Deep-Learning-Based Artificial Intelligence for PI-RADS Classification to Assist Multiparametric Prostate MRI Interpretation: A Development Study.

BACKGROUND: The Prostate Imaging Reporting and Data System (PI-RADS) provides guidelines for risk stratification of lesions detected on multiparametric MRI (mpMRI) of the prostate but suffers from high intra/interreader variability. PURPOSE: To develop an artificial intelligence (AI) solution for PI-RADS classification and compare its performance with an expert radiologist using targeted biopsy results. STUDY TYPE: Retrospective study including data from our institution and the publicly available ProstateX dataset. POPULATION: In all, 687 patients who underwent mpMRI of the prostate and had one or more detectable lesions (PI-RADS score >1) according to PI-RADSv2. FIELD STRENGTH/SEQUENCE: T2 -weighted, diffusion-weighted imaging (DWI; five evenly spaced b values between b = 0-750 s/mm2 ) for apparent diffusion coefficient (ADC) mapping, high b-value DWI (b = 1500 or 2000 s/mm2 ), and dynamic contrast-enhanced T1 -weighted series were obtained at 3.0T. ASSESSMENT: PI-RADS lesions were segmented by a radiologist. Bounding boxes around the T2 /ADC/high-b value segmentations were stacked and saved as JPEGs. These images were used to train a convolutional neural network (CNN). The PI-RADS scores obtained by the CNN were compared with radiologist scores. The cancer detection rate was measured from a subset of patients who underwent biopsy. STATISTICAL TESTS: Agreement between the AI and the radiologist-driven PI-RADS scores was assessed using a kappa score, and differences between categorical variables were assessed with a Wald test. RESULTS: For the 1034 detection lesions, the kappa score for the AI system vs. the expert radiologist was moderate, at 0.40. However, there was no significant difference in the rates of detection of clinically significant cancer for any PI-RADS score in 86 patients undergoing targeted biopsy (P = 0.4-0.6). DATA CONCLUSION: We developed an AI system for assignment of a PI-RADS score on segmented lesions on mpMRI with moderate agreement with an expert radiologist and a similar ability to detect clinically significant cancer. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

HARNESSING SOCIAL MEDIA FOR HEALTH INFORMATION MANAGEMENT.

The remarkable upsurge of social media has dramatic impacts on health care research and practice in the past decade. Social media are reshaping health information management in a variety of ways, ranging from providing cost-effective ways to improve clinician-patient communication and exchange health-related information and experience, to enabling the discovery of new medical knowledge and information. Despite some demonstrated initial success, social media use and analytics for improving health as a research field is still at its infancy. Information systems researchers can potentially play a key role in advancing the field. This study proposes a conceptual framework for social media-based health information management by drawing on multi-disciplinary research. With the guidance of the framework, this research presents related research challenges, identifies important yet under-explored research issues, and discusses promising directions for future research.

Can Telemedicine Improve Adherence to Resuscitation Guidelines for Critically Ill Children at Community Hospitals? A Randomized Controlled Trial Using High-Fidelity Simulation.

OBJECTIVES: Children transferred from community hospitals lacking specialized pediatric care are more seriously ill than those presenting to pediatric centers. Pediatric consultation and adherence to management guidelines improve outcomes. The aims of the study were (1) to assess whether telemedicine consultation in critical situations is feasible and (2) to compare the impact of pediatric critical care medicine (PCCM) consultation via telemedicine versus telephone on community hospital adherence to resuscitation guidelines through a randomized controlled telemedicine trial. METHODS: In situ, high-fidelity simulation scenarios of critically ill children presenting to a community hospital and progressing to cardiopulmonary arrest were performed. Scenarios were randomized to PCCM consultation via telephone (control) or telemedicine (intervention). Primary outcome measure was proportion of teams who successfully defibrillated in 180 seconds or less from presentation of pulseless ventricular tachycardia. RESULTS: The following 30 scenarios were completed: 15 control and 15 intervention. Only 11 (37%) of 30 teams, defibrillated in 180 seconds or less from presentation of pulseless ventricular tachycardia; control: 6 (40%) of 15 versus intervention: 5 (33%) of 15, P = 0.7. Request for or use of backboard during cardiopulmonary resuscitation occurred in 24 (80%) of 30 scenarios; control: 9 (60%) of 15 versus intervention: 15 (100%) of 15, P = 0.006. Request for or use of stepstool during cardiopulmonary resuscitation occurred in 6 (20%) of 30 scenarios; control: 1 (7%) of 15 versus intervention: 5 (33%) of 15, P = 0.07. CONCLUSIONS: This study demonstrates the feasibility of using telemedicine to support acute management of children who present to community hospitals. Neither study arm adhered to current resuscitation guidelines and telemedicine consultation with PCCM experts was not associated with improvement. However, further research on optimizing telemedicine impact on the quality of pediatric care at community hospitals is warranted.

The reduction corporoplasty: the answer to the improbable urologic question "can you make my penis smaller?".

INTRODUCTION: Aneurysmal dilatation of the corpora cavernosa can occur because of recurrent priapism in the setting of sickle cell disease. AIM: We present the first case of a successful implementation of the reduction corporoplasty technique for treatment of a phallus that was "too large for intercourse." METHODS: We describe the presentation of a 17-year-old male with a history of sickle cell disease with a phallus "too large for intercourse." Patient reported normal erectile function and response with masturbation but also reported inability to penetrate his partner due to the enlarged and disfigured morphology. He had three priapismic episodes since the age of 10 that progressively led to an aneurysmal morphologic deformity of his phallus. Evaluation included a magnetic resonance imaging, which revealed true aneurysmal dilatation of bilateral corpora cavernosa in the middle and distal portions, and diffusely hyperplastic tunica. MAIN OUTCOME MEASURE: The main outcome measure is the successful management of phallic disfiguration. RESULTS: Reduction corporoplasty was performed, and the patient reported intact erectile function without aneurysmal recurrence. CONCLUSIONS: Patients with significant corporal aneurysmal defects secondary to recurrent priapism can be successfully managed with reduction corporoplasty.

Preclinical characterization of the novel hepatitis C virus NS3 protease inhibitor GS-9451.

GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50 = 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.

"ABC-SBAR" training improves simulated critical patient hand-off by pediatric interns.

OBJECTIVES: This study was done to assess whether a modified "ABC-SBAR" mnemonic (airway, breathing, circulation followed by situation, background, assessment, and recommendation) improves hand-offs by pediatric interns in a simulated critical patient scenario. METHODS: Each of 26 interns reviewed a scenario involving a decompensating pediatric patient and gave a simulated hand-off to a responder. They received a didactic session on ABC-SBAR, then performed a second hand-off using another scenario. Two blinded reviewers assessed 52 video-recorded hand-offs for inclusion, order, and elapsed time to essential hand-off information using a scoring tool. RESULTS: Mean score of hand-offs increased after ABC-SBAR training (preintervention: 3.1/10 vs postintervention: 7.8/10, P < 0.001). In hand-offs after ABC-SBAR training, the reason for the emergency call was more often prioritized before background information (preintervention: 4% vs postintervention: 81%, P < 0.001) and stated earlier (elapsed time preintervention: 19 seconds vs postintervention: 7 seconds, P < 0.001). Hand-offs including an airway or breathing assessment increased after training (preintervention: 35% vs postintervention: 85%, P = 0.001), and this information was also stated earlier (preintervention: 25 seconds vs postintervention: 5 seconds, P < 0.001). Total hand-off duration was increased (preintervention: 29 seconds vs postintervention: 36 seconds, P = 0.004). CONCLUSIONS: Unstructured hand-off by interns in a simulated patient emergency emphasizes background information, leaving essential information (such as reason for the call and ABCs) delayed or omitted. ABC-SBAR was associated with improved inclusion and timeliness of essential information in simulated critical patient hand-offs by pediatric interns; however, hand-off duration was increased. Further studies are needed to elucidate optimal hand-off in an emergency situation.

Delayed Presentations and Worse Outcomes After Aneurysmal Subarachnoid Hemorrhage in the Early COVID-19 Era.

BACKGROUND: The early phase of the COVID-19 pandemic led to significant healthcare avoidance, perhaps explaining some of the excess reported deaths that exceeded known infections. The impact of the early COVID-19 era on aneurysmal subarachnoid hemorrhage (aSAH) care remains unclear. OBJECTIVE: To determine the impact of the early phase of the COVID-19 pandemic on latency to presentation, neurological complications, and clinical outcomes after aSAH. METHODS: We performed a retrospective cohort study from March 2, 2012, to June 30, 2021, of all patients with aSAH admitted to our center. The early COVID-19 era was defined as March 2, 2020, through June 30, 2020. The pre-COVID-19 era was defined as the same interval in 2012 to 2019. RESULTS: Among 499 patients with aSAH, 37 presented in the early COVID-19 era. Compared with the pre-COVID-19 era patients, patients presenting during this early phase of the pandemic were more likely to delay presentation after ictus (median, interquartile range; 1 [0-4] vs 0 [0-1] days, respectively, P < .001). Radiographic-delayed cerebral ischemia (29.7% vs 10.2%, P < .001) was more common in the early COVID-19 era. In adjusted analyses, presentation in the early COVID-19 era was independently associated with increased inhospital death or hospice disposition (adjusted odds ratio 3.29 [1.02-10.65], P = .046). Both latency and adverse outcomes returned to baseline in 2021. CONCLUSION: aSAH in the early COVID-19 era was associated with delayed presentation, neurological complications, and worse outcomes at our center. These data highlight how healthcare avoidance may have increased morbidity and mortality in non-COVID-19-related neurosurgical disease.

Food and Drug Administration approval for medications used in the pediatric intensive care unit: a continuing conundrum.

OBJECTIVES: Many drugs used in the pediatric intensive care unit are administered "off label," i.e., they have been neither thoroughly tested for efficacy and safety nor approved for use in children. The U.S. Congress has enacted legislation to promote standards and requirements for Food and Drug Administration labeling for drugs used in pediatrics. Nevertheless, we hypothesized that most medications used in our pediatric intensive care unit were not Food and Drug Administration approved for use in pediatric patients. DESIGN: A list of medications dispensed in the pediatric intensive care unit from January through February 2008 was obtained from our pharmacy database. We then determined whether each medication had been granted Food and Drug Administration approval for use in children. Medications were divided into the following categories: not approved for use in any pediatric age group, approved for use in limited age groups only, and approved for use in all pediatric age groups. SETTING: A pediatric intensive care unit at a tertiary care hospital with 26 beds and 1,500 admissions per year. MEASUREMENTS AND MAIN RESULTS: In the 2-month period, 248 different medications were dispensed with a total of 49,707 medication orders. Sixty (24.2%) of the medications dispensed were not Food and Drug Administration approved for use in any pediatric age group, 106 (42.7%) were approved for use in limited age groups, and 82 (33%) were approved for use in all pediatric age groups. Eleven of the 25 most frequently dispensed medications were approved for use in limited age groups, but none of them was used for the indication or age group for which they were approved. CONCLUSIONS: Despite the efforts of Congress, 67% of medications prescribed and administered in the pediatric intensive care unit did not have Food and Drug Administration approval or had only limited approval, underscoring the need for the medical community to demand oversight and research to improve drug labeling for our patient population.

Immediate Implant Placement and Provisionalization in the Esthetic Zone Using Flapless Technique.

Immediately placed implants into a fresh extraction socket have high survival and success rates comparable to those of conventionally placed implants in healed sites. This approach shortens the treatment time by reducing the number of surgical appointments, preserves alveolar bone from collapsing during the healing process, and allows for earlier contouring of the soft tissue for predictable esthetic results.

Multiresolution Application of Artificial Intelligence in Digital Pathology for Prediction of Positive Lymph Nodes From Primary Tumors in Bladder Cancer.

PURPOSE: To develop an artificial intelligence (AI)-based model for identifying patients with lymph node (LN) metastasis based on digital evaluation of primary tumors and train the model using cystectomy specimens available from The Cancer Genome Atlas (TCGA) Project; patients from our institution were included for validation of the leave-out test cohort. METHODS: In all, 307 patients were identified for inclusion in the study (TCGA, n = 294; in-house, n = 13). Deep learning models were trained from image patches at 2.5×, 5×, 10×, and 20× magnifications, and spatially resolved prediction maps were combined with microenvironment (lymphocyte infiltration) features to derive a final patient-level AI score (probability of LN metastasis). Training and validation included 219 patients (training, n = 146; validation, n = 73); 89 patients (TCGA, n = 75; in-house, n = 13) were reserved as an independent testing set. Multivariable logistic regression models for predicting LN status based on clinicopathologic features alone and a combined model with AI score were fit to training and validation sets. RESULTS: Several patients were determined to have positive LN metastasis in TCGA (n = 105; 35.7%) and in-house (n = 3; 23.1%) cohorts. A clinicopathologic model that considered using factors such as age, T stage, and lymphovascular invasion demonstrated an area under the curve (AUC) of 0.755 (95% CI, 0.680 to 0.831) in the training and validation cohorts compared with the cross validation of the AI score (likelihood of positive LNs), which achieved an AUC of 0.866 (95% CI, 0.812 to 0.920; P = .021). Performance in the test cohort was similar, with a clinicopathologic model AUC of 0.678 (95% CI, 0.554 to 0.802) and an AI score of 0.784 (95% CI, 0.702 to 0.896; P = .21). In addition, the AI score remained significant after adjusting for clinicopathologic variables (P = 1.08 × 10-9), and the combined model significantly outperformed clinicopathologic features alone in the test cohort with an AUC of 0.807 (95% CI, 0.702 to 0.912; P = .047). CONCLUSION: Patients who are at higher risk of having positive LNs during cystectomy can be identified on primary tumor samples using novel AI-based methodologies applied to digital hematoxylin and eosin-stained slides.

The Role of MicroRNAs in Recurrence and Metastasis of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) affects 650,000 people worldwide and has a dismal 50% 5-year survival rate. Recurrence and metastasis are believed the two most important factors causing this high mortality. Understanding the biological process and the underlying mechanisms of recurrence and metastasis is critical to develop novel and effective treatment, which is expected to improve patients' survival of HNSCC. MicroRNAs are small, non-coding nucleotides that regulate gene expression at the transcriptional and post-transcriptional level. Oncogenic and tumor-suppressive microRNAs have shown to regulate nearly every step of recurrence and metastasis, ranging from migration and invasion, epithelial-mesenchymal transition (EMT), anoikis, to gain of cancer stem cell property. This review encompasses an overview of microRNAs involved in these processes. The recent advances of utilizing microRNA as biomarkers and targets for treatment, particularly on controlling recurrence and metastasis are also reviewed.

Ap4A Regulates Directional Mobility and Antigen Presentation in Dendritic Cells.

The significance of intracellular Ap4A levels over immune activity of dendritic cells (DCs) has been studied in Nudt2fl/fl/CD11c-cre mice. The transgenic mice have been generated by crossing floxed NUDT2 gene mice with DC marker CD11c recombinase (cre) mice. The DCs derived from these mice have higher levels of Ap4A (≈30-fold) compared with those derived from Nudt2+/+ mice. Interestingly, the elevated Ap4A in DCs has led them to possess higher motility and lower directional variability. In addition, the DCs are able to enhance immune protection indicated by the higher cross-presentation of antigen and priming of CD8+ OT-I T cells. Overall, the study denotes prominent impact of Ap4A over the functionality of DCs. The Nudt2fl/fl/CD11c-cre mice could serve as a useful tool to study the influence of Ap4A in the critical immune mechanisms of DCs.

Preclinical characterization of the novel HCV NS3 protease inhibitor GS-9256.

BACKGROUND: GS-9256 is an inhibitor of HCV NS3 protease with a macrocyclic structure and novel phosphinic acid pharmacophore. METHODS: Key preclinical properties of GS-9256 including in vitro antiviral activity, cross-resistance and pharmacokinetic properties were investigated in non-human species. RESULTS: In genotype (GT) 1b Huh-luc cells with a replicon encoding luciferase, GS-9256 had a mean 50% effective concentration (EC50) value of 20.0 nM, with minimal cytotoxicity. Antiviral activity was similar in a number of additional GT1b and GT1a replicon cell lines. Similar potency was observed in chimeric replicons encoding the NS3 protease of GT1 clinical isolates. GS-9256 was less active in GT2a replicon cells (14.2-fold increase in EC50). Additive to synergistic in vitro antiviral activity was observed when GS-9256 was combined with other agents including interferon-α, ribavirin, NS5B polymerase inhibitors GS-6620 and tegobuvir, as well as the NS5A inhibitor ledipasvir. GS-9256 retained wild-type activity against all tested NS5B and NS5A inhibitor resistance mutations. GS-9256 was metabolically stable in microsomes and hepatocytes of tested species, including rodents, dogs and humans. GS-9256 had high bioavailability in mice (near 100%) and moderate bioavailability in rats (14%), dogs (21%) and monkeys (14%). Elimination half-lives were approximately 2 h in mice, 0.6 h in rats, 5 h in dogs and 4 h in monkey. A study in bile duct-cannulated rats indicated that the major route of elimination is through biliary excretion of unmetabolized GS-9256. CONCLUSIONS: GS-9256 showed a favourable preclinical profile supportive of clinical development for the treatment of chronic HCV infection in GT1 patients.

Signaling pathways in interleukin-1beta-mediated middle ear mucin secretion.

OBJECTIVES: The objectives of this study were to investigate the role of the phosphatidylcholine-specific phospholipase C (PC-PLC), protein kinase C (PKC), and nitric oxide synthase (NOS) pathways during upregulation of mucin secretion by middle ear epithelium after exposure to interleukin-1beta and to examine the ability of a specific interleukin-1 receptor antagonist (IL-1betara) to block this increased secretion. MATERIALS AND METHODS: Primary chinchilla middle ear epithelial cultures were established and exposed to IL-1beta. Specific inhibitors of calmodulin, PC-PLC, PKC, and NOS pathways were used to investigate the potential role of these pathways leading to increased epithelial mucin secretion after exposure to IL-1beta. Mucin secretion was characterized by exclusion chromatography and liquid scintillation. RESULTS: Epithelial cultures exposed to IL-1beta demonstrate an increase in mucin secretion that is blocked by specific inhibitors of PC-PLC, PKC, and NOS, but not by inhibitors of calmodulin. In addition, mucin secretion stimulated by IL-1beta was reversible with use of a specific IL-1betara. CONCLUSIONS: IL-1beta stimulates mucin secretion from middle ear epithelium and its effects can be reversed by IL-1betara. PC-PLC, PKC, and NOS pathways play a role in the increased secretion of mucin in middle ear epithelial cells after exposure to IL-1beta.

Upper airway physiology and obstructive sleep-disordered breathing.

Upper airway competence involves complex interactions between anatomy and physiology. The common final denominator of OSDB is a structurally small and abnormally collapsible upper airway. The mechanisms contributing are often an accumulation of many skeletal or soft tissue abnormalities and respiratory physiology that individually may or may not be pathologic. So far, simplistic models have hampered progress in this field. Successful medical and surgical treatment of OSDB continues to be elusive for too many patients. Great strides remain to be taken, but the possibility seems within reach.

Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection.

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Pediatric residents do not feel prepared for the most unsettling situations they face in the pediatric intensive care unit.

BACKGROUND: Critical care rotations involve emotionally unsettling situations with greater frequency and intensity than those that are encountered in other portions of residency training. New approaches are needed to optimize the preparation and professionalism of postgraduate medical trainees when managing crisis management scenarios. METHODS: An anonymous survey was conducted that focused on preparedness for dealing with emotionally unsettling situations, training preferences for these encounters, and the utility of resource personnel. A total of 58% of four classes of pediatric residents responded over a 2-year period. RESULTS: Pediatric residents in our program identified sudden patient death and conflicts about goals of care within the team as the most unsettling situations. These were also the scenarios with which they had the least experience and for which they felt least prepared. Team discussion was designated as the most helpful educational tool, in addition to a combination of didactic educational programs and end-of-rotation sessions. CONCLUSIONS: The focus and design of clinical education programming on preparation for crisis management during the care of critically ill patients benefit from the incorporation of trainee perceptions of preparedness and the efficacy of educational formats. Trainee feedback in these areas can be harnessed as a continuous quality improvement tool and as a metric of success in meeting professional training goals.

Middle ear epithelial mucin production in response to interleukin-6 exposure in vitro.

OBJECTIVES: To investigate the role of the inflammatory cytokine interleukin-6 (IL-6) in the regulation of mucin secretion by middle ear epithelia. MATERIALS AND METHODS: Primary chinchilla middle ear epithelial cultures were established and exposed to IL-6 in a dose- and time-dependent manner. Mucin secretion was characterized by exclusion chromatography and liquid scintillation. RESULTS: Epithelial cultures exposed to increasing doses of IL-6 demonstrated greater amounts of mucin secretion (p=0.018). Additionally, cultures exposed to IL-6 at 50 ng/ml showed significant increased secretion of mucin over control in time-dependent experiments at 6-, 15- and 24-h time points (p=0.003). CONCLUSIONS: IL-6 upregulates mucin secretion from cultured middle ear epithelial cells in a dose- and time-dependent manner. Elucidating the effect of specific cytokines on the regulation of mucin secretion is vital to understanding the pathophysiology of otitis media and the development of novel therapeutic strategies.