Recurrent and complicated urinary tract infections in women: Utility of advanced testing to enhance care.

BACKGROUND: The United States currently faces a public health crisis with regarding to antibiotic-resistant bacteria, and new urinary tract infection (UTI) diagnostics are needed. Women with recurrent UTI (rUTI) and complicated UTI (cUTI) are at particular risk given their complexity and the paucity of adequate testing modalities. The standard urine culture (SUC) is the cornerstone for diagnosis, but it has many shortcomings. These pitfalls lead to dissatisfaction and frustration among women afflicted with rUTI and cUTI, as well as overuse of antibiotics. One innovation is PCR UTI testing, which has been shown to outperform SUC among symptomatic women. AIMS: This article discusses UTI PCR testing, as well as a possible role in clinical practice. MATERIALS AND METHODS: Published literature was reviewed and summarized. RESULTS: Management of rUTI and cUTI is complex, and providers should have all diagnostics available to facilitate providing optimal care. Urine PCR testing faces reimbursement issues despite fulfilling clinical indication parameters as described by insurance companies. DISCUSSION: The role of UTI PCR testing remains unclear. Reimbursement issues have led to underuse and limited real-world outcomes reinforcing benefit. CONCLUSION: This study proposes an algorithm for PCR testing among women with rUTI and cUTI.

Recurrent urinary tract infection management and prevention techniques among a population-based cohort of women.

INTRODUCTION: Recurrent urinary tract infection (rUTI), defined as three or more UTIs in 12 months, has psychological, physical, and financial burden. Many women with rUTI are not satisfied with care and report only starting preventative measures after several infections. The goal of this study is to elucidate current UTI management trends and the implementation of UTI prevention strategies. METHODS: A web-based study was sent to a national sample of adult women enrolled in ResearchMatch.org. Women were recruited to participate if they had a self-reported UTI in the past 12 months. RESULTS: Of the 755 subjects, nearly 30% reported rUTI. Among women with rUTI, more than 50% reported being peri- or postmenopausal, and two-thirds reported vaginal symptoms. 15.8% of women with rUTI reported dissatisfaction with care versus 7.9% of women without rUTI. Most women see their primary care physician for UTI management and only 26% of women with rUTI follow with a urologist. More than 65% of women increase their fluid intake, wipe from front to back, and urinate after sexual activity to prevent UTIs. Significantly more women with rUTI use transvaginal estrogen, cranberry extract, and low-dose prophylactic antibiotics. These interventions appear to be driven by urologists. CONCLUSION: Most women who have had a UTI in the last 12 months implement lifestyle changes to prevent future infections. Most women see their PCP for UTI management and women with rUTI are twice as likely to report dissatisfaction with care. Despite urologists optimizing medical rUTI prevention, they appear to be underutilized.

Associations Between Unmet Social Needs and Overactive Bladder.

PURPOSE: There is growing interest in how social determinants of health may explain relationships between social conditions and health. Overactive bladder is common in the United States, posing a significant public health burden. It was the goal of the present study to assess whether overactive bladder was associated with unmet social needs in a large, cross-sectional sample of patients. MATERIALS AND METHODS: A community-based sample of adults was recruited electronically to complete questionnaires on clinical and demographic information, urinary symptoms and unmet social needs. Multivariable logistic regression was used to assess for association between overactive bladder and multiple unmet social needs. RESULTS: The sample of 3,617 participants had a mean±SD age of 47.9±17.3 years. The majority of participants identified as White, non-Hispanic (83.5%), and female (77.6%). A total of 1,391 patients (38.5%) were found to have overactive bladder. The presence of overactive bladder was associated with numerous unmet social needs, including housing instability, food insecurity, worry about utilities, lack of transportation, skipping medical appointments, needing legal help, stress in personal relationships, worry about toilet access and plumbing at home, and lack of social supports. On multivariable analysis adjusting for multiple covariates, all associations between overactive bladder and social needs remained significant. CONCLUSIONS: Multiple unmet social needs were associated with overactive bladder, which may have implications for the overall management of overactive bladder patients. It is important for providers to consider these unmet social needs of patients, as highlighting and addressing these factors hopefully can help improve care of individuals with overactive bladder.

The cumulative effect of unmet social needs on noncancerous genitourinary conditions and severity of lower urinary tract symptoms.

PURPOSE: There is growing awareness on how social determinants of health may significantly influence health outcomes. The purpose of this study was to investigate the relationship between unmet social needs and the incidence and severity of multiple noncancerous genitourinary conditions. MATERIALS AND METHODS: A community-based sample of United States adults was recruited electronically to complete questionnaires on clinical and demographic information, urinary symptoms, and social needs. Logistic regression was used to assess the effect between the number of unmet social needs and various noncancerous genitourinary conditions and severity of lower urinary tract symptoms. Model was adjusted for age, gender, race, insurance, and type of living community. RESULTS: A total of 4,224 participants were included for final analysis. The incidence of all genitourinary conditions assessed was associated with an increasing number of unmet social needs. Additionally, having three or more unmet social needs, as compared to no needs, was associated with an increased risk of all conditions and worse symptoms-including a 23.7% increased risk of interstitial cystitis (95% confidence interval [CI] 18.8%-28.7%, p < 0.001), 21.9% risk of urge urinary incontinence (95% CI 16.8%-27.0%, p < 0.001), and 20.6% risk of overactive bladder (95% CI 15.6-25.7, p < 0.001). CONCLUSIONS: Unmet social needs are associated with an increased incidence of noncancerous genitourinary conditions as well as worse symptom severity, with multiple unmet social needs displaying a cumulative effect. These findings suggest that there is utility in screening patients for unmet social needs, and that the healthcare system should develop a more integrated approach to manage  patients with urinary conditions.

The burdens of incontinence: Quantifying incontinence product usage and costs in women.

INTRODUCTION: Urinary incontinence is a common condition in women, who often use incontinence containment products to self-manage. Few studies have sought to quantify use and costs of incontinence products associated with subtypes of incontinence and severity, therefore this study aimed to quantify incontinence product use and personal costs to women. METHODS: This is a secondary analysis from a sample of adult women recruited electronically via ResearchMatch for a study on urinary symptoms and social determinants of health. Participants completed validated questionnaires on urinary symptoms, and were asked about daily numbers and types of incontinence products used and weekly costs, along with demographic and baseline clinical information, and information about unmet social needs. Descriptive statistics were performed, in addition to Wilcoxon rank sum and Kruskal-Wallis tests to compare incontinence product usage and cost based on type of incontinence, symptom severity, and other demographics, in addition to multivariable linear regression. RESULTS: A total of 702 women who reported using weekly incontinence products were included in the final analytic sample. Overall, women reported using a mean of 1.8 ± 2.1 incontinence products in 24 h (median: 1, interquartile range [IQR]: 1), with a maximum of 32. Mean weekly cost of was $5.42 ± $8.59 (median: $3, IQR: $4), with cost up to $100. Nonwhite women trended towards having higher product usage and cost, with significant cost increase seen among non-Hispanic Black women and Hispanic women. Usage and cost were higher in women who had less education, had household income below the poverty line, were on disability, were using Medicaid or were uninsured, had more unmet social needs, and in those with mixed incontinence. Additionally, daily product use and weekly costs increased with incontinence symptom severity, with the biggest increase between those with severe and very severe symptoms. CONCLUSIONS: In this study, we were able to quantify the number of incontinence products used daily and the weekly costs in incontinent women across types and severity of incontinence. Costs were even greater and may be prohibitive, in women with more unmet social needs, Medicaid or no insurance, less than a college education, lower income, or on disability.

Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers.

BACKGROUND: Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men. METHODS: A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database. RESULTS: Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%). CONCLUSIONS: BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. © 2016 Wiley Periodicals, Inc.

Assessment and Acquisition of Knowledge Regarding Urinary Tract Infection Among Adult Women in the United States.

OBJECTIVE: To assess baseline UTI knowledge, interest in health resources, and platform preferences for information acquisition and dissemination. MATERIALS AND METHODS: Adult women who had a UTI in the past 12 months were recruited from Researchmatch.org to participate in a web-based quantitative study. Women with recurrent UTI (rUTI) were compared to women with a history of UTI (without rUTI). RESULTS: Six hundred and eighty-seven women were included in the study of which 27.4% (N = 188) had rUTI. Regarding knowledge, significantly more women without rUTI believe UTIs are caused by lack of cleanliness and that most women suffer from UTIs. Significantly more women with rUTI believe that UTIs are inherited and that getting older is associated with getting more UTIs. Regarding barriers to health information, significantly more women without rUTI feel that information is too complex and language barriers exist. More than 90% of subjects utilize their healthcare provider (HCP) for health information and most prefer office-based HCPs for health information. More than 50% of women with rUTI would like to receive UTI health updates. CONCLUSION: Misinformation exists regarding causes, management, and prevention of UTIs. This study identified perceived barriers as well as preferred educational platforms with the hope that this will drive improvements in UTI-related health education.

Management of Localized T1c Prostate Cancer Among Men 75 Years and Older: A National Cancer Database Study.

INTRODUCTION: Elderly men are underrepresented in prostate cancer (PCa) literature, with management based on individualized care pathways and life expectancy. Reports have shown survival benefit with radiation (XRT), surgery, and hormone (ADT) in localized disease. The objective of this study was to assess treatment trends and overall survival (OS) among men 75 years of age and older with cT1c PCa. METHODS: The National Cancer Database was queried to identify patients with cT1c PCa, aged 75 years and older, between 2004 and 2016. We excluded individuals with N1/NX or M1/MX disease, unknown treatment, treatment with both XRT and surgery, surgery other than radical prostatectomy (RP), or PSA > 10 ng/ml. We described 4 treatment cohorts: observation, XRT, surgery, and ADT alone. Treatment trends and OS were analyzed using SPSS. RESULTS: Among 49,843 patients, 7% had surgery, 66% had XRT, 5% had ADT alone, and 22% were observed. From 2004-2016, a large decline in XRT was noted, with an increase in surgery and observation. Men receiving ADT alone were significantly older, with higher Gleason's score, and lower incomes. Cox regression revealed survival benefit for surgery and XRT (HR 0.44 and 0.69, P < .001 respectively); ADT had worse survival than observation (HR 1.23, P < .001). CONCLUSION: Fewer men 75 years of age and older with cT1c PCa are being diagnosed and treated. Rates of XRT have declined, with rises in surgery and observation. Survival benefit was seen for surgery and XRT among elderly men, which highlights the importance of proper patient selection for improved outcomes in a highly individualized sphere.

Vibegron for the treatment of overactive bladder: a comprehensive update.

INTRODUCTION: Overactive bladder (OAB) is associated with physical, emotional, and financial burden. After failed conservative measures, second-line therapy includes medications, such as antimuscarinics and beta-3 adrenergic receptor (ß3AR) agonists. Antimuscarinics are most commonly prescribed but have systemic side effects that lead to poor compliance. ß3AR agonists include mirabegron and vibegron. Mirabegron is a first-generation ß3AR agonist that is effective for frequency, urgency urinary incontinence (UUI) and urgency, but has interactions with cytochrome P450 enzymes (CYPs) and cardiovascular sequelae. Vibegron is a second-generation ß3AR agonist that is highly selective and does not interact with CYPs. It is effective for reducing UUI episodes and daily micturition number and has a favorable side effect profile. AREAS COVERED: Clinical background, pharmacology, and clinical studies for vibegron. EXPERT OPINION: Vibegron is a welcomed addition to the OAB therapeutic landscape. This single dose, once daily option is effective, especially for patients with wet OAB, with a favorable side effect profile. Sub-analyses of patients ≥ 65 years have shown continued efficacy and safety. The few drug interactions are of benefit, especially for older patients with polypharmacy. As long-term data accrues, vibegron has the potential to drive the OAB therapeutic market.

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer.

Nearly one third of men will incur biochemical recurrence after treatment for localized prostate cancer. Androgen deprivation therapy (ADT) is the therapeutic mainstay; however, some patients will transition to a castrate resistant state (castrate resistant prostate cancer, CRPC). Subjects with CRPC may develop symptomatic metastatic disease (mCRPC) and incur mortality several years later. Prior to metastatic disease, however, men acquire non-metastatic CRPC (nmCRPC) which lends the unique opportunity for intervention to delay disease progression and symptoms. This review addresses current therapies for nmCRPC, as well as novel therapeutics and pathway strategies targeting men with nmCRPC.

Comprehensive genomic profiling of metastatic collecting duct carcinoma, renal medullary carcinoma, and clear cell renal cell carcinoma.

INTRODUCTION AND OBJECTIVE: Unlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy. MATERIAL AND METHODS: DNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations. RESULTS: mCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb. CONCLUSION: Genomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies.

Association Between Stress Urinary Incontinence and the Components of Metabolic Syndrome Among Females 20-59 Years.

OBJECTIVE: To assess the relationship between stress urinary incontinence (SUI) and metabolic syndrome among a population-based cohort of women 20-59 years. METHODS: National Health and Nutrition Examination Survey database was used between the years of 2013 and 2016 and included women aged 20-59 years. SUI was defined as "Urinary leakage with physical activity." Metabolic syndrome was defined as >2 risk factors: fasting blood glucose (FBG) >99 mg/dL, triglyceride >149 mg/dL, high-density lipoprotein <50 mg/dL, waistline >88 cm, and blood pressure >130/85. We generated weighted estimated prevalence and ran multivariable logistic regression models. RESULTS: Among 3430 female subjects, the estimated prevalence of SUI was 38.7% (95% confidence interval [CI] 36.7-40.7%) and metabolic syndrome was 10.2% (95% CI 8.9-11.6). Higher rates of SUI were seen with large waistlines, elevated FBG, and elevated triglycerides. Among women with metabolic syndrome, 56.1% (95% CI 39.7-49.0%) had SUI. Among all women, metabolic syndrome and elevated FBG significantly increase the risk of SUI (odds ratio [OR] 1.53 [95% CI 1.02-2.28] and OR 1.86 [95% CI 1.14-3.03], respectively). In women 20-39 years, a large waistline significantly increased the risk of SUI (OR 1.72 [95% CI 1.00-2.99]). CONCLUSION: Among females 20-59 years in the United States, 38.7% report SUI and 10% have metabolic syndrome. Metabolic syndrome and an elevated FBG significantly increase the risk of SUI among all women. A large waistline increases the risk of SUI in women aged 20-39 years. Weight loss and adequate control of metabolic syndrome should be considered key strategies in the management of SUI.

Looking beyond hypogonadism: association between low testosterone and metabolic syndrome in men 20-59 years.

PURPOSE: Rates of low testosterone and metabolic syndrome are increasing among adult men in the United States. Both are associated with increased cardiovascular mortality. This study aims to assess the association between low testosterone and metabolic syndrome with a population-based contemporary cohort of men aged 20-59 years. METHODS: National Health and Nutrition Examination Survey (NHANES) was used between the years of 2013 and 2016. Men aged 20-59 years with testosterone levels were included. Metabolic syndrome was defined by National Cholesterol Education Program (NCEP) Adult Treatment Protocol (ATP) III. RESULTS: 24.4% of the cohort had low testosterone and 26.4% had metabolic syndrome. Univariate analysis revealed that men with low testosterone had a significantly higher prevalence of metabolic syndrome and metabolic syndrome criteria. Multivariable logistic regression revealed a significant association between low testosterone and a large waistline (Odds ratio (OR) 4.32), as well as low levels of high-density lipoprotein (HDL) (OR 1.67) among all men. Age-stratification revealed that men 20-39 years with a large waistline had an OR 6.43 for low testosterone. CONCLUSION: Nearly one quarter of men aged 20-59 years have low testosterone and metabolic syndrome. A large waistline increases the risk of low testosterone six-fold among young men.

Co-chaperones TIMP2 and AHA1 Competitively Regulate Extracellular HSP90:Client MMP2 Activity and Matrix Proteolysis.

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a "reactivating" mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.

p107-Dependent recruitment of SWI/SNF to the alkaline phosphatase promoter during osteoblast differentiation.

The retinoblastoma protein family is intimately involved in the regulation of tissue specific gene expression during mesenchymal stem cell differentiation. The role of the following proteins, pRB, p107 and p130, is particularly significant in differentiation to the osteoblast lineage, as human germ-line mutations of RB1 greatly increase susceptibility to osteosarcoma. During differentiation, pRB directly targets certain osteogenic genes for activation, including the alkaline phosphatase-encoding gene Alpl. Chromatin immunoprecipitation (ChIP) assays indicate that Alpl is targeted by p107 in differentiating osteoblasts selectively during activation with the same dynamics as pRB, which suggests that p107 helps promote Alpl activation. Mouse models indicate overlapping roles for pRB and p107 in bone and cartilage formation, but very little is known about direct tissue-specific gene targets of p107, or the consequences of targeting by p107. Here, the roles of p107 and pRB were compared using shRNA-mediated knockdown genetics in an osteoblast progenitor model, MC3T3-E1 cells. The results show that p107 has a distinct role along with pRB in induction of Alpl. Deficiency of p107 does not impede recruitment of transcription factors recognized as pRB co-activation partners at the promoter; however, p107 is required for the efficient recruitment of an activating SWI/SNF chromatin-remodeling complex, an essential event in Alpl induction.