Full-colour 3D holographic augmented-reality displays with metasurface waveguides.

Emerging spatial computing systems seamlessly superimpose digital information on the physical environment observed by a user, enabling transformative experiences across various domains, such as entertainment, education, communication and training1-3. However, the widespread adoption of augmented-reality (AR) displays has been limited due to the bulky projection optics of their light engines and their inability to accurately portray three-dimensional (3D) depth cues for virtual content, among other factors4,5. Here we introduce a holographic AR system that overcomes these challenges using a unique combination of inverse-designed full-colour metasurface gratings, a compact dispersion-compensating waveguide geometry and artificial-intelligence-driven holography algorithms. These elements are co-designed to eliminate the need for bulky collimation optics between the spatial light modulator and the waveguide and to present vibrant, full-colour, 3D AR content in a compact device form factor. To deliver unprecedented visual quality with our prototype, we develop an innovative image formation model that combines a physically accurate waveguide model with learned components that are automatically calibrated using camera feedback. Our unique co-design of a nanophotonic metasurface waveguide and artificial-intelligence-driven holographic algorithms represents a significant advancement in creating visually compelling 3D AR experiences in a compact wearable device.

Data integration and inference of gene regulation using single-cell temporal multimodal data with scTIE.

Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space by using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal data sets, we show scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome data set we generated from differentiating mouse embryonic stem cells over time, we show scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.

High-brightness holographic projection.

We propose a holographic projection system that achieves high image quality, brightness, and light efficiency. Using a novel, to the best of our knowledge, light-efficiency loss function, we are able to concentrate more light on the projection region and improve display brightness compared with conventional projectors. Leveraging emerging artificial intelligence-driven computer-generated holography and camera-in-the-loop calibration techniques, we learn a holographic wave propagation model using experimentally captured holographic images and demonstrate state-of-the-art light reallocation performance with high image quality.

scTIE: data integration and inference of gene regulation using single-cell temporal multimodal data.

Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mechanisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal datasets, we demonstrate scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome dataset we generated from differentiating mouse embryonic stem cells over time, we demonstrate scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.

Anterolateral Thigh Phalloplasty With Staged Skin Graft Urethroplasty: Technique and Outcomes.

OBJECTIVE: 1) To describe the authors' technique of anterolateral thigh (ALT) phalloplasty with staged skin graft urethroplasty and 2) to report the surgical outcomes and complications of this technique in a preliminary patient cohort. METHODS: Following IRB (Institutional Review Board) approval, retrospective chart review identified all patients undergoing primary three-stage ALT phalloplasty by the senior authors. Stage I involves single tube, pedicled ALT transfer. Stage II involves vaginectomy, pars fixa urethroplasty, scrotoplasty, and opening the ALT ventrally and construction of a urethral plate with split-thickness skin graft. Stage III involves tubularization of the urethral plate to create the penile urethra. Data collected included patient demographics, intraoperative details, postoperative courses, and complications. RESULTS: Twenty-four patients were identified. Twenty-two patients (91.7%) underwent ALT phalloplasty prior to vaginectomy. All patients underwent staged split-thickness skin grafting for the penile urethra reconstruction. Twenty-one patients (87.5%) achieved standing micturition at the time of data collection. Eleven patients (44.0%) experienced at least 1 urologic complication requiring additional operative intervention, most commonly urethrocutaneous fistulae (8 patients, 33.3%), and urethral strictures (5 patients, 20.8%). CONCLUSION: ALT phalloplasty with split-thickness skin grafting for urethral lengthening is an alternative technique to achieve standing micturition with an acceptable complication rate in gender-affirming phalloplasty.

Robotic-Assisted Testicular Autotransplantation.

Silber and Kelly first described the successful autotransplantation of an intra-abdominal testis in 1976. Subsequent authors incorporated laparoscopy and demonstrated the viability of transplanted testes based on serial postoperative exams. We sought to extend this experience with use of the da Vinci surgical robot, thereby demonstrating a novel robotic technique for the management of cryptorchidism. The procedure was performed for an 18-year-old male with a solitary left intra-abdominal testis. Following establishment of pneumoperitoneum, the robot is docked with four trocars oriented towards the left lower quadrant. Testicular dissection is carried out as shown. The gonadal and inferior epigastric vessels are isolated and mobilized; once adequate length is achieved, the former is clipped and transected, and the testicle and inferior epigastric vessels are delivered out of the body. The robot is then undocked and exchanged for the operating microscope. Arterial and venous anastomoses are completed with interrupted and running 9-0 Nylon, respectively, and satisfactory re-anastomosis is confirmed visually and with Doppler. The transplanted testicle is then fixed inferiorly and laterally within the left hemiscrotum, and all incisions are closed. We note that intraoperative testicular biopsy was not performed, for three reasons: (1) to avoid further risk to an already tenuous, solitary organ, (2) because our primary aim was to preserve testicular endocrine function, and (3) because the presence of ITGCN would neither prompt orchiectomy nor obviate the need for ongoing surveillance via periodic self-examination and ultrasonography. The patient is maintained on bed rest for two days and discharged on postoperative day seven in good condition. Over one year since autotransplantation, his now intra-scrotal testicle remains palpable and stable in size. Serum testosterone is unchanged from preoperative measurements. Robotic-assisted testicular autotransplantation is a feasible and efficacious management option for the solitary intra-abdominal testis.

5-Year Outcomes Following Focal Laser Ablation of Prostate Cancer.

OBJECTIVE: To characterize the oncologic outcomes 5 years following focal laser ablation (FLA) of localized prostate cancer. METHODS: 36 men underwent in-bore FLA of prostate cancer at our institution between 2013 and 2015. Follow up included digital rectal examination and PSA testing, multiparametric MRI, and MR-guided biopsies. The primary outcome of interest was failure-free survival (FFS), defined as avoidance of salvage whole gland treatment, systemic therapy, metastasis, or death from prostate cancer. RESULTS: Of the 36 men enrolled, 6 were ultimately lost to follow-up. Of the remaining 30, 25 (83%) have remained free from failure over a median follow-up of 71 months'. Among these patients, 10 (40%) developed in-field recurrence, with 9 undergoing salvage partial gland ablation with FLA, cryotherapy, or high-intensity focused ultrasound. Five patients underwent salvage whole gland or systemic treatment and were thus considered to have failed treatment. Two patients developed metastatic disease, and after receiving radiation and ADT, both currently have undetectable PSA levels. No patients in the cohort died from prostate cancer. Limitations include a small study cohort and lack of standardized surveillance protocols 2 years after treatment. CONCLUSION: FLA for select cases of prostate cancer provides high rates of FFS, defined as freedom from whole gland or systemic treatment, metastasis, or death from prostate cancer. However, in- or out-of-field recurrence is common and often necessitates salvage ablation.

Followup of Men with PI-RADS™ 4 or 5 Abnormality on Prostate Magnetic Resonance Imaging and Nonmalignant Pathological Findings on Initial Targeted Prostate Biopsy.

PURPOSE: A benign magnetic resonance imaging targeted prostate biopsy in the setting of a PI-RADS™ 4/5 abnormality presents a clinical dilemma for future management. We evaluated benign histological features on magnetic resonance imaging targeted prostate biopsy to determine if they predict the likelihood of missed cancer on subsequent biopsy. MATERIALS AND METHODS: Between June 2012 and September 2016, 1,595 men were enrolled in a prospective study of magnetic resonance imaging targeted and systematic biopsy outcomes. We re-reviewed pathology from benign biopsies of PI-RADS 4/5 abnormalities and divided them into 5 groups for comparison to outcomes of clinical followup: inflammation (38%), stroma/glandular hyperplasia (9%), normal prostate tissue (28%), atypical small acinar proliferation/high grade prostatic intraepithelial neoplasia (9%) and cancer in adjacent systematic cores (16%). RESULTS: Of 497 men 88 (18%) with PI-RADS 4/5 abnormality prior to initial biopsy had no cancer on magnetic resonance imaging targeted prostate biopsy. On followup, 45 men underwent repeat magnetic resonance imaging: 12 (27%) had persistent PI-RADS 4/5 abnormalities, 17 (38%) had PI-RADS 2/3, 16 (35%) had PI-RADS 1. On repeat magnetic resonance imaging targeted prostate biopsy, cancer was found in 62.5% of men with PI-RADS 4/5 and 23% of men with PI-RADS 2/3. Histological groups on initial biopsy were not predictive of the likelihood of PI-RADS downgrade on repeat magnetic resonance imaging or cancer detection on repeat biopsy. CONCLUSIONS: Among men with no cancer on magnetic resonance imaging targeted prostate biopsy performed for PI-RADS abnormality, downgrade of PI-RADS score is noted in 73% on repeat magnetic resonance imaging. Persistence of PI-RADS 4/5 predicts a higher risk of missed cancer, warranting prompt re-biopsy. While histological findings such as inflammation may underlie some PI-RADS 4/5 abnormalities, initial histology is a poor predictor of cancer likelihood on repeat biopsy.

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.

Multi-institutional Experience Comparing Outcomes of Adult Patients Undergoing Secondary Versus Primary Robotic Pyeloplasty.

OBJECTIVE: To describe surgical techniques and peri-operative outcomes with secondary robotic pyeloplasty (RP), and compare them to those of primary RP. METHODS: We retrospectively reviewed our multi-institutional, collaborative of reconstructive robotic ureteral surgery (CORRUS) database for all consecutive patients who underwent RP between April 2012 and September 2019. Patients were grouped according to whether they underwent a primary or secondary pyeloplasty (performed for a recurrent stricture after previously failed pyeloplasty). Perioperative outcomes and surgical techniques were compared using nonparametric independent sample median tests and chi-square tests; P < .05 was considered significant. RESULTS: Of 158 patients, 28 (17.7%) and 130 (82.3%) underwent secondary and primary RP, respectively. Secondary RP, compared to primary RP, was associated with a higher median estimated blood loss (100.0 vs 50.0 milliliters, respectively; P < .01) and longer operative time (188.0 vs 136.0 minutes, respectively; P = .02). There was no difference in major (Clavien >2) complications (P = .29). At a median follow-up of 21.1 (IQR: 11.8-34.7) months, there was no difference in success between secondary and primary RP groups (85.7% vs 92.3%, respectively; P = .44). Buccal mucosa graft onlay ureteroplasty was performed more commonly (35.7% vs 0.0%, respectively, P < .01) and near-infrared fluorescence imaging with indocyanine green was utilized more frequently (67.9% vs 40.8%, respectively; P < .01) for secondary vs primary repair. CONCLUSION: Although performing secondary RP is technically challenging, it is a safe and effective method for recurrent ureteropelvic junction obstruction after a previously failed pyeloplasty. Buccal mucosa graft onlay ureteroplasty and utilization of near-infrared fluorescence with indocyanine green may be particularly useful in the re-operative setting.

Psychiatric Diagnoses and Treatment Preceding Schizophrenia in Adolescents Aged 9-17 Years.

OBJECTIVE: Our study aimed to examine psychiatric diagnoses and treatment preceding a schizophrenia diagnosis in adolescents, stratified by sex and race/ethnicity. METHODS: Using Medicaid physical and behavioral health and pharmacy claims data, we identified 1,459 adolescents who were aged 9-17 years and diagnosed with schizophrenia between January 2006 through June 2009. Psychiatric diagnosis, mental health service use including psychiatric hospitalization, residential treatment and outpatient therapy and psychotropic medication use preceding schizophrenia were identified. RESULTS: Forty-five percent of the adolescents were diagnosed with one or more psychiatric conditions. More than 40% of the adolescents were hospitalized or placed in a residential treatment facility for other psychiatric conditions preceding schizophrenia. Overall, 72% of the adolescents were prescribed with one or more psychotropic medications and 22% were prescribed with three or more psychotropic medications in the year prior to their first schizophrenia diagnosis. We found that sex and race/ethnicity influence preceding psychiatric conditions and psychiatric treatment use. CONCLUSIONS: Careful screening and evaluation to validate diagnoses is important as the presence of certain psychiatric morbidity is common among adolescents with schizophrenia during the prodromal period. Developing acceptable and accessible interventions that will reduce psychiatric hospitalization and residential treatment care and improve care connection for schizophrenia treatment is important to mitigate complexity in treatment for adolescents and reduce cost burden for families and the society. Integrating health claims data in the development of schizophrenia risk conversion models can be useful in effectively predicting ideal timing of tailored interventions for adolescents with preceding psychiatric conditions.

High Response Rates to Neoadjuvant Chemotherapy in High-Grade Upper Tract Urothelial Carcinoma.

OBJECTIVE: To evaluate the impact of cisplatin-based neoadjuvant chemotherapy (NAC) in patients who underwent nephroureterectomy for high-grade (HG) upper tract urothelial carcinoma (UTUC). METHODS: Retrospective review was conducted of patients with HG UTUC from 2011 to 2017 who underwent nephroureterectomy at 2 institutions. Patients with eGFR >50 mL/min/1.73 m2 were considered eligible for NAC and were referred for evaluation of NAC prior to nephroureterectomy. Patient demographics, kidney function, clinical and pathologic response rates, and outcomes were analyzed. RESULTS: Of 95 patients with HG UTUC meeting inclusion criteria (mean age 72.3 years, mean preop eGFR 57.0 mL/min/1.73 m2), 61 patients were considered eligible for NAC with eGFR >50 mL/min/1.73 m2, of which 25 (41%) received NAC. Of the patients who received NAC, 80% (20/25) of the patients had clinical response on imaging and 80% (20/25) had pathologic response (

Discordance between Ureteroscopic Biopsy and Final Pathology for Upper Tract Urothelial Carcinoma.

PURPOSE: We evaluated the discordance between ureteroscopic biopsy and surgical pathology findings for grading and staging upper tract urothelial carcinoma. We also sought to establish preoperative predictors of aggressive tumors. MATERIALS AND METHODS: We retrospectively reviewed the records of 314 patients who underwent ureteroscopic biopsy followed by surgical management of upper tract urothelial carcinoma from 2000 to 2016 at a total of 3 institutions. Our primary outcomes were muscle invasive (pT2 or greater) disease at surgical pathology and upgrading of clinical low grade tumors to pathological high grade. RESULTS: At biopsy 61% of the patients had clinical high grade tumors and 21% had subepithelial connective tissue invasion (cT1+). On final pathology 79% of the patients had pathological high grade tumors and 45% had stage pT2 or greater. On multivariate analysis advanced patient age, clinical high grade and cT1+ were independently associated with pT2 or greater. The combined presence of clinical high grade and cT1+ had 86% positive predictive value for muscle invasion while the combined absence of clinical high grade and cT1+ had 80% negative predictive value. The likelihood of missing invasion on biopsy in patients with muscle invasive disease was increased when biopsy fragments were limited to 1 mm or less. Of clinical low grade cases on biopsy 51% were upgraded at surgery. The presence of positive urine cytology was associated with an increased risk of upgrading but this was not statistically significant. CONCLUSIONS: Clinical high grade, cT1+ on biopsy and advanced patient age are independent risk factors for muscle invasive upper tract urothelial carcinoma. There is a significant risk of upgrading in patients with clinical low grade tumors on biopsy, especially when urine cytology is positive. The predictive value of biopsy can likely be improved by more extensive ureteroscopic sampling.

Two-year Outcomes Following Focal Laser Ablation of Localized Prostate Cancer.

BACKGROUND: There is no consensus regarding how to assess oncological control following focal ablation of prostate cancer. OBJECTIVE: To assess quality of life and in-field recurrence following focal laser ablation (FLA). DESIGN, SETTING, AND PARTICIPANTS: Of 34 men participating in a prospective outcomes study following FLA, 32 underwent prostate-specific antigen (PSA) testing and magnetic resonance imaging (MRI) at 6 mo and 2 yr. All underwent assessment of urinary and sexual function at 1 yr. INTERVENTION: FLA and MRI-targeted biopsy of the ablation zone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The American Urological Association Symptom Score and the Sexual Health Inventory for Men at baseline and 12 mo were compared using a two-sided Wilcoxon signed-rank test with a significance level of p=0.05. The percentage of positive and negative in-field biopsies was calculated for suspicious and nonsuspicious post-ablation MRI scans. RESULTS AND LIMITATIONS: FLA was associated with no adverse impact on urinary or sexual function. For men with suspicious MRI (MRI+) findings, in-field disease recurrence of intermediate and low risk disease was detected in 75% and 25% of cases, respectively. For men with nonsuspicious MRI (MRI-) findings, in-field disease recurrence of intermediate- and low-risk disease was detected in 22.4% and 50% of cases, respectively. The change in PSA from baseline did not discriminate cases with MRI- findings with and without cancer at 2 yr. CONCLUSIONS: MRI reliably identifies in-field recurrence of only intermediate-risk prostate cancer at 2 yr after FLA. A biopsy of the ablation zone must be performed for MRI+ findings. The decision to perform an ablation-zone biopsy for men with MRI- scans should be influenced by whether detection of low-risk disease would influence management. PATIENT SUMMARY: Our study provides compelling evidence that men should undergo interval magnetic resonance imaging to assess the probability of intermediate-risk disease in the ablation zone following focal laser ablation of localized prostate cancer.

Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics.

Islet amyloidosis by IAPP contributes to pancreatic ß-cell death in diabetes, but the nature of toxic IAPP species remains elusive. Using concurrent time-resolved biophysical and biological measurements, we define the toxic species produced during IAPP amyloid formation and link their properties to induction of rat INS-1 ß-cell and murine islet toxicity. These globally flexible, low order oligomers upregulate pro-inflammatory markers and induce reactive oxygen species. They do not bind 1-anilnonaphthalene-8-sulphonic acid and lack extensive ß-sheet structure. Aromatic interactions modulate, but are not required for toxicity. Not all IAPP oligomers are toxic; toxicity depends on their partially structured conformational states. Some anti-amyloid agents paradoxically prolong cytotoxicity by prolonging the lifetime of the toxic species. The data highlight the distinguishing properties of toxic IAPP oligomers and the common features that they share with toxic species reported for other amyloidogenic polypeptides, providing information for rational drug design to treat IAPP induced ß-cell death.