Longitudinal study of cognitive decline among women with and without urinary incontinence.

BACKGROUND: Cross-sectional and short-term cohort studies have demonstrated an association between urinary incontinence and dementia, as well as lower performance on cognitive testing. The Health and Retirement Study, a longitudinal study of community-dwelling older adults, offers an opportunity to assess the temporal association between these conditions because it included an assessment of incontinence symptoms and biennial assessments of cognitive function. OBJECTIVE: This study aimed to evaluate if urinary incontinence before the age of 70 years had an effect on changes in cognitive function among women participating in the Health and Retirement Study. STUDY DESIGN: This secondary analysis included data from female respondents in the Health and Retirement Study aged 58 to 67 years with ≥2 cognitive assessments. Urinary incontinence was defined as any involuntary loss of any urine in the preceding 12 months. A control group without incontinence was reweighted for better comparability using coarsened exact matching for age and comorbidities. Validated methods, including neuropsychological test data, estimated a memory score and dementia probability for each participant biennially. Coprimary outcomes were the changes in memory score and dementia probability. Linear regression models were used to estimate the association of urinary incontinence with change in memory score and dementia probability, adjusting for baseline demographics and comorbidities. A subgroup analysis was performed to assess the effects of urinary incontinence frequency on these outcomes. The infrequent subgroup reported <15 days of leakage per month and the frequent subgroup reported ≥15 days of leakage per month. RESULTS: Among eligible female respondents, 40.6% reported urinary incontinence between the ages of 58 and 69 years. Baseline memory scores and dementia probability were similar between those with urinary incontinence (n=1706) and controls (n=2507). Memory score declined significantly in both cohorts, indicating poorer memory over time (-0.222 among those with incontinence [95% confidence interval, -0.245 to -0.199] vs -0.207 in controls [95% confidence interval, -0.227 to -0.188]). The decline of memory score was not statistically significantly different between cases and controls (mean difference, -0.015; 95% confidence interval, -0.045 to 0.015). Dementia probability increased significantly in both groups, indicating a greater probability of developing dementia by 0.018 among those with incontinence (95% confidence interval, 0.015-0.020) and by 0.020 among controls (95% confidence interval, 0.017-0.022). The change in dementia probability was not significantly different between groups (mean difference, -0.002; 95% confidence interval, -0.006 to 0.002). Frequent urinary incontinence was reported in 105 of 1706 (6%) of those with urinary incontinence. Memory score declined and dementia probability increased with time (P<.001) in frequent and infrequent urinary incontinence subgroups. There was no dose-response relationship. CONCLUSION: Measures of cognitive performance declined during approximately 10 years of observation. The changes in performance were not associated with the presence of urinary incontinence in the participants' younger years.

Vesicovaginal Fistula Repair Simulation Model and Hierarchical Task Analysis.

IMPORTANCE: There is a need for surgeons skilled in vesicovaginal fistula (VVF) repair, yet training opportunities are limited. OBJECTIVES: This study aimed to create a low-fidelity simulation model for transvaginal VVF repair, identify essential steps of VVF repair, and evaluate the model's ability to replicate essential steps. STUDY DESIGN: First, a low-fidelity VVF repair simulation model was designed and built by the authors. Next, a hierarchical task analysis was performed by urogynecologic surgeons with expertise in VVF repair. Each expert submitted an outline of tasks required to perform VVF repair. To control for bias, an education specialist de-identified, reviewed, and collated the submitted outlines. The education specialist then led a focus group, and through a modified Delphi process, the experts reached consensus on the essential steps. A separate group of urogynecologic surgeons then tested the model and completed an anonymous questionnaire assessing how well the model replicated the essential steps. Descriptive analyses were performed. RESULTS: Five experts submitted an outline of steps for transvaginal VVF repair, and 4 experts participated in a focus group to reach consensus on the essential steps. Nine urogynecologic surgeons, with a median of 10 years in practice (interquartile range, 7-12 years), tested the model and completed the postsimulation questionnaire. Most testers thought that tasks involving identification and closure of the fistula were replicated by the model. Testers thought that tasks involving cystoscopy or bladder filling were not replicated by the model. CONCLUSIONS: We developed a novel, low-fidelity transvaginal VVF repair simulation model that consistently replicated tasks involving identification and closure of the fistula.

Overactive Bladder and Cognitive Impairment: The American Urogynecologic Society and Pelvic Floor Disorders Research Foundation State-of-the-Science Conference Summary Report.

IMPORTANCE: Overactive bladder (OAB) is prevalent in older adults in whom management is complicated by comorbidities and greater vulnerability to the cognitive effects of antimuscarinic medications. OBJECTIVES: The aim of this study is to provide a comprehensive evidence-based summary of the 2021 State-of-the-Science (SOS) conference and a multidisciplinary expert literature review on OAB and cognitive impairment. STUDY DESIGN: The American Urogynecologic Society and the Pelvic Floor Disorders Research Foundation convened a 3-day collaborative conference. Experts from multidisciplinary fields examined cognitive function, higher neural control of the OAB patient, risk factors for cognitive impairment in older patients, cognitive effects of antimuscarinic medications for OAB treatment, OAB phenotyping, conservative and advanced OAB therapies, and the need for a multidisciplinary approach to person-centered treatment. Translational topics included the blood-brain barrier, purine metabolome, mechanotransduction, and gene therapy for OAB targets. RESULTS: Research surrounding OAB treatment efficacy in cognitively impaired individuals is limited. Short- and long-term outcomes regarding antimuscarinic effects on cognition are mixed; however, greater anticholinergic burden and duration of use influence risk. Oxybutynin is most consistently associated with negative cognitive effects in short-term, prospective studies. Although data are limited, beta-adrenergic agonists do not appear to confer the same cognitive risk. CONCLUSIONS: The 2021 SOS summary report provides a comprehensive review of the fundamental, translational, and clinical research on OAB with emphasis on cognitive impairment risks to antimuscarinic medications. Duration of use and antimuscarinic type, specifically oxybutynin when examining OAB treatments, appears to have the most cognitive impact; however, conclusions are limited by the primarily cognitively intact population studied. Given current evidence, it appears prudent to minimize anticholinergic burden by emphasizing nonantimuscarinic therapeutic regimens in the older population and/or those with cognitive impairment.

Evidence-Informed, Interdisciplinary, Multidimensional Action Plan to Advance Overactive Bladder Research and Treatment Initiatives: Directives From State-of-the-Science Conference on Overactive Bladder and Cognitive Impairment.

ABSTRACT: This article outlines an evidence-informed, interdisciplinary, multidimensional, comprehensive action plan for the American Urogynecologic Society to improve care of women with overactive bladder (OAB) while minimizing treatment-related adverse events, including cognitive impairment. It is a "call to action" to advance basic, translational, and clinical research and summarizes initiatives developed at the State-of-the-Science Conference on OAB and Cognitive Impairment to (1) develop framework for a new OAB treatment approach in women, (2) define research gaps and future research priorities, (3) champion health equity and diversity considerations in OAB treatment, (4) foster community and promote education to remove stigma surrounding OAB and urinary incontinence, and (5) elevate visibility and impact of OAB, by creating partnerships through education and engagement with health care professionals, industry, private and public payers, funding agencies, and policymakers.

The Impact of Language Discordance on Patients' Perception of a Clinical Encounter and Trust in Provider.

IMPORTANCE: The impact of language discordance on care for Spanish-speaking patients with pelvic floor disorders is unknown. OBJECTIVE: The aim of this study was to compare the impact of language concordance with the impact of language discordance on the patient experience and trust in their provider. METHODS: This cross-sectional cohort study enrolled English- and Spanish-speaking patients during initial evaluation in a urogynecology clinic. English- and Spanish-speaking patients seen by native English- or Spanish-speaking providers were recruited to the language-concordant group. The language-discordant group included Spanish-speaking patients seen with a translator or by nonnative Spanish-speaking providers. Patients completed the Trust in Physician Scale and the Consumer Assessment of Healthcare Providers and Systems Clinician and Group Survey (CG-CAHPS). Patients and providers rated the provider's Spanish proficiency on a 10-point scale from 0 (low) to 10 (high). Symptom bother questionnaires were completed 4-6 months after enrollment. RESULTS: Eighty women were recruited, with 40 in each group. Mean age was 55.4 ± 12.9 years. The majority identified as White (75%) and Hispanic (77.5%). Trust in Physician Scale scores were similar between groups (46.2 ± 8.5 vs 44.4 ± 7.5, P > 0.05). The provider communication, provider rating, and recommendation domains of the CG-CAHPS did not differ between groups (all P > 0.05). Provider self-rating of Spanish proficiency was lower than patient ratings (7.5 ± 1.8 vs 9.8 ± 0.5, P < 0.001). There was no difference between groups in symptom bother at 4-6 months (all P > 0.05). CONCLUSIONS: Patient-provider language discordance does not affect patient trust in the provider or perception of the encounter as measured by the Trust in Physician Scale and CG-CAHPS questionnaires.

An evidence-based microscopic hematuria care pathway optimizes decision-making among providers.

INTRODUCTION AND HYPOTHESIS: Microscopic hematuria (MH) has many etiologies in women and requires specific gynecologic evaluation. We created a standardized MH pathway to serve as an evidence-based decision aid for providers in our practice. METHODS: Using a modified Delphi process, a multidisciplinary team reviewed existing guidelines for MH diagnosis and treatment to reach consensus on care pathway components. RESULTS: Entry into the care pathway by an advanced practice provider is determined by the finding of ≥3 red blood cells per high-power field (RBC/HPF) on microscopic urinalysis. Initial evaluation includes history and physical exam. If there are signs of a gynecologic cause of MH, the conditions are treated and repeat urinalysis is performed in 6 months. If repeat urinalysis shows persistent MH or there are no other apparent causes for MH, we proceed with risk stratification. Through shared decision-making, low-risk patients may undergo repeat urinalysis in 6 months or cystoscopy with urinary tract ultrasound. For intermediate-risk patients, cystoscopy and urinary tract ultrasound are recommended. For high-risk patients, cystoscopy and axial upper urinary tract imaging are recommended. If evaluation is positive, urology referral is provided. If evaluation is negative, low-risk patients are released from care, but intermediate-risk or high-risk patients undergo repeat urinalysis in 12 months. If repeat urinalysis is positive, shared decision-making is used to determine a plan. CONCLUSIONS: We developed an MH care pathway to standardize care of women with MH across a multidisciplinary group. This pathway serves as a component of value-based care and supports evidence-based care by providers.

The effect of oral medications on fMRI brain activation: A randomized, double blind, controlled pilot trial of older women with overactive bladder.

INTRODUCTION AND AIM: Observational studies have associated oral anticholinergic medications for overactive bladder (OAB) with cognitive impairment. This is the first pilot trial to compare the effects of two classes of OAB medications on brain activity in women. We evaluated the effect of anticholinergic versus non-anticholinergic (Non-Ach) interventions on regional brain activation during a cognitive task. METHODS: Twelve cognitively normal women seeking OAB therapy were recruited to a randomized, double-blind, parallel, controlled pilot trial. Whole-brain regional activity at baseline and 29 ± 1 days postintervention was assessed with functional magnetic resonance imaging during a working memory task. Average activation strength by region was compared after anticholinergic, beta-3 agonist, or placebo. Two-way ANOVA compared effects of group and time on average activation strength in anticholinergic versus Non-Ach (beta-3 agonists or placebo) groups. RESULTS: The mean (SD) age and body mass index of 12 women were 61 (7) years and 36 (7) kg/m2. Baseline depression and learning scores differed in the anticholinergic group (n = 3) versus the Non-Ach group (n = 9). Right mamillary body activation postintervention was higher after Non-Ach exposure (F 4.9, p < 0.04). In the full sample of participants at follow-up, there was less activation of the right middle frontal gyrus (p = 0.02), superior frontal gyrus (p < 0.01), and supramarginal (p < 0.01) gyrus. CONCLUSION: Activation strength in brain regions underlying working memory was lower over time, and recognition scores improved. A powered trial is needed to adequately evaluate for differential effects of OAB oral medications on regional brain activation.

Sacral neuromodulation for symptomatic chronic urinary retention in females: do age and comorbidities make a difference?

OBJECTIVES: To evaluate if age and medical comorbidities are associated with progression to implantation of sacral neuromodulation devices in women with symptomatic chronic urinary retention. METHODS: This multisite retrospective cohort included women with symptomatic chronic urinary retention who had a trial phase of sacral neuromodulation. The primary outcome was progression to implantation. Post-implantation outcomes were assessed as stable response versus decreased efficacy. A sub-analysis of catheter-reliant (intermittent-self catheterization or indwelling) patients was performed. Age was analyzed by 10-year units (decades of age). Multivariate logistic regression determined odds ratios for outcomes of implantation and for post-implantation stable response. RESULTS: Implantation occurred in 86% (243/284) women across six academic institutions. Most patients (160/243, 66%) were catheter reliant at the time of trial phase. Increased decade of age was associated with reduced implantation in all women [OR 0.54 (95% CI 0.42, 0.70)] and in the subgroup of catheter-reliant women [OR 0.52 (95% CI 0.37, 0.73)]. Post-implantation stable response occurred in 68% (193/243) of women at median follow-up of 2 years (range 0.3-15 years). Medical comorbidities present at the time of trials did not impact progression to implantation or post-implantation success. CONCLUSIONS: Increasing decade of age is associated with reduced implantation in women with symptomatic chronic urinary retention. There is no age cutoff at which outcomes change. Post-implantation stable response was not associated with age or medical comorbidities.

Sacral neuromodulation for overactive bladder in women: do age and comorbidities make a difference?

OBJECTIVE: To evaluate if age and comorbidities are associated with progression from trial phase to implantation of an implantable pulse generator in women with overactive bladder. METHODS: This multisite retrospective cohort included women with overactive bladder with or without urinary incontinence who had a trial phase for sacral neuromodulation. The primary outcome was progression to implantation. A sub-analysis of implanted patients was performed for the outcome of additional therapies or "implant only" for the duration of follow-up. Multivariate logistic regression models including potential predictors of implantation and post-implantation addition of therapies were performed. RESULTS: At six academic institutions, 91% (785/864) of patients progressed to implantation. Post-implantation success was achieved by 69% (536/782) of patients at median follow-up of 2 (range 0.3 to 15) years. Odds of implantation [OR 0.73 (CI 0.61, 0.88)] and post-implantation success [OR 0.78 (CI 0.98, 0.97)] were lower with increasing decades of age. Medical comorbidities evaluated did not affect implantation rates or post-implant success. CONCLUSIONS: Most women have successful sacral neuromodulation trials despite older age and comorbidities. Higher decade of age has a negative effect on odds of implantation and is associated with addition of therapies post-implantation. Comorbidities assessed in this study did not affect implantation or addition of therapies post-implantation. Most women add therapies to improve efficacy post-implantation, and explantation rates are low.

Treatment of urethral stricture disease in women: A multi-institutional collaborative project from the SUFU research network.

AIM: Female urethral stricture disease is rare and has several surgical approaches including endoscopic dilations (ENDO), urethroplasty with local vaginal tissue flap (ULT) or urethroplasty with free graft (UFG). This study aims to describe the contemporary management of female urethral stricture disease and to evaluate the outcomes of these three surgical approaches. METHODS: This is a multi-institutional, retrospective cohort study evaluating operative treatment for female urethral stricture. Surgeries were grouped into three categories: ENDO, ULT, and UFG. Time from surgery to stricture recurrence by surgery type was analyzed using a Kaplan-Meier time to event analysis. To adjust for confounders, a Cox proportional hazard model was fit for time to stricture recurrence. RESULTS: Two-hundred and ten patients met the inclusion criteria across 23 sites. Overall, 64% (n = 115/180) of women remained recurrence free at median follow-up of 14.6 months (IQR, 3-37). In unadjusted analysis, recurrence-free rates differed between surgery categories with 68% ENDO, 77% UFG and 83% ULT patients being recurrence free at 12 months. In the Cox model, recurrence rates also differed between surgery categories; women undergoing ULT and UFG having had 66% and 49% less risk of recurrence, respectively, compared to those undergoing ENDO. When comparing ULT to UFG directly, there was no significant difference of recurrence. CONCLUSION: This retrospective multi-institutional study of female urethral stricture demonstrates that patients undergoing endoscopic management have a higher risk of recurrence compared to those undergoing either urethroplasty with local flap or free graft.

Protocol for a multicenter randomized, double blind, controlled pilot trial of higher neural function in overactive bladder patients after anticholinergic, beta-3 adrenergic agonist, or placebo.

INTRODUCTION: Overactive bladder (OAB) syndrome has a negative impact on quality of life and prevalence increases with advanced age. Anticholinergics (AC) and beta-3 adrenergic agonists (ß3a) are commonly prescribed medications for treatment of OAB. AC medication has been associated with dementia in population studies and with cortical atrophy in imaging studies. Higher neural effects of both classes of OAB medications have not been evaluated with functional neuroimaging. Longitudinal clinical assessments of cognition after OAB therapy with AC has produced conflicting results. ß3a medication is has not been associated with dementia in clinical studies; however, higher neural effects are unknown.Our multicenter, double blind, randomized, placebo-controlled trial uses functional magnetic resonance imaging (fMRI) and cognitive testing to evaluate the effects of AC and ß3a on brain functional connectivity in females with non-neurogenic OAB. METHODS AND ANALYSIS: and analysis: Female patients with OAB symptoms ages 50-90 years old without baseline cognitive impairment, moderate to severe depression or anxiety, neurologic disorders, or significant incomplete bladder emptying are invited to participate. Subjects are randomized to one of three interventions for 29 ± 1 day: AC (Solifenacin succinate, Teva), ß3a (Mirabegron, Myrbetriq, Astellas), or placebo. Functional neuroimaging data at baseline and post-intervention will be analyzed accordingly. Clinical cognitive assessments will be compared from baseline to post-intervention. ETHICS: All qualifying patients are properly consented before enrolling in this study that has been approved by the Institutional Review Board of participating institutions.

Overactive Bladder Symptoms After Pelvic Organ Prolapse Repair.

OBJECTIVES: This study aimed to identify the characteristics associated with overactive bladder (OAB) symptoms perioperatively in patients undergoing pelvic organ prolapse (POP) surgery with and without slings and to determine the rate of OAB symptom resolution postoperatively. METHODS: This retrospective, single-institution study involved women undergoing prolapse surgery with and without concomitant midurethral sling from 2011 to 2016. A validated questionnaire was used to determine OAB symptoms preoperatively and postoperatively. The primary outcome was rate of resolution in OAB symptoms after POP surgery with and without midurethral sling. Baseline characteristics and surgery type were presented, and univariate and multivariate logistic regression models were applied to evaluate characteristics associated with OAB symptoms at the first postoperative visit. RESULTS: The analysis included 203 patients. Among those with baseline OAB symptoms, 103 (61%) had symptom resolution, whereas 66 (39.1%) reported persistent symptoms. Among 34 patients without baseline OAB symptoms, 6% developed de novo symptoms. Older age was found to be a significant risk factor for persistence of symptoms postoperatively both on univariate (odds ratio, 0.97; 95% confidence interval, 0.94-1; P = 0.038) and multivariate logistic regression (odds ratio, 0.96, 95% confidence interval, 0.92-1; P = 0.049). The rate of medication discontinuation postoperatively was 25%. CONCLUSIONS: Approximately 61% of patients undergoing POP surgery had resolution of OAB symptoms postoperatively whether or not an incontinence procedure was performed. Older age was significantly related to persistent OAB symptoms in both univariate (P = 0.038) and multivariate (P = 0.049) models. The rate of de novo OAB symptoms was 6%.

The Landscape of Long Non-Coding RNA Dysregulation and Clinical Relevance in Muscle Invasive Bladder Urothelial Carcinoma.

Bladder cancer is one of the most common cancers in the United States, but few advancements in treatment options have occurred in the past few decades. This study aims to identify the most clinically relevant long non-coding RNAs (lncRNAs) to serve as potential biomarkers and treatment targets for muscle invasive bladder cancer (MIBC). Using RNA-sequencing data from 406 patients in The Cancer Genome Atlas (TCGA) database, we identified differentially expressed lncRNAs in MIBC vs. normal tissues. We then associated lncRNA expression with patient survival, clinical variables, oncogenic signatures, cancer- and immune-associated pathways, and genomic alterations. We identified a panel of 20 key lncRNAs that were most implicated in MIBC prognosis after differential expression analysis and prognostic correlations. Almost all lncRNAs we identified are correlated significantly with oncogenic processes. In conclusion, we discovered previously undescribed lncRNAs strongly implicated in the MIBC disease course that may be leveraged for diagnostic and treatment purposes in the future. Functional analysis of these lncRNAs may also reveal distinct mechanisms of bladder cancer carcinogenesis.

In vivo assessment of extracellular pH of joint tissues using acidoCEST-UTE MRI.

BACKGROUND: Degradation of cartilage and meniscus may be mediated by changes in extracellular pH. The purpose of this study was to optimize saturation powers used with the acidoCEST magnetic resonance imaging (MRI) technique with a 3D ultrashort echo time readout (acidoCEST-UTE) and to demonstrate feasibility of the method for measuring pH in cartilage and meniscus in vivo. METHODS: Magnetization transfer ratio asymmetry and ratio of radiofrequency (RF) power mismatch at different powers were evaluated in cartilage and meniscus tissue phantoms for iopamidol and iohexol. Using optimized RF powers, the acidoCEST-UTE MRI sequence was used to assess pH of joint fluid and tissues in four patients after direct intra-articular administration of iodinated contrast. RESULTS: In the phantoms, the ratio of powers 0.54/1.10 µT showed the strongest correlation with pH. In vivo acidoCEST-UTE pH measurements of intra-articular fluid were similar to electrode measurements of the contrast agent (7.22 vs. 7.1 for iopamidol, respectively; 7.65 vs. 7.5 for iohexol, respectively). As measured with the acidoCEST-UTE technique, overall mean cartilage pH was significantly lower than overall mean meniscus pH (6.60 vs. 6.72, respectively; P=0.043). CONCLUSIONS: AcidoCEST-UTE MRI after direct intra-articular administration of either iopamidol or iohexol can be used to measure cartilage and meniscus pH in vivo.

Extracellular acidosis differentiates pancreatitis and pancreatic cancer in mouse models using acidoCEST MRI.

Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model treated with caerulein, which causes pancreatitis followed by development of pancreatic cancer. We also evaluated the KC model treated with PBS, and wild-type mice treated with caerulein or PBS as controls. The caerulein-treated KC cohort had lower pHe of 6.85-6.92 before and during the first 48 h after initiating treatment, relative to a pHe of 6.92 to 7.05 pHe units for the other cohorts. The pHe of the caerulein-treated KC cohort decreased to 6.79 units at 5 weeks when pancreatic tumors were detected with anatomical MRI, and sustained a pHe of 6.75 units at the 8-week time point. Histopathology was used to evaluate and validate the presence of tumors and inflammation in each cohort. These results showed that acidoCEST MRI can differentiate pancreatic cancer from pancreatitis in this mouse model, but does not appear to differentiate pancreatitis that progresses to pancreatic cancer vs. pancreatitis that does not progress to cancer.

Assessment of an in vitro model of rotator cuff degeneration using quantitative magnetic resonance and ultrasound imaging with biochemical and histological correlation.

PURPOSE: Quantitative imaging methods could improve diagnosis of rotator cuff degeneration, but the capability of quantitative MR and US imaging parameters to detect alterations in collagen is unknown. The goal of this study was to assess quantitative MR and US imaging measures for detecting abnormalities in collagen using an in vitro model of tendinosis with biochemical and histological correlation. METHOD: 36 pieces of supraspinatus tendons from 6 cadaveric donors were equally distributed into 3 groups (2 subjected to different concentrations of collagenase and a control group). Ultrashort echo time MR and US imaging measures were performed to assess changes at baseline and after 24 h of enzymatic digestion. Biochemical and histological measures, including brightfield, fluorescence, and polarized microscopy, were used to verify the validity of the model and were compared with quantitative imaging parameters. Correlations between the imaging parameters and biochemically measured digestion were analyzed. RESULTS: Among the imaging parameters, macromolecular fraction (MMF), adiabatic T1ρ, T2*, and backscatter coefficient (BSC) were useful in differentiating between the extent of degeneration among the 3 groups. MMF strongly correlated with collagen loss (r=-0.81; 95% confidence interval [CI]: -0.90,-0.66), while the adiabatic T1ρ (r = 0.66; CI: 0.42,0.81), T2* (r = 0.58; CI: 0.31,0.76), and BSC (r = 0.51; CI: 0.22,0.72) moderately correlated with collagen loss. CONCLUSIONS: MMF, adiabatic T1ρ, and T2* measured and US BSC can detect alterations in collagen. Of the quantitative MR and US imaging measures evaluated, MMF showed the highest correlation with collagen loss and can be used to assess rotator cuff degeneration.

Differentiating lung cancer and infection based on measurements of extracellular pH with acidoCEST MRI.

Lung cancer diagnosis via imaging may be confounded by the presence of indolent infectious nodules in imaging studies. This issue is pervasive in the southwestern US where coccidioidomycosis (Valley Fever) is endemic. AcidoCEST MRI is a noninvasive imaging method that quantifies the extracellular pH (pHe) of tissues in vivo, allowing tumor acidosis to be used as a diagnostic biomarker. Using murine models of lung adenocarcinoma and coccidoidomycosis, we found that average lesion pHe differed significantly between tumors and granulomas. Our study shows that acidoCEST MRI is a promising tool for improving the specificity of lung cancer diagnosis.

AcidoCEST-UTE MRI for the Assessment of Extracellular pH of Joint Tissues at 3 T.

OBJECTIVES: The goal of this study was to demonstrate feasibility of measuring extracellular pH in cartilage and meniscus using acidoCEST technique with a 3-dimensional ultrashort echo time readout (acidoCEST-UTE) magnetic resonance imaging (MRI). MATERIALS AND METHODS: Magnetization transfer ratio asymmetry, radiofrequency (RF) power mismatch, and relative saturation transfer were evaluated in liquid phantoms for iopromide, iopamidol, and iohexol over a pH range of 6.2 to 7.8, at various agent concentrations, temperatures, and buffer concentrations. Tissue phantoms containing cartilage and meniscus were evaluated with the same considerations for iopamidol and iohexol. Phantoms were imaged with the acidoCEST-UTE MRI sequence at 3 T. Correlation coefficients and coefficients of variations were calculated. Paired Wilcoxon rank-sum tests were used to evaluate for statistically significant differences. RESULTS: The RF power mismatch and relative saturation transfer analyses of liquid phantoms showed iopamidol and iohexol to be the most promising agents for this study. Both these agents appeared to be concentration independent and feasible for use with or without buffer and at physiologic temperature over a pH range of 6.2 to 7.8. Ultimately, RF power mismatch fitting of iohexol showed the strongest correlation coefficients between cartilage, meniscus, and fluid. In addition, ratiometric values for iohexol are similar among liquid as well as different tissue types. CONCLUSIONS: Measuring extracellular pH in cartilage and meniscus using acidoCEST-UTE MRI is feasible.

Calcium carbonate nanoparticles stimulate tumor metabolic reprogramming and modulate tumor metastasis.

AIM: CaCO3 nanoparticles (nano-CaCO3) can neutralize the acidic pHe of solid tumors, but the lack of intrinsic imaging signal precludes noninvasive monitoring of pH-perturbation in tumor microenvironment. We aim to develop a theranostic version of nano-CaCO3 to noninvasively monitor pH modulation and subsequent tumor response. MATERIALS & METHODS: We synthesized ferromagnetic core coated with CaCO3 (magnetite CaCO3). Magnetic resonance imaging (MRI) was used to determine the biodistribution and pH modulation using murine fibrosarcoma and breast cancer models. RESULTS: Magnetite CaCO3-MRI imaging showed that nano-CaCO3 rapidly raised tumor pHe, followed by excessive tumor-associated acid production after its clearance. Continuous nano-CaCO3 infusion could inhibit metastasis. CONCLUSION: Nano-CaCO3 exposure induces tumor metabolic reprogramming that could account for the failure of previous intermittent pH-modulation strategies to achieve sustainable therapeutic effect.