misfolded proteins accumulate within the ER. Here, we induced the UPR in maize (Zea mays) seedlings to characterize the molecular events that occur over time during persistent ER stress. We found that a multiphasic program of gene expression was interwoven among other cellular events, including the induction of autophagy. One of the earliest phases involved the degradation by regulated IRE1-dependent RNA degradation (RIDD) of RNA transcripts derived from a family of peroxidase genes. RIDD resulted from the activation of the promiscuous ribonuclease activity of ZmIRE1 that attacks the mRNAs of secreted proteins. This was followed by an upsurge in expression of the canonical UPR genes indirectly driven by ZmIRE1 due to its splicing of Zmbzip60 mRNA to make an active transcription factor that directly upregulates many of the UPR genes. At the peak of UPR gene expression, a global wave of RNA processing led to the production of many aberrant UPR gene transcripts, likely tempering the ER stress response. During later stages of ER stress, ZmIRE1's activity declined, as did the expression of survival modulating genes, Bax inhibitor1 and Bcl-2-associated athanogene7, amid a rising tide of cell death. Thus, in response to persistent ER stress, maize seedlings embark on a course of gene expression and cellular events progressing from adaptive responses to cell death.

Analysis validation has been neglected in the Age of Reproducibility.

Increasingly complex statistical models are being used for the analysis of biological data. Recent commentary has focused on the ability to compute the same outcome for a given dataset (reproducibility). We argue that a reproducible statistical analysis is not necessarily valid because of unique patterns of nonindependence in every biological dataset. We advocate that analyses should be evaluated with known-truth simulations that capture biological reality, a process we call "analysis validation." We review the process of validation and suggest criteria that a validation project should meet. We find that different fields of science have historically failed to meet all criteria, and we suggest ways to implement meaningful validation in training and practice.

The Emperor's New Clothes: PRospective Observational Evaluation of the Association Between Initial VancomycIn Exposure and Failure Rates Among ADult HospitalizEd Patients With Methicillin-resistant Staphylococcus aureus Bloodstream Infections (PROVIDE).

BACKGROUND: Vancomycin is the most commonly administered antibiotic in hospitalized patients, but optimal exposure targets remain controversial. To clarify the therapeutic exposure range, this study evaluated the association between vancomycin exposure and outcomes in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. METHODS: This was a prospective, multicenter (n = 14), observational study of 265 hospitalized adults with MRSA bacteremia treated with vancomycin. The primary outcome was treatment failure (TF), defined as 30-day mortality or persistent bacteremia ≥7 days. Secondary outcomes included acute kidney injury (AKI). The study was powered to compare TF between patients who achieved or did not achieve day 2 area under the curve to minimum inhibitory concentration (AUC/MIC) thresholds previously found to be associated with lower incidences of TF. The thresholds, analyzed separately as co-primary endpoints, were AUC/MIC by broth microdilution ≥650 and AUC/MIC by Etest ≥320. RESULTS: Treatment failure and AKI occurred in 18% and 26% of patients, respectively. Achievement of the prespecified day 2 AUC/MIC thresholds was not associated with less TF. Alternative day 2 AUC/MIC thresholds associated with lower TF risks were not identified. A relationship between the day 2 AUC and AKI was observed. Patients with day 2 AUC ≤515 experienced the best global outcomes (no TF and no AKI). CONCLUSIONS: Higher vancomycin exposures did not confer a lower TF risk but were associated with more AKI. The findings suggest that vancomycin dosing should be guided by the AUC and day 2 AUCs should be ≤515. As few patients had day 2 AUCs <400, further study is needed to define the lower bound of the therapeutic range.

Escherichia coli Resistance to Fluoroquinolones in Community-Acquired Uncomplicated Urinary Tract Infection in Women: a Systematic Review.

Antibiotic resistance is a threat to public health, and uncomplicated urinary tract infections (uUTIs) are an example of this concern. This systematic review (International Prospective Register of Systematic Reviews [PROSPERO] ID: CRD42020156674) is the first to determine the prevalence of Escherichia coli resistance to fluoroquinolones in women with community-acquired uUTI. PubMed and Embase searches were conducted; 38 studies fulfilled eligibility criteria and were included in the systematic review. Within Europe, ciprofloxacin resistance in E. coli isolates varied between countries and increased in some from 2006 to 2008 and 2014 to 2016, specifically in the United Kingdom (0.5% to 15.3%), Germany (8.7% to 15.1%), and Spain (22.9% to 30.8%), although methodologies and settings were often not comparable. In Asia, there was a substantial increase in ciprofloxacin resistance during 2008 to 2014 from 25% to more than 40%. In North America, resistance to ciprofloxacin also increased between 2008 and 2017, from 4% to 12%. Data exploring different age groups did not show a consistent relationship with resistance, whereas two studies found that fluoroquinolone resistance was higher in postmenopausal women than premenopausal women. One study indicated a link between fluoroquinolone resistance and uUTI recurrence. These findings may have implications for the empirical treatment of uUTI with fluoroquinolones globally, but more data are needed to fully understand regional situations and impact patient management.

A Bayesian multivariate meta-analysis of prevalence data.

When conducting a meta-analysis involving prevalence data for an outcome with several subtypes, each of them is typically analyzed separately using a univariate meta-analysis model. Recently, multivariate meta-analysis models have been shown to correspond to a decrease in bias and variance for multiple correlated outcomes compared with univariate meta-analysis, when some studies only report a subset of the outcomes. In this article, we propose a novel Bayesian multivariate random effects model to account for the natural constraint that the prevalence of any given subtype cannot be larger than that of the overall prevalence. Extensive simulation studies show that this new model can reduce bias and variance when estimating subtype prevalences in the presence of missing data, compared with standard univariate and multivariate random effects models. The data from a rapid review on occupation and lower urinary tract symptoms by the Prevention of Lower Urinary Tract Symptoms Research Consortium are analyzed as a case study to estimate the prevalence of urinary incontinence and several incontinence subtypes among women in suspected high risk work environments.

Normative noninvasive bladder function measurements in healthy women: A systematic review and meta-analysis.

AIM: To conduct an evidence synthesis of normative reference values for bladder function parameters in women. METHODS: We conducted a systematic review and meta-analysis of studies reporting bladder function parameters obtained from noninvasive tests in healthy women. Seven databases were searched for relevant studies from inception through December 2018, with manual searching of reference lists. We included English language articles that provided quantitative data on urination frequency, voided and postvoid residual volumes, and uroflowmetry results in women without lower urinary tract symptoms. Study selection, data extraction, and quality assessment were undertaken by at least two independent reviewers. Random-effects meta-analytic models were used to derive study-level pooled mean estimates and 95% confidence intervals. RESULTS: A total of 24 studies (N = 3090 women, age range, 18-91 years) met eligibility criteria. Pooled mean estimates of bladder function parameters were: 6.6 daytime voids (95% confidence interval (95% CI), 6.2, 7.0), 0.4 nighttime voids (95% CI, 0.0, 0.8), 1577 mL for 24-hour voided volume (95% CI 1428,1725); 12 mL for postvoid residual volume (95% CI, 4, 20); and 28 mL/sec for maximum flow rate (95% CI, 27,30). Between-study heterogeneity was high for all outcomes (I2 = 61.1-99.6%), but insufficient data were available to explore reasons for this high heterogeneity (eg, differences by age). CONCLUSION: Although summary mean estimates of bladder function parameters were calculated, the wide heterogeneity across studies precludes generalization of these estimates to all healthy women. Further research is needed to determine normative reference values within specific groups, such as those defined by age.

Applying concepts of life course theory and life course epidemiology to the study of bladder health and lower urinary tract symptoms among girls and women.

AIMS: Although lower urinary tract symptoms (LUTS) may occur at different periods during the life course of women, a little research on LUTS has adopted a life course perspective. The purpose of this conceptual paper is to demonstrate how life course theory and life course epidemiology can be applied to study bladder health and LUTS trajectories. We highlight conceptual work from the Prevention of Lower Urinary Tract Symptoms Research Consortium to enhance the understanding of life course concepts. METHODS: Consortium members worked in transdisciplinary teams to generate examples of how life course concepts may be applied to research on bladder health and LUTS in eight prioritized areas: (a) biopsychosocial ecology of stress and brain health; (b) toileting environment, access, habits, and techniques; (c) pregnancy and childbirth; (d) physical health and medical conditions; (e) musculoskeletal health; (f) lifestyle behaviors; (g) infections and microbiome; and (h) hormonal status across the life span. RESULTS: Life course concepts guided consortium members' conceptualization of how potential risk and protective factors may influence women's health. For example, intrapartum interventions across multiple pregnancies may influence trajectories of bladder health and LUTS, illustrating the principle of life span development. Consortium members also identified and summarized methodologic and practical considerations in designing life course research. CONCLUSIONS: This paper may assist researchers from a variety of disciplines to design and implement research identifying key risk and protective factors for LUTS and bladder health across the life course of women. Results from life course research may inform health promotion programs, policies, and practices.

Development of Conceptual Models to Guide Public Health Research, Practice, and Policy: Synthesizing Traditional and Contemporary Paradigms.

This applied paper is intended to serve as a "how to" guide for public health researchers, practitioners, and policy makers who are interested in building conceptual models to convey their ideas to diverse audiences. Conceptual models can provide a visual representation of specific research questions. They also can show key components of programs, practices, and policies designed to promote health. Conceptual models may provide improved guidance for prevention and intervention efforts if they are based on frameworks that integrate social ecological and biological influences on health and incorporate health equity and social justice principles. To enhance understanding and utilization of this guide, we provide examples of conceptual models developed by the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium. PLUS is a transdisciplinary U.S. scientific network established by the National Institutes of Health in 2015 to promote bladder health and prevent lower urinary tract symptoms, an emerging public health and prevention priority. The PLUS Research Consortium is developing conceptual models to guide its prevention research agenda. Research findings may in turn influence future public health practices and policies. This guide can assist others in framing diverse public health and prevention science issues in innovative, potentially transformative ways.

Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline.

PURPOSE: This document seeks to establish guidance for the evaluation and management of women with recurrent urinary tract infections (rUTI) to prevent inappropriate use of antibiotics, decrease the risk of antibiotic resistance, reduce adverse effects of antibiotic use, provide guidance on antibiotic and non-antibiotic strategies for prevention, and improve clinical outcomes and quality of life by reducing recurrence of urinary tract infection (UTI) events. MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. A research librarian conducted searches in Ovid MEDLINE (1946 to January Week 1 2018), Cochrane Central Register of Controlled Trials (through December 2017) and Embase (through January 16, 2018). An update literature search was conducted on September 20, 2018. RESULTS: When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low). Such evidence-based statements are provided as Strong, Moderate, or Conditional Recommendations. In instances of insufficient evidence, additional guidance is provided as Clinical Principles and Expert Opinions. CONCLUSIONS: Our ability to diagnose, treat, and manage rUTI long-term has evolved due to additional insights into the pathophysiology of rUTI, a new appreciation for the adverse effects of repetitive antimicrobial therapy, rising rates of bacterial antimicrobial resistance (AMR), and better reporting of the natural history and clinical outcomes of acute cystitis and rUTI. As new data continue to emerge in this space, this document will undergo review to ensure continued accuracy.

Terminology for bladder health research in women and girls: Prevention of Lower Urinary Tract Symptoms transdisciplinary consortium definitions.

AIM: To report research terminology and definitions for describing healthy bladder function among women and girls. METHODS: The Prevention of Lower Urinary tract Symptoms (PLUS) Consortium developed research terminology and definitions for elements of healthy bladder function based on existing understanding of storage and emptying functions of the bladder and accepted definitions of lower urinary tract symptoms (LUTS). The novel concept of a bladder "bioregulatory" function was also proposed. Elements of bladder function corresponding to bladder health (BH) and LUTS were developed and refined using an iterative process. A comprehensive reference table structured by bladder function (Storage, Emptying, and Bioregulatory) and elements of each function was created to document proposed research terminology and definitions. RESULTS: The BH research definitions for each bladder function are: (1) Storage: the ability to hold urine for a reasonable duration of time and sense bladder fullness without fear of or concern about urgency, discomfort or leakage; (2) Emptying: the ability to empty the bladder completely in a timely, efficient, effortless, comfortable manner; and (3) Bioregulatory: the bladder barrier protects the individual/host from pathogens, chemicals, and malignancy. Research definitions for seven Storage, seven Emptying, and three Bioregulatory elements of function are presented. Novel LUTS research definitions were developed when gaps in existing definitions were identified or nonclinical language was desired. CONCLUSIONS: PLUS BH definitions reflect a transdisciplinary approach to standardizing research definitions for elements of bladder function from a perspective of health rather than dysfunction and provide a framework for studying BH in clinical practice, public health promotion, and LUTS prevention.

Treatment and Prevention of Recurrent Lower Urinary Tract Infections in Women: A Rapid Review with Practice Recommendations.

PURPOSE: Recurrent lower urinary tract infections in women are a highly prevalent and burdensome condition for which best practice guidelines for treatment and prevention that minimize harm and optimize well-being are greatly needed. To inform development of practice recommendations, a rapid literature review of original research, systematic reviews, meta-analyses and practice guidelines was conducted. MATERIALS AND METHODS: PubMed®, Embase®, Opus, Scopus®, Google Scholar, The Cochrane Library and the U.S. National Guideline Clearinghouse electronic databases were searched from inception to September 22, 2017. Articles and practice guidelines were included if they were in English, were peer reviewed, included women, involved treatment or prevention strategies for recurrent urinary tract infection and reported an outcome related to recurrence rates of urinary tract infection. Critical appraisal of original studies was conducted using the Cochrane risk of bias tool, and of systematic reviews using the AMSTAR 2 tool. RESULTS: Of 1,582 citations identified 74 met our study inclusion criteria. These comprised 49 randomized controlled trials, 23 systematic reviews (16 with meta-analyses) and 2 practice guidelines. No study reported a multi-targeted treatment approach. There was a lack of high quality studies and systematic reviews evaluating prevention strategies for recurrent urinary tract infection. CONCLUSIONS: We recommend an algorithmic approach to care that includes education on lifestyle and behavioral modifications, and addresses specific populations of women with antimicrobial based and nonantibiotic alternatives. This approach includes the use of vaginal estrogen with or without lactobacillus containing probiotics in postmenopausal women, low dose post-coital antibiotics for recurrent urinary tract infection associated with sexual activity in premenopausal women, low dose daily antibiotic prophylaxis in premenopausal women with infections unrelated to sexual activity, and methenamine hippurate and/or lactobacillus containing probiotics as nonantibiotic alternatives. Future research should involve consistent use of terminology, validated instruments to assess response to interventions and patient perspectives on care. Our treatment algorithm is based on the best available evidence, and fills a gap in the literature and practice regarding effective strategies to prevent recurrent urinary tract infection in women.

Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine.

In human urinary tract infections, host cells release the antimicrobial protein siderocalin (SCN; also known as lipocalin-2, neutrophil gelatinase-associated lipocalin, or 24p3) into the urinary tract. By binding to ferric catechol complexes, SCN can sequester iron, a growth-limiting nutrient for most bacterial pathogens. Recent evidence links the antibacterial activity of SCN in human urine to iron sequestration and metabolomic variation between individuals. To determine whether these metabolomic associations correspond to functional Fe(III)-binding SCN ligands, we devised a biophysical protein binding screen to identify SCN ligands through direct analysis of human urine. This screen revealed a series of physiologic unconjugated urinary catechols that were able to function as SCN ligands of which pyrogallol in particular was positively associated with high urinary SCN activity. In a purified, defined culture system, these physiologic SCN ligands were sufficient to activate SCN antibacterial activity against Escherichia coli In the presence of multiple SCN ligands, native mass spectrometry demonstrated that SCN may preferentially combine different ligands to coordinate iron, suggesting that availability of specific ligand combinations affects in vivo SCN antibacterial activity. These results support a mechanistic link between the human urinary metabolome and innate immune function.