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.

Non-invasive bladder function measures in healthy, asymptomatic female children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Lower urinary tract symptoms (LUTS) are common in children and adolescents. Non-invasive tests evaluating bladder function are generally preferred over invasive tests, yet few studies have explored the range of normative values for these tests in healthy, asymptomatic children. OBJECTIVE: To define normative reference ranges for non-invasive tests of bladder function in healthy, asymptomatic girls and adolescents. STUDY DESIGN: A comprehensive search strategy was performed in seven electronic databases through October 2019. English-language studies reporting data on voiding frequency, voided and postvoid residual volumes (PVR) and uroflowmetry results in healthy, asymptomatic girls (mean age ≥ 5 years) were included. Two independent reviewers performed study review, data extraction, and quality assessment. Overall mean estimates and 95% confidence intervals for each bladder function parameter were calculated using random effects models, and 95% normative reference values were estimated. RESULTS: Ten studies met eligibility criteria for the meta-analysis (n = 2143 girls, age range: 3-18). Mean estimates of maximum voided volume and PVR were 233.4 ml (95% CI 204.3-262.6; n = 1 study) and 8.6 ml (95% CI 4.8-12.4; n = 2 studies) respectively. Pooled mean estimates for uroflowmetry parameters were: 21.5 ml/s (95% CI 20.5-2.5) for maximum flow rate (n = 6 studies), 12.5 ml/s (95% CI 11.2-13.8) for mean flow rate (n = 6 studies), 6.8 s (95% CI 4.4-9.3) for time to maximum flow (n = 3 studies), 15.7 s (95% CI 13.0-18.5) for flow time (n = 3 studies), and 198.7 ml (95% CI 154.2-234.2) for voided volume (n = 9 studies). No studies reported estimates of voiding frequency. Between-study heterogeneity was high (89.0-99.6%). CONCLUSIONS: Although we were able to calculate pooled mean estimates for several parameters, the small number of included studies and the wide age ranges of participants preclude generalization of reference values to all healthy girls. Further research is needed to determine normative reference values within specific age groups.

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.

Robust mosaicking of maize fields from aerial imagery.

PREMISE: Aerial imagery from small unmanned aerial vehicle systems is a promising approach for high-throughput phenotyping and precision agriculture. A key requirement for both applications is to create a field-scale mosaic of the aerial imagery sequence so that the same features are in registration, a very challenging problem for crop imagery. METHODS: We have developed an improved mosaicking pipeline, Video Mosaicking and summariZation (VMZ), which uses a novel two-dimensional mosaicking algorithm that minimizes errors in estimating the transformations between successive frames during registration. The VMZ pipeline uses only the imagery, rather than relying on vehicle telemetry, ground control points, or global positioning system data, to estimate the frame-to-frame homographies. It exploits the spatiotemporal ordering of the image frames to reduce the computational complexity of finding corresponding features between frames using feature descriptors. We compared the performance of VMZ to a standard two-dimensional mosaicking algorithm (AutoStitch) by mosaicking imagery of two maize (Zea mays) research nurseries freely flown with a variety of trajectories. RESULTS: The VMZ pipeline produces superior mosaics faster. Using the speeded up robust features (SURF) descriptor, VMZ produces the highest-quality mosaics. DISCUSSION: Our results demonstrate the value of VMZ for the future automated extraction of plant phenotypes and dynamic scouting for crop management.

Functional gene categories differentiate maize leaf drought-related microbial epiphytic communities.

The phyllosphere epiphytic microbiome is composed of microorganisms that colonize the external aerial portions of plants. Relationships of plant responses to specific microorganisms-both pathogenic and beneficial-have been examined, but the phyllosphere microbiome functional and metabolic profile responses are not well described. Changing crop growth conditions, such as increased drought, can have profound impacts on crop productivity. Also, epiphytic microbial communities provide a new target for crop yield optimization. We compared Zea mays leaf microbiomes collected under drought and well-watered conditions by examining functional gene annotation patterns across three physically disparate locations each with and without drought treatment, through the application of short read metagenomic sequencing. Drought samples exhibited different functional sequence compositions at each of the three field sites. Maize phyllosphere functional profiles revealed a wide variety of metabolic and regulatory processes that differed in drought and normal water conditions and provide key baseline information for future selective breeding.

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.

Plant growth regulators interact with elevated temperature to alter heat stress signaling via the Unfolded Protein Response in maize.

Plants are increasingly exposed to high temperatures, which can cause accumulation of unfolded protein in the endoplasmic reticulum (ER). This condition, known as ER stress, evokes the unfolded protein response (UPR), a cytoprotective signaling pathway. One important branch of the UPR is regulated by splicing of bZIP60 mRNA by the IRE1 stress sensor. There is increasing evidence that commercial plant growth regulators may protect against abiotic stressors including heat stress and drought, but there is very little mechanistic information about these effects or about the regulatory pathways involved. We evaluated evidence in the B73 Zea mays inbred for differences in the activity of the UPR between permissive and elevated temperature in conjunction with plant growth regulator application. Treatment with elevated temperature and plant growth regulators increased UPR activation, as assessed by an increase in splicing of the mRNA of the IRE1 target bZIP60 following paclobutrazol treatment. We propose that plant growth regulator treatment induces bZIP60 mRNA splicing which 'primes' plants for rapid adaptive response to subsequent endoplasmic reticulum-stress inducing conditions.

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.

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.

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.

Loci That Control Nonlinear, Interdependent Responses to Combinations of Drought and Nitrogen Limitation.

Crop improvement must accelerate to feed an increasing human population in the face of environmental changes. Including anticipated climatic changes with genetic architecture in breeding programs could better optimize improvement strategies. Combinations of drought and nitrogen limitation already occur world-wide. We therefore analyzed the genetic architecture underlying the response of Zea mays to combinations of water and nitrogen stresses. Recombinant inbreds were subjected to nine combinations of the two stresses using an optimized response surface design, and their growth was measured. Three-dimensional response surfaces were fit globally and to each polymorphic allele to determine which genetic markers were associated with different response surfaces. Three quantitative trait loci that produced nonlinear surfaces were mapped. To better understand the physiology of the response, we developed a model that reproduced the shapes of the surfaces, their most characteristic feature. The model contains two components that each combine the nitrogen and water inputs. The relative weighting of the two components and the inputs is governed by five parameters, and each QTL affects all five parameters.We estimated the model's parameter values for the experimental surfaces using a mesh of points that covered the surfaces' most distinctive regions. Surfaces computed using these values reproduced the experimental surfaces well, as judged by three different criteria at the mesh points. The modeling and shape comparison techniques used here can be extended to other complex, high-dimensional, nonlinear phenotypes. We encourage the application of our findings and methods to experiments that mix crop protection measures, stresses, or both, on elite and landrace germplasm.

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria.

Escherichia coli and other Enterobacteriaceae are among the most common pathogens of the human urinary tract. Among the genetic gains of function associated with urinary E. coli isolates is the Yersinia high pathogenicity island (HPI), which directs the biosynthesis of yersiniabactin (Ybt), a virulence-associated metallophore. Using a metabolomics approach, we found that E. coli and other Enterobacteriaceae expressing the Yersinia HPI also secrete escherichelin, a second metallophore whose chemical structure matches a known synthetic inhibitor of the virulence-associated pyochelin siderophore system in Pseudomonas aeruginosa. We detected escherichelin during clinical E. coli urinary tract infection (UTI) and experimental human colonization with a commensal, potentially probiotic E. coli bacteriuria strain. Escherichelin production by colonizing enterobacteria may help human hosts resist opportunistic infections by Pseudomonas and other pyochelin-expressing bacteria. This siderophore-based mechanism of microbial antagonism may be one of many elements contributing to the protective effects of the human microbiome. Future UTI-preventive probiotic strains may benefit by retaining the escherichelin biosynthetic capacity of the Yersinia HPI while eliminating the Ybt biosynthetic capacity.

Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections.

Urinary tract infections (UTIs) are caused by uropathogenic Escherichia coli (UPEC) strains. In contrast to many enteric E. coli pathogroups, no genetic signature has been identified for UPEC strains. We conducted a high-resolution comparative genomic study using E. coli isolates collected from the urine of women suffering from frequent recurrent UTIs. These isolates were genetically diverse and varied in their urovirulence, that is, their ability to infect the bladder in a mouse model of cystitis. We found no set of genes, including previously defined putative urovirulence factors (PUFs), that were predictive of urovirulence. In addition, in some patients, the E. coli strain causing a recurrent UTI had fewer PUFs than the supplanted strain. In competitive experimental infections in mice, the supplanting strain was more efficient at colonizing the mouse bladder than the supplanted strain. Despite the lack of a clear genomic signature for urovirulence, comparative transcriptomic and phenotypic analyses revealed that the expression of key conserved functions during culture, such as motility and metabolism, could be used to predict subsequent colonization of the mouse bladder. Together, our findings suggest that UTI risk and outcome may be determined by complex interactions between host susceptibility and the urovirulence potential of diverse bacterial strains.

Maize Phyllosphere Microbial Community Niche Development Across Stages of Host Leaf Growth.

Background: The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. Methods: We examined how the Zea mays L. leaf microbial community structure changed with plant age. Ribosomal spacer length and scanning electron microscopic imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Results: Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Conclusions: Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves.

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.

Urine Culture in Uncomplicated UTI: Interpretation and Significance.

Acute uncomplicated urinary tract infection (UTI) is a common clinical problem, accounting for millions of outpatient visits in the USA annually. Although routinely obtaining urine cultures in UTI is not recommended, there are circumstances in which obtaining a pre-therapy culture may be warranted or chosen by clinicians, such as when indicated by the need for careful antimicrobial stewardship. This review focuses on understanding reasons for obtaining a pre-therapy culture, methods of collection, and appropriately interpreting urine culture data.

The Vaginal Microbiota and Urinary Tract Infection.

The vagina is a key anatomical site in the pathogenesis of urinary tract infection (UTI) in women, serving as a potential reservoir for infecting bacteria and a site at which interventions may decrease the risk of UTI. The vaginal microbiota is a dynamic and often critical factor in this pathogenic interplay, because changes in the characteristics of the vaginal microbiota resulting in the loss of normally protective Lactobacillus spp. increase the risk of UTI. These alterations may result from the influence of estrogen deficiency, antimicrobial therapy, contraceptives, or other causes. Interventions to reduce adverse effects on the vaginal microbiota and/or to restore protective lactobacilli may reduce the risks of UTI.