Targeting prostate cancer with Clostridium perfringens enterotoxin functionalized nanoparticles co-encapsulating imaging cargo enhances magnetic resonance imaging specificity.

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ±â€¯15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ±â€¯33.8 nm) NPs (RS4). There was a 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P < 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability.

Reporting and Implementing Interventions Involving Machine Learning and Artificial Intelligence.

Increasingly, interventions aimed at improving care are likely to use such technologies as machine learning and artificial intelligence. However, health care has been relatively late to adopt them. This article provides clinical examples in which machine learning and artificial intelligence are already in use in health care and appear to deliver benefit. Three key bottlenecks toward increasing the pace of diffusion and adoption are methodological issues in evaluation of artificial intelligence-based interventions, reporting standards to enable assessment of model performance, and issues that need to be addressed for an institution to adopt these interventions. Methodological best practices will include external validation, ideally at a different site; use of proactive learning algorithms to correct for site-specific biases and increase robustness as algorithms are deployed across multiple sites; addressing subgroup performance; and communicating to providers the uncertainty of predictions. Regarding reporting, especially important issues are the extent to which implementing standardized approaches for introducing clinical decision support has been followed, describing the data sources, reporting on data assumptions, and addressing biases. Although most health care organizations in the United States have adopted electronic health records, they may be ill prepared to adopt machine learning and artificial intelligence. Several steps can enable this: preparing data, developing tools to get suggestions to clinicians in useful ways, and getting clinicians engaged in the process. Open challenges and the role of regulation in this area are briefly discussed. Although these techniques have enormous potential to improve care and personalize recommendations for individuals, the hype regarding them is tremendous. Organizations will need to approach this domain carefully with knowledgeable partners to obtain the hoped-for benefits and avoid failures.

Association of type of renal surgery and access to robotic technology for kidney cancer: results from a population-based cohort.

OBJECTIVE: To evaluate the relationship between partial nephrectomy (PN) and hospital availability of robot-assisted surgery from a population-based cohort in the USA. METHODS: After merging the Nationwide Inpatient Sample (NIS) and the American Hospital Association survey from 2006 to 2008, we identified 21 179 patients who underwent either PN or radical nephrectomy (RN) for renal cell carcinoma (RCC). The primary outcome assessed was the type of nephrectomy performed. Multivariable logistic regression identified the patient and hospital characteristics associated with receipt of PN. RESULTS: We identified 4832 (22.8%) and 16 347 (77.2%) patients who were treated for RCC with PN and RN, respectively. On multivariable analysis, patients were more likely to receive PN at academic centres (odds ratio [OR] 2.77; P < 0.001), urban centres (OR 3.66; P < 0.001) and American College of Surgeons (ACOS)-designated cancer centres (OR: 1.10; P < 0.05) compared with non-academic, rural and non-ACOS-designated cancer centre hospitals, respectively. Robot-assisted surgery availability at a hospital was also associated with a higher adjusted odds of PN compared with centres without that availability (OR 1.28; P < 0.001). CONCLUSIONS: Although academic and urban locations are established factors that affect the receipt of PN for RCC, the availability of robot-assisted surgery at a hospital was also independently associated with higher use of PN. Our results are informative in identifying other key hospital characteristics which may facilitate greater adoption of PN.

Implantable electrolyte conductance-based pressure sensing catheter, II. Device construction and testing.

Direct measurements of arterial blood pressure most commonly use bulky external instrumentation containing a pressure transducer connected to an ex vivo fluid-filled arterial line, which is subject to several sensing artifacts. In situ blood pressure sensors, typically solid state piezoresistive, capacitive, and interferometric sensors, are unaffected by these artifacts, but can be expensive to produce and miniaturize. We have developed an alternative approach to blood pressure measurement based on deformation of an elastic tube filled with electrolyte solution. Simple measurement of the electrical conductance of this solution as the tube dimensions change allows determination of the external pressure. The sensor is made from inexpensive materials and its miniaturization is straightforward. In vitro static testing of initial sensor prototypes mounted on a catheter tip showed a linear response with applied pressure and a resolution of 1 mmHg. In vivo sensing followed catheterization of the sensor into the femoral artery of a porcine model through a 7F catheter port. The sensor performed comparably to a commercial pressure transducer also connected to the catheter port. Due to its scalability and cost, this sensor has the potential for use in a range of pressure sensing applications, such as measurement of intracranial, spinal, or interstitial pressures.

Implantable electrolyte conductance-based pressure sensing catheter, I. Modeling.

Direct measurements of arterial blood pressure most commonly use bulky external instrumentation containing a pressure transducer connected to an ex vivo fluid-filled arterial line, which is subject to several sensing artifacts. In situ blood pressure sensors, typically solid state piezoresistive, capacitive, and interferometric sensors, are unaffected by these artifacts, but can be expensive to produce and miniaturize. We have developed an alternative approach to blood pressure measurement based on deformation of an elastic tube filled with electrolyte solution. We have constructed an analytical model describing the deformation of a fluid-filled tube part of which is exposed to external pressure, with the remaining part unexposed. The model predicts pressure-induced change in dimension of the internal electrolyte-filled volume and a resultant change in its electrical resistance, which can be measured to determine the pressure and is the basis for the sensor operation. We have applied the model to find the pressure sensitivity of fractional change in resistance as a function of device material and dimensional parameters. Construction and testing of a device is described in the following paper.

Conductometric catheter-mounted pressure sensor.

We are developing an in vivo pressure sensor that measures the change in conductance of a deformable electrolyte-filled catheter resulting from external pressure. The sensor design and materials are easily scaled and inexpensive. The compact, in vivo nature of the device may result in the compact instrumentation being unobtrusively affixed to the patient externally and removing the tethered to an external apparatus, the current practice. We describe our initial device construction and in vitro pressure measurements.

A transurethral catheter-based ultrasound system for multi-modal fusion.

Current methods of prostate cancer diagnosis and therapy rely on accurate imaging of the prostate using real-time ultrasound. Transurethral ultrasound (TUUS) may improve upon the current gold standard through improved 3D visualization and co-registration (fusion) with CT and MRI. A prototype transurethral ultrasound (TUUS) catheter-based transducer array and system was developed, featuring 32 elements with a diameter of 18F (6mm). A robust, multi-channel ultrasound transceiver was also developed to enable TUUS imaging using pulse-echo and frequency-based signal processing methods. The feasibility of a TUUS imaging system suitable for multi-modal image fusion and novel ultrasound signaling techniques was demonstrated.

Distinguishing Benign Renal Tumors with an Oncocytic Gene Expression (ONEX) Classifier.

Renal oncocytoma (RO) accounts for 5% of renal cancers and generally behaves as a benign tumor with favorable long-term prognosis. It is difficult to confidently distinguish between benign RO and other renal malignancies, particularly chromophobe renal cell carcinoma (chRCC). Therefore, RO is often managed aggressively with surgery. We sought to identify molecular biomarkers to distinguish RO from chRCC and other malignant renal cancer mimics. In a 44-patient discovery cohort, we identified a significant differential abundance of nine genes in RO relative to chRCC. These genes were used to train a classifier to distinguish RO from chRCC in an independent 57-patient cohort. The trained classifier was then validated in five independent cohorts comprising 89 total patients. This nine-gene classifier trained on the basis of differential gene expression showed 93% sensitivity and 98% specificity for distinguishing RO from chRCC across the pooled validation cohorts, with a c-statistic of 0.978. This tool may be a useful adjunct to other diagnostic modalities to decrease the diagnostic and management uncertainty associated with small renal masses and to enable clinicians to recommend more confidently less aggressive management for some tumors. PATIENT SUMMARY: Renal oncocytoma is generally a benign form of kidney cancer that does not necessarily require surgical removal. However, it is difficult to distinguish renal oncocytoma from other more aggressive forms of kidney cancer, so it is treated most commonly with surgery. We built a classification tool based on the RNA levels of nine genes that may help avoid these surgeries by reliably distinguishing renal oncocytoma from other forms of kidney cancer.

Development and Validation of ARC, a Model for Anticipating Acute Respiratory Failure in Coronavirus Disease 2019 Patients.

OBJECTIVES: To evaluate factors predictive of clinical progression among coronavirus disease 2019 patients following admission, and whether continuous, automated assessments of patient status may contribute to optimal monitoring and management. DESIGN: Retrospective cohort for algorithm training, testing, and validation. SETTING: Eight hospitals across two geographically distinct regions. PATIENTS: Two-thousand fifteen hospitalized coronavirus disease 2019-positive patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anticipating Respiratory failure in Coronavirus disease (ARC), a clinically interpretable, continuously monitoring prognostic model of acute respiratory failure in hospitalized coronavirus disease 2019 patients, was developed and validated. An analysis of the most important clinical predictors aligns with key risk factors identified by other investigators but contributes new insights regarding the time at which key factors first begin to exhibit aberrency and distinguishes features predictive of acute respiratory failure in coronavirus disease 2019 versus pneumonia caused by other types of infection. Departing from prior work, ARC was designed to update continuously over time as new observations (vitals and laboratory test results) are recorded in the electronic health record. Validation against data from two geographically distinct health systems showed that the proposed model achieved 75% specificity and 77% sensitivity and predicted acute respiratory failure at a median time of 32 hours prior to onset. Over 80% of true-positive alerts occurred in non-ICU settings. CONCLUSIONS: Patients admitted to non-ICU environments with coronavirus disease 2019 are at ongoing risk of clinical progression to severe disease, yet it is challenging to anticipate which patients will develop acute respiratory failure. A continuously monitoring prognostic model has potential to facilitate anticipatory rather than reactive approaches to escalation of care (e.g., earlier initiation of treatments for severe disease or structured monitoring and therapeutic interventions for high-risk patients).

Percutaneous cystolithotomy for calculi in reconstructed bladders: initial UCLA experience.

PURPOSE: Following bladder augmentation, patients are at significant risk for bladder calculi. We present our experience with a minimally invasive treatment approach using endoscopically assisted percutaneous cystolithotomy. MATERIALS AND METHODS: A retrospective chart review identified 74 patients who underwent percutaneous cystolithotomy following bladder augmentation between 2002 and 2009. Cystogram was performed to determine the ideal location for percutaneous bladder access and a guidewire was inserted in the bladder through a bile needle. A balloon dilator was used to place a 30Fr sheath. Rigid cystoscopy with a 26Fr nephroscope allowed stone treatment by basketing and ultrasonic lithotripsy. A suprapubic 22Fr catheter was then placed. Patients were seen on postoperative day 14 and abdominal ultrasound was performed. If no significant residual calculi were visualized, the suprapubic tube was removed. RESULTS: Mean +/- SD patient age at operation was 20 +/- 10.7 months (range 4 to 40). Mean +/- SD time between bladder augmentation and percutaneous cystolithotomy was 4.8 +/- 2.05 years. Of the patients 38 (51%) were male and 36 (49%) were female. Mean +/- SD number of stones per patient was 4.6 +/- 7.8 (range 1 to 60). Ultrasonic lithotripsy was performed in 49 cases (66%). In 25 cases (34%) only stone basketing was performed. A total of 70 patients (95%) were stone-free on abdominal plain film at 14 days. Of the procedures 24 (32%) were performed on an outpatient basis and 50 were performed on an inpatient basis with a mean +/- SD hospital stay of 1.3 +/- 2.7 days (range 1 to 21). There were 9 minor complications noted (12%). CONCLUSIONS: Endoscopic percutaneous cystolithotomy offers a safe and effective treatment option for bladder calculi in reconstructed bladders and is the preferred method at our institution.

Comparison of accuracy of 14-, 18- and 20-G needles in ex-vivo renal mass biopsy: a prospective, blinded study.

OBJECTIVE: To prospectively determine the accuracy of 14-, 18- and 20-G core needle biopsies to render the appropriate histological diagnosis of solid, enhancing renal masses, using a controlled, ex-vivo biopsy technique. PATIENTS AND METHODS: From March 2007 to September 2007, 31 patients undergoing partial or radical nephrectomy were randomly selected for biopsy. After extirpative surgery, three ex-vivo biopsies were taken from each lesion with 14-, 18- and 20-G biopsy needles. One experienced genitourinary pathologist, unaware of patient identifiers and final pathology results, determined the biopsy histology and tumour grade, based on standard haematoxylin and eosin (H&E) techniques and immunohistochemistry. RESULTS: The final pathological evaluation classified 21 masses (68%) as clear cell renal cell carcinoma (RCC), three (10%) as papillary RCC, three (10%) as chromophobe RCC, three (10%) as oncocytoma and one (3%) as a benign lymphoid infiltrate. The biopsy histology correlated with the final pathology in 29/31 cases (94%) with the 14-G, 30/31 cases (97%) with the 18-G and 25/31 cases (81%) with the 20-G needles. In two cases chromophobe RCC was misdiagnosed with oncocytoma, and vice versa. CONCLUSION: In this study a minimum of an 18-G biopsy needle was the most accurate in determining the histological diagnosis. Clear cell and papillary RCCs were accurately diagnosed on biopsy using an 18-G, whereas oncocytoma and chromophobe RCC were difficult to differentiate using standard H&E techniques and immunohistochemistry.

A Review of Challenges and Opportunities in Machine Learning for Health.

Modern electronic health records (EHRs) provide data to answer clinically meaningful questions. The growing data in EHRs makes healthcare ripe for the use of machine learning. However, learning in a clinical setting presents unique challenges that complicate the use of common machine learning methodologies. For example, diseases in EHRs are poorly labeled, conditions can encompass multiple underlying endotypes, and healthy individuals are underrepresented. This article serves as a primer to illuminate these challenges and highlights opportunities for members of the machine learning community to contribute to healthcare.

Development of a fully implantable wireless pressure monitoring system.

A fully implantable wireless pressure sensor system was developed to monitor bladder pressures in vivo. The system comprises a small commercial pressure die connected via catheter to amplifying electronics, a microcontroller, wireless transmitter, battery, and a personal digital assistant (PDA) or computer to receive the wireless data. The sensor is fully implantable and transmits pressure data once every second with a pressure detection range of 1.5 psi gauge and a resolution of 0.02 psi. In vitro calibration measurements of the device showed a high degree of linearity and excellent temporal response. The implanted device performed continuously in vivo in several porcine studies lasting over 3 days. This system can be adapted for other pressure readings, as well as other vital sign measurements; it represents the first step in developing a ubiquitous sensing platform for telemedicine and remote patient monitoring.

Development of a minimally invasive implantable wireless vital signs sensor platform.

A wireless implantable pressure sensing system has been developed for short term urological studies. In in vitro testing, it was able to sense a physiologically relevant pressure range (0-1.5 psi gauge) with a resolution of 0.02 psi. In vivo testing demonstrated its ability to operate for >90 hours while implanted in a porcine model. Possible urination events and peristalsis were measured. The design of a second generation of this device is also presented.

A non-enzymatic method for dissection of mouse bladder urothelial tissue.

Urothelial cells contribute to bladder functions, including urine storage, urine emptying, and innate immune response. Functional studies of urothelial cells usually use either freshly isolated cells or cultured cells. Most methods of isolating urothelial cells require enzymes; however, these techniques remove proteins that connect the cells and disrupt the orientation of the cells within the multilayered urothelium. In addition, PCR or immunoblot results obtained from homogenates of bladder mucosa or whole bladder do not represent pure urothelial cells. We describe a dissection process that does not require enzymes and is able to obtain pure urothelial tissues from mice and humans. This method can isolate single urothelial cells for electrophysiology in situ and can also isolate pure urothelial tissue for PCR, microarray, and immunoblot procedures. The time required to obtain urothelial tissue from one mouse bladder is 15-20 min. This method is simple and time efficient as compared with alternative methods and therefore facilitates our understanding of urothelial biology.

The Yale Center for Biomedical Innovation and Technology (CBIT): One Model to Accelerate Impact From Academic Health Care Innovation.

The process of translating academic biomedical advances into clinical care improvements is difficult, risky, expensive, and poorly understood. Notably, many clinicians who identify health care problems do not have the time or expertise to solve the problems, and many academic researchers are unaware of important gaps in clinical care to which their expertise may apply.Recognizing an opportunity to connect people who can identify health care problems with those who can solve them, the Yale Center for Biomedical Innovation and Technology (CBIT) was established in 2014 to educate and enhance the impact of health care innovators. The authors review other health care innovation centers and describe best practices borrowed by Yale CBIT, which tailored its activities and approach to its unique ecosystem.In four years, Yale CBIT has affected over 3,000 people and established a health care innovation cycle as an efficient strategy to guide translational research. Yale CBIT has created or supported graduate and undergraduate courses, clinical immersion programs for industry partners, and large health care hackathon events. Over 200 projects have been submitted to CBIT for mentorship, and some of those projects have been commercialized and raised millions of dollars of follow-on funding.The authors present Yale CBIT as one model of accelerating the impact of academic medicine on clinical practice and outcomes. The project advising strategy is intended to be a template to maximize the efficiency of biomedical innovation and ultimately improve the outcomes and experiences of future patients.

Flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater--is this the new frontier?

PURPOSE: Percutaneous nephrolithotomy has been the standard of care for intrarenal calculi greater than 2 cm. Flexible ureteroscopy with holmium laser lithotripsy is a minimally invasive treatment modality that is able to treat large intrarenal calculi with the potential to decrease morbidity, while maintaining a high level of efficacy. MATERIALS AND METHODS: A total of 15 patients with a single intrarenal calculus 2 cm or greater were treated with retrograde ureteroscopic nephrolithotripsy. Lithotripsy was performed with a 7.2Fr flexible ureteroscope and 200 micron laser fiber. The stone-free rate was defined as the absence of any stones in the kidney or residual stone fragments less than 1 mm, which is too small to be extracted with a basket or a grasper. All patients underwent followup ureteroscopy within 15 days after the last procedure and renal ultrasound 30 days after the last treatment. RESULTS: There were a total of 15 intrarenal calculi 20 to 25 mm (mean 22) in diameter. The mean number of procedures was 2.3 (range 2 to 4). The overall stone-free rate was 93.3%. One patient (6.6%) had a residual 5 mm stone fragment in the lower pole of the kidney, which was followed expectantly for 2 years with no change in size. There were no major complications. There were 3 minor complications (20%), including 1 emergency room visit for fever and pain, and 2 cases of gross hematuria. All cases were performed on an outpatient basis. CONCLUSIONS: In select patients with a single intrarenal calculus 2 cm or greater small diameter flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to standard percutaneous nephrolithotomy with acceptable efficacy and low morbidity.

In vivo efficacy of laparoscopic assisted percutaneous renal cryotherapy: evidence based guidelines for the practicing urologist.

PURPOSE: The treatment of small renal tumors continues to evolve in parallel with advances in ablative technology. We compared the lesion geometry of 3, 17 gauge cryoneedles to determine the most effective distance and configuration of the cryoneedles in an in vivo porcine kidney model. MATERIALS AND METHODS: Argon gas based renal cryoablation was performed in 6 pigs using a laparoscopically assisted percutaneous approach. Cryoablation using a single cryoneedle and a template of 3 cryoneedles with various ice ball shapes, including elliptical, bulb-shaped and standard 17 gauge cryoneedles (Galil Medical, Plymouth Meadow, Pennsylvania) was performed in 3 pigs. Three additional pigs underwent renal cryoablation using elliptical cryoneedles in 3 triangular template configurations with the cryoneedles spaced 1, 1.5 and 2 cm apart, respectively. The animals were sacrificed a minimum of 2 weeks following treatment. RESULTS: Elliptical cryoneedles achieved the largest area of necrosis when used in single and template configurations. When used in a template configuration of 3 needles 1, 1.5 and 2 cm apart from each other the calculated volume of necrosis was 4.3 x 4.5 x 2.5, 4.9 x 4.1 x 2.5 and 4.0 x 4.5 x 2.5 cm, respectively. CONCLUSIONS: Using a single 17 gauge cryoneedle is inadequate for treating most small renal tumors. Cryoneedles with an elliptical ice ball are most effective for achieving consistent and reliable tissue destruction. The 1.5 cm template configuration generated the largest area of necrosis. Our data suggest that with the current technology renal cryoablation should be limited to lesions not greater than 4 cm.

Ultrashort intracorporeally maneuverable cryoprobes for laparoscopic renal cryoablation in the porcine model.

AIM: To determine the feasibility and efficacy of laparoscopic renal cryosurgery using a novel ultrathin ultrashort intracorporeal cryoprobe in a porcine model. MATERIAL AND METHODS: Novel cryoprobes 4 cm in length and 1.5 mm in diameter were manipulated intracorporeally after insertion via a designated 15 mm laparoscopic port. Renal cryoablative lesions were induced laparoscopically in four 40 kg female piglets. We correlated between intraoperative temperature, ice ball geometry, intraoperative ultrasonographic properties, and histology. RESULTS: Laparoscopic manipulation of the cryoprobes was straightforward. No port site bleeding occurred during insertion, freezing, thawing or upon removal of the probes. The 0 degrees C, -20 degrees C, and -40 degrees C isotherms were measured at 6, 8, and 12 mm from the probe circumferentially. Ice-ball volume stabilization as determined by ultrasound occurred after 10 min of activation. Lower temperatures were reached after 10 min of probe activation as compared with 5 min (ice ball diameter 30 mm, DeltaT = 13-21 degrees C). Using a second 10-min-long freeze cycle resulted in a 14-22 degrees C lower temperature within the ice ball compared to a single cycle. Full coagulative necrosis was noted in the areas between the inserted probes with an additional 1-2 mm circumferential rim of severe tubular damage and apoptosis. CONCLUSIONS: Our novel cryoprobe can be used effectively and conveniently in laparoscopic renal cryosurgery. Considering the size of the cryogenic lesion, using a cluster of probes may be advisable.

Importance of surgical margins in the management of renal cell carcinoma.

Surgical resection remains the standard treatment for clinically localized renal cell carcinoma. Pathological features of the surgical specimen, including the margin status, play an important part in determining the patient's prognosis. Negative surgical margins have traditionally been sought to maximize the efficacy of treatment. Initial concerns that partial nephrectomy might have high local recurrence rates compared with radical nephrectomy have now been minimized as a result of technological advances and refinements in surgical technique. Current concerns in relation to partial nephrectomy include the width of parenchymal tissue that should be removed to avoid positive surgical margins, effects of positive margins on recurrence-free survival, and the use of frozen-section analysis to determine margin status. Size of the surgical margin in partial nephrectomy does not seem to affect the risk of local tumor recurrence, and not all positive surgical margins lead to recurrent disease. Intraoperative frozen-section analysis is not definitive and its value in guiding the surgical management of renal tumors remains to be defined. Laparoscopic partial nephrectomy is emerging as an attractive approach for selected renal masses. Intraoperative use of ultrasound, cold-scissor parenchymal transection, embolization, and hilar clamping to achieve a bloodless operative field with clear visibility, may minimize the risk of positive margins during partial nephrectomy.