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Risk engineers conduct comprehensive risk assessments for many types of large projects, often singularly focused on the technical assessment. Overlooking comprehensive community stakeholders in the assessment process increases stakeholder skepticism, apprehension, and mistrust regarding safety, health and welfare of nearby stakeholders, for complex projects. Social experts repeatedly document connections between problem framing, communication processes, and risks. This paper considers formalizing connections between the risk register to stakeholder perceptions and communication plans. A theoretical Risk Perception Management (RPM) plan connects risks into communication plans based upon including social expert suggestions for four large projects: two bio-safety-level 4 (BSL-4) laboratories and two levee system assessment projects. The concept of a Risk Perception Management (RPM) Plan integrated with the risk register is presented. The paper shows how the RPM concept iteratively captures stakeholder perceptions to build associated communication plans, thus potentially increasing risk assessment value for stakeholders and decision-makers. [ABSTRACT FROM AUTHOR]

Introduction: Assessments in medical education play a central role in evaluating trainees' progress and eventual competence. Generative artificial intelligence is finding an increasing role in clinical care and medical education. The objective of this study was to evaluate the ability of the large language model ChatGPT to generate examination questions that are discriminating in the evaluation of graduating urology residents., Methods: Graduating urology residents representing all Canadian training programs gather yearly for a mock examination that simulates their upcoming board certification examination. The examination consists of a written multiple-choice question (MCQ) examination and an oral objective structured clinical examination. In 2023, ChatGPT Version 4 was used to generate 20 MCQs that were added to the written component. ChatGPT was asked to use Campbell-Walsh Urology, AUA, and Canadian Urological Association guidelines as resources. Psychometric analysis of the ChatGPT MCQs was conducted. The MCQs were also researched by 3 faculty for face validity and to ascertain whether they came from a valid source., Results: The mean score of the 35 examination takers on the ChatGPT MCQs was 60.7% vs 61.1% for the overall examination. Twenty-five of ChatGPT MCQs showed a discriminating index >0.3, the threshold for questions that properly discriminate between high and low examination performers. Twenty-five percent of ChatGPT MCQs showed a point biserial >0.2, which is considered a high correlation with overall performance on the examination. The assessment by faculty found that ChatGPT MCQs often provided incomplete information in the stem, provided multiple potentially correct answers, and were sometimes not rooted in the literature. Thirty-five percent of the MCQs generated by ChatGPT provided wrong answers to stems., Conclusions: Despite what seems to be similar performance on ChatGPT MCQs and the overall examination, ChatGPT MCQs tend not to be highly discriminating. Poorly phrased questions with potential for artificial intelligence hallucinations are ever present. Careful vetting for quality of ChatGPT questions should be undertaken before their use on assessments in urology training examinations.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)-treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea-treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0-240 minutes) for total GLP-1 and GIP were compared between groups, using non-parametric statistical methods. Post-meal GLP-1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate-sensitive potassium channel-independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Patient education is a fundamental aspect of self-management of diabetes. The aim of this study was to understand whether a social media platform is a viable method to deliver education to people with diabetes and understand if people would engage and interact with it., Methods: Education sessions were provided via 3 platforms in a variety of formats. "Tweetorials" and quizzes were delivered on the diabetes101 Twitter account, a virtual conference via Zoom and video presentations uploaded to YouTube. Audience engagement during and after the sessions were analyzed using social media metrics including impressions and engagement rate using Twitter analytics, Tweepsmap, and YouTube Studio., Results: A total of 22 "tweetorial" sessions and 5 quizzes with a total of 151 polls (both in tweetorial and quiz sessions) receiving a total of 21,269 votes took place. Overall, the 1-h tweetorial sessions gained 1,821,088 impressions with an engagement rate of 6.3%. The sessions received a total of 2,341 retweets, 2,467 replies and 10,060 likes. The quiz days included 113 polls receiving 16,069 votes. The conference covered 8 topics and was attended live by over 100 people on the day. The video presentations on YouTube have received a total of 2,916 views with a watch time of 281 h and 8,847 impressions., Conclusion: Despite the limitations of social media, it can be harnessed to provide relevant reliable information and education about diabetes allowing people the time and space to learn at their own pace.

High-throughput (HT) screening drug discovery, during which thousands or millions of compounds are screened, remains the key methodology for identifying active chemical matter in early drug discovery pipelines. Recent technological developments in mass spectrometry (MS) and automation have revolutionized the application of MS for use in HT screens. These methods allow the targeting of unlabelled biomolecules in HT assays, thereby expanding the breadth of targets for which HT assays can be developed compared to traditional approaches. Moreover, these label-free MS assays are often cheaper, faster, and more physiologically relevant than competing assay technologies. In this review, we will describe current MS techniques used in drug discovery and explain their advantages and disadvantages. We will highlight the power of mass spectrometry in label-free in vitro assays, and its application for setting up multiplexed cellular phenotypic assays, providing an exciting new tool for screening compounds in cell lines, and even primary cells. Finally, we will give an outlook on how technological advances will increase the future use and the capabilities of mass spectrometry in drug discovery., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: The International Urology Journal Club attracts global participation; however, its effectiveness as an educational resource is undetermined., Objective: To evaluate the effectiveness of the international Twitter-based urology journal club (#urojc) using Kirkpatrick's evaluation model and to quantify the development of #urojc into a robust educational platform., Design, Setting, and Participants: A 13-item survey was sent to 3127 followers of #urojc. Twitter metrics including number of users, tweets, and impressions during 24 mo of operation were obtained via a third-party service "Symplur." Tweets were qualitatively analyzed to assess for relevance. Kirkpatrick's four-level evaluation model (reaction, learning, behavior, and results) was applied to analyze impact and effectiveness., Results and Limitations: Survey participation rate was 48% (after accounting for spam and inactive accounts). The reaction (Kirkpatrick level 1) to #urojc was overwhelmingly positive. Consultant urologists were the most active participants while trainees reported highest educational value. As much as 45% of junior consultant urologists and trainees reported a change in practice as a result of #urojc participation. The number of unique users of #urojc almost doubled from yr 1 to 2. The number of tweets per month and author participation increased from yr 1 to 2. The proportion of content-relevant tweets remained stably high at approximately 60%. This study was unable to document any impact on knowledge, behavior, or outcomes of #urojc (Kirkpatrick levels 2-4). Silent observers who do not follow #urojc were not captured., Conclusions: To our knowledge, this is the first time Kirkpatrick's evaluation model has been applied to a journal club. The reaction to #urojc among survey responders is positive with change in practice also reported. It appears that #urojc achieves level 1 of Kirkpatrick's evaluation model. Further investigation is required for levels 2-4. Twitter-based journal clubs draw robust global participation and have inspired journal clubs in other specialties., Patient Summary: This report highlights the importance of the International Urology Journal Club as a potential educational resource of consultant urologists and trainees alike. Global participation was a major advantage of this platform. This journal club has inspired other medical specialties to follow suit., (Copyright © 2019 European Association of Urology. All rights reserved.)

Introduction: Crowdfunding is becoming an increasingly used resource for patients to cover costs related to medical care. These costs can be related directly to treatments or indirectly to loss of income or travel-related costs. Little is known as to the extent of which crowdfunding is used for urological disease here in Canada. This study offers a first look at the prevalence of crowdfunding for urological disease and the factors surrounding its use., Methods: In January 2020, we queried the GoFundMe internal search engine for fundraising campaigns regarding urological ailments. Results were categorized according to the major organs of urological disease., Results: Crowdfunding campaigns are very prevalent within several areas of urology. Prostate cancer and chronic kidney disease represent the most frequent reason for campaigns. Fundraising goals and actual funds raised for malignant disease were significantly more than for benign disease. Interestingly, there was a significant portion of crowdfunding campaigns to cover costs for non-conventional treatments and transplant tourism., Conclusion: Crowdfunding use to help cover direct and indirect costs of medical care is becoming increasingly apparent through several facets of medicine. This study shows that this statement holds true when looking at patients with urological disease in Canada. As urologists, we need to be aware of this trend, as it highlights the often-unforeseen financial burdens experienced by our patients.

Competing Interests: Conflicts of Interest: No conflict of interest to state by either author.

Drug discovery usually begins with a high-throughput screen (HTS) of thousands to millions of molecules to identify starting points for medicinal chemistry. Conventional HTS platforms require expensive reagents and typically have complex assay formats. HTS platforms based on radioactivity are expensive, both in terms of reagent cost and disposal. Furthermore, nonspecific interferences common to these technologies result in an extensive attrition of hits during validation experiments. Mass spectrometry (MS) is a highly selective, label-free technology that can quantify multiple analytes in a single experiment. However, most commercial MS platforms typically involve a separation or cleanup prior to analysis and are too slow for large-scale screening campaigns. Recently, an MS platform (AMI-MS) was introduced that uses acoustically generated droplets to deliver analyte molecules directly from microtiter plates into the mass spectrometer at subsecond per well sampling rates. Here, we demonstrate the application of AMI-MS by developing an HTS-compatible assay that measures the inhibition of histone acetyltransferase activity. Real-time kinetic measurements from a single well were used to determine enzyme K m and V max values. We compare the AMI-MS readout with conventional platforms in single-shot screening and multipoint profiling modes. The AMI-MS assay identified 86% of hits previously identified, with a pIC 50 ≥ 5.0, in a scintillation proximity assay (SPA) HTS at a lower hit rate and with a significantly reduced cost per well compared to the SPA-based readout. Furthermore, pIC 50 s, as measured by AMI-MS, showed a good correlation with values generated by RapidFire-MS. AMI-MS has the potential to provide significant improvements to high-throughput bioassays.

CRISPR/Cas9 is increasingly being used as a tool to prosecute functional genomic screens. However, it is not yet possible to apply the approach at scale across a full breadth of cell types and endpoints. In order to address this, we developed a novel and robust workflow for array-based lentiviral CRISPR/Cas9 screening. We utilized a β-lactamase reporter gene assay to investigate mediators of TNF-α-mediated NF-κB signaling. The system was adapted for CRISPR/Cas9 through the development of a cell line stably expressing Cas9 and application of a lentiviral gRNA library comprising mixtures of four gRNAs per gene. We screened a 743-gene kinome library whereupon hits were independently ranked by percent inhibition, Z' score, strictly standardized mean difference, and T statistic. A consolidated and optimized ranking was generated using Borda-based methods. Screening data quality was above acceptable limits (Z' ≥ 0.5). In order to determine the contribution of individual gRNAs and to better understand false positives and negatives, a subset of gRNAs, against 152 genes, were profiled in singlicate format. We highlight the use of known reference genes and high-throughput, next-generation amplicon and RNA sequencing to assess screen data quality. Screening with singlicate gRNAs was more successful than screening with mixtures at identifying genes with known regulatory roles in TNF-α-mediated NF-κB signaling and was found to be superior to previous RNAi-based methods. These results add to the available data on TNF-α-mediated NF-κB signaling and establish a high-throughput functional genomic screening approach, utilizing a vector-based arrayed gRNA library, applicable across a wide variety of endpoints and cell types at a genome-wide scale.

Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the n -butyl group as an atypical KAc methyl mimetic allowed generation of 31 (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The n -butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.

Objective: Insulin secretion in sulfonylurea-treated KCNJ11 permanent neonatal diabetes mellitus (PNDM) is thought to be mediated predominantly through amplifying non-K ATP -channel pathways such as incretins. Affected individuals report symptoms of postprandial hypoglycemia after eating protein/fat-rich foods. We aimed to assess the physiological response to carbohydrate and protein/fat in people with sulfonylurea-treated KCNJ11 PNDM., Research Design and Methods: 5 adults with sulfonylurea-treated KCNJ11 PNDM and five age, sex and body mass index-matched controls without diabetes had a high-carbohydrate and high-protein/fat meal on two separate mornings. Insulin(i) and glucose(g) were measured at baseline then regularly over 4 hours after the meal. Total area under the curve (tAUC) for insulin and glucose was calculated over 4 hours and compared between meals in controls and KCNJ11 cases., Results: In controls, glucose values after carbohydrate and protein/fat were similar (median glucose tAUC 0-4h 21.4 vs 19.7 mmol/L, p=0.08). In KCNJ11 cases glucose levels were higher after carbohydrate than after protein/fat (median glucose tAUC 0-4h 58.1 vs 31.3 mmol/L, p=0.04). These different glycemic responses reflected different patterns of insulin secretion: in controls, insulin secretion was greatly increased after carbohydrate versus protein/fat (median insulin tAUC 0-4h 727 vs 335 pmol/L, p=0.04), but in KCNJ11 cases insulin secretion was similar after carbohydrate and protein/fat (median insulin tAUC 0-4h 327 vs 378 pmol/L, p=0.50)., Conclusions: Individuals with sulfonylurea-treated KCNJ11 PNDM produce similar levels of insulin in response to both carbohydrate and protein/fat meals despite carbohydrate resulting in much higher glucose levels and protein/fat resulting in relatively low glucose levels. This suggests in an inability to modulate insulin secretion in response to glucose levels, consistent with a dependence on non-K ATP pathways for insulin secretion., Trial Registration Number: NCT02921906., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

There has been much debate around the success rates of various screening strategies to identify starting points for drug discovery. Although high-throughput target-based and phenotypic screening has been the focus of this debate, techniques such as fragment screening, virtual screening, and DNA-encoded library screening are also increasingly reported as a source of new chemical equity. Here, we provide examples in which integration of more than one screening approach has improved the campaign outcome and discuss how strengths and weaknesses of various methods can be used to build a complementary toolbox of approaches, giving researchers the greatest probability of successfully identifying leads. Among others, we highlight case studies for receptor-interacting serine/threonine-protein kinase 1 and the bromo- and extra-terminal domain family of bromodomains. In each example, the unique insight or chemistries individual approaches provided are described, emphasizing the synergy of information obtained from the various tactics employed and the particular question each tactic was employed to answer. We conclude with a short prospective discussing how screening strategies are evolving, what this screening toolbox might look like in the future, how to maximize success through integration of multiple tactics, and scenarios that drive selection of one combination of tactics over another.

Androgen Receptor (AR) is a key driver in prostate cancer. Direct targeting of AR has valuable therapeutic potential. However, the lack of disease relevant cellular methodologies capable of discriminating between inhibitors that directly bind AR and those that instead act on AR co-regulators has made identification of novel antagonists challenging. The Cellular Thermal Shift Assay (CETSA) is a technology enabling confirmation of direct target engagement with label-free, endogenous protein in living cells. We report the development of the first high-throughput CETSA assay (CETSA HT) to identify direct AR binders in a prostate cancer cell line endogenously expressing AR. Using this approach, we screened a pharmacology library containing both compounds reported to directly engage AR, and compounds expected to target AR co-regulators. Our results show that CETSA HT exclusively identifies direct AR binders, differentiating them from co-regulator inhibitors where other cellular assays measuring functional responses cannot. Using this CETSA HT approach we can derive apparent binding affinities for a range of AR antagonists, which represent an intracellular measure of antagonist-receptor Ki performed for the first time in a label-free, disease-relevant context. These results highlight the potential of CETSA HT to improve the success rates for novel therapeutic interventions directly targeting AR.