Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

An observed, prospective field study to evaluate the performance and acceptance of a blood-based HIV self-test in Canada.

BACKGROUND: Self testing for HIV is a targeted intervention with the potential to increase the access, uptake and frequency of HIV testing and more effectively reach the undiagnosed, especially in priority populations. The objectives of this study were to (1) evaluate the INSTI HIV self-test performance compared with laboratory reference testing, (2) document if intended users can perform the steps to use the HIV self-test device, and (3) document if intended users can successfully interpret contrived positive, negative, and invalid results. Study was intended to be submitted to Health Canada for review for regulatory approval purposes. METHODS: The study used a cross-sectional design and recruited consenting adults who were representative of intended users of HIV self-testing from four community sites across Ontario, Québec, and Manitoba between August 2019 and March 2020. The results of the observed HIV self-test were compared with results of the Abbott Architect HIV Ag/Ab Combo test. Usability outcomes for critical (e.g., lancing finger, blood droplet into bottle, shaking bottle four times) and noncritical self-test procedure steps were also determined. RESULTS: Overall, 77% (n = 522) of participants were between 18 and 45 years of age, 61% (n = 410) were male, 71% (n = 480) had some college or more education, and 45% (n = 307) were employed; identity for race and ethnicity: Caucasian (44%; n = 296), African, Caribbean or Black (17%; n = 113), Indigenous [First Nations, Métis or Inuit] (14%; n = 95), Asian (16%; n = 106), Latin American (7%; n = 46). Primary performance analysis on 678 completed HIV self-tests revealed a positive percent agreement of 100% (5/5, 95% CI: 43.6-97.0%) and a negative percent agreement of 99.5% (614/617, 95% CI: 98.6-99.8%) with the comparator method. The overall percent agreement of results interpretation between participant and observer was 93.5% (n = 633). For the 708 participants who took part in the usability study, the average success rate for steps determined to be "critical" for successful completion of the test was 92.4%. 97% (n = 670) of participants found the instructions easy to follow, and 95% (n = 655) of participants indicated that they would use the test again. Of the 404 participants who interpreted the strong positive, weak positive, negative, and invalid contrived results, successful interpretation ranged from 90.6% (for weak positive, n = 366) to 99.3% (for negative, n = 401). CONCLUSIONS: The addition of a regulatory-approved self-test into the Canadian HIV testing landscape could significantly increase HIV testing rates. Having a blood-based HIV self-test approved in Canada can offer an accurate, acceptable, and simple alternative to facility-based HIV testing, particularly when impacted by Coronavirus pandemic restrictions.

Therapeutic living donor nephrectomy.

Therapeutic living donor nephrectomy is defined as a nephrectomy that is performed as therapy for an underlying medical condition. The patient directly benefits from having their kidney removed, but the kidney is deemed transplantable. The kidney is subsequently used as an allograft for an individual with advanced renal disease. Therapeutic donor nephrectomy can be successfully utilized for a heterogenous cohort of disease processes as both treatment for the donor and to increase the number of suitable organs available for transplantation. We describe four cases of therapeutic donor nephrectomy that were performed at our institution. Of the four cases, two patients elected to undergo therapeutic donor nephrectomy as treatment for loin pain hematuria syndrome; one after blunt abdominal trauma that resulted in complete proximal ureteral avulsion; and the fourth after being diagnosed with a small renal mass. Based on our data presented to the United Network for Organ Sharing Board of Directors (UNOS) in December 2015, living donor evaluation has been made simpler for patients electing to undergo therapeutic donor nephrectomy. UNOS eliminated the requirement for a psychosocial evaluation for these patients. As the organ shortage continues to limit transplantation, therapeutic donor nephrectomy should be considered when appropriate.

Simple re-instantiation of small databases using cloud computing.

BACKGROUND: Small bioinformatics databases, unlike institutionally funded large databases, are vulnerable to discontinuation and many reported in publications are no longer accessible. This leads to irreproducible scientific work and redundant effort, impeding the pace of scientific progress. RESULTS: We describe a Web-accessible system, available online at http://biodb100.apbionet.org, for archival and future on demand re-instantiation of small databases within minutes. Depositors can rebuild their databases by downloading a Linux live operating system (http://www.bioslax.com), preinstalled with bioinformatics and UNIX tools. The database and its dependencies can be compressed into an ".lzm" file for deposition. End-users can search for archived databases and activate them on dynamically re-instantiated BioSlax instances, run as virtual machines over the two popular full virtualization standard cloud-computing platforms, Xen Hypervisor or vSphere. The system is adaptable to increasing demand for disk storage or computational load and allows database developers to use the re-instantiated databases for integration and development of new databases. CONCLUSIONS: Herein, we demonstrate that a relatively inexpensive solution can be implemented for archival of bioinformatics databases and their rapid re-instantiation should the live databases disappear.

Design, optimization, and in vivo evaluation of a series of pyridine derivatives with dual NK1 antagonism and SERT inhibition for the treatment of depression.

A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.

Diagnostic radiation exposure risk in a contemporary cohort of male patients with germ cell tumor.

PURPOSE: We determined the total amount of diagnostic radiation that a patient with testicular cancer receives during the course of treatment and the associated risk of secondary malignancy. MATERIALS AND METHODS: At a single institution 119 men with seminomatous and nonseminomatous germ cell tumors of the testis were retrospectively identified. Annual and lifetime exposure to radiation was determined for each histological subtype. Values were assessed for compliance with International Commission of Radiological Protection guidelines. RESULTS: The cohorts included 55 patients with seminomatous and 64 with nonseminomatous germ cell tumor. Between the groups no difference was found in the lifetime (215.5 and 214.1 mSV, p = 0.96) or the annual (104.6 and 104.6 mSV, respectively, p = 1.0) radiation dose. Of the 41 patients with more than 5-year followup 32 (78%) were in violation of guidelines by exceeding 20 mSV per year of radiation. Also, 74 patients (61.7%) received 50 mSV or greater of radiation during a 1-year period. Using the previously calculated excess relative risk for solid cancer and leukemia, excluding chronic lymphocytic leukemia, the RR was 1.06 and 1.33, [corrected] respectively, with a 2.1% lifetime risk of fatal cancer over the baseline risk. CONCLUSIONS: At a tertiary care center with experience with managing testicular cancer 78% of patients with more than 5 years of followup exceeded current national and standard safety limits for radiation exposure. Imaging should be done judiciously in this population at high risk for radiation overexposure.

Delirium in COVID-19: An Atypical Case Managed With Quetiapine.

Coronavirus disease 2019 (COVID-19) can present without the typical symptoms of respiratory tract infection. Delirium has been reported as a prominent feature leading to an atypical presentation in older adults infected with COVID-19. Here, we present the case of a 65-year-old female who came to our hospital with confusion and altered mental status. The patient maintained an asymptomatic course of illness after testing positive for COVID-19 two weeks prior to the hospital visit. An appropriate workup was done to rule out other causes of the patient's symptoms. During the next couple of days, the patient developed classic symptoms suggestive of delirium. The patient was eventually treated based on the general guidelines for delirium management due to the absence of adequate medical literature specifying the management of delirium in the population of interest. Thus, the patient was given a trial of an atypical antipsychotic, quetiapine, to which she responded well and was subsequently discharged one week later.

Lessons of the month 1: Longitudinal extensive transverse myelitis following AstraZeneca COVID-19 vaccination.

Longitudinal extensive transverse myelitis (LETM) is a rare but recognised complication of vaccination. We report the case of a 58-year-old man admitted to hospital 10 days after his first AstraZeneca COVID-19 vaccination with progressive neurological symptoms and signs, and investigations and imaging consistent with LETM.This case reviews the literature and the investigative process behind excluding other diagnoses given the patient's background of pulmonary sarcoidosis. It is unique in being the first UK report of a case of LETM with a strong temporal link to COVID-19 vaccination.

100% N4-acetyl-sulfamethoxazole stone induced by Trimethoprim-Sulfamethoxazole in an HIV patient being treated for toxoplasmosis.

Trimethoprim-Sulfamethoxazole is a common antibiotic used to treat urinary tract infections, as well as a prophylactic agent in HIV patients with low CD4 counts. Exceedingly rare are stones consisting purely of its metabolite, N4-acetyl-sulfamethoxazole, and management strategies are not well documented in the literature. We present a case of a patient with HIV who was found to have obstructing ureteral calculi composed of 100% N4-acetyl-sulfamethoxazole. Our report contributes a unique case of a Bactrim-induced stone in an immunocompromised patient. Similar patients can be prophylactically treated with diuresis and urinary alkalinization, as well as consideration for alternative medication use.

A Novel MEMS Capacitive Microphone with Semiconstrained Diaphragm Supported with Center and Peripheral Backplate Protrusions.

Audio applications such as mobile phones, hearing aids, true wireless stereo earphones, and Internet of Things devices demand small size, high performance, and reduced cost. Microelectromechanical system (MEMS) capacitive microphones fulfill these requirements with improved reliability and specifications related to sensitivity, signal-to-noise ratio (SNR), distortion, and dynamic range when compared to their electret condenser microphone counterparts. We present the design and modeling of a semiconstrained polysilicon diaphragm with flexible springs that are simply supported under bias voltage with a center and eight peripheral protrusions extending from the backplate. The flexible springs attached to the diaphragm reduce the residual film stress effect more effectively compared to constrained diaphragms. The center and peripheral protrusions from the backplate further increase the effective area, linearity, and sensitivity of the diaphragm when the diaphragm engages with these protrusions under an applied bias voltage. Finite element modeling approaches have been implemented to estimate deflection, compliance, and resonance. We report an 85% increase in the effective area of the diaphragm in this configuration with respect to a constrained diaphragm and a 48% increase with respect to a simply supported diaphragm without the center protrusion. Under the applied bias, the effective area further increases by an additional 15% as compared to the unbiased diaphragm effective area. A lumped element model has been also developed to predict the mechanical and electrical behavior of the microphone. With an applied bias, the microphone has a sensitivity of -38 dB (ref. 1 V/Pa at 1 kHz) and an SNR of 67 dBA measured in a 3.25 mm × 1.9 mm × 0.9 mm package including an analog ASIC.

Advancing standards for bioinformatics activities: persistence, reproducibility, disambiguation and Minimum Information About a Bioinformatics investigation (MIABi).

The 2010 International Conference on Bioinformatics, InCoB2010, which is the annual conference of the Asia-Pacific Bioinformatics Network (APBioNet) has agreed to publish conference papers in compliance with the proposed Minimum Information about a Bioinformatics investigation (MIABi), proposed in June 2009. Authors of the conference supplements in BMC Bioinformatics, BMC Genomics and Immunome Research have consented to cooperate in this process, which will include the procedures described herein, where appropriate, to ensure data and software persistence and perpetuity, database and resource re-instantiability and reproducibility of results, author and contributor identity disambiguation and MIABi-compliance. Wherever possible, datasets and databases will be submitted to depositories with standardized terminologies. As standards are evolving, this process is intended as a prelude to the 100 BioDatabases (BioDB100) initiative whereby APBioNet collaborators will contribute exemplar databases to demonstrate the feasibility of standards-compliance and participate in refining the process for peer-review of such publications and validation of scientific claims and standards compliance. This testbed represents another step in advancing standards-based processes in the bioinformatics community which is essential to the growing interoperability of biological data, information, knowledge and computational resources.

Bilateral Open Ureteroceles with Concomitant Bladder Calculi in an Adult Male.

Background: Bilateral ureteroceles in adult males are a rare occurrence, made even more so with simultaneous presence of bladder calculi. Management strategies for such patients are not well documented in the literature. We present a rare case of bilateral open ureteroceles with large concomitant bladder calculi to contribute to the paucity of literature on management of such patients. Case Presentation: We present the case of a 35-year-old man whose gross hematuria work-up demonstrated right-sided hydroureteronephrosis in the setting of bilateral ureteroceles and multiple large bladder calculi up to 3.8 cm. Conclusion: Bilateral orthotopic single-system ureteroceles in an adult male are a rare finding especially when intraoperatively found to be open secondary to traumatic effects of large calculi. Ultrasonic and pneumatic lithotripsy is a safe, appropriate, and effective option for bilateral ureteroceles contributing to a large bladder stone burden. Our report contributes to the growing body of literature on orthotopic bilateral single-system ureteroceles in the adult population with concomitant significant stone burden.

The implementation of e-learning tools to enhance undergraduate bioinformatics teaching and learning: a case study in the National University of Singapore.

BACKGROUND: The rapid advancement of computer and information technology in recent years has resulted in the rise of e-learning technologies to enhance and complement traditional classroom teaching in many fields, including bioinformatics. This paper records the experience of implementing e-learning technology to support problem-based learning (PBL) in the teaching of two undergraduate bioinformatics classes in the National University of Singapore. RESULTS: Survey results further established the efficiency and suitability of e-learning tools to supplement PBL in bioinformatics education. 63.16% of year three bioinformatics students showed a positive response regarding the usefulness of the Learning Activity Management System (LAMS) e-learning tool in guiding the learning and discussion process involved in PBL and in enhancing the learning experience by breaking down PBL activities into a sequential workflow. On the other hand, 89.81% of year two bioinformatics students indicated that their revision process was positively impacted with the use of LAMS for guiding the learning process, while 60.19% agreed that the breakdown of activities into a sequential step-by-step workflow by LAMS enhances the learning experience CONCLUSION: We show that e-learning tools are useful for supplementing PBL in bioinformatics education. The results suggest that it is feasible to develop and adopt e-learning tools to supplement a variety of instructional strategies in the future.

Endoscopic Combined Intrarenal Surgery Can Accurately Predict High Stone Clearance Rates on Postoperative CT.

OBJECTIVE: To determine stone clearance rates using endoscopic combined intrarenal surgery (ECIRS) and assess the accuracy of intraoperative prediction of stone-free (SF) status compared to postoperative CT scan. METHODS: A single institution, prospectively maintained database of ECIRS was queried for procedures performed 8/2017 to 1/2018. Retrograde access was performed using a ureteral sheath and flexible ureteroscope. Percutaneous nephrolithotomy was performed through a 30fr or 18fr sheath in prone position. Residual stone status was estimated at the end of each procedure and was verified with postoperative CT scan. SF was defined as no single stone >2mm3 on CT. RESULTS: One hundred and ten procedures were reviewed. Average age was 58.9 ± 12.6 years (range 26-87) and 69 (63%) were male. The mean stone size was 33.3 ± 23.5 mm (range 4-140 mm). Ninty-three patients (84.5%) were endoscopically estimated to be SF, of which 84 (90% of predicted SF cohort, 76% of total cohort) were confirmed SF via CT scan. The sensitivity for estimating SF status with ECIRS was 65.4% (95%CI 44.3%-82.8%), specificity was 100% (95%CI 95.7%-100.0%) and accuracy was 91.8% (95%CI 85.0%-96.2%). SF patients had significantly smaller stones than those with residual fragments (28.5 ± 2.1 vs 48.4 ± 5.7mm, P <.0001). On logistic regression, the factors associated with residual stones were preoperative stone burden (OR 1.03 per mm, 95%CI 1.01-1.05, P = .0004) and fluoroscopy time (OR 1.01 per minute, 95%CI 1.0-1.02, P = .0081). CONCLUSION: ECIRS accurately predicts clinical SF status and may obviate the need for additional CT scans. Consistent with prior studies, the primary determinant of residual stone after percutaneous nephrolithotomy is initial stone size.

Innovation in Robotics and Pediatric Urology: Robotic Ureteroureterostomy for Duplex Systems with Ureteral Ectopia.

INTRODUCTION: Robotic technology has been increasingly utilized for complicated reconstructive surgeries in pediatric urology, such as ureteroureterostomy (UU). The literature is limited regarding the performance of minimally invasive UU in children, and the existing published series utilize indwelling ureteral stents. We sought to report on our pediatric experience with robot-assisted laparoscopic (RAL)-UU using a temporary ureteral catheter in duplex systems with ureteral ectopia. METHODS: A retrospective chart review was performed of all pediatric patients who underwent RAL-UU at a single institution over a 2-year period. An externalized ureteral catheter was kept overnight and removed with the indwelling catheter on postoperative day 1. Intraoperative as well as postoperative complications, length of stay (LOS), and analgesia were recorded. Follow-up renal ultrasound (US) and evaluation for symptom resolution were completed 3 months postoperatively. RESULTS: Twelve patients (four male, eight female) underwent RAL-UU at a mean age of 19.4 months (range 9-48 months) during the study period. The majority of patients (83.3%) presented with hydronephrosis, and all were found to have duplicated systems with ureteral ectopia. No child had ipsilateral vesicoureteral reflux. Two children had bilateral duplicated systems, one of which required bilateral surgery. Median operative time was 138 minutes (IQR 119-180 minutes), and mean estimated blood loss was 1.5 mL. There were no intraoperative complications, and no case required open conversion. Median hospital LOS was 31 hours (IQR 30-39 hours). Median follow-up time was 11 months (range 3-22 months). One patient developed a postoperative febrile upper respiratory infection. All patients had improved hydroureteronephrosis on US at 3 months postoperatively. One patient with preoperative urinary incontinence was dry postoperatively. Therefore, the overall success rate was 100%. CONCLUSION: Our institutional results demonstrate that RAL-UU utilizing a temporary ureteral catheter is a safe and effective technique for managing duplicated, ectopic ureters in children and infants.

A Prospective Randomized Trial of the Effects of Early Enteral Feeding After Radical Cystectomy.

OBJECTIVE: To investigate the role of early feeding on recovery after radical cystectomy and urinary diversion. Enhanced recovery protocols have helped to standardize postoperative recovery. This is the first study to directly review the impact of early feeding on recovery in a randomized multi-institutional protocol. METHODS: From 2011 to 2014, patients at 2 large hospitals were randomized after radical cystectomy to receive access to liquids and then a regular diet on postoperative days 1 and 2 or conventional care with introduction of a liquid diet after return of bowel activity, typically days 3-5. Early ambulation, use of metoclopramide, and no nasogastric tube were standard for all patients. The study was powered to detect a 50% decrease in 90-day complication rate with secondary end points of length of stay, time to bowel activity, and time to diet tolerance. The study was terminated early due to slow accrual (102 of 328). RESULTS: Overall complications for the early vs standard groups were similar (34 vs 31, P = .86). Immediate inpatient and postdischarge complication rates were also similar (P = .63 and P = .44). Length of stay was not different (8.74 days vs 9.69 days, P = .43). Rates of ileus (27% vs 41%, P = .21) and return of bowel function (4.67 days vs 4.09 days, P = .62) were the same in arms. CONCLUSION: Although this prospective randomized study did not meet the accrual target, early introduction of diet was well tolerated and did not show a negative or positive difference in any outcomes. Enhanced recovery protocols standardize postoperative care and early feeding is a well-tolerated addition.

Is peri-operative urethral catheter drainage enough? The case for stentless pediatric robotic pyeloplasty.

BACKGROUND: The necessity for urinary diversion with trans-anastomotic ureteral stenting during pyeloplasty is currently under debate. Performing a stentless repair could eliminate stent-related morbidity, including: stent migration, urinary tract infection, flank pain, and bladder spasms. In addition, there would be no need for a second procedure and associated anesthesia required for stent removal. This study describes the outcomes of robotic-assisted laparoscopic pyeloplasty without use of a ureteral stent. MATERIALS AND METHODS: An IRB-approved prospective database of all pediatric patients undergoing robotic pyeloplasty from July 2012 to July 2014 at a single institution was reviewed. The 'bypass pyeloplasty' or Anderson-Hynes dismembered pyeloplasty (DP) technique was performed. In both groups, neither a ureteral stent nor an abdominal drainage catheter was utilized. Complications were recorded, including: postoperative pain, bladder spasms, fever, and urinary tract infections. Follow-up renal ultrasound was reviewed for hydronephrosis. RESULTS: Twenty-seven children (17 male, 10 female) with a mean age of 25 months (range 6-157 months) underwent robotic ureteral stentless pyeloplasty during the study time period. The bypass pyeloplasty technique was performed on 19 children (70%). Mean length of stay was 20.2 hours (range 11-46). No fever, urinary tract infections, or hematuria requiring intervention were experienced. Additionally, there were no reports of bladder spasms or pain requiring pharmacotherapy. The mean follow-up was 8 months (range 4-21). Pre-operative Society of Fetal Urology grading was 3.5 and 3.4 for the dismembered and bypass cohort, respectively, with improvements to 1.1 for both groups at 3 months. Postoperative renal ultrasound hydronephrosis resolved in eight children (29.6%), improved in 14 (51.9%), and was stable in five (18.5%). The overall success rate was 100%. DISCUSSION: This study was limited by its small cohort and short follow-up, which may not thoroughly describe the efficacy of the stentless repair as it has been shown that stricture and re-obstruction can occur several years after surgery. CONCLUSIONS: Robotic stentless pyeloplasty is a feasible alternative to conventional methods, with excellent success rates and minimal complications. Importantly, this technique circumvents the need for a second procedure and the associated risks of anesthesia.

Male Urethral, Penile, and Incontinence Surgery: Is Resident Exposure Adequate?

OBJECTIVE: To evaluate trends in male urethral and penis/incontinence case volumes among urology residents and assess these for adequate surgical training/competency. METHODS: Accreditation Council for Graduate Medical Education (ACGME) case logs of urology residents graduating from U.S. programs from 2009 to 2013 were reviewed to determine the surgical volume of select index categories. Male urethral cases encompass urethrectomy and urethroplasty, whereas male penis/incontinence cases include urethral slings and sphincters. Case volumes as "surgeon," "assistant," and "teaching assistant" were reviewed and compared to ACGME minimum requirements. RESULTS: A total of 1032 graduating residents reported case logs. For male urethral surgery, residents reported weighted averages (standard deviation [SD]) of 12.7 (9.0) cases as "surgeon," 1.5 (3.5) cases as "assistant," and 0.2 (1.0) as "teaching assistant." The minimum requirement for these cases is 5. The annual 10th percentiles as "surgeon" ranged from 4 to 5 cases throughout the study period. For male penis/incontinence cases, residents reported weighted averages (SD) of 45.5 (22.7) cases as "surgeon," 3.6 (5.5) cases as "assistant," and 1.5 (3.0) cases as "teaching assistant." The minimum requirement is 10 cases. The 10th percentiles as "surgeon" ranged from 19 to 23 cases. CONCLUSION: Although the majority of residents met the minimum standard for these cases, about 10% of residents did not meet the requirement for male urethral surgery. In addition, a review of learning curves for these procedures suggests that the ACGME minimum requirements may be insufficient to confer actual competency in skill. Increasing this number in training or specialized postgraduate training programs is needed to provide actual competency.