Adequate Induction Research Articles

Analysis of Enceladus’s Time-variable Space Environment to Magnetically Sound its Interior

We provide a comprehensive study of Enceladus’s time-variable magnetic field environment and identify in measurements of the Cassini spacecraft signatures that appear to be consistent with induced fields from the moon’s interior. Therefore, we first analyze the background field Enceladus is exposed to within 21 flybys and 50 crossings of the moon’s orbit by the Cassini spacecraft. Considering magnetic field variability due to Enceladus’s eccentric orbit, Saturn’s planetary period oscillations, and local time effects within the magnetospheric current sheet, we construct predictive, time-variable background fields near Enceladus with a correlation coefficient of 0.75 and larger compared to the measured background fields. Subsequently, we build a geophysically based electrical conductivity model of Enceladus’s ocean from the equation of state for saline water and mixing laws for a porous core permeated by water. Using this conductivity model and the derived time-variable fields, we calculate expected induced fields. For close flybys, we identify within mostly plume-dominated magnetic field perturbations of 10–30 nT much smaller perturbations of 1–3 nT, which could be consistent with induction. The flybys over Enceladus’s north pole are best suited for induction studies, and the associated measurements suggest that a conductivity of the ocean with 1–3 S m–1 is not sufficient to produce an adequate induction response, but they support a highly conductive, porous core of 20–30 S m–1 and/or a more conductive ocean. Our study also provides strategies for future magnetic sounding of Enceladus.

Cohort Profile: VZNKUL-NMIBC Quality Indicators Program: A Flemish Prospective Cohort to Evaluate the Quality Indicators in the Treatment of Non-Muscle-Invasive Bladder Cancer.

Purpose: Bladder cancer (BC) is a heterogeneous disease with varying outcomes, influenced by disease heterogeneity and variability in treatment and follow-up. Risk groups have been established for non-muscle-invasive BC (NMIBC) to standardize therapy, and several quality control indicators (QCIs) monitor adherence to these risk group-based guidelines. However, controversial results had been obtained regarding the oncological benefits of these QCIs until recent high-quality studies from large registries showed their usefulness. To improve adherence to the European Association of Urology (EAU) Guidelines and benchmark current care in Flemish hospitals within Vlaams Ziekenhuisnetwerk-KU Leuven (VZNKUL), a QCI program for NMIBC was initiated in 2013. This study aims to describe the demographic, clinical, and treatment data of patients enrolled in this program. Participants: The VZNKUL-NMIBC Quality Indicators Program Registry is a prospective cohort including patients treated and followed up with at seven academic and non-academic Flemish hospitals since June 2013. Data collection includes patient characteristics, tumor data, treatment, and oncological outcomes. Findings to date: From June 2013 to December 2020, 4744 transurethral resections of bladder tumors (TURBTs) from 2237 unique patients were analyzed. Most patients (80%) were men with a median age of 73. The median time from diagnosis to TURBT was 19 days. A single tumor was detected in 37% of TURBTs. Tumors larger than 3 cm were found in 20.8% of cases. In 46% of TURBTs, a reTURBT was scheduled according to guidelines. The complication rates were 7.5% and 2.4% for bladder perforation and bleeding, respectively. Postoperative single intravesical instillation of chemotherapy (SIVIC) was administered to 56.9% of 1533 indicated patients with a median time to administration of 4.7 h. Among the cohort, 60.4% had NMIBC, and 9.3% had muscle-invasive BC. Of 972 high-risk patients, 60.7% received adequate BCG induction, while 39.4% received adequate maintenance. After BCG induction ± maintenance, 39.7% were tumor-free, with 17.7% recurrence and 4% progression to muscle-invasive BC. BCG treatment was terminated early for 17% of patients due to intolerance. Early cystectomy was performed for 2.4% of the BCG-naïve patients, and 27.7% of patients with BCG failure underwent a BCG rechallenge. For intermediate-risk patients, 2.1% received adequate BCG, and 23% received intravesical chemotherapy. The median follow-up was 57 months. Five-year recurrence-free, progression-free, cancer-free, overall, and cancer-specific survival rates were 53%, 91.6%, 89%, 70.6%, and 95.6%, respectively, for the NMIBC patients. Of 400 non-metastatic MIBC patients, 217 (54.3%) underwent radical cystectomy (RC), of whom 46% received neoadjuvant chemotherapy, while 18 (4.5%) refused RC, and 74 (18.5%) were considered unfit for the surgery. Future plans: The VZNKUL-NMIBC Quality Indicators Program Registry will continue collecting data to evaluate QCIs and monitor treatment quality, enabling hospitals to benchmark their performance and improve patient care. Additionally, the registry's real-world data can support research and international collaboration. Trial registration: The study was registered on ClinicalTrials.gov (NCT04167332).

Adherence to First-Line Intravesical Bacillus Calmette-Guérin Therapy in the Context of Guideline Recommendations for US Patients With High-Risk Non-muscle Invasive Bladder Cancer.

Background: Bacillus Calmette-Guérin (BCG) can reduce recurrence and delay progression among patients with high-risk non-muscle invasive bladder cancer (NMIBC), but is associated with a substantial emotional, physical, and social burden. Objectives: This study evaluated the adequacy of first-line intravesical BCG treatment among high-risk NMIBC patients in the United States, including the subgroup with carcinoma in situ (CIS) of the bladder. Methods: Adults with high-risk NMIBC treated with BCG were selected from de-identified MarketScan® Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Adequacy of BCG induction and maintenance was evaluated from the first BCG claim until the end of the patient's observation, using a previously published claims-based algorithm (induction: ≥5 instillations within 70 days; induction and maintenance: ≥7 instillations within 274 days of first instillation) and a definition based on the landmark Southwest Oncology Group (SWOG) trial (induction: ≥5 instillations without gaps >7 days; followed by ≥2 instillations at month 3, 6, and every 6 months thereafter). Proportions of patients with adequate BCG induction and maintenance were reported overall and compared between those with and without CIS. Results: Of 5803 high-risk NMIBC patients treated with first-line BCG (mean age, 67.3 years; 20.6% female), 930 (16.0%) had CIS. After first-line BCG, 56.6% received another treatment. Although 86.9% had adequate BCG induction based on the claims-based algorithm (SWOG, 73.6%), only 41.5% had adequate BCG induction and maintenance (SWOG, 1.6%). Similar trends were observed for patients with and without CIS, with higher adherence to guidelines for patients with CIS (adequate induction using claims-based algorithm: 90.3% vs 86.2%; adequate induction and maintenance: 50.8% vs 39.7%, all P < .001). A greater proportion of CIS patients than non-CIS patients had cystectomy (CIS, 14.4%, non-CIS, 8.5%; P < .001) after first-line BCG. Discussion: Among patients with NMIBC treated with first-line intravesical BCG, most received adequate BCG induction but less than half had adequate BCG maintenance. BCG treatment was also inadequate for patients with CIS, with only half of patients receiving adequate BCG maintenance and a higher proportion undergoing cystectomy following first-line BCG. Conclusions: Results emphasize the need for additional treatment options for patients with NMIBC.

Adherence to First-Line Intravesical Bacillus Calmette-Guérin Therapy in the Context of Guideline Recommendations for US Patients With High-Risk Non-muscle Invasive Bladder Cancer

Background: Bacillus Calmette-Guérin (BCG) can reduce recurrence and delay progression among patients with high-risk non–muscle invasive bladder cancer (NMIBC), but is associated with a substantial emotional, physical, and social burden. Objectives: This study evaluated the adequacy of first-line intravesical BCG treatment among high-risk NMIBC patients in the United States, including the subgroup with carcinoma in situ (CIS) of the bladder. Methods: Adults with high-risk NMIBC treated with BCG were selected from de-identified MarketScan® Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Adequacy of BCG induction and maintenance was evaluated from the first BCG claim until the end of the patient’s observation, using a previously published claims-based algorithm (induction: ≥5 instillations within 70 days; induction and maintenance: ≥7 instillations within 274 days of first instillation) and a definition based on the landmark Southwest Oncology Group (SWOG) trial (induction: ≥5 instillations without gaps &gt;7 days; followed by ≥2 instillations at month 3, 6, and every 6 months thereafter). Proportions of patients with adequate BCG induction and maintenance were reported overall and compared between those with and without CIS. Results: Of 5803 high-risk NMIBC patients treated with first-line BCG (mean age, 67.3 years; 20.6% female), 930 (16.0%) had CIS. After first-line BCG, 56.6% received another treatment. Although 86.9% had adequate BCG induction based on the claims-based algorithm (SWOG, 73.6%), only 41.5% had adequate BCG induction and maintenance (SWOG, 1.6%). Similar trends were observed for patients with and without CIS, with higher adherence to guidelines for patients with CIS (adequate induction using claims-based algorithm: 90.3% vs 86.2%; adequate induction and maintenance: 50.8% vs 39.7%, all P &lt; .001). A greater proportion of CIS patients than non-CIS patients had cystectomy (CIS, 14.4%, non-CIS, 8.5%; P &lt; .001) after first-line BCG. Discussion: Among patients with NMIBC treated with first-line intravesical BCG, most received adequate BCG induction but less than half had adequate BCG maintenance. BCG treatment was also inadequate for patients with CIS, with only half of patients receiving adequate BCG maintenance and a higher proportion undergoing cystectomy following first-line BCG. Conclusions: Results emphasize the need for additional treatment options for patients with NMIBC.

Characterization of Male Flower Induction by Silver Thiosulfate Foliar Spray in Female Cannabis at the Middle Reproductive Stage for Breeding.

Cannabis (Cannabis sativa) is a versatile crop belonging to the Cannabaceae family, and is dioecious, typically with separate male and female plants. The flowers of female plants, especially the trichomes, accumulate relatively higher contents of cannabinoids compared with those of male plants. For this reason, to obtain seeds that are genetically female, it is desirable to induce the development of male flowers on a female plant that produces genetically female haploid gametes. Silver thiosulfate (STS) is a highly effective chemical for male flower induction. We investigated male flower induction in three commercial cultivars of female cannabis (Spectrum303, SuperwomanS1, and CBGambit) regarding the treatment frequency, stage of application, and concentration of STS applied as a foliar spray. All three cultivars showed adequate induction of male flowers in response to 1.5 mM STS applied at the early reproductive stage. In particular, SuperwomanS1 was most highly responsive to induction of male flowers, even when treated with 0.3 mM STS at the early reproductive stage. Treatment with three applications of STS was more effective compared with a single application, but a single application of 1.5 mM STS at the early reproductive stage was sufficient for male flower induction. A single STS application during the middle stage of reproductive growth was inadequate for induction of male flowers. However, 6 weeks after three applications of STS, CBGambit exhibited approximately 54% male flower induction at 0.3 mM STS, Spectrum303 showed approximately 56% induction at 3 mM STS, and SuperwomanS1 yielded approximately 26% induction at 1.5 mM (expressed as percentage of total number of individuals with the induced male flowers). Pollen stainability tests using KI-I2 solution and Alexander's staining showed high pollen viability with over 65% at different single STS concentrations, indicating that pollen grains induced by STS have sufficient viability for the self-pollination. This study demonstrated that different cultivars of cannabis respond diversely to different STS concentrations and highlighted the potential benefits of three STS applications during the middle reproductive stage for cannabis breeding.

Indirect in vitro Regeneration in Four Varieties of Potato (Solanum tuberosum L.) from Internodal Segments and Leaf Explants

Internodal segments and leaf explants from four varieties of potato (Solanum tuberosum L.) cultivated in Bangladesh, namely, Asterix, Diamant, Granola and Lady Rosseta were utilized for indirect in vitro regeneration of shoots through callus culture. The best responses regarding the reaeration of shoots were obtained when the explants were cultured on MS medium supplemented with 4.0 mg/l BAP and 1.0 mg/l IAA and 0.5 mg/l GA3. The highest frequency of multiple shoot regeneration was recorded from internodal segments rather than from the leaf explants. Hormone free MS medium was found to be the most effective for healthy root induction from the in vitro raised excised shoots. Following adequate root induction, the in vitro regenerated plantlets were successfully transplanted and established to soil for further growth and development of tubers. Plant Tissue Cult. &amp; Biotech. 34(1): 83-92, 2024 (June)

#5615 VALIDITY AND ADEQUACY OF ANIMAL MODELS IN HAEMODIALYSIS RESEARCH: A SYSTEMATIC REVIEW

Abstract Background and Aims with the worldwide dialysis population growing rapidly, improving haemodialysis (HD) outcomes is crucial and HD innovations are urgently needed. Prior to clinical application, novel HD technologies must undergo extensive preclinical testing. However, to date there is no consensus on the induction method of kidney failure in animal models nor which animal species is most suitable for research on HD innovations. Moreover, there is no consensus on which parameters should be used to validate adequate induction of kidney failure and functioning of novel HD devices. Using a systematic review approach, we summarized available literature of HD in kidney failure animal models. Method we performed a systematic search on PubMed and Embase for relevant studies up to February 4th 2022. After removal of duplicates, 5723 abstracts were screened for eligibility by three independent reviewers (JdV, KW and MK). Inclusion was based on publication of a HD intervention in an animal model with adequate (acute or chronic) kidney failure (independent of induction method). Detailed in- and exclusion criteria were registered in PROSPERO 2022 CRD42022307144. Data from individual reports, including animal species and sex, kidney injury parameters and HD details, were extracted in a pre-set data extraction form. Future efforts will focus on risk of bias and key quality indicators. Results of the 5723 abstracts screened, 195 records were included as full text and 41 full text articles were included for data-extraction (Figure 1). Current data extraction is completed for 31 articles (75%). Publication years range from 1973 to 2021 with over half (16/31) published after 2000. HD experiments were most frequently performed on dogs (45%), followed by rats (29%), goats (13%), pigs (10%), and sheep (3%) respectively. Parameters such as weight (81% reported), sex (58%) and age (29%) were not systematically reported. Most studies (67% of records reporting sex) used male animals only. Dog models were found in older studies, with no records after 2009. Other large animal studies were almost exclusively (88%) performed from the year 2007 onwards. Independent of animal species, studies mainly used acute kidney injury (AKI) models (84%), induced by bilateral nephrectomy (48%) or bilateral ureteral ligation (29%). The majority confirmed kidney failure by an increase in BUN and/or plasma creatinine. In AKI models, dialysis was on average initiated on AKI day 2 ± 0.8, and generally either HD (61%) or veno-venous hemofiltration as a single session (35%) was applied. Except for one clearance study, dialysis efficiency was reported as reduction ratios of BUN and/or plasma creatinine. Conclusion both large and small animal models have been used in HD research and preclinical validation of dialysis innovations. The use of dogs to test HD innovations has seen a sharp decline over the past decades, possibly resulting from a shift in public ethical perception. However, large animal models such as goat, sheep and pigs remain popular. A pressing issue appears the overall lack of adequate ARRIVE guideline adherence for reporting of animal parameters. We found no apparent improvement in reporting over time, emphasizing the need for clear guidelines to drive innovative HD research. Further (quantitative) analysis and meta-analysis are ongoing.

Propofol and thiopental for intravenous induction in neonates: study protocol for a dose-finding trial.

Propofol and thiopental are commonly used induction agents in neonatal anesthesia. Even though both hypnotics have been used off-label for many years, pharmacological knowledge regarding these agents is scarce in neonates. The significant variability in neonates' body composition, organ function, and maturation makes pharmacological studies highly relevant albeit challenging. As a result, there is currently limited data about the anesthetic induction dose of thiopental and propofol in neonates. In addition, a knowledge gap exists concerning the pharmacodynamics of induction doses. To determine the median effective anesthetic induction dose of propofol and thiopental in neonatal patients of different gestational and postnatal ages and evaluate the pharmacodynamics of the anesthesia induction doses on the neonatal systemic and cerebral hemodynamics. This is a single-center, prospective, open-label, interventional, dose-finding study, including neonatal patients from birth up to 28 postnatal days undergoing general anesthesia for surgical or diagnostic procedures. The patients will be stratified according to their gestational and postnatal age and allocated to one of the two trial arms: anesthesia induction with propofol or anesthesia induction with thiopental. We will use Dixon's up-and-down method to estimate the median effective anesthesia induction dose of both agents in neonates of different gestational and postnatal ages. In addition, we will study the relationship between anesthesia induction doses and changes in systemic and cerebral hemodynamics. Alterations in the systemic and cerebral regional hemodynamics secondary to anesthesia induction may be harmful in neonates, especially premature and critically ill newborns, due to their immature organ systems, reduced physiological reserves, and impaired cerebral autoregulation. Perfusion homeostasis is considered one of the significant and modifiable determinants of anesthesia-related neurocognitive outcomes. Therefore, dose-finding and safety pharmacological studies of the anesthetic induction agents in neonates are urgently needed and acknowledged as a high priority by the European Medicine Agency. Estimating adequate induction doses to ensure optimal depth of anesthesia while avoiding systemic and cerebral hemodynamic disturbances will help ensure safe anesthesia and potentially improve anesthesia-related outcomes in this group of patients. This article is protected by copyright. All rights reserved.

Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice

AbstractThe erythroid growth factor erythropoietin (EPO) is mainly produced by the kidneys in adult mammals and induces expansion of erythroid cells and iron use for hemoglobin synthesis. The liver also produces EPO at a lower level than the kidneys. Renal and hepatic EPO production is fundamentally regulated by hypoxia-inducible transcription factors (HIFs) in a hypoxia/anemia-inducible manner. Recently, small compounds that activate HIFs and EPO production in the kidneys by inhibiting HIF-prolyl hydroxylases (HIF-PHIs) have been launched to treat EPO-deficiency anemia in patients with kidney disease. However, the roles of the liver in the HIF-PHI–mediated induction of erythropoiesis and iron mobilization remain controversial. Here, to elucidate the liver contributions to the therapeutic effects of HIF-PHIs, genetically modified mouse lines lacking renal EPO-production ability were analyzed. In the mutant mice, HIF-PHI administration marginally increased plasma EPO concentrations and peripheral erythrocytes by inducing hepatic EPO production. The effects of HIF-PHIs on the mobilization of stored iron and on the suppression of hepatic hepcidin, an inhibitory molecule for iron release from iron-storage cells, were not observed in the mutant mice. These findings demonstrate that adequate induction of EPO mainly in the kidney is essential for achieving the full therapeutic effects of HIF-PHIs, which include hepcidin suppression. The data also show that HIF-PHIs directly induce the expression of duodenal genes related to dietary iron intake. Furthermore, hepatic EPO induction is considered to partially contribute to the erythropoietic effects of HIF-PHIs but to be insufficient to compensate for the abundant EPO induction by the kidneys.

Study of real-world treatment patterns and adherence to bacillus Calmette-Guerin (BCG) in the context of guideline recommendations for patients with high-risk non-muscle invasive bladder cancer (NMIBC).

470 Background: Intravesical BCG is considered a first-line (1L) treatment for high-risk NMIBC patients. Since the presence of carcinoma in situ (CIS) in NMIBC is associated with increased disease progression rates and poor clinical outcomes, BCG is prioritized in clinical guidelines for NMIBC patients with CIS. However, BCG’s US shortage may negatively affect clinical outcomes in patients. This study evaluated the adequacy of BCG treatment patterns among NMIBC patients, including a subgroup with CIS. Methods: Adults with NMIBC treated with BCG were selected from de-identified IBM MarketScan Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Treatment patterns were assessed from the first BCG claim (triggering the start of 1L treatment) until the end of the patient’s observation. Consistent with real-world literature, adequate BCG induction was defined as ≥5 BCG claims within 70 days of the first BCG claim whereas adequate BCG induction and maintenance was defined as ≥7 BCG claims within 274 days of the first BCG claim. Proportions of patients with adequate BCG induction and maintenance were compared between CIS subgroup and overall NMIBC cohorts using chi square tests. Results: Of 5,803 NMIBC patients treated with 1L BCG, 1,182 (20.4%) had documentation of CIS. Overall and CIS cohorts had similar mean age (67 years; range 18-101 years). After 1L BCG, 56.6% and 71.8% of the overall and CIS cohorts had another treatment (P&lt;.001; table). While 86.9% and 90.0% of the overall and CIS cohorts had adequate BCG induction (P=0.003), only 41.5% and 50.8% had adequate BCG maintenance (P&lt;.001). More patients in the CIS versus overall cohort had a cystectomy (13.9% vs 9.7%; P&lt;.001). Conclusions: In this study, most NMIBC patients treated with BCG received adequate induction; however, BCG maintenance was inadequate and most patients had another treatment following 1L BCG. Patients with CIS were more likely to have cystectomy after BCG, suggesting higher risk of progression in this subgroup. Results of this study further emphasize a need for additional available treatment options that are safe, efficacious, and tolerable. [Table: see text]

Cooperative effects of RIG-I-like receptor signaling and IRF1 on DNA damage-induced cell death

Properly responding to DNA damage is vital for eukaryotic cells, including the induction of DNA repair, growth arrest and, as a last resort to prevent neoplastic transformation, cell death. Besides being crucial for ensuring homeostasis, the same pathways and mechanisms are at the basis of chemoradiotherapy in cancer treatment, which involves therapeutic induction of DNA damage by chemical or physical (radiological) measures. Apart from typical DNA damage response mediators, the relevance of cell-intrinsic antiviral signaling pathways in response to DNA breaks has recently emerged. Originally known for combatting viruses via expression of antiviral factors including interferons (IFNs) and establishing of an antiviral state, RIG-I-like receptors (RLRs) were found to be critical for adequate induction of cell death upon the introduction of DNA double-strand breaks. We here show that presence of IRF3 is crucial in this process, most likely through direct activation of pro-apoptotic factors rather than transcriptional induction of canonical downstream components, such as IFNs. Investigating genes reported to be involved in both DNA damage response and antiviral signaling, we demonstrate that IRF1 is an obligatory factor for DNA damage-induced cell death. Interestingly, its regulation does not require activation of RLR signaling, but rather sensing of DNA double-strand breaks by ATM and ATR. Hence, even though independently regulated, both RLR signaling and IRF1 are essential for full-fledged induction/execution of DNA damage-mediated cell death programs. Our results not only support more broadly developing IRF1 as a biomarker predictive for the effectiveness of chemoradiotherapy, but also suggest investigating a combined pharmacological stimulation of RLR and IRF1 signaling as a potential adjuvant regimen in tumor therapy.

Real-world treatment patterns, survival outcomes, and health care resource utilization among individuals with nonmuscle-invasive bladder cancer in Canada.

470 Background: Real-world evidence pertaining to high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) is limited. We aimed to describe real-world treatment patterns and outcomes of this study population within a Canadian setting. Methods: A retrospective cohort study was conducted by linking various population-based administrative datasets from a large Canadian province. The study population consisted of all individuals ≥ 18 years who were diagnosed with Tis or high-grade Ta/T1 NMIBC in Alberta, Canada between 2010-2019. High-grade disease was defined using the WHO 1973 system. Individuals who initiated BCG therapy were classified as having received adequate induction therapy if they completed 5+ cycles. BCG unresponsive was defined as receipt of TURBT, intravesical chemotherapy, cystectomy, or radiation within 1 year of the last BCG dose. Overall survival (OS), cystectomy-free survival (CFS), progression-free survival (PFS), and healthcare resource utilization (HCRU) were examined from the time of being classified as BCG unresponsive following adequate induction therapy. CFS was defined as time until death or radical cystectomy and PFS was defined as time until death or disease progression. Disease progression was classified using a proxy based on subsequent receipt of cystectomy, systemic therapy, or radiation. Kaplan-Meier survival curves were estimated for OS, CFS, and PFS and the mean number of healthcare encounters within each year of follow-up were estimated for HCRU. Results: 5369 individuals were diagnosed with NMIBC in Alberta between 2010-2019, of whom 2679 (49.9%) had Tis or HG Ta/T1 disease at initial diagnosis. Among individuals with high-risk NMIBC, 1044 (39%) initiated BCG therapy. 885 (84.8%) individuals received 5+ BCG doses. Despite receiving adequate induction treatment, 249 (28.1%) individuals became unresponsive. The mean age at BCG unresponsive was 72.9 years and 213 (58.5%) were males. Among those who were BCG unresponsive, 25.7% underwent radical cystectomy (median time to cystectomy: 4.4 months, IQR: 1.7 to 8.2). Median OS was 50.7 months (95% CI: 37.2-65.5), CFS was 22.4 months (18.9-31.1), and PFS was 14.4 months (11.6-20.9). Within the first year of becoming BCG unresponsive, individuals spent an average of 6.2 days in hospital, had 28.8 visits with healthcare practictitioners, and had 2.2 emergency and 13.6 non-emergency encounters with ambulatory care services. Conclusions: A considerable proportion of individuals with high-risk NMIBC became unresponsive to BCG therapy despite adequate treatment. The time from becomining BCG unresponsive to radical cystectomy was relatively short. These findings highlight an unmet need in this patient population for alternative therapeutic options.

An Experimental Safety Response Mechanism for an Autonomous Moving Robot in a Smart Manufacturing Environment Using Q-Learning Algorithm and Speech Recognition.

The industrial manufacturing sector is undergoing a tremendous revolution moving from traditional production processes to intelligent techniques. Under this revolution, known as Industry 4.0 (I40), a robot is no longer static equipment but an active workforce to the factory production alongside human operators. Safety becomes crucial for humans and robots to ensure a smooth production run in such environments. The loss of operating moving robots in plant evacuation can be avoided with the adequate safety induction for them. Operators are subject to frequent safety inductions to react in emergencies, but very little is done for robots. Our research proposes an experimental safety response mechanism for a small manufacturing plant, through which an autonomous robot learns the obstacle-free trajectory to the closest safety exit in emergencies. We implement a reinforcement learning (RL) algorithm, Q-learning, to enable the path learning abilities of the robot. After obtaining the robot optimal path selection options with Q-learning, we code the outcome as a rule-based system for the safety response. We also program a speech recognition system for operators to react timeously, with a voice command, to an emergency that requires stopping all plant activities even when they are far away from the emergency stops (ESTOPs) button. An ESTOP or a voice command sent directly to the factory central controller can give the factory an emergency signal. We tested this functionality on real hardware from an S7-1200 Siemens programmable logic controller (PLC). We simulate a simple and small manufacturing environment overview to test our safety procedure. Our results show that the safety response mechanism successfully generates paths without obstacles to the closest safety exits from all the factory locations. Our research benefits any manufacturing SME intending to implement the initial and primary use of autonomous moving robots (AMR) in their factories. It also impacts manufacturing SMEs using legacy devices such as traditional PLCs by offering them intelligent strategies to incorporate current state-of-the-art technologies such as speech recognition to improve their performances. Our research empowers SMEs to adopt advanced and innovative technological concepts within their operations.

1496 Building Inclusivity and Diversity from our Foundations: A Cross-Sectional Study Identifying Barriers to Theatre Based Training for Foundation Doctors

Abstract Aim Theatre experience is a powerful factor enabling trainees to determine whether they possess the enthusiasm and aptitude to undertake a surgical career. Removing barriers to theatre learning should allow a more meritorious and diverse cohort of surgical trainees. Method An 18 -point open and closed question Likert scale survey was distributed to Foundation Doctors in three hospitals within the Northern Deanery. The survey was designed via focus group and literature review, ascertaining perceived levels of preparedness, acceptance, enjoyment, and barriers to theatre access. Results The survey dichotomized respondents (n = 54) into those who attended theatre (n = 40) and those who did not (n = 14). Of those attending 38% (n = 15) reported intimidation and 15% (n = 6) cited a cultural barrier to attendance. Of those who did not attend 79% (n = 11) were interested in surgery. These respondents predominantly reported concerns around prohibitive ward workload and unfamiliarity with protocols. Covid restricted surgical rotations for some. There was a statistically significant difference (p fishers exact test = 0.001) between 83% of respondents who felt welcomed by the surgeons compared to just 45% made to feel welcome by the wider theatre team. Only 20% (n = 11) of respondents felt prepared for theatre by medical school. 50% (n = 27) were confident with theatre protocols. Conclusions The study raises concerns around apprehension surrounding the theatre environment and ward workload which appear to impede access to theatre. Adequate undergraduate surgical teaching, appropriate induction and allocation of theatre time are crucial to improve safety, diversity of applicants, confidence for trainees and compliance within the team.

Apnoeic Oxygenation during Simulated Difficult Intubation in Obese Patients: Comparison of Buccal Ring, Adair and Elwyn Tube Versus Nasal Cannula: A Prospective Randomized Controlled Trial.

Background:Apnoeic oxygenation is an established method of increasing safe apnoea times during intubation and this is of more importance in obese patients. The usefulness of buccal Ring, Adair and Elwyn (RAE) oxygenation has been established in previous studies, however a head-to-head comparison with nasal cannula (NC) is lacking.Aim:The aim of this study was to compare apnoea time with buccal RAE (BR) versus NC in obese patients.Setting and Design:This was a prospective, nonblinded randomized controlled trial conducted in a tertiary hospital where fifty American Society of Anaesthesiologists Physical Status Class I and II, obese patients with body mass index ≥30, posted for elective surgery were included.Materials and Methods:Following adequate preoxygenation and standard induction of anaesthesia, a prolonged simulated difficult laryngoscopy was performed during which oxygen was provided via either BR or NC. The primary outcome was time to desaturation to <95% or 10 min, which ever occurred first. Other outcomes recorded were lowest saturation, time to resaturation and highest end tidal carbon di oxide.Statistical Analysis:Mean with standard deviation (SD) or median with inter quartile range were used for continuous variables and absolute number with percentage were used for categorical variables. The primary outcome was analyzed using Kaplan-Meier survival curves, and log-rank tests were applied.Results:Patient characteristics were similar in both arms. The mean apnoea time in seconds (SD) in the BR group, 375.3 (116.6) was higher than the NC group 316.1 (94.1), P = 0.054. From the Kapan Meier curves the probability of desaturating to <95% was earlier in the NC group than the BR group (P = 0.092). The other outcomes were similar in both groups.Conclusion:This is the first study that demonstrates that oxygenation via a BR is better than NC in providing apnoeic oxygenation in obese patients and can safely be used when NC are contraindicated.

MP16-06 A NOVEL NOMOGRAM TO PREDICT BCG RESPONSE IN PATIENTS WITH HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Non-invasive II (MP16)1 Sep 2021MP16-06 A NOVEL NOMOGRAM TO PREDICT BCG RESPONSE IN PATIENTS WITH HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER Kelly Bree, Patrick Hensley, Nathan Brooks, Lianchun Xiao, Yu Shen, Neema Navai, H. Barton Grossman, Colin Dinney, and Ashish Kamat Kelly BreeKelly Bree More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Nathan BrooksNathan Brooks More articles by this author , Lianchun XiaoLianchun Xiao More articles by this author , Yu ShenYu Shen More articles by this author , Neema NavaiNeema Navai More articles by this author , H. Barton GrossmanH. Barton Grossman More articles by this author , Colin DinneyColin Dinney More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002001.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current risk tables for outcome prediction in patients with non-muscle invasive bladder cancer (NMIBC) are based upon studies comprised primarily of low-grade tumors. We developed nomograms that predict disease recurrence and progression in patients with high-grade NMIBC using a large institutional dataset. METHODS: The log rank test, univariate and multivariate Cox proportional hazards regression models were used to identify risk factors of histologically confirmed disease recurrence and progression using data on 519 patients treated with adequate induction bacillus Calmette-Guerin (BCG) at our institution from 2000 to 2018. The first set of models predicted bladder cancer recurrence free survival (RFS), and the second set predicted tumor progression (any upstaging) free survival (PFS). RESULTS: At an estimated median follow-up time was 60.4 months (95% CI: 54-66.2), recurrence or death, whichever occurred first was recorded in 248 patients (47.8%) with a median RFS time of 73 months (95% CI, 52.6-91.2). Recurrent tumors (HR 1.78, 95% CI 1.33-2.33, p<0.0001), larger tumor size (HR 1.07, 95% CI 1.00-1.15, p=0.0487), and diabetes mellitus (HR 1.57, 95% CI 1.14-2.15, p=0.0055) were significantly associated with a higher risk of recurrence or death. Conversely, the receipt of maintenance BCG (mBCG) (HR 0.46, 95% CI 0.29-0.73, p=0.0008) and number of doses of mBCG (HR 0.92, 95% CI 0.89-0.94, p<0.0001) were associated with lower risk of events. Progression or death occurred in 128 patients (24.7%) with a median PFS time of 151 months (95% CI, 121.32-NA). Prior BCG (HR 2.19, 95% CI 1.23-3.88, p=0.0075) and older age (HR 1.041, 95% CI 1.02-1.06, p<0.001) were associated with higher risk of progression or death, while BMI≥25 (HR 0.519, 95% CI 0.35-0.78, p=0.0015) and number of doses of mBCG (HR 0.88, 95% CI 0.86-0.91, p<0.0001) were associated with lower risk of progression or death. These prognostic factors were integrated to construct nomograms for prediction of PFS and RFS. CONCLUSIONS: These nomograms provide personalized prediction of recurrence and progression in patients with high-grade NMIBC treated with BCG, and may help identify patients who may benefit most from early radical cystectomy. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research, the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant to AMK, and NIH/NCI UTMD Anderson SPORE in Genitourinary Cancer (Bladder) (P50CA091846) to CPND © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e298-e298 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kelly Bree More articles by this author Patrick Hensley More articles by this author Nathan Brooks More articles by this author Lianchun Xiao More articles by this author Yu Shen More articles by this author Neema Navai More articles by this author H. Barton Grossman More articles by this author Colin Dinney More articles by this author Ashish Kamat More articles by this author Expand All Advertisement Loading ...

MP48-14 UTUC SURVEILLANCE FOLLOWING BCG-TREATED NMIBC: TIMING AND RISK FACTORS ASSOCIATED WITH RECURRENCE

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP48)1 Sep 2021MP48-14 UTUC SURVEILLANCE FOLLOWING BCG-TREATED NMIBC: TIMING AND RISK FACTORS ASSOCIATED WITH RECURRENCE Kelly Bree, Patrick Hensley, Nathan Brooks, Supriya Nagaraju, Neema Navai, Colin Dinney, Surena Matin, and Ashish Kamat Kelly BreeKelly Bree More articles by this author , Patrick HensleyPatrick Hensley More articles by this author , Nathan BrooksNathan Brooks More articles by this author , Supriya NagarajuSupriya Nagaraju More articles by this author , Neema NavaiNeema Navai More articles by this author , Colin DinneyColin Dinney More articles by this author , Surena MatinSurena Matin More articles by this author , and Ashish KamatAshish Kamat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002074.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Following a diagnosis of non-muscle invasive bladder cancer (NMIBC), patients are at risk for developing upper tract urothelial carcinoma (UTUC). Guidelines vary on the frequency of upper tract imaging during surveillance from yearly (EAU) to every 1-2 years (AUA/SUO) but this is based on admittedly ‘weak evidence’ or ‘expert opinion’ due to a paucity of data. Herein, we sought to characterize the timing of UTUC following NMIBC diagnosis, as well as to identify risk factors for UTUC which could inform future screening recommendations. METHODS: An IRB approved review of patients with NMIBC who received adequate induction BCG, as defined by the US FDA, at our institution from 2000-2018 was performed. Patients were stratified by development of metachronous UTUC (any time after NMIBC diagnosis). Patients with UTUC prior to or synchronous with NMIBC diagnosis were excluded. RESULTS: Of 537 patients with NMIBC who received induction BCG, 22 (4.1%) developed metachronous UTUC. Factors associated with the development of UTUC included pure Tis (22.7% vs. 5.0%, p=0.002) and multifocal disease (86.4% vs. 50.1%, p=0.0009). Notably, bladder tumor grade and size were not associated with UTUC recurrence (p=0.569 and p=1.00, respectively). UTUC onset occurred within 5 years in the majority of patients (86.4%, 19/22), however, one patient did develop UTUC more than 10 years after initial NMIBC diagnosis. Rates of radical cystectomy (45.5% vs. 14.0%, p=<0.001) and urothelial cancer-specific mortality (27.3% vs. 4.1%, p<0.001) were higher in patients with metachronous UTUC. CONCLUSIONS: UTUC occurs within the first five years following NMIBC diagnosis in the overwhelming majority of patients, however, late recurrences (>10 years) were noted. The presence of Tis and multifocal NMIBC are associated with increased risk of UTUC and screening efforts may be focused on this subgroup of patients. Source of Funding: This research was supported by the Wayne B. Duddlesten Professorship in Cancer Research and the Raymond and Maria Floyd Bladder Cancer Research Foundation Grant © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e870-e870 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kelly Bree More articles by this author Patrick Hensley More articles by this author Nathan Brooks More articles by this author Supriya Nagaraju More articles by this author Neema Navai More articles by this author Colin Dinney More articles by this author Surena Matin More articles by this author Ashish Kamat More articles by this author Expand All Advertisement Loading ...

The impact of the social construct of race on outcomes among bacille Calmette-Guérin-treated patients with high-risk non-muscle-invasive bladder cancer in an equal-access setting.

The objective of this study was to describe bladder cancer outcomes as a function of race among patients with high-risk non-muscle-invasive bladder cancer (NMIBC) in an equal-access setting. A total of 412 patients with high-risk NMIBC who received bacille Calmette-Guérin (BCG) from January 1, 2010, to December 31, 2015, were assessed. The authors used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, disease-specific, and overall survival outcomes. A total of 372 patients who had complete data were included in the analysis; 48 (13%) and 324 (87%) were Black and White, respectively. There was no difference in age, sex, smoking status, or Charlson Comorbidity Index by race. White patients had a higher socioeconomic status with a greater percentage of patients living above the poverty level in comparison with Black patients (median, 85% vs 77%; P < .001). A total of 360 patients (97%) received adequate induction BCG, and 145 patients (39%) received adequate maintenance BCG therapy. There was no significant difference in rates of adequate induction or maintenance BCG therapy according to race. There was no significant difference in recurrence (hazard ratio [HR], 1.53; 95% confidence interval [CI], 0.64-3.63), progression (HR, 0.77; 95% CI, 0.33-1.82), bladder cancer-specific survival (HR, 1.01; 95% CI, 0.30-3.46), or overall survival (HR, 0.97; 95% CI, 0.56-1.66) according to Black race versus White race. In this small study from an equal-access setting, there was no difference in the receipt of BCG or any differences in bladder cancer outcomes according to race.

Formalising the induction of patient and public involvement contributors on trial oversight committees

BackgroundClinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, running and oversight. This research explored the induction and training of PPI Contributors joining trial oversight committees and was used to update the Medical Research Council Clinical Trials Unit at University College London’s (MRC CTU at UCL) induction pack for new PPI Contributors.MethodsPublished and unpublished materials provided by other CTUs and research organisations on training for PPI Contributors on oversight committees were reviewed, with themes then triangulated to identify the most common topics covered in induction training. A face-to-face workshop with PPI Contributors from the MRC CTU at UCL reviewed a draft updated Induction Pack. Findings from these discussions were incorporated into a revised induction pack which was then re-reviewed by the workshop attendees.ResultsNo published literature on this subject was found. However, several common themes were identified from unpublished materials. Workshop attendees agreed with most of the themes suggested in the initial draft pack based on the literature search and also provided a number of additional topics for discussion.ConclusionsThere is very little consistency in the induction of PPI Contributors on oversight committees. Whilst most local guidance explains the general role of a PPI Contributor, more context and background of the particular trial needs to be provided to allow for adequate induction of new committee members. The Induction Pack created provides a framework upon which trial managers can build a full picture of their study.

Application of Pulsed Rhythmic Drug Administration to Ovulation Induction Therapy in PCOS Patients with Clomiphene-Resistance: a Retrospective Research

There is currently a dispute over the choice of ovulation induction treatment for infertile women with polycystic ovary syndrome (PCOS). The objective of this study is to compare the therapeutic effect of pulsed rhythmic administration protocol (PRAP) with conventional letrozole + human menopausal gonadotropin (HMG) in patients with clomiphene-resistance polycystic ovary syndrome (PCOS). A retrospective analysis of 821 intrauterine insemination (IUI) cycles between January 2015 and January 2020 was performed. Of these, 483 cycles were treated with a pulsed rhythmic administration protocol (PRAP), and 338 cycles were treated with conventional letrozole + HMG protocol (LHP). The therapeutic effect of the two protocols has been compared. The pregnancy rate was 18.07% in the LHP and 27.07% in the PRAP. The ongoing pregnancy rate in LHP was 14.46% and in PRAP was 22.73%. The research suggests that PRAP is more effective than LHP and could be an adequate ovulation induction strategy for the IUI cycle of patients with clomiphene-resistance PCOS.