Risk Classification for Interstitial Cystitis/Bladder Pain Syndrome Using Machine Learning Based Predictions.

OBJECTIVE: To improve diagnosis of interstitial cystitis (IC)/bladder pain syndrome(IC) we hereby developed an improved IC risk classification using machine learning algorithms. METHODS: A national crowdsourcing resulted in 1264 urine samples consisting of 536 IC (513 female, 21 male, 2 unspecified), and 728 age-matched controls (318 female, 402 male, 8 unspecified) with corresponding patient-reported outcome (PRO) pain and symptom scores. In addition, 296 urine samples were collected at three academic centers: 78 IC (71 female, 7 male) and 218 controls (148 female, 68 male, 2 unspecified). Urinary cytokine biomarker levels were determined using Luminex assay. A machine learning predictive classification model, termed the Interstitial Cystitis Personalized Inflammation Symptom (IC-PIS) Score, that utilizes PRO and cytokine levels, was generated and compared to a challenger model. RESULTS: The top-performing model using biomarker measurements and PROs (area under the curve [AUC]=0.87) was a support vector classifier, which scored better at predicting IC than PROs alone (AUC=0.83). While biomarkers alone (AUC=0.58) did not exhibit strong predictive performance, their combination with PROs produced an improved predictive effect. CONCLUSION: IC-PIS represents a novel classification model designed to enhance the diagnostic accuracy of IC/bladder pain syndrome by integrating PROs and urine biomarkers. The innovative approach to sample collection logistics, coupled with one of the largest crowdsourced biomarker development studies utilizing ambient shipping methods across the US, underscores the robustness and scalability of our findings.

Comparing online crowdsourcing with clinic patient enrollment: Findings from the IP4IC Study on interstitial cystitis/bladder pain syndrome.

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) manifests as urinary symptoms including urgency, frequency, and pain. The IP4IC Study aimed to establish a urine-based biomarker score for diagnosing IC/BPS. To accomplish this objective, we investigated the parallels and variances between patients enrolled via physician/hospital clinics and those recruited through online crowdsourcing. Methods: Through a nationwide crowdsource effort, we collected surveys from patients with history of IC/BPS. Study participants were asked to complete the validated instruments of Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI), as well as provide demographic information. We then compared the survey responses of patients recruited through crowdsourcing with those recruited from three specialized tertiary care urology clinics engaged in clinical research. Results: Survey responses of 1300 participants were collected from all 50 states of the USA via crowdsourcing and 319 from a clinical setting. ICSI and ICPI were similar for IC/BPS patients diagnosed by the physicians in clinic and self-reported by subjects via crowdsourcing stating they have a history of previous physician diagnosis of IC/BPS. Surprisingly, ICSI and ICPI were significantly lower in crowdsourced control than in-clinic control subjects. Conclusion: The IP4IC Study provides valuable insights into the similarities and differences between patients recruited through clinics and those recruited through online crowdsourcing. There were no significant differences in disease symptoms among these groups. Individuals who express an interest in digital health research and self-identify as having been previously diagnosed by physicians with IC/BPS can be regarded as reliable candidates for crowdsourcing research.

Descriptive Epidemiology of Upper Extremity Septic Arthritis in Children-Review of a Retrospective Multicenter Database.

BACKGROUND: There is limited information on the presentation and management of upper extremity septic arthritis (UESA) in children. Our purpose was to report on the characteristics and short-term treatment outcomes of pediatric UESA from a multicenter database. METHODS: Patients with UESA were identified from a multicenter retrospective musculoskeletal infection database. Demographics, laboratory tests, culture results, number of surgeries, and complications were collected. RESULTS: Of 684 patients with septic arthritis (SA), 68 (10%) patients had UESA. Septic arthritis was most common in the elbow (53%), followed by the shoulder (41%) and wrist (4%). The median age at admission was 1.7 years [interquartile range(IQR, 0.8-8.0 y)] and 66% of the cohort was male. Blood cultures were collected in 65 (96%) patients with 23 (34%) positive results. Joint aspirate and/or tissue cultures were obtained in 66 (97%) patients with 49 (72%) positive results. Methicillin-sensitive Staphylococcus aureus (MSSA) was the most common causative organism overall, but Streptococcus was the most common pathogen in the shoulder. Sixty-six (97%) patients underwent irrigation and debridement, with 5 (7%) patients requiring 2 surgeries and 1 patient (1%) requiring 3 surgeries. The median length of stay was 4.9 days (IQR, 4.0-6.3 d). Thirty-one (46%) children had adjacent musculoskeletal infections and/or persistent bacteremia. No patients experienced venous thromboembolism, and 4 patients with associated osteomyelitis experienced a musculoskeletal complication (3 avascular necrosis, 1 pathologic fracture). One child had re-admission and 3 children with associated osteomyelitis had a recurrence of UESA. Comparison between elbow and shoulder locations showed that children with septic arthritis of the shoulder were younger (4.6 vs. 1.0 y, P =0.001), and there was a difference in minimum platelet count (280 vs. 358 ×10 9 cells/L, P =0.02). CONCLUSIONS: UESA comprises 10% of cases of septic arthritis in children. The elbow is the most common location. Shoulder septic arthritis affects younger children. MSSA is the most common causative organism in UESA, but Streptococcus is common in shoulder septic arthritis. Irrigation and debridement result in excellent short-term outcomes with a low complication rate. Re-admissions and repeat surgical interventions are rare. LEVEL OF EVIDENCE: Level IV, prognostic.

Interobserver and Intraobserver Agreement are Unsatisfactory When Determining Abstract Study Design and Level of Evidence.

BACKGROUND: Understanding differences between types of study design (SD) and level of evidence (LOE) are important when selecting research for presentation or publication and determining its potential clinical impact. The purpose of this study was to evaluate interobserver and intraobserver reliability when assigning LOE and SD as well as quantify the impact of a commonly used reference aid on these assessments. METHODS: Thirty-six accepted abstracts from the Pediatric Orthopaedic Society of North America (POSNA) 2021 annual meeting were selected for this study. Thirteen reviewers from the POSNA Evidence-Based Practice Committee were asked to determine LOE and SD for each abstract, first without any assistance or resources. Four weeks later, abstracts were reviewed again with the guidance of the Journal of Bone and Joint Surgery (JBJS) LOE chart, which is adapted from the Oxford Centre for Evidence-Based Medicine. Interobserver and intraobserver reliability were calculated using Fleiss' kappa statistic (k). χ2 analysis was used to compare the rate of SD-LOE mismatch between the first and second round of reviews. RESULTS: Interobserver reliability for LOE improved slightly from fair (k=0.28) to moderate (k=0.43) with use of the JBJS chart. There was better agreement with increasing LOE, with the most frequent disagreement between levels 3 and 4. Interobserver reliability for SD was fair for both rounds 1 (k=0.29) and 2 (k=0.37). Similar to LOE, there was better agreement with stronger SD. Intraobserver reliability was widely variable for both LOE and SD (k=0.10 to 0.92 for both). When matching a selected SD to its associated LOE, the overall rate of correct concordance was 82% in round 1 and 92% in round 2 (P<0.001). CONCLUSION: Interobserver reliability for LOE and SD was fair to moderate at best, even among experienced reviewers. Use of the JBJS/Oxford chart mildly improved agreement on LOE and resulted in less SD-LOE mismatch, but did not affect agreement on SD. LEVEL OF EVIDENCE: Level II.

A Cost, Time, and Demographic Analysis of Participant Recruitment and Urine Sample Collection Through Social Media Optimization.

INTRODUCTION: Clinical research can be expensive and time consuming due to high associated costs and/or duration of the study. We hypothesized that urine sample collection using online recruitment and engagement of research participants via social medial has the potential to reach a large population in a small timeframe, at a reasonable cost. METHODS: We performed a retrospective cost analysis of a cohort study comparing cost per sample and time per sample for both online and clinically recruited participants for urine sample collection. During this time, cost data were collected based on study associated costs from invoices and budget spreadsheets. The data were subsequently analyzed using descriptive statistics. RESULTS: Each sample collection kit contained 3 urine cups, 1 for the disease sample and 2 for control samples. Out of the 3,576 (1,192 disease + 2,384 control) total sample cups mailed, 1,254 (695 control) samples were returned. Comparatively, the 2 clinical sites collected 305 samples. Although the initial startup cost of online recruitment was higher, cost per sample for online recruited was found to be $81.45 compared to $398.14 for clinic sample. CONCLUSIONS: We conducted a nationwide, contactless, urine sample collection through online recruitment in the midst of the COVID-19 pandemic. Results were compared with the samples collected in the clinical setting. Online recruitment can be utilized to collect urine samples rapidly, efficiently, and at a cost per sample that was 20% of an in-person clinic, and without risk of COVID-19 exposure.

Defining the volume of consultations for musculoskeletal infection encountered by pediatric orthopaedic services in the United States.

OBJECTIVE: Adequate resources are required to rapidly diagnose and treat pediatric musculoskeletal infection (MSKI). The workload MSKI consults contribute to pediatric orthopaedic services is unknown as prior epidemiologic studies are variable and negative work-ups are not included in national discharge databases. The hypothesis was tested that MSKI consults constitute a substantial volume of total consultations for pediatric orthopaedic services across the United States. STUDY DESIGN: Eighteen institutions from the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study (CORTICES) group retrospectively reviewed a minimum of 1 year of hospital data, reporting the total number of surgeons, total consultations, and MSKI-related consultations. Consultations were classified by the location of consultation (emergency department or inpatient). Culture positivity rate and pathogens were also reported. RESULTS: 87,449 total orthopaedic consultations and 7,814 MSKI-related consultations performed by 229 pediatric orthopaedic surgeons were reviewed. There was an average of 13 orthopaedic surgeons per site each performing an average of 154 consultations per year. On average, 9% of consultations were MSKI related and 37% of these consults yielded positive cultures. Finally, a weak inverse monotonic relationship was noted between percent culture positivity and percent of total orthopedic consults for MSKI. CONCLUSION: At large, academic pediatric tertiary care centers, pediatric orthopaedic services consult on an average of ~3,000 'rule-out' MSKI cases annually. These patients account for nearly 1 in 10 orthopaedic consultations, of which 1 in 3 are culture positive. Considering that 2 in 3 consultations were culture negative, estimating resources required for pediatric orthopaedic consult services to work up and treat children based on culture positive administrative discharge data underestimates clinical need. Finally, ascertainment bias must be considered when comparing differences in culture rates from different institution's pediatric orthopaedics services, given the variability in when orthopaedic physicians become involved in a MSKI workup.

Displaced Distal Radius Fracture Treatment: A Survey of POSNA Membership.

BACKGROUND: Distal radius fractures (DRFs) are the most common pediatric orthopaedic fracture, of which 20% are displaced injuries. Displaced metaphyseal DRFs are often treated with sedated or anesthetized reduction. The necessity of reduction treatment of displaced fractures to achieve good clinical outcomes is unclear. The purpose of this investigation was to determine the treatment preferences for DRFs among pediatric orthopaedic surgeons and to determine whether they were uncertain enough in their decisions to randomize treatment. METHODS: Twenty-eight DRF scenarios in children aged 3 to 10 years were constructed in an electronic survey to represent a spectrum of age, angulation in sagittal and coronal planes, and displacement. The survey was disseminated to the full membership of the Pediatric Orthopaedic Society of North America (POSNA). Respondents could select either a treatment of (a) attempt anatomic reduction with sedation or (b) nonsedated immobilization. Respondents also denoted whether they would be willing to randomize the treatment of each injury scenario. Patient, fracture, and surgeon characteristics were analyzed to develop predictors of treatment recommendations and willingness to randomize treatment. RESULTS: A total of 319 surgeons responded (23% of POSNA membership). Respondents were a characteristic representation of POSNA membership (well distributed by years in practice, 78% academic, 91% whose work is >80% pediatrics, and 84% work with residents). Predictors of sedated reduction were complete displacement [odds ratio (OR), 9.23; 95% confidence interval (CI), 2.27-37.51; P=0.002] and coronal angulation (per 1-degree increase, OR, 1.09; 95% CI, 1.02-1.17; P=0.016), Willingness to randomize was inversely related to larger coronal plane angulation (per 1-degree increase, OR, 0.96; 95% CI, 0.93-0.99; P=0.01). A majority of surgeons were willing to randomize 7 of the 8 scenarios involving complete displacement and shortening, and >64% of surgeons were willing to randomize 5 of these 8 scenarios. CONCLUSIONS: POSNA members recommend sedated reduction of DRFs primarily based on existence of complete displacement. Although most completely displaced DRFs would undergo reduction, most surgeons would be willing to randomize the treatment of these injuries. This suggests that most POSNA members do not know whether their recommended treatment for displaced DRFs is necessary or correct. This survey establishes the groundwork for a randomized, prospective trial comparing nonsedated immobilization with sedated/anesthetized reduction in the treatment of displaced pediatric DRFs. LEVELS OF EVIDENCE: Level II-survey study.

Validation of Pediatric Self-Report Patient-Reported Outcomes Measurement Information System (PROMIS) Measures in Different Stages of Legg-Calvé-Perthes Disease.

OBJECTIVES: Patient-reported outcomes (PRO) assessing health-related quality of life (HRQoL) are important outcome measures, especially in Legg-Calvé-Perthes disease (LCPD) where symptoms (pain and limping), activity restrictions, and treatments vary depending on the stage of the disease. The purpose of this study was to investigate the validity of the Patient-reported Outcomes Measurement Information System (PROMIS) for measuring HRQoL of patients with LCPD in various stages of the disease. METHODS: This is a multicenter validity study. Patients with LCPD between 4 and 18 years old were included and classified into modified Waldenström stages of disease: Early (1 or 2A), Late (2B or 3), or Healed (4). Seven PROMIS domains were collected, including Pain Interference, Fatigue, Mobility, Depression, Anger, Anxiety, and Peer Relationships. Convergent, discriminant, and known group validity was determined. RESULTS: A total of 190 patients were included (mean age: 10.4±3.1 y). All 7 domains showed the worst scores in patients in the Early stage (known group validity). Within each domain, all domains positively correlated to each other (convergent validity). Patients who reported more anxiety, depression, and anger were associated with decreased mobility and increased fatigue and pain. Peer relationships had no to weak associations with other domains (discriminant validity). CONCLUSIONS: PROMIS has construct validity in measuring the HRQoL of patients in different stages of LCPD, suggesting that PROMIS has potential to serve as a patient-reported outcome tool for this population. LEVEL OF EVIDENCE: Diagnostic level III study.

Pediatric Type II Tibial Spine Fractures: Addressing the Treatment Controversy With a Mixed-Effects Model.

BACKGROUND: Tibial spine fractures, although relatively rare, account for a substantial proportion of pediatric knee injuries with effusions and can have significant complications. Meyers and McKeever type II fractures are displaced anteriorly with an intact posterior hinge. Whether this subtype of pediatric tibial spine fracture should be treated operatively or nonoperatively remains controversial. Surgical delay is associated with an increased risk of arthrofibrosis; thus, prompt treatment decision making is imperative. PURPOSE: To assess for variability among pediatric orthopaedic surgeons when treating pediatric type II tibial spine fractures. STUDY DESIGN: Cross-sectional study. METHODS: A discrete choice experiment was conducted to determine the patient and injury attributes that influence the management choice. A convenience sample of 20 pediatric orthopaedic surgeons reviewed 40 case vignettes, including physis-blinded radiographs displaying displaced fractures and a description of the patient's sex, age, mechanism of injury, and predominant sport. Surgeons were asked whether they would treat the fracture operatively or nonoperatively. A mixed-effects model was then used to determine the patient attributes most likely to influence the surgeon's decision, as well as surgeon training background, years in practice, and risk-taking behavior. RESULTS: The majority of respondents selected operative treatment for 85% of the presented cases. The degree of fracture displacement was the only attribute significantly associated with treatment choice (P < .001). Surgeons were 28% more likely to treat the fracture operatively with each additional millimeter of displacement of fracture fragment. Over 64% of surgeons chose to treat operatively when the fracture fragment was displaced by ≥3.5 mm. Significant variation in surgeon's propensity for operative treatment of this fracture was observed (P = .01). Surgeon training, years in practice, and risk-taking scores were not associated with the respondent's preference for surgical treatment. CONCLUSION: There was substantial variation among pediatric orthopaedic surgeons when treating type II tibial spine fractures. The decision to operate was based on the degree of fracture displacement. Identifying current treatment preferences among surgeons given different patient factors can highlight current variation in practice patterns and direct efforts toward promoting the most optimal treatment strategies for controversial type II tibial spine fractures.

Timing of Pavlik Harness Initiation: Can We Wait?

BACKGROUND: Developmental dysplasia of the hip is effectively treated with a Pavlik harness (PH) within the first 6 months of life. Over 80% of unstable hips in the newborn period will naturally stabilize by 2 months of age. If there is no difference in the effectiveness of initiating PH treatment at 1 week compared with 4 weeks of age, waiting may allow the hips to naturally stabilize and avoid treatment. The purpose of this study is to evaluate whether the timing of PH implementation influences its effectiveness in the treatment of developmental dysplasia of the hip. METHODS: A retrospective review was conducted between 2004 and 2010. Patients were included if PH therapy was prescribed for hip instability or dislocation at or before 6 months of age. PH failure was defined as requiring any operative procedure for definitive management. Groups were divided based on the age at which the PH was initiated-group1=<30 days, group 2=30 to 60 days, group 3=>60 days. RESULTS: A total of 176 children were included with 38 (21.6%) failing PH treatment. The mean age at PH initiation was 1.3 months (SD=1.3) in the successfully treated children and 1.4 months (SD=1.2) in the failures (P=0.77). There was no difference in the failure rates by age with group 1=19.1% (18/94), group 2=22.5% (9/40), and group 3=26.2% (11/42) (P=0.87). There was no statistical difference with respect to sex or breech positioning in the success or failure groups; however, there was a higher percentage of bilateral involvement in the failure group (P=0.04). CONCLUSIONS: Patients who had PH initiation before 30 days of age were no more or less likely to fail than when PH was initiated after 30 days of age. Parents can be counseled that waiting until after 30 days of age is appropriate before PH implementation. By avoiding swaddling during this period, the hips may stabilize without treatment and allow for more parental-infant bonding before implementation of PH. LEVEL OF EVIDENCE: Level III-therapeutic, case control study.

Regulation of Cardiac Mast Cell Maturation and Function by the Neurokinin-1 Receptor in the Fibrotic Heart.

Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.

Pavlik Harness initiation on Barlow positive hips: Can we wait?

We investigated if infants with a Barlow positive hip(s) have natural hip stabilization and can thus avoid Pavlik Harness (PH) treatment. We conducted a chart review for infants who presented within two weeks of life, had a Barlow positive hip, and were deferred treatment. Of the thirty infants, eighteen were treated with PH at 4-6 weeks or 12 weeks due to persistent dysplasia. Twelve infants avoided PH entirely. There were zero cases of PH failure. Parents can be counseled that deferring treatment until at least 4-6 weeks of age might avoid treatment altogether without an increased risk of harness failure.

Substance P-mediated cardiac mast cell activation: An in vitro study.

The neuropeptide substance P can induce degranulation of cardiac mast cells at high concentrations. Herein, we seek to further understand substance P activation of cardiac mast cells in the context of other neuropeptides as well as modulation by non-neuropeptides. This is important given the increasingly recognized role of both cardiac mast cells and substance P in adverse cardiac remodeling. To address this, we isolated cardiac mast cells and compared their response to substance P as well as other members from the tachykinin family of peptides, including neurokinin A and hemokinin-1. We also tested the ability of other factors to manipulate the cardiac mast cell response to substance P. We found that while neurokinin A did not induce cardiac mast cell degranulation, both substance P and hemokinin-1 induced a concentration-dependent release of histamine; the maximal response to hemokinin-1 was greater than to substance P. Neurokinin-1 receptor blockade prevented substance P-induced histamine release, while only partially attenuating hemokinin-1-induced histamine release. The antioxidant N-acetylcysteine attenuated histamine release in response to hemokinin-1 and had no effect on substance P-induced histamine release. Selective PPAR-γ agonists attenuated histamine release in response to substance P. These data indicate that substance P activates cardiac mast cells via the neurokinin-1 receptor, and that the activation response is different to other tachykinins. That the response to substance P is receptor mediated and can be modulated by activation of other receptors (PPAR-γ), argues that substance P activation of cardiac mast cells has potential biological significance.

Recent advances in imaging and understanding interstitial cystitis.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition associated with intense pelvic pain and bladder storage symptoms. Since diagnosis is difficult, prevalence estimates vary with the methodology used. There is also a lack of proven imaging tools and biomarkers to assist in differentiation of IC/BPS from other urinary disorders (overactive bladder, vulvodynia, endometriosis, and prostatitis). Current uncertainty regarding the etiology and pathology of IC/BPS ultimately impacts its timely and successful treatment, as well as hampers future drug development. This review will cover recent developments in imaging methods, such as magnetic resonance imaging, that advance the understanding of IC/BPS and guide drug development.

Late Presentation of Developmental Hip Dislocation: A Case Report.

CASE: We describe a patient who was diagnosed with developmental hip dislocation at 21 months of age despite having had normal ultrasonography findings at 5 weeks of age. CONCLUSION: This case report provides evidence that late developmental hip dislocation can occur despite normal clinical and sonographic findings early in life, and that it is difficult to know the cause of developmental hip dislocation when it presents late.

What's New in Pediatric Orthopaedic Quality, Safety, and Value? A Systematic Review With Results of the 2016 POSNA Quality, Safety, and Value Initiative (QSVI) Challenge.

BACKGROUND: Enhancing the safety, quality, and value of care provided is a point of emphasis for modern health care systems. We performed a review of recent literature to highlight those efforts relevant to pediatric musculoskeletal care. METHODS: We searched the PubMed database for all papers related to quality improvement, patient safety, and/or value in pediatric orthopaedics published from October 1, 2012 to October 31, 2017, yielding 193 papers. RESULTS: A total of 36 papers were selected for review based upon new findings. Papers were selected based on significant contributions in the following categories: casting safety, antibiotic stewardship/infection prevention, perioperative care pathways, blood conservation, venous thromboembolic disease prevention, and imaging safety/appropriateness. CONCLUSIONS: There have been numerous advances in safety, quality, and value in pediatric orthopaedic care. Quality improvement efforts emphasizing provider education and safety monitoring can lead to a decrease in cast-related complications. Perioperative care pathways and bundles are associated with a decrease risk of surgical site infection and decreased length of stay in pediatric spinal deformity surgery. Increased scrutiny has been placed on the value of routine follow-up radiographs in pediatric fracture and spinal deformity care. LEVEL OF EVIDENCE: Level 4-literature review.

Novel contrast mixture achieves contrast resolution of human bladder wall suitable for T1 mapping: applications in interstitial cystitis and beyond.

PURPOSE: Instillation of novel contrast mixture (NCM) was recently shown to improve the contrast resolution of rat bladder wall with high contrast-to-noise ratio (CNR). Here, the clinical safety and the feasibility of NCM-enhanced MRI to achieve artifact-free visualization of human bladder wall suitable for quantitative measurement of the magnetic resonance (MR) longitudinal relaxation time (T1) was assessed. METHODS: Six female subjects [two controls and two with Hunner-type interstitial cystitis IC and two with non-Hunner-type IC] consented for MRI at 3 T before and after instillation of NCM [4 mM gadobutrol and 5 mM ferumoxytol in 50 mL of sterile water for injection]. Single breath-hold fast MR acquisition in large readout bandwidth for 5-mm-thick single slice with variable flip angle was applied to minimize the motion and chemical shift artifacts in measurements of bladder wall thickness (BWT), CNR and T1 from 20 pixels. RESULTS: NCM instillation in subjects did not evoke pain or discomfort. Fourfold increase in bladder wall CNR (*p < 0.02) and pixel size of 0.35 mm with minimal influence of artifacts allowed accurate determination of bladder wall thinning ~ 0.46 mm from 50 mL NCM (*p < 0.05). Pre-contrast bladder wall T1 of 1544 ± 34.2 ms was shortened to 860.09 ± 13.95 ms in Hunner-type IC (*p < 0.0001) relative to only 1257.42 ± 20.59 and 1258.16 ± 6.16 ms in non-Hunner-type IC and controls, respectively. CONCLUSION: Findings demonstrate the safety and feasibility of NCM-enhanced MRI to achieve artifact-free differential contrast and spatial resolution of human bladder wall, which is suitable for measuring BWT and pixel-wise measurement of T1 in post-contrast setting.

Development of an interstitial cystitis risk score for bladder permeability.

BACKGROUND: Interstitial cystitis/bladder pain syndrome (IC) is a multifactorial syndrome of severe pelvic and genitalia pain and compromised urinary function; a subset of IC patients present with Hunner's lesions or ulcers on their bladder walls (UIC). UIC is diagnosed by cystoscopy, which may be quite painful. The objective of this study was to determine if a calculated Bladder Permeability Defect Risk Score (BP-RS) based on non-invasive urinary cytokines could discriminate UIC patients from controls and IC patients without Hunner's ulcers. METHODS: A national crowdsourcing effort targeted IC patients and age-matched controls to provide urine samples. Urinary cytokine levels for GRO, IL-6, and IL-8 were determined using a Luminex assay. RESULTS: We collected 448 urine samples from 46 states consisting of 153 IC patients (147 female, 6 male), of which 54 UIC patients (50 females, 4 male), 159 female controls, and 136 male controls. A defined BP-RS was calculated to classify UIC, or a bladder permeability defect etiology, with 89% validity. CONCLUSIONS: The BP-RS Score quantifies UIC risk, indicative of a bladder permeability defect etiology in a subset of IC patients. The Bladder Permeability Defect Risk Score is the first validated urine biomarker assay for interstitial cystitis/bladder pain syndrome.

Novel contrast mixture improves bladder wall contrast for visualizing bladder injury.

Here, we tested whether combined contrast-enhanced magnetic resonance imaging (CCE-MRI), using a mixture of gadolinium- and iron oxide-based contrast agents, can segment the bladder wall from the bladder lumen. CCE-MRI relies on the differences in particle size and contrast mechanisms of two agents for improved image contrast. Under isoflurane anesthesia, T1-weighted imaging of adult female Sprague-Dawley rat bladder was performed using standard turbospin echo sequences at 7 Tesla, before and after transurethral instillation of 0.3 ml of single-contrast MRI or CCE-MRI composed of 0.4-64 mM of gadolinium chelate (Gd-DTPA/Gadavist) and 5 mM ferumoxytol. Bladder wall contrast was assessed in the control group exposed to saline and in the bladder injury group exposed to 0.5 ml of protamine sulfate (10 mg/ml) for 30 min. CCE-MRI following instillation of 0.4-4 mM Gd-DTPA and 5 mM ferumoxytol mixture achieved segmentation between the bladder lumen and bladder wall. Hyperintensity in the bladder wall combined with hypointensity in the lumen is consistent with the increased diffusion of the dissolved Gd-DTPA and simultaneous localization of the larger nanoparticles of ferumoxytol in the lumen. The normalized hyperintense signal in the bladder wall increased from 0.46 ± 0.07 in control group to 0.73 ± 0.14 in the protamine sulfate-exposed group (P < 0.0001). CCE-MRI following instillation of contrast mixture identifies bladder wall changes likely associated with bladder injury with improved image contrast.

Vitamin D Insufficiency and Fracture Risk in Urban Children.

BACKGROUND: Investigation into the role of vitamin D in fractures in the pediatric population has been limited despite estimates that as many as 70% of American children have inadequate vitamin D levels (measured as 25-hydroxyvitamin D, 25(OH)D). The purpose of this study was to evaluate vitamin D's role in pediatric fracture risk by comparing 25(OH)D between fractured and nonfractured cohorts. METHODS: A 12-month prospective case-control study was completed in children aged 2 to 14 years in an urban, academic hospital. Sixty fractured children requiring conscious sedation or general anesthesia for management were compared with 60 nonfractured controls. All participants and their guardians were surveyed for low bone density risk factors, and total serum 25(OH)D was measured. Statistical analysis was completed using Student t tests, χ tests, analysis of variance, and logistic regression models. RESULTS: After controlling for age and daily sun exposure, lower total serum 25(OH)D was associated with higher fracture risk (odds ratio=0.94; 95% confidence interval, 0.90-0.99; P=0.023). In the fractured cohort, 6 (10%) patients were deficient (25(OH)D<20 ng/mL) and 33 (55%) were insufficient (25(OH)D, 20 to 30 ng/mL). Of the nonfractured population, 8 (13%) were deficient and 19 (32%) were insufficient. There were more insufficient patients in the fractured than in the nonfractured cohort (odds ratio=2.99; 95% confidence interval, 1.27-7.0; P=0.037). CONCLUSIONS: Higher fracture incidence is associated with serum 25(OH)D insufficiency. Hypovitaminosis D may place the pediatric population at increased risk for fracture. Consideration should be given to routine assessment of vitamin D in fractured children. LEVEL OF EVIDENCE: Prognostic level III-prospective case-control study.