FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer.

FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.

Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor.

BACKGROUND: Prostate cancer is dependent on androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) has proven effective in targeting prostate cancer. However, castration-resistant prostate cancer (CRPC) eventually emerges. AR signaling inhibitors (ARSI) have been also used, but resistance to these agents develops due to genetic AR alterations and epigenetic dysregulation. METHODS: In this study, we investigated the role of OCT1, a member of the OCT family, in an AR-positive CRPC patient-derived xenograft established from a patient with resistance to ARSI and chemotherapy. We conducted a genome-wide analysis chromatin immunoprecipitation followed by sequencing and bioinformatic analyses using public database. RESULTS: Genome-wide analysis of OCT1 target genes in PDX 201.1 A revealed distinct OCT1 binding sites compared to treatment-naïve cells. Bioinformatic analyses revealed that OCT1-regulated genes were associated with cell migration and immune system regulation. In particular, C-terminal Binding Protein 2 (CTBP2), an OCT1/AR target gene, was correlated with poor prognosis and immunosuppressive effects in the tumor microenvironment. Metascape revealed that CTBP2 knockdown affects genes related to the immune response to bacteria. Furthermore, TISIDB analysis suggested the relationship between CTBP2 expression and immune cell infiltration in prostate cancer, suggesting that it may contribute to immune evasion in CRPC. CONCLUSIONS: Our findings shed light on the genome-wide network of OCT1 and AR in AR-positive CRPC and highlight the potential role of CTBP2 in immune response and tumor progression. Targeting CTBP2 may represent a promising therapeutic approach for aggressive AR-positive CRPC. Further validation will be required to explore novel therapeutic strategies for CRPC management.

Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer.

There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing.

Natural killer (NK) cells' unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials and likely require advanced genome engineering to reach their full potential as a cancer therapeutic. Multiplex genome editing with CRISPR/Cas9 base editors (BE) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations. We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function. Next, we combined multiplex BE with non-viral TcBuster transposon-based integration to generate IL-15 armored CD19 CAR-NK cells with significantly improved functionality in a highly suppressive model of Burkitt's lymphoma both in vitro and in vivo. The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated.

Defining the challenges and opportunities for using patient-derived models in prostate cancer research.

BACKGROUND: There are relatively few widely used models of prostate cancer compared to other common malignancies. This impedes translational prostate cancer research because the range of models does not reflect the diversity of disease seen in clinical practice. In response to this challenge, research laboratories around the world have been developing new patient-derived models of prostate cancer, including xenografts, organoids, and tumor explants. METHODS: In May 2023, we held a workshop at the Monash University Prato Campus for researchers with expertise in establishing and using a variety of patient-derived models of prostate cancer. This review summarizes our collective ideas on how patient-derived models are currently being used, the common challenges, and future opportunities for maximizing their usefulness in prostate cancer research. RESULTS: An increasing number of patient-derived models for prostate cancer are being developed. Despite their individual limitations and varying success rates, these models are valuable resources for exploring new concepts in prostate cancer biology and for preclinical testing of potential treatments. Here we focus on the need for larger collections of models that represent the changing treatment landscape of prostate cancer, robust readouts for preclinical testing, improved in vitro culture conditions, and integration of the tumor microenvironment. Additional priorities include ensuring model reproducibility, standardization, and replication, and streamlining the exchange of models and data sets among research groups. CONCLUSIONS: There are several opportunities to maximize the impact of patient-derived models on prostate cancer research. We must develop large, diverse and accessible cohorts of models and more sophisticated methods for emulating the intricacy of patient tumors. In this way, we can use the samples that are generously donated by patients to advance the outcomes of patients in the future.

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.

Impact of the COVID-19 pandemic on diagnosis of renal cell carcinoma and disease stage at presentation.

INTRODUCTION: Renal cell carcinoma (RCC) is often associated with significant morbidity and mortality, with overall survival contingent on multiple factors - most importantly, disease stage at diagnosis. Disruptions in healthcare delivery during the COVID-19 pandemic have resulted in various reported diagnostic and treatment delays, which have had detrimental impacts on malignancies such as RCC. METHODS: Surgically managed cases of RCC at our center were identified using a retrospective chart review of all nephrectomies conducted from March 1, 2018, to February 28, 2023. Examination of disease characteristics in three time period cohorts (before, during, and following the COVID-19 pandemic) was undertaken. Timeframes were consistent with implementation and abolition of public health restrictions in the province of Newfoundland and Labrador. RESULTS: A total of 483 surgically managed RCC cases were identified during the study period. The median age was 65 years (interquartile range [IQR] 56-71), and 62.3% of patients were male. Demographics did not vary across timeframes. Before and during the pandemic, pathologic stage 3 (pT3) disease was reported in 38.9% and 35.4% of cases, respectively, whereas the post-pandemic period saw this presentation in 50.0% of patients. Surgical wait times increased significantly across study timeframes (p=0.003). CONCLUSIONS: The first year following the COVID-19 pandemic saw an 11.1% increase in patients presenting with pT3 RCC. These findings are suggestive of a clinically significant stage migration, which paired with prolonged wait times for surgery, provide critical consideration in the urgency of diagnostic and treatment decisions for RCC in the immediate future.

The commercial promotion of electronic cigarettes on social media and its influence on positive perceptions of vaping and vaping behaviours in Anglophone countries: A scoping review.

There is ongoing scientific and policy debate about the role e-cigarettes play in tobacco control, with concerns centring around unknown long-term effects, and the potential industry co-option of harm reduction efforts, including marketing to youths. There is substantial evidence of the influence of conventional cigarette promotion on smoking behaviours in Anglophone countries, and the popularity of social networking sites, as well as the lack of marketing regulations on the commercial promotion of electronic cigarettes online, suggest an urgent need to explore this topic further. This scoping review aims to map the existing evidence related to the influence of e-cigarette commercial promotion on social media on positive perceptions of vaping and vaping behaviours in core Anglophone countries. Searches were conducted in CENTRAL, Cochrane Database of Systematic Reviews (CDSR), Embase, Epistemonikos, MEDLINE, PsycINFO and Science Citation Index, on the 21st of July 2022. From 1,385 studies, 11 articles were included in the final review, using diverse study designs, including focus groups, content analysis, cross-sectional studies, and experiments. The studies were primarily based in the U.S. and evidenced the association between the commercial promotion of e-cigarettes on social media with positive perceptions of vaping and vaping behaviours, particularly among young people, addressing diverse themes including celebrities' sponsorship, e-liquid appeal (including flavours and nicotine levels), users' engagement with ads, and other marketing strategies. Further, social networking sites commercially promoting e-cigarettes might increase positive attitudes towards vaping and vaping behaviours, particularly among youths. Future research should be conducted in broader settings, incorporate larger and diverse sample sizes, ensure research transparency, cover multiple social networking sites, emphasize ecological validity, and foment longitudinal studies.

FGFR1 Signaling Facilitates Obesity-Driven Pulmonary Outgrowth in Metastatic Breast Cancer.

Survival of dormant, disseminated breast cancer cells contributes to tumor relapse and metastasis. Women with a body mass index greater than 35 have an increased risk of developing metastatic recurrence. Herein, we investigated the effect of diet-induced obesity (DIO) on primary tumor growth and metastatic progression using both metastatic and systemically dormant mouse models of breast cancer. This approach led to increased PT growth and pulmonary metastasis. We developed a novel protocol to induce obesity in Balb/c mice by combining dietary and hormonal interventions with a thermoneutral housing strategy. In contrast to standard housing conditions, ovariectomized Balb/c mice fed a high-fat diet under thermoneutral conditions became obese over a period of 10 weeks, resulting in a 250% gain in fat mass. Obese mice injected with the D2.OR model developed macroscopic pulmonary nodules compared with the dormant phenotype of these cells in mice fed a control diet. Analysis of the serum from obese Balb/c mice revealed increased levels of FGF2 as compared with lean mice. We demonstrate that serum from obese animals, exogenous FGF stimulation, or constitutive stimulation through autocrine and paracrine FGF2 is sufficient to break dormancy and drive pulmonary outgrowth. Blockade of FGFR signaling or specific depletion of FGFR1 prevented obesity-associated outgrowth of the D2.OR model. IMPLICATIONS: Overall, this study developed a novel DIO model that allowed for demonstration of FGF2:FGFR1 signaling as a key molecular mechanism connecting obesity to breakage of systemic tumor dormancy and metastatic progression.

Development of a job-exposure matrix-like exposure assessment method for the US general population based on Occupational Information Network (O*NET) job tasks.

BACKGROUND: Job-exposure matrices (JEMs) are often used for exposure assessment in occupational exposure and epidemiology studies. However, general population JEMs are difficult to find and access for workers in the United States of America. OBJECTIVE: We aimed to use publicly available information to develop a JEM-like exposure assessment method to determine exposure to a wide range of occupational agents in a wide range of occupations for US general population studies. METHODS: We used information from the US Department of Labor's Occupational Information Network database (O*NET) for 19,636 job tasks and 974 civilian occupations. We used automated keyword searches to identify 1,804 job tasks that involved exposure to 50 occupational agents. We had 2 reviewers determine whether each identified job task actually involved exposure to the 50 occupational agents. We had a third reviewer, a certified industrial hygienist, assess any job task and exposure for which the first 2 reviewers disagreed. For each U.S. Census 2010 occupation code, we used this information to derive 3 exposure variables for each occupational agent: ever exposure, number of job tasks of exposure, and frequency of exposure. RESULTS: Our keyword searches identified a median of 10 (interquartile range [IQR]: 43.75) job tasks for each occupational agent, and the maximum was 308. We determined job tasks actually involved exposure to 45 occupational agents, including solvents, air pollution, pesticides, radiation, metals, etc. We derived the 3 exposure variables for these 45 occupational agents for 516 U.S. Census 2010 occupation codes. The median percentage for ever exposure to individual occupational agents was 1.16% (IQR: 1.74%), and the maximum was 11.43%. CONCLUSIONS: Our JEM-like exposure assessment method based on O*NET information can be used to determine exposure to a wide range of occupational agents in a wide range of occupations for the US general population.

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice.

Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Republication of "Open Repair of Acute Achilles Tendon Ruptures: Is the Incidence of Clinically Significant Wound Complications Overestimated?"

Background: Conflicting evidence exists regarding the optimal management of acute Achilles tendon ruptures. Operative repair is thought to afford patients a lower risk of rerupture, albeit at a higher overall risk of wound complications. Methods: A retrospective chart review of 369 consecutive patients undergoing open repair of acute Achilles tendon ruptures performed by a single foot and ankle fellowship-trained orthopedic surgeon was undertaken. Healing was classified as no complications, complications without prolonging treatment, complications requiring prolonged local treatment, and complications requiring operative intervention. A statistical analysis comparing the rates of complications in this cohort to that reported in the literature was conducted. Results: There were a total of 33 (8.94%) wound complications. Compared to the rates reported in the literature, no significant difference was detected (P = .3943; CI 6.24-12.33). However, when the complications not requiring additional treatment or prolonged care were excluded, only 9 wound complications (2.44%) were identified-a significantly lower complication rate than that reported in the literature (P < .0001; CI 1.12-4.58). There were only 2 (0.54%) major complications requiring operative intervention, also a significantly lower rate than in the literature (P < .0001; CI 0.067-1.94). Conclusion: In the past, wound-healing complications have been cited as a concern when treating patients operatively. We found that when solely looking at healing complications prolonging the patients' overall recovery, a significantly lower rate of complications existed compared to that reported in the literature. Level of Evidence: Level IV.

Transcriptome architecture of the three main lineages of agrobacteria.

Agrobacteria are a diverse, polyphyletic group of prokaryotes with multipartite genomes capable of transferring DNA into the genomes of host plants, making them an essential tool in plant biotechnology. Despite their utility in plant transformation, genome-wide transcriptional regulation is not well understood across the three main lineages of agrobacteria. Transcription start sites (TSSs) are a necessary component of gene expression and regulation. In this study, we used differential RNA-seq and a TSS identification algorithm optimized on manually annotated TSS, then validated with existing TSS to identify thousands of TSS with nucleotide resolution for representatives of each lineage. We extend upon the 356 TSSs previously reported in Agrobacterium fabrum C58 by identifying 1,916 TSSs. In addition, we completed genomes and phenotyping of Rhizobium rhizogenes C16/80 and Allorhizobium vitis T60/94, identifying 2,650 and 2,432 TSSs, respectively. Parameter optimization was crucial for an accurate, high-resolution view of genome and transcriptional dynamics, highlighting the importance of algorithm optimization in genome-wide TSS identification and genomics at large. The optimized algorithm reduced the number of TSSs identified internal and antisense to the coding sequence on average by 90.5% and 91.9%, respectively. Comparison of TSS conservation between orthologs of the three lineages revealed differences in cell cycle regulation of ctrA as well as divergence of transcriptional regulation of chemotaxis-related genes when grown in conditions that simulate the plant environment. These results provide a framework to elucidate the mechanistic basis and evolution of pathology across the three main lineages of agrobacteria. IMPORTANCE Transcription start sites (TSSs) are fundamental for understanding gene expression and regulation. Agrobacteria, a group of prokaryotes with the ability to transfer DNA into the genomes of host plants, are widely used in plant biotechnology. However, the genome-wide transcriptional regulation of agrobacteria is not well understood, especially in less-studied lineages. Differential RNA-seq and an optimized algorithm enabled identification of thousands of TSSs with nucleotide resolution for representatives of each lineage. The results of this study provide a framework for elucidating the mechanistic basis and evolution of pathology across the three main lineages of agrobacteria. The optimized algorithm also highlights the importance of parameter optimization in genome-wide TSS identification and genomics at large.

Development of a Classification System for Live Surgical Feedback.

Importance: Live feedback in the operating room is essential in surgical training. Despite the role this feedback plays in developing surgical skills, an accepted methodology to characterize the salient features of feedback has not been defined. Objective: To quantify the intraoperative feedback provided to trainees during live surgical cases and propose a standardized deconstruction for feedback. Design, Setting, and Participants: In this qualitative study using a mixed methods analysis, surgeons at a single academic tertiary care hospital were audio and video recorded in the operating room from April to October 2022. Urological residents, fellows, and faculty attending surgeons involved in robotic teaching cases during which trainees had active control of the robotic console for at least some portion of a surgery were eligible to voluntarily participate. Feedback was time stamped and transcribed verbatim. An iterative coding process was performed using recordings and transcript data until recurring themes emerged. Exposure: Feedback in audiovisual recorded surgery. Main Outcomes and Measures: The primary outcomes were the reliability and generalizability of a feedback classification system in characterizing surgical feedback. Secondary outcomes included assessing the utility of our system. Results: In 29 surgical procedures that were recorded and analyzed, 4 attending surgeons, 6 minimally invasive surgery fellows, and 5 residents (postgraduate years, 3-5) were involved. For the reliability of the system, 3 trained raters achieved moderate to substantial interrater reliability in coding cases using 5 types of triggers, 6 types of feedback, and 9 types of responses (prevalence-adjusted and bias-adjusted κ range: a 0.56 [95% CI, 0.45-0.68] minimum for triggers to a 0.99 [95% CI, 0.97-1.00] maximum for feedback and responses). For the generalizability of the system, 6 types of surgical procedures and 3711 instances of feedback were analyzed and coded with types of triggers, feedback, and responses. Significant differences in triggers, feedback, and responses reflected surgeon experience level and surgical task being performed. For example, as a response, attending surgeons took over for safety concerns more often for fellows than residents (prevalence rate ratio [RR], 3.97 [95% CI, 3.12-4.82]; P = .002), and suturing involved more errors that triggered feedback than dissection (RR, 1.65 [95% CI, 1.03-3.33]; P = .007). For the utility of the system, different combinations of trainer feedback had associations with rates of different trainee responses. For example, technical feedback with a visual component was associated with an increased rate of trainee behavioral change or verbal acknowledgment responses (RR, 1.11 [95% CI, 1.03-1.20]; P = .02). Conclusions and Relevance: These findings suggest that identifying different types of triggers, feedback, and responses may be a feasible and reliable method for classifying surgical feedback across several robotic procedures. Outcomes suggest that a system that can be generalized across surgical specialties and for trainees of different experience levels may help galvanize novel surgical education strategies.

A Multi-institution Study on the Association of Virtual Reality Skills with Continence Recovery after Robot-assisted Radical Prostatectomy.

BACKGROUND: Virtual reality (VR) simulators are increasingly being used for surgical skills training. It is unclear what skills are best improved via VR, translate to live surgical skills, and influence patient outcomes. OBJECTIVE: To assess surgeons in VR and live surgery using a suturing assessment tool and evaluate the association between technical skills and a clinical outcome. DESIGN, SETTING, AND PARTICIPANTS: This prospective five-center study enrolled participants who completed VR suturing exercises and provided live surgical video. Graders provided skill assessments using the validated End-To-End Assessment of Suturing Expertise (EASE) suturing evaluation tool. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A hierarchical Poisson model was used to compare skill scores among cohorts and evaluate the association of scores with clinical outcomes. Spearman's method was used to assess correlation between VR and live skills. RESULTS AND LIMITATIONS: Ten novices, ten surgeons with intermediate expertise (median 64 cases, interquartile range [IQR] 6-80), and 26 expert surgeons (median 850 cases, IQR 375-3000) participated in this study. Intermediate and expert surgeons were significantly more likely to have ideal scores in comparison to novices for the subskills needle hold angle, wrist rotation, and wrist rotation needle withdrawal (p < 0.01). For both intermediate and expert surgeons, there was positive correlation between VR and live skills for needle hold angle (p < 0.05). For expert surgeons, there was a positive association between ideal scores for VR needle hold angle and driving smoothness subskills and 3-mo continence recovery (p < 0.05). Limitations include the size of the intermediate surgeon sample and clinical data limited to expert surgeons. CONCLUSIONS: EASE can be used in VR to identify skills to improve for trainee surgeons. Technical skills that influence postoperative outcomes may be assessable in VR. PATIENT SUMMARY: This study provides insights into surgical skills that translate from virtual simulation to live surgery and that have an impact on urinary continence after robot-assisted removal of the prostate. We also highlight the usefulness of virtual reality in surgical education.

Severity Grading Systems for Intraoperative Adverse Events. A Systematic Review of the Literature and Citation Analysis.

INTRODUCTION: The accurate assessment and grading of adverse events (AE) is essential to ensure comparisons between surgical procedures and outcomes. The current lack of a standardized severity grading system may limit our understanding of the true morbidity attributed to AEs in surgery. The aim of this study is to review the prevalence in which intraoperative adverse event (iAE) severity grading systems are used in the literature, evaluate the strengths and limitations of these systems, and appraise their applicability in clinical studies. METHODS: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. PubMed, Web of Science, and Scopus were queried to yield all clinical studies reporting the proposal and/or the validation of iAE severity grading systems. Google Scholar, Web of Science, and Scopus were searched separately to identify the articles citing the systems to grade iAEs identified in the first search. RESULTS: Our search yielded 2957 studies, with 7 studies considered for the qualitative synthesis. Five studies considered only surgical/interventional iAEs, while 2 considered both surgical/interventional and anesthesiologic iAEs. Two included studies validated the iAE severity grading system prospectively. A total of 357 citations were retrieved, with an overall self/nonself-citation ratio of 0.17 (53/304). The majority of citing articles were clinical studies (44.1%). The average number of citations per year was 6.7 citations for each classification/severity system, with only 2.05 citations/year for clinical studies. Of the 158 clinical studies citing the severity grading systems, only 90 (56.9%) used them to grade the iAEs. The appraisal of applicability (mean%/median%) was below the 70% threshold in 3 domains: stakeholder involvement (46/47), clarity of presentation (65/67), and applicability (57/56). CONCLUSION: Seven severity grading systems for iAEs have been published in the last decade. Despite the importance of collecting and grading the iAEs, these systems are poorly adopted, with only a few studies per year using them. A uniform globally implemented severity grading system is needed to produce comparable data across studies and develop strategies to decrease iAEs, further improving patient safety.

Ureteral Stent Placement Prior to Definitive Stone Treatment Is Associated With Higher Postoperative Emergency Department Visits and Opioid Prescriptions for Youth Having Ureteroscopy or Shock Wave Lithotripsy.

PURPOSE: Little is known about the impact of ureteral stents on youth having stone surgery. We evaluated the association of ureteral stent placement before or concurrent with ureteroscopy and shock wave lithotripsy with emergency department visits and opioid prescriptions among pediatric patients. MATERIALS AND METHODS: We conducted a retrospective cohort study of individuals aged 0-24 years who underwent ureteroscopy or shock wave lithotripsy from 2009-2021 at 6 hospitals in PEDSnet, a research network that aggregates electronic health record data from children's health systems in the United States. The exposure, primary ureteral stent placement, was defined as a stent placed concurrent with or within 60 days before ureteroscopy or shock wave lithotripsy. Associations between primary stent placement and stone-related ED visits and opioid prescriptions within 120 days of the index procedure were evaluated with mixed-effects Poisson regression. RESULTS: Two-thousand ninety-three patients (60% female; median age 15 years, IQR 11-17) had 2,477 surgical episodes; 2,144 were ureteroscopy and 333 were shock wave lithotripsy. Primary stents were placed in 1,698 (79%) ureteroscopy episodes and 33 (10%) shock wave lithotripsy episodes. Ureteral stents were associated with a 33% higher rate of emergency department visits (IRR 1.33; 95% CI 1.02-1.73) and a 30% higher rate of opioid prescriptions (IRR 1.30; 95% CI 1.10-1.53). The magnitudes of both associations were greater for shock wave lithotripsy. Results were similar for age <18 and were lost when restricted to concurrent stent placement. CONCLUSIONS: Primary ureteral stent placement was associated with more frequent emergency department visits and opioid prescriptions, driven by pre-stenting. These results support elucidating situations where stents are not necessary for youth with nephrolithiasis.

Automated Capture of Intraoperative Adverse Events Using Artificial Intelligence: A Systematic Review and Meta-Analysis.

Intraoperative adverse events (iAEs) impact the outcomes of surgery, and yet are not routinely collected, graded, and reported. Advancements in artificial intelligence (AI) have the potential to power real-time, automatic detection of these events and disrupt the landscape of surgical safety through the prediction and mitigation of iAEs. We sought to understand the current implementation of AI in this space. A literature review was performed to PRISMA-DTA standards. Included articles were from all surgical specialties and reported the automatic identification of iAEs in real-time. Details on surgical specialty, adverse events, technology used for detecting iAEs, AI algorithm/validation, and reference standards/conventional parameters were extracted. A meta-analysis of algorithms with available data was conducted using a hierarchical summary receiver operating characteristic curve (ROC). The QUADAS-2 tool was used to assess the article risk of bias and clinical applicability. A total of 2982 studies were identified by searching PubMed, Scopus, Web of Science, and IEEE Xplore, with 13 articles included for data extraction. The AI algorithms detected bleeding (n = 7), vessel injury (n = 1), perfusion deficiencies (n = 1), thermal damage (n = 1), and EMG abnormalities (n = 1), among other iAEs. Nine of the thirteen articles described at least one validation method for the detection system; five explained using cross-validation and seven divided the dataset into training and validation cohorts. Meta-analysis showed the algorithms were both sensitive and specific across included iAEs (detection OR 14.74, CI 4.7-46.2). There was heterogeneity in reported outcome statistics and article bias risk. There is a need for standardization of iAE definitions, detection, and reporting to enhance surgical care for all patients. The heterogeneous applications of AI in the literature highlights the pluripotent nature of this technology. Applications of these algorithms across a breadth of urologic procedures should be investigated to assess the generalizability of these data.