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A novel SUCNR1 inhibitor alleviates dysbiosis through inhibition of host responses without direct interaction with host microbiota

Thomas, Scott C; Guo, Yuqi; Xu, Fangxi; Saxena, Deepak; Li, Xin
Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.
PMID: 37715517
ISSN: 2041-1014
CID: 5593302

Predictors of Care-Seeking Behavior for Treatment of Urinary Incontinence in Women

LaPier, Zoe; Jericevic, Dora; Lang, Diane; Gregg, Steven; Brucker, Benjamin; Escobar, Christina
IMPORTANCE/OBJECTIVE:Urinary incontinence (UI) is a common and treatable medical condition among women, but only approximately one third of women seek care. OBJECTIVE:The objective of this study was to determine factors associated with care-seeking behavior in women with UI. STUDY DESIGN/METHODS:This was a cross-sectional study using patient-reported survey data collected by the National Association for Continence from November 2018 to January 2019. This survey included 60 questions and was conducted using SurveyMonkey. Descriptive statistics were used for baseline characteristics, the χ2 test was used for categorical variables, and multivariate logistic regression was used to determine predictors of care-seeking behavior. RESULTS:Four hundred eighty-five women completed the survey, 30.7% were not care seeking, and 69.3% were care seeking for UI. Most women were 55 years or older and had UI for more than 4 years. Care-seeking women had more overactive bladder symptoms. Women who sought care were more likely to report feelings of anger, depression, hopelessness, isolation, and report greater social effects from UI than non-care-seeking women. Less than 10% of women who sought care were asked about their UI by a medical professional. In the multivariate logistic regression expenditure of $5 or more on monthly incontinence maintenance, daily UI and older age were associated with seeking care. CONCLUSIONS:Most women in our study population sought care for UI. Factors associated with seeking care were expenditure greater than $5 per month on incontinence, daily UI, and age. This information demonstrates the need for effective implementation of screening interventions to increase treatment access.
PMID: 38484253
ISSN: 2771-1897
CID: 5639852

Who Progresses to Third-Line Therapies for Overactive Bladder? Trends From the AQUA Registry

Jericevic, Dora; Shapiro, Katherine; Bowman, Max; Vélez, Camille A; Mbassa, Rachel; Fang, Raymond; Van Kuiken, Michelle; Brucker, Benjamin M
INTRODUCTION/UNASSIGNED:Overactive bladder (OAB) patients who do not achieve satisfactory results with second-line OAB medications should be offered third-line therapies (percutaneous tibial nerve stimulation, sacral neuromodulation, onabotulinumtoxinA bladder injection [BTX-A]). We aimed to determine which clinical factors affect progression from second- to third-line OAB therapy. METHODS/UNASSIGNED:Between 2014 and 2020, the AUA Quality Registry was queried for adult patients with idiopathic OAB. For the primary outcome, patient and provider factors associated with increased odds of progression from second- to third-line therapy were assessed. Secondary outcomes included median time for progression to third-line therapy and third-line therapy utilization across subgroups. RESULTS/UNASSIGNED:A total of 641,122 patients met inclusion criteria and were included in analysis. Of these, only 7487 (1.2%) received third-line therapy after receiving second-line therapy. On multivariate analysis, patients aged 65 to 79, women, White race, history of dual anticholinergic and β3 agonist therapy, metropolitan area, government insurance, and single specialty practice had the greatest odds of progressing to third-line therapy. Black and Asian race, male gender, and rural setting had lower odds of progressing to third-line therapy. BTX-A was the most common therapy overall (40% BTX-A, 32% sacral neuromodulation, 28% percutaneous tibial nerve stimulation). The median time of progression from second- to third-line therapy was 15.4 months (IQR 5.9, 32.4). Patients < 50 years old and women progressed fastest to third-line therapy. CONCLUSIONS/UNASSIGNED:Very few patients received third-line therapies, and the time to progression from second- to third-line therapies is > 1 year. The study findings highlight a potential need to improve third-line therapy implementation.
PMID: 38226920
ISSN: 2352-0787
CID: 5633832

Representation Matters: Trust in Digital Health Information Among Black Patients With Prostate Cancer

Loeb, Stacy; Sanchez Nolasco, Tatiana; Byrne, Nataliya; Allen, Laura; Langford, Aisha T; Ravenell, Joseph; Gomez, Scarlett Lin; Washington, Samuel L; Borno, Hala T; Griffith, Derek M; Criner, Nickole
PURPOSE/UNASSIGNED:Although the majority of US adults obtain health information on the internet, the quality of information about prostate cancer is highly variable. Black adults are underrepresented in online content about prostate cancer despite a higher incidence of and mortality from the disease. The goal of this study was to explore the perspectives of Black patients with prostate cancer on the importance of racial representation in online content and other factors influencing trust. MATERIALS AND METHODS/UNASSIGNED:We conducted 7 virtual focus groups with Black patients with prostate cancer in 2022 and 2023. Participants completed an intake questionnaire with demographics followed by a group discussion, including feedback on purposefully selected online content. Transcripts were independently analyzed by 2 investigators experienced in qualitative research using a constant comparative method. RESULTS/UNASSIGNED:Most participants use online sources to look for prostate cancer information. Racial representation is an important factor affecting trust in the content. A lack of Black representation has consequences, including misperceptions about a lower risk of prostate cancer and discouraging further information-seeking. Other key themes affecting trust in online content included the importance of a reputable source of information, professional website structure, and soliciting money. CONCLUSIONS/UNASSIGNED:Underrepresentation of Black adults in prostate cancer content has the potential to worsen health disparities. Optimal online communications should include racially diverse representation and evidence-based information in a professional format from reputable sources without financial conflict.
PMID: 38329047
ISSN: 1527-3792
CID: 5632372

Prostate cancer and podcasts: an analysis and assessment of the quality of information about prostate cancer available on podcasts

Scott, Colin; Campbell, Peter; Nemirovsky, Amy; Loeb, Stacy; Malik, Rena
Podcasts represent a new source of information for patients and families dealing with prostate cancer, but no studies have been conducted evaluating the quality of information in them. Evaluating for: (1) quality based on the validated DISCERN criteria, (2) understandability and actionability based on the Patient Education Materials Assessment Tool (PEMAT), (3) misinformation, and (4) commercial bias, we concluded that podcasts are currently not good sources of information for lay health consumers.
PMID: 37491431
ISSN: 1476-5608
CID: 5618832

Qualitative Study on Internet Use and Care Impact for Black Men With Prostate Cancer

Loeb, Stacy; Sanchez Nolasco, Tatiana; Byrne, Nataliya; Allen, Laura; Langford, Aisha T; Ravenell, Joseph E; Gomez, Scarlett Lin; Washington, Samuel L; Borno, Hala T; Griffith, Derek M; Criner, Nickole
Black men have a greater risk of prostate cancer as well as worse quality of life and more decisional regret after prostate cancer treatment compared to non-Hispanic White men. Furthermore, patients with prostate cancer who primarily obtain information on the internet have significantly more decisional regret compared to other information sources. Our objective was to explore the perspectives of Black patients on the use and impact of the internet for their prostate cancer care. In 2022-2023, we conducted seven virtual focus groups with Black patients with prostate cancer (n = 22). Transcripts were independently analyzed by two experienced researchers using a constant comparative method. Online sources were commonly used by participants throughout their cancer journey, although informational needs varied over time. Patient factors affected use (e.g., physical health and experience with the internet), and family members played an active role in online information-seeking. The internet was used before and after visits to the doctor. Key topics that participants searched for online included nutrition and lifestyle, treatment options, and prostate cancer in Black men. Men reported many downstream benefits with internet use including feeling more empowered in decision-making, reducing anxiety about treatment and providing greater accountability for research. However, they also reported negative impacts such as feeling overwhelmed or discouraged sorting through the information to identify high-quality content that is personally relevant, as well as increased anxiety or loss of sleep from overuse. In summary, online sources have the potential to positively impact the cancer journey by reinforcing or supplementing information from health care providers, but can be harmful if the information is poor quality, not representative, or the internet is overused.
PMID: 38366884
ISSN: 1552-6127
CID: 5636122

A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC)

Wise, David R; Pachynski, Russell K; Denmeade, Samuel R; Aggarwal, Rahul R; Deng, Jiehui; Febles, Victor Adorno; Balar, Arjun V; Economides, Minas P; Loomis, Cynthia; Selvaraj, Shanmugapriya; Haas, Michael; Kagey, Michael H; Newman, Walter; Baum, Jason; Troxel, Andrea B; Griglun, Sarah; Leis, Dayna; Yang, Nina; Aranchiy, Viktoriya; Machado, Sabrina; Waalkes, Erika; Gargano, Gabrielle; Soamchand, Nadia; Puranik, Amrutesh; Chattopadhyay, Pratip; Fedal, Ezeddin; Deng, Fang-Ming; Ren, Qinghu; Chiriboga, Luis; Melamed, Jonathan; Sirard, Cynthia A; Wong, Kwok-Kin
BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
PMID: 38341461
ISSN: 1476-5608
CID: 5635542

Incidence, complications, and long-term outcomes of gender-affirming phalloplasty: analysis of a large statewide population-based dataset

Zhang, Tenny R; Harel, Daphna; Rivera, Adrian; Shahnawaz, Samia; Qian, Yingzhi; Berry, Carolyn; Zhao, Lee C; Radix, Asa; Bluebond-Langner, Rachel; Mmonu, Nnenaya A
OBJECTIVE:To evaluate the incidence of gender-affirming phalloplasty and complications in a large population-based dataset. METHODS:Retrospective cohort study was done using the California Department of Health Care Access and Information datasets which include patient-level data from all licensed hospitals, emergency departments, and ambulatory surgery facilities in California. Adult patients 18 years or older undergoing gender-affirming phalloplasty in California from January 1, 2009 to December 31, 2019 were included. We examined phalloplasty-related complications using International Classification of Disease diagnosis and procedure codes and Current Procedural Terminology codes. Unique record linkage number identifiers were used to follow patients longitudinally. Statistical analysis included Kaplan-Meier survival analysis and Cox proportional hazards analysis. RESULTS:We identified 766 patients who underwent gender-affirming phalloplasty in 23 facilities. Of 475 patients with record linkage numbers, 253 (55.3%) had subsequent re-presentations to the inpatient, emergency department, and ambulatory surgery settings related to phalloplasty complications. Survival analysis indicated that 50% of patients re-presented by 1 year post-phalloplasty. Asian/Pacific Islander patients had lower risk of complications, and California residents had higher risk of complications. CONCLUSIONS:This population-based study confirms that gender-affirming phalloplasty has a high complication rate, and demonstrates for the first time an association with high rates of return to hospitals, emergency departments, and ambulatory centers. These findings provide additional higher-level evidence that may aid patient counseling, shared surgical decision making, and institutional and government policy.
PMID: 38340965
ISSN: 1527-9995
CID: 5635512

Factors influencing medication selection for management of overactive bladder: Trends and insights from AUA Quality Registry

Bowman, Max; Vélez, Camille A; Jericevic, Dora; Shapiro, Katherine; Mbassa, Rachel; Fang, Raymond; Brucker, Benjamin M; Van Kuiken, Michelle
OBJECTIVE:To determine how a patient's demographics, including insurance type, race/ethnicity, gender, and age, may impact the choice of medication prescribed for overactive bladder. METHODS:We queried the AUA Quality Registry for adults between 2014 and 2020 with a diagnosis of overactive bladder for >1 year, excluding neurogenic causes. Variables included age, race/ethnicity, gender, insurance type, medication first prescribed, year of prescription, provider metropolitan status, and provider practice type. Primary outcome was which factors were associated with increased odds of beta-3 prescription as first medication choice. RESULTS:We found 1,453,566 patients with overactive bladder, 641,122 (44.1%) with complete data. Of these, 112,021 (17.5%) were prescribed medication. On multivariate analysis, patients with Medicaid, Medicare, and other/self-pay insurance were less likely to receive a beta-3 versus an anticholinergic compared to private or military insurance. Compared to white patients, Asian, Black, and other races were less likely to receive a beta-3, as were patients outside of metropolitan areas. Age >50, prescriptions after 2014, and non-academic settings were associated with increased odds of beta-3 prescription. There was no difference between genders. CONCLUSIONS:Many nonclinical factors, including insurance type and race, may affect which medication is first prescribed for overactive bladder. This is useful for practicing urologists and may help lower barriers to beta-3 prescription through policy change and advocacy.
PMID: 38081481
ISSN: 1527-9995
CID: 5589122

A Randomized Clinical Trial Evaluating Indigo Carmine as a Visualization Aid for Evaluating Ureteral Patency

Lepor, Herbert; Wiegand, Lucas; Patel, Kalpesh; Du, Wei; Gagnon, Suzanne; ,
OBJECTIVES/OBJECTIVE:To determine whether intravenous indigo carmine provides a visualization advantage compared to saline in the evaluation of ureteral patency in a randomized, controlled clinical trial. METHODS:Patients undergoing urological or gynecological surgical procedures in which the patency of the ureter was to be assessed received a saline injection and were randomized to receive 2.5 mL or 5.0 mL of indigo carmine. Blinded video assessments were conducted by independent reviewers using a conspicuity scale ranked 1 (poorest) to 5 (best), and subjects with scores ≥ 3 and at least a +1-point difference from saline were considered responders. Time to visualization was recorded for indigo carmine. A responder analysis evaluated whether indigo carmine showed improved visualization. RESULTS:There were 96 ureters evaluated with the 5.0 mL dose of indigo carmine, 92 with the 2.5 mL dose, and 180 with saline. Most ureters were scored a 4 or higher on the conspicuity scale following indigo carmine; both doses were significantly better than saline (p<0.0001). Overall, 92.3% of patients were rated as a responder for either ureter. The median time to visualization of blue color was not significantly different (6.0 minutes in the 5.0 mL group and 5.9 minutes in the 2.5 mL group). There were no adverse events related to indigo carmine use. CONCLUSIONS:Both dose levels of indigo carmine were significantly better than saline as a visualization aid for ureter patency.
PMID: 38061609
ISSN: 1527-9995
CID: 5591382