Part II: Effect of different evaluation methods to the application of a computer-aided prostate MRI detection/diagnosis (CADe/CADx) device on reader performance.

INTRODUCTION: The construction and results of a multiple-reader multiple-case prostate MRI study are described and reported to illustrate recommendations for how to standardize artificial intelligence (AI) prostate studies per the review constituting Part I1. METHODS: Our previously reported approach was applied to review and report an IRB approved, HIPAA compliant multiple-reader multiple-case clinical study of 150 bi-parametric prostate MRI studies across 9 readers, measuring physician performance both with and without the use of the recently FDA cleared CADe/CADx software ProstatID. RESULTS: Unassisted reader AUC values ranged from 0.418 - 0.759, with AI assisted AUC values ranging from 0.507 - 0.787. This represented a statistically significant AUC improvement of 0.045 (α = 0.05). A free-response ROC (FROC) analysis similarly demonstrated a statistically significant increase in θ from 0.405 to 0.453 (α = 0.05). The standalone performance of ProstatID performed across all prostate tissues demonstrated an AUC of 0.929, while the standalone lesion level performance of ProstatID at all biopsied locations achieved an AUC of 0.710. CONCLUSION: This study applies and illustrates suggested reporting and standardization methods for prostate AI studies that will make it easier to understand, evaluate and compare between AI studies. Providing radiologists with the ProstatID CADe/CADx software significantly increased diagnostic performance as assessed by both ROC and free-response ROC metrics. Such algorithms have the potential to improve radiologist performance in the detection and localization of clinically significant prostate cancer.

Part I: prostate cancer detection, artificial intelligence for prostate cancer and how we measure diagnostic performance: a comprehensive review.

MRI has firmly established itself as a mainstay for the detection, staging and surveillance of prostate cancer. Despite its success, prostate MRI continues to suffer from poor inter-reader variability and a low positive predictive value. The recent emergence of Artificial Intelligence (AI) to potentially improve diagnostic performance shows great potential. Understanding and interpreting the AI landscape as well as ever-increasing research literature, however, is difficult. This is in part due to widely varying study design and reporting techniques. This paper aims to address this need by first outlining the different types of AI used for the detection and diagnosis of prostate cancer, next deciphering how data collection methods, statistical analysis metrics (such as ROC and FROC analysis) and end points/outcomes (lesion detection vs. case diagnosis) affect the performance and limit the ability to compare between studies. Finally, this work explores the need for appropriately enriched investigational datasets and proper ground truth, and provides guidance on how to best conduct AI prostate MRI studies. Published in parallel, a clinical study applying this suggested study design was applied to review and report a multiple-reader multiple-case clinical study of 150 bi-parametric prostate MRI studies across nine readers, measuring physician performance both with and without the use of a recently FDA cleared Artificial Intelligence software.1.

Prototype Description and Ex Vivo Evaluation of a System for Combined Endorectal Magnetic Resonance Imaging and In-Bore Biopsy of the Prostate.

ABSTRACT: We describe early ex vivo proof-of-concept testing of a novel system composed of a disposable endorectal coil and converging multichannel needle guide with a reusable clamp stand, embedded electronics, and baseplate to allow for endorectal magnetic resonance (MR) imaging and in-bore MRI-targeted biopsy of the prostate as a single integrated procedure. Using prostate phantoms imaged with standard T 2 -weighted sequences in a Siemens 3T Prisma MR scanner, we measured the signal-to-noise ratio in successive 1-cm distances from the novel coil and from a commercially available inflatable balloon coil and measured the lateral and longitudinal deviation of the tip of a deployed MR compatible needle from the intended target point. Signal-to-noise ratio obtained with the novel system was significantly better than the inflatable balloon coil at each of five 1-cm intervals, with a mean improvement of 78% ( P < 0.05). In a representative sampling of 15 guidance channels, the mean lateral deviation for MR imaging-guided needle positioning was 1.7 mm and the mean longitudinal deviation was 2.0 mm. Our ex vivo results suggest that our novel system provides significantly improved signal-to-noise ratio when compared with an inflatable balloon coil and is capable of accurate MRI-guided needle deployment.

Veteran Engagement in Survey Research to Prevent Suicide.

Suicide rates among veterans remain high, underscoring the necessity of identifying modifiable suicide risk and protective factors that can be targeted through public health approaches. One way to ensure that survey-based research yields information necessary to translate findings into patient-centered interventions is through veteran engagement. The current manuscript describes perspectives of members of a national Veterans Engagement Board (VEB) in contributing to the Assessing Social and Community Environments with National Data (ASCEND) for Veteran Suicide Prevention project. Contributions have included strengthening communication with potential veteran participants, addressing sensitive survey topics such as firearms and suicide, and ensuring that ASCEND is responsive to current national and global events. Additionally, Veterans Engagement Board members described the personal impact of engagement. These contributions highlight the value of veteran engagement as an integral component of suicide risk and prevention research.

Improving Prostate Cancer Detection With MRI: A Multi-Reader, Multi-Case Study Using Computer-Aided Detection (CAD).

RATIONALE AND OBJECTIVES: To evaluate whether addition of a computer-aided diagnostic (CAD) generated MRI series improves detection of clinically significant prostate cancer. MATERIALS AND METHODS: Nine radiologists retrospectively interpreted 150 prostate MRI examinations without and then with an additional random forest-based CAD model-generated MRI series. Characteristics of biopsy negative versus positive (Gleason ≥ 7 adenocarcinoma) groups were compared using the Wilcoxon test for continuous and Pearson's chi-squared test for categorical variables. The diagnostic performance of readers was compared without versus with CAD using MRMC methods to estimate the area under the receiver operator characteristic curve (AUC). Inter-reader agreement was assessed using weighted inter-rater agreement statistics. Analyses were repeated in peripheral and transition zone subgroups. RESULTS: Among 150 men with median age 67 ± 7.4 years, those with clinically significant prostate cancer were older (68 ± 7.6 years vs. 66 ± 7.0 years; p < .02), had smaller prostate volume (43.9 mL vs. 60.6 mL; p < .001), and no difference in prostate specific antigen (PSA) levels (7.8 ng/mL vs. 6.9 ng/mL; p = .08), but higher PSA density (0.17 ng/mL/cc vs. 0.10 ng/mL/cc; p < .001). Inter-rater agreement (IRA) for PI-RADS scores was moderate without CAD and significantly improved to substantial with CAD (IRA = 0.47 vs. 0.65; p < .001). CAD also significantly improved average reader AUC (AUC = 0.72, vs. AUC = 0.67; p = .02). CONCLUSION: Addition of a random forest method-based, CAD-generated MRI image series improved inter-reader agreement and diagnostic performance for detection of clinically significant prostate cancer, particularly in the transition zone.

Spheno-orbital Lesions-A Major Review of Nonmeningioma Causes.

PURPOSE: To review the imaging features of the broad range of nonmeningioma lesions of the greater wing of the sphenoid (GWS) bone and adjacent orbit to assist clinicians in differentiating these lesions from each other and from the most common lesion of the GWS and adjacent orbit, meningioma. METHODS: We reviewed 32 cases of spheno-orbital lesions involving the GWS from our own practice, as well as 109 published cases (total 141), with emphasis on available imaging features on computerized tomography (CT) and MRI. Features that might assist in differentiating meningioma from its mimics were analyzed for each lesion, including the presence of an osteoblastic or hyperostotic response, bone erosion or osteolysis, homogeneous hypo- or hyperintensity on T2-weighted MRI, leptomeningeal involvement, and the absence of a "dural tail" on contrast-enhanced MRI. The clinical and imaging features were also briefly summarized for each diagnostic group. RESULTS: The largest diagnostic group was metastasis (67 cases, 47.5%). The most useful imaging features that helped differentiate meningioma from its mimics were the presence of bone erosion and the absence of a "dural tail." Other features were helpful in a small minority of cases only. Metastatic prostate cancer was the largest single group (21 cases), and 18 (85.7%) of these were osteoblastic and most closely mimicked meningioma. Prostate cancer patients were generally older than males with GWS meningioma. Almost all other (44/46, or 95.7%) metastatic lesions showed evidence of bone erosion. Almost half (30 of 61, 49.2%) of patients with metastasis presented without a known diagnosis of malignancy. Among children 16 years of age and less, Langerhans cell histiocytosis (10 cases), dermoid cyst (5), and Ewing's sarcoma (5) were the most common diagnoses. CONCLUSIONS: A combination of a careful history and both CT and MRI gives information, which can best guide the management of patients with spheno-orbital lesions. Metastatic prostate cancer to the GWS most closely mimics GWS meningioma but can in most cases be differentiated on clinical and imaging features. Older males with hyperostotic lesions of the GWS should be investigated for prostate cancer. Other metastatic lesions and primary tumors of the GWS, as well as benign and structural lesions can readily be differentiated from meningioma on clinical and imaging features.

Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis.

BACKGROUND: B cells are critical mediators of systemic lupus erythematosus (SLE) and lupus nephritis (LN), and antinuclear antibodies can be found in the serum of approximately 98% of patients with SLE. Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase that mediates signaling from immunoreceptors, including the B cell receptor. Active, phosphorylated SYK has been observed in tissues from patients with SLE or cutaneous lupus erythematosus, and its inhibition is hypothesized to ameliorate disease pathogenesis. We sought to evaluate the efficacy and characterize the mechanism of action of lanraplenib, a selective oral SYK inhibitor, in the New Zealand black/white (NZB/W) murine model of SLE and LN. METHODS: Lanraplenib was evaluated for inhibition of primary human B cell functions in vitro. Furthermore, the effect of SYK inhibition on ameliorating LN-like disease in vivo was determined by treating NZB/W mice with lanraplenib, cyclophosphamide, or a vehicle control. Glomerulopathy and immunoglobulin G (IgG) deposition were quantified in kidneys. The concentration of proinflammatory cytokines was measured in serum. Splenocytes were analyzed by flow cytometry for B cell maturation and T cell memory maturation, and the presence of T follicular helper and dendritic cells. RESULTS: In human B cells in vitro, lanraplenib inhibited B cell activating factor-mediated survival as well as activation, maturation, and immunoglobulin M production. Treatment of NZB/W mice with lanraplenib improved overall survival, prevented the development of proteinuria, and reduced blood urea nitrogen concentrations. Kidney morphology was significantly preserved by treatment with lanraplenib as measured by glomerular diameter, protein cast severity, interstitial inflammation, vasculitis, and frequency of glomerular crescents; treatment with lanraplenib reduced glomerular IgG deposition. Mice treated with lanraplenib had reduced concentrations of serum proinflammatory cytokines. Lanraplenib blocked disease-driven B cell maturation and T cell memory maturation in the spleen. CONCLUSIONS: Lanraplenib blocked the progression of LN-like disease in NZB/W mice. Human in vitro and murine in vivo data suggest that lanraplenib may be efficacious in preventing disease progression in patients with LN at least in part by inhibiting B cell maturation. These data provide additional rationale for the use of lanraplenib in the treatment of SLE and LN.

Development of a virtual reality clinically oriented temporal bone anatomy module with randomised control study of three-dimensional display technology.

Objective: To investigate the effectiveness of a virtual reality (VR), three-dimensional (3D) clinically orientated temporal bone anatomy module, including an assessment of different display technologies. Methods: A clinically orientated, procedural and interactive anatomy module was generated from a micro-CT of a cadaveric temporal bone. The module was given in three different display technologies; 2D, 3D with monoscopic vision, and 3D with stereoscopic vision. A randomised control trial assessed the knowledge acquisition and attitudes of 47 medical students though a pretutorial and post-tutorial questionnaire. The questionnaire included questions identifying anatomic structures as well as understanding structural relations and clinical relevance. Furthermore, a five-point Likert scale assessed the students' attitudes to the module and alternative learning outcomes, such as interest in otology and preparedness for clinical rotations. Results: As a whole cohort, the total test score improved significantly, with a large effect size (p≤0.005, Cohen's d=1.41). The 23 students who returned the retention questionnaire had a significant improvement in total test score compared with their pretutorial score, with a large effect size (p≤0.005, Cohen's d=0.83). Display technology did not influence the majority of learning outcomes, with the exception of 3D technologies, showing a significantly improvement in understanding of clinical relevance and structural relations (p=0.034). Students preferred 3D technologies for ease of use, perceived effectiveness and willingness to use again. Conclusions: The developed VR temporal bone anatomy tutor was an effective self-directed education tool. 3D technology remains valuable in facilitating spatial learning and superior user satisfaction.

Discovery of Lanraplenib (GS-9876): A Once-Daily Spleen Tyrosine Kinase Inhibitor for Autoimmune Diseases.

Spleen tyrosine kinase (SYK) is a critical regulator of signaling in a variety of immune cell types such as B-cells, monocytes, and macrophages. Accordingly, there have been numerous efforts to identify compounds that selectively inhibit SYK as a means to treat autoimmune and inflammatory diseases. We previously disclosed GS-9973 (entospletinib) as a selective SYK inhibitor that is under clinical evaluation in hematological malignancies. However, a BID dosing regimen and drug interaction with proton pump inhibitors (PPI) prevented development of entospletinib in inflammatory diseases. Herein, we report the discovery of a second-generation SYK inhibitor, GS-9876 (lanraplenib), which has human pharmacokinetic properties suitable for once-daily administration and is devoid of any interactions with PPI. Lanraplenib is currently under clinical evaluation in multiple autoimmune indications.

Short Peripheral Catheter Quality and Economics: The Intravenous Quotient.

Peripheral intravenous therapy is an established therapy with known complications and failures. The burden of the cost of unsuccessful short peripheral catheter (SPC) placement and maintenance is not always clearly identified. This often-obscured cost of poor quality needs to be defined and addressed. The scope of the problem is defined here, and a metric that can be applied to measure the magnitude of the problem and identify targets for focused improvement initiatives that would improve the quality of infusion therapy using SPCs is proposed.

Expected Net Benefit of Vaccinating Rangeland Sheep against Bluetongue Virus Using a Modified-Live versus Killed Virus Vaccine.

Recurring outbreaks of bluetongue virus in domestic sheep of the US Intermountain West have prompted questions about the economic benefits and costs of vaccinating individual flocks against bluetongue (BT) disease. We estimate the cost of a BT outbreak on a representative rangeland sheep operation in the Big Horn Basin of the state of Wyoming using enterprise budgets and stochastic simulation. The latter accounts for variability in disease severity and lamb price, as well as uncertainty about when an outbreak will occur. We then estimate the cost of purchasing and administering a BT vaccine. Finally, we calculate expected annual net benefit of vaccinating under various outbreak intervals. Expected annual net benefit is calculated for both a killed virus (KV) vaccine and modified-live virus vaccine, using an observed price of $0.32 per dose for modified-live and an estimated price of $1.20 per dose for KV. The modified-live vaccine's expected annual net benefit has a 100% chance of being positive for an outbreak interval of 5, 10, or 20 years, and a 77% chance of being positive for a 50-year interval. The KV vaccine's expected annual net benefit has a 97% chance of being positive for a 5-year outbreak interval, and a 42% chance of being positive for a 10-year interval. A KV vaccine is, therefore, unlikely to be economically attractive to producers in areas exposed less frequently to BT disease. A modified-live vaccine, however, requires rigorous authorization before legal use can occur in Wyoming. To date, no company has requested to manufacture a modified-live vaccine for commercial use in Wyoming. The KV vaccine poses less risk to sheep reproduction and less risk of unintentional spread, both of which facilitate approval for commercial production. Yet, our results show an economically consequential tradeoff between a KV vaccine's relative safety and higher cost. Unless the purchase price is reduced below our assumed $1.20 per dose, producer adoption of a KV vaccine for BT is likely to be low in the study area. This tradeoff between cost and safety should be considered when policymakers regulate commercial use of the two vaccine types.

Cortical functioning in children with developmental coordination disorder: a motor overflow study.

This study examined brain activation in children with developmental coordination disorder (DCD) to reveal areas that may contribute to poor movement execution and/or abundant motor overflow. Using functional magnetic resonance imaging, 13 boys with DCD (mean age = 9.6 years ±0.8) and 13 typically developing controls (mean age = 9.3 years ±0.6) were scanned performing two tasks (finger sequencing and hand clenching) with their dominant hand, while a four-finger motion sensor recorded contralateral motor overflow on their non-dominant hand. Despite displaying increased motor overflow on both functional tasks during scanning, there were no obvious activation deficits in the DCD group to explain the abundant motor overflow seen. However, children with DCD were found to display decreased activation in the left superior frontal gyrus on the finger-sequencing task, an area which plays an integral role in executive and spatially oriented processing. Decreased activation was also seen in the left inferior frontal gyrus, an area typically active during the observation and imitation of hand movements. Finally, increased activation in the right postcentral gyrus was seen in children with DCD, which may reflect increased reliance on somatosensory information during the execution of complex fine motor tasks.

Early adolescent Body Mass Index and the constructed environment.

Previous research has shown that macro-level environmental features such as access to walking trails and recreational facilities are correlated with adolescent weight. Additionally, a handful of studies have documented relationships between micro-level environmental features, such as the presence (or absence) of a television in the bedroom, and adolescent weight. In this exploratory study we focus exclusively on features of the micro-level environment by examining objects that are found within adolescent personal bedrooms in relation to the adolescent occupant's Body Mass Index score (BMI). Participants were 234 early adolescents (eighth graders and ninth graders) who lived with both biological parents and who had their own private bedroom. Discriminant analyses were used to identify the bedrooms belonging to adolescents with below and above average BMI using objects contained within the micro-level environment as discriminating variables. Bedrooms belonging to adolescents with above average BMI were more likely to contain objects associated with sedentary behavior (e.g., magazines, electronic games, dolls), whereas the bedrooms belonging to the average and below average BMI adolescents were more likely to contain objects that reflect past physical activity (e.g., trophies, souvenirs, pictures of places that they had visited). If causal connections between micro-environmental variables and adolescent BMI can be established in future longitudinal research, environmental manipulations may affect adolescent BMI.

Initial clinical experience with the Coherex FlatStent™ and FlatStent™ EF PFO closure system for in-tunnel PFO closure: results of the Coherex-EU study.

OBJECTIVE: The Coherex-EU Study evaluated the safety and efficacy of PFO closure utilizing novel in-tunnel PFO closure devices. BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) followed the development of transcatheter closure devices designed to patch atrial septal defects (ASDs). The Coherex FlatStent™ and FlatStent™ EF devices were designed specifically to treat PFO anatomy. METHODS: A total of 95 patients with a clinical indication for PFO closure were enrolled in a prospective, multicenter first in man study at six clinical sites. Thirty-six patients received the first-generation FlatStent study device, and 57 patients received the second-generation FlatStent EF study device, which was modified based on clinical experience during the first 38 cases. Two patients enrolled to receive the first generation did not receive a device. RESULTS: At 6 months post-procedure, 45% (17/38) of the intention-to-treat (ITT) cohort receiving the first-generation FlatStent device had complete closure, 26% (10/38) had a trivial residual shunt, and 29% (11/38) had a moderate to large residual shunt. In the ITT cohort receiving the second-generation FlatStent EF device, 76% (43/57) had complete closure, 12% (7/57) had a trivial shunt, and 12% had a moderate to large shunt. Five major adverse events occurred, all without sequelae. CONCLUSION: This initial study of the Coherex FlatStent/FlatStent EF PFO Closure System demonstrated the potential for in-tunnel PFO closure. The in-tunnel Coherex FlatStent EF may offer an alternative to septal repair devices for PFO closure in appropriately selected patients; however, further investigation will be necessary to establish the best use of this device.

Central nervous system and head and neck imaging findings of MYC/BCL2 "double hit" B cell lymphoma.

MYC/BCL2 double hit lymphoma (DHL) is a rare, recently recognised and highly aggressive subtype of non-Hodgkin lymphoma, with an affinity to involve the central nervous system and the head and neck either at initial presentation or during relapse. We present a case of 43-year-old woman with MYC/BCL2 DHL relapse in the nasopharynx with extensive spread to the neck, skull base, and the central nervous system. To our knowledge, this is the first reported case in the literature describing the MRI and CT scan findings and the profound pattern of disease involvement of this rare neoplasm.

Texting and accessing the web while driving: traffic citations and crashes among young adult drivers.

OBJECTIVE: We examined relations between young adult texting and accessing the web while driving with driving outcomes (viz. crashes and traffic citations). Our premise is that engaging in texting and accessing the web while driving is not only distracting but that these activities represent a pattern of behavior that leads to an increase in unwanted outcomes, such as crashes and citations. METHODS: College students (N = 274) on 3 campuses (one in California and 2 in Utah) completed an electronic questionnaire regarding their driving experience and cell phone use. RESULTS: Our data indicate that 3 out of 4 (74.3%) young adults engage in texting while driving, over half on a weekly basis (51.8%), and some engage in accessing the web while driving (16.8%). Data analysis revealed a relationship between these cell phone behaviors and traffic citations and crashes. CONCLUSION: The findings support Jessor and Jessor's (1977) "problem behavior syndrome" by showing that traffic citations are related to texting and accessing the web while driving and that crashes are related to accessing the web while driving. Limitations and recommendations are discussed.

Specific Btk inhibition suppresses B cell- and myeloid cell-mediated arthritis.

Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1ß and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.

Percutaneous closure of patent foramen ovale with a novel FlatStent.

Patent foramen ovale (PFO) is a congenital, small tunnel-like connection between the right and left atria that usually closes spontaneously after birth. However, frequently (in up to 35% of the normal population) it persists into adulthood. It is associated with 'paradoxical' embolism from the venous to the arterial system and may result in stroke or peripheral embolism. One prophylactic treatment option is transcatheter closure of the PFO. Currently available closure devices extend into both atria and therefore occasionally cause complications, such as thrombus formation or erosion of adjacent structures. The Coherex FlatStent is a flat, self-expanding stent that is designed to be positioned within the PFO tunnel. It is a very small, low-mass device that minimizes the amount of implanted foreign material to reduce the risk of device-related complications. This article focuses on the anatomy of PFOs and compares the Coherex FlatStent with currently available and experimental PFO closure devices.

Bedroom design and decoration: gender differences in preference and activity.

This investigation examined gender differences in niche-building preference and activity among 238 8th and 9th grade boys and girls. A questionnaire was developed to measure both the actual and preferred bedroom content, bedroom design activity, and the level of perceived influence by the immediate and extended family, friends, and social institutions. Gender differences were identified for preference, activity, and influence in bedroom design and decoration. Girls and boys differed in the type of items contained in their bedrooms. Girls' rooms contained stuffed animals and pictures of people, including themselves, more frequently than the boys' rooms. In contrast, boys' rooms contained sports-related items, and things for building or that they had built themselves. Although bedroom design activity for both boys and girls was influenced by older teens, friends, media, and popular culture, boys (but not girls) were also influenced by their mothers, fathers, girlfriends, and activities such as sports, Boy or Girl Scouts, and music lessons.