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Introduction: Holmium laser enucleation of the prostate (HoLEP) is routinely performed with a 24F, 26F, or a 28F scope. Proponents of the larger scopes propose that a bigger sheath size allows for superior flow and visibility leading to a more efficient operation and better hemostasis. Those utilizing the smaller scopes suggest that the smaller sheath is less traumatic, resulting in lower stricture rates and temporary incontinence. We sought to compare outcomes of ambulatory HoLEP using the 24F and 28F laser scope. Materials and Methods: From May 2022 to March 2023, we randomized patients undergoing HoLEP (<200 cm3 in size) 1:1 to either a 24F or 28F scope. The primary outcome was differences in surgical duration between groups (minutes). Secondary outcomes included surgeon scope evaluation and postoperative patient results. Results: There was no difference in patient characteristics in those randomized to 28F (n = 76) vs 24F (n = 76) (p > 0.05) scopes. Procedural duration and efficiencies were not different between groups (all p > 0.05). The 28F scope was associated with improved surgeon-graded irrigation flow and visibility (p < 0.001). Patients treated with the 28F scope were more likely to achieve effective same-day trial of void (SDTOV) (28F 94.3% vs 24F 82.1%, p = 0.048) and have a shorter length of stay (LOS) (28F 7.0 vs 24F 11.9 hours, p = 0.014), however, rates of same-day discharge (SDD) were not statistically different (28F 87.8% vs 24F 78.4%, p = 0.126). There was no difference between the cohorts in rates of 90-day emergency room presentations, re-admissions, complications, or functional ouctomes (p > 0.05). Conclusions: We identified no clear advantage of scope size with regard to intraoperative or postoperative outcomes at 3-month follow-up due to scope size. However, if SDD is part of your postoperative pathway, the 28F scope may shorten LOS and increase rates of effective SDTOV. Clinicaltrials.gov: NCT05308017. [ABSTRACT FROM AUTHOR]

Introduction: The effect of prophylactic bladder neck incision (BNI) at time of holmium laser enucleation of the prostate (HoLEP) is unknown. The aim of our study was to examine HoLEP outcomes with a specific focus on rates of bladder neck contractures (BNCs), with and without utilizing prophylactic BNI. Materials and Methods: We performed a retrospective review of HoLEP patients from January 2021 until January 2022. Outcomes of patients who underwent BNI at time of HoLEP were compared with those who underwent standard HoLEP alone. Student's t-tests, chi-square tests, and logistic regressions were performed using SAS Studio. Results: In total, 421 patients underwent HoLEP. BNI was concurrently performed in 74 (17.6%) HoLEP patients. BNI patients were younger (67.5 ± 9.0 years vs 71.1 ± 8.2 years, p = 0.00007) and had smaller prostates (60.7 ± 30.3 cc vs 133.2 ± 64.5 cc, p < 0.0001). Procedure, enucleation, and morcellation times were shorter in the BNI group (all p < 0.0001). There was no statistical difference in same-day discharge rates (90.4% vs 87.7%, p = 0.5), short-term functional outcomes, emergency department (ED) visits, or readmission rates between the two groups. At 14 months mean follow-up, two BNCs occurred in patients in the control group (0.6%), and no BNCs occurred in patients who underwent BNI (0.0%, p = 0.5). Conclusions: BNI at time of HoLEP did not decrease the ability to achieve same-day discharge or increase 90-day complications, ED visits, or readmission rates. No BNCs occurred in patients who underwent prophylactic BNI (0.0%) despite a smaller gland size and lower specimen weight in this cohort. Further prospective studies are required to conclude if concurrent BNI at time of HoLEP is protective against BNC. [ABSTRACT FROM AUTHOR]

To evaluate if implementation of a percutaneous nephrolithotomy (PCNL) equipment whiteboard can improve communication accuracy of surgical equipment, streamline operative efficiency, and decrease unnecessary case equipment costs. A real-time editable equipment whiteboard was designed and implemented for all PCNL cases between October and December 2021. The relative difference in pre- and post-intervention surgical equipment accuracy as well as overall case costing was compared from 90 days prior to implementation to the period after intervention. Quality assessment surveys were completed prior to whiteboard implementation (N = 25) and cost implementation (n = 15). Pre- and postoperative assessment of equipment communication, assessed on a 10-point scale, improved after implementation of the communication whiteboard (Pre-op: 6.7/10 vs. 8.9/10, P <.001. Post-op: 7.0/10 vs. 9.3/10, P <.001). On average 64% (3.2/5) of items were accurate on preintervention cases. Postintervention accuracy improved to 88% (4.4/5 items) (P =.049). There was a significant relative case cost improvement after implementing the PCNL equipment whiteboard with an average of $436.81 USD savings per case (P =.001) and $488.22 USD per renal moiety (P =.002). Our baseline quality assessment of surgical team communication regarding PCNL equipment identified an area for improvement. Multidisciplinary feedback resulted in the development of a real-time editable PCNL equipment whiteboard which improved team perception of equipment communication, case item accuracy and resulted in a relative average cost savings for PCNL. [ABSTRACT FROM AUTHOR]

To compare perioperative outcomes between Holmium laser enucleation of the prostate (HoLEP), open simple prostatectomy (OSP), and robotic simple prostatectomy (RSP) for large prostates (> 80 cc). A retrospective study of 340 patients who underwent HoLEP (n = 209), OSP (n = 66), or RSP (n = 65) at a large academic medical center between January 2013 – September 2021 was performed. Length of stay (LOS), operative time, catheter duration, estimated blood loss (EBL), blood transfusion, and 30-day ED visits and readmissions were compared between the three groups. Univariate analyses consisted of ANOVA with Tukey's corrections and Chi-square tests. Linear and multivariate logistic regression was also performed. All tests were two-sided and a p-value <0.05 was pre-determined to be statistically significant. Analyses were performed with SAS v9.4. HoLEP was found to have the shortest: operative time (1.4 vs 2.7 vs 3.8h), LOS (0.65 vs 4.2 vs 2.6d), and catheter duration (0.38 vs 9.9 vs 11.2d) compared to OSP and RSP, respectively (all P <.0001). HoLEP also had the lowest EBL (66 vs 795 vs 326 mL, P <.0001). HoLEP and RSP had a lower risk of blood transfusion compared to OSP (P <.0001). These associations remained significant on multivariable analyses. HoLEP is a minimally invasive treatment option for large prostates that was found to have shorter operative time, LOS, and catheter duration as well as lower EBL compared to OSP and RSP. [ABSTRACT FROM AUTHOR]

Introduction: Tranexamic acid (TXA) is a clot promoting agent utilized during orthopedic procedures to decrease bleeding. Urologists have demonstrated the benefits of TXA in percutaneous surgery. Our objective was to assess the safety and efficacy of single-dose TXA on same-day holmium laser enucleation of the prostate (HoLEP) outcomes. Methods: From September 2021 to January 2022, we prospectively randomized 110 patients undergoing HoLEP to either 1 g of TXA after induction or no treatment. Institutional Review Board (IRB) approval (STU00215134) and registry with ClinicalTrials.gov (NCT05082142) were obtained before enrollment. Primary outcome was the rate of effective same-day discharge (SDD). Secondary outcomes included transfusion rate, same-day catheter removal, length of stay (LOS), and 90-day complications. Power analysis determined that 110 patients should be enrolled to detect a 25% difference in SDD rate. Results: There was no difference in patient demographic and prostate features between the control (n = 55) and TXA groups (n = 55; all p > 0.05). The overall rate of effective SDD was not different between the control and TXA groups (49/55 [89%] vs 51/55 [93%], p = 0.74). Median LOS (hh:mm) was not different between groups (03:07 vs 02:50, p = 0.23) with only 3/110 (2.7%) having an LOS >24 hours. Effective same-day catheter removal occurred in 99/110 (90%) patients with no difference between groups (49/55 vs 50/55, p = 0.99). There was no difference in operative parameters (time, energy, specimen weight) and postoperative complications between groups (all p > 0.05). No patients required transfusions and there were no major 90-day complications related to surgery (Clavien–Dindo ≥IIIb). Conclusion: TXA administration is safe but did not impact SDD after HoLEP. [ABSTRACT FROM AUTHOR]

Introduction: To improve surgeon-patient communication of postoperative expectations, a multidisciplinary team created and evaluated a holmium laser enucleation of the prostate (HoLEP) expectations handout. Although an effective benign prostatic hyperplasia (BPH) surgery, it is crucial that patients understand the HoLEP recovery. A quality assessment previously performed at our center revealed 11% of patients were not aware of potential ejaculate volume changes. Methods: Patients presenting for consultation prior to HoLEP were assessed with post-procedure patient-reported outcomes (PRO) questionnaires before (n=50) and after (n=50) the implementation of a surgeon-patient expectations handout. Patient demographics and perioperative course were examined in the context of responses. Comparisons were made with a Chi-squared test (p<0.05). Results: We observed a response rate of 96% (pre-handout: 46/50 vs. post-handout: 50/50). Overall, 89/96 (93%) patients felt they had a reasonable understanding of HoLEP expectations, with no difference between cohorts (45/46 vs. 48/50, p=0.71). There was no difference in reporting an understanding of post-HoLEP hematuria (p=0.12) or urinary incontinence (UI) (p=0.99). The implementation of the handout improved understanding of retrograde ejaculation (pre-handout: 41/46 vs. post-handout: 50/50, p=0.022) and dysuria (pre-handout: 35/46 vs. post-handout: 46/50, p=0.048). Fiftyfive patients experienced any dysuria postoperatively, with 89% reporting less than or equal to what they expected. Close to 30% (28/94) of respondents offering ways to improve communication suggested an educational website. Conclusions: The implementation of a surgeon-patient handout during HoLEP consultation improved understanding of postoperative retrograde ejaculation and dysuria at our center. We identified areas for future technology-aided improvements in post-HoLEP communication. [ABSTRACT FROM AUTHOR]

Purpose: To identify a threshold for intrarenal pressure (IRP), that if exceeded, will result in renal parenchymal damage. Herein, we attempt to identify an IRP threshold by subjecting in vivo porcine kidneys to various levels of extreme pressurized irrigation. Our objective was not to simulate ureteroscopy treatment, but to attempt identify a threshold of IRP injury. Methods: Ten female pigs were intubated and sedated. The abdomen was opened; the ureters were isolated and incised. A LithoVue™ (Boston Scientific) ureteroscope was inserted. A 0-silk tie was then used to tie the ureter around the scope to create a closed system (to achieve a constant level of pressure). Real-time IRPs were measured using the Comet™ Pressure guidewire (Boston Scientific). Kidneys were exposed to pressurized, saline for 36 min (at control, 50, 100, 150 mmHg and higher pressures). Kidneys were then immediately harvested. Two expert histologists independently analyzed kidney slides to identify areas of renal damage. Results: The two kidneys exposed to IRPs > 185 mmHg resulted in forniceal rupture and large areas of hematoma. The other IRP groups (control, 50, 100, and 150 mmHg) had no identifiable gross or histologic renal parenchymal damage. Conclusions: No differences in renal parenchymal morphology were identified between pressure groups of control, 50, 100, or 150 mmHg. However, IRPs > 185 mmHg did result in forniceal rupture in this closed-system in vivo porcine model. Further study is required to elucidate the damage threshold. [ABSTRACT FROM AUTHOR]

Purpose: We sought to objectively compare laser fiber degradation for holmium laser enucleation of the prostate (HoLEP) cases performed with 550 μm standard fibers versus 550 μm Moses 2.0 fiber in BPH mode on a macroscopic and microscopic level. Methods: We prospectively collected outcomes for 50 standardized HoLEP cases using 550 μm Moses fiber with 2.0 BPH mode compared to our historical cohort of 50 patients using 550 μm standard fibers on regular mode. Macroscopic degradation length was the difference in length of exposed fiber at the start and end of each case. Five consecutive 550 μm standard fibers, five 550 μm Moses fibers and their respective controls underwent novel utilization of three objective corroborating imaging techniques: Brightfield high resolution microscopy, high resolution 3-D microCT and Confocal Reflection Surface Analysis. Mann–Whitney U, 2-tailed T tests and Chi-squared tests were used. Results: Standard fibers demonstrated greater degradation than the Moses fibers with 2.0 BPH mode [2.9 cm (IQR 1.7–4.3 cm) vs 0.2 cm (IQR 0.1–0.4 cm), p < 0.01]. This difference remained significant when comparing degradation per energy used, per minute enucleation and per gram enucleated (all p < 0.05). None of the cases with Moses fiber and 2.0 BPH mode required intraoperative interruption to re-strip the fiber. Objective fiber degradation by three microscopic techniques confirmed more damage to the standard fibers with regular mode. Conclusion: Overall, use of the 550 μm Moses fiber with 2.0 BPH mode resulted in less fiber degradation compared to a standard 550 μm fiber with regular mode as confirmed using 4 corroborating macroscopic and microscopic techniques. [ABSTRACT FROM AUTHOR]

Introduction: Holmium laser enucleation of the prostate (HoLEP) is a size-independent treatment option for the management of benign prostatic hypertrophy. Although advancements in laser technology have led to clinical improvements in the enucleation portion of HoLEP, the morcellation aspect of HoLEP is often the rate-limiting step. We sought to compare efficiency and surgeon satisfaction in four commercial morcellators. Methods: This was an ex vivo study comparing four commercial morcellators: the Wolf Piranha™, the Lumenis VersaCut™, the JenaSurgical MultiCut Solo™, and the Hawk™ Morcellator. Four surgeons with significant experience performing HoLEPs participated. Surgeons tested each device to morcellate two different prostate models (1) morcellating as much microwave-cooked chicken breast in 10 minutes and (2) timed morcellation of bull testicles. Surgeons completed subjective surveys after each morcellator trial. Objective outcomes included the following: morcellation efficiency (g/min morcellated) and aspiration power (time to aspirate 1 L of saline). Means of continuous variables were compared using analysis of variance. Categorical variables were compared using chi-square tests. Statistical analyses were performed using SAS 9.4 (2019). Results: Comparing subjective outcomes, the Piranha™ was chosen as the safest morcellator (p = 0.0058). The least safe morcellator was thought to be the MultiCut by 75% of surgeons (p = 0.046). The Piranha™ was chosen as the most effective morcellator by 75% of surgeons (p = 0.046). Comparing objective parameters between the morcellators, the Piranha™ had the fastest aspiration time (43.50 ± 10.34 seconds, p = 0.0116). There were no significant differences in morcellation efficiency when using chicken breast (p = 0.3096). However, when comparing the morcellation efficiency using bull testicles, the Piranha™ had the highest efficiency at 39.68 ± 3.57 g/min (p = 0.0268). Conclusion: In this ex vivo study comparing four different commercially available morcellators, the Piranha™ had the highest aspiration power. No significant differences were found in morcellation efficiency using microwave-cooked chicken breast. The Piranha™ was felt to be the safest and most effective morcellator. [ABSTRACT FROM AUTHOR]

Objective: To investigate perceived barriers to successful same-day discharge (SDD) after holmium laser enucleation of the prostate (HoLEP) from the perspective of surgical and nursing staff members.Methods: A 17-question survey was administered to intraoperative and postoperative surgical staff in June 2021 after a six-month period of implementing a SDD HoLEP pathway with same-day catheter removal. McNemar's and Stuart-Maxwell tests were performed for statistical analysis.Results: Surveys were completed by 30 respondents. The majority of respondents had less than 5 years of surgical experience (63%). Almost all respondents (96%) felt that HoLEP patients could be discharged safely on day of surgery. Overall, 60% felt that HoLEP had a lower risk of post-operative bleeding compared to other transurethral surgeries. There was a significant decrease in number of respondents that felt apprehensive when comparing initiation of SDD HoLEP pathway to 6-months post-implementation (43% vs 7%, P = .003). The most common factors causing apprehension both pre- and post-implementation included: degree of hematuria (43% vs 40%, P = .56), risk of failure of trial of void (40% vs 30%, P = .26), and risk of readmission or unplanned emergency department (ED) visit (33% vs 30%, P = .48). There was a significant decrease in the number of respondents who were apprehensive about lack of experience with SDD after HoLEP comparing pre- and post-implementation (20% vs 0%, P = .01).Conclusion: While staff report initial apprehension regarding implementation of a SDD HoLEP pathway, adequate support to intraoperative and postoperative teams helps build experience that alleviates these concerns. [ABSTRACT FROM AUTHOR]

Objective: To define risk factors and perioperative outcomes for matrix stones and compare these outcomes with struvite and calcium stone cohorts.Methods: A retrospective cohort study comparing matrix stones (n=32), struvite stones (n=23) and a matched, calcium stone control group (n=32) was performed. Two-way ANOVA was used to compare the groups for continuous variables. Chi-square tests were used to compare categorical variables. Significance was set at P <.05. All statistical tests were performed using R (v1.73).Results: We identified no differences in age, gender, or BMI between the three groups. Matrix and struvite stones were more likely to have a history of prior stone surgery and recurrent UTIs compared to calcium stones (P=.027 and P <.001, respectively). Struvite stones were more likely to present as staghorn calculi compared to matrix or calcium stones (56.5% vs 21.7% vs 18.8%, P=.006). There were no significant differences in postoperative stone free rates (P=.378). No significant differences in postoperative infectious complications were identified. Matrix stones were more likely to have Candida on stone culture compared to the struvite or calcium stones (P <.0001).Conclusion: Matrix and struvite stones were more likely have a history of stone surgery and preoperative recurrent UTIs. Struvite stones were more likely to present as staghorn calculi. Matrix stones were more likely to have Candida present in stone cultures. However, no difference in postoperative infectious outcomes or stone free rates were identified. Further study with larger cohorts is necessary to distinguish matrix stone postoperative outcomes from struvite and calcium stones. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) changed the practice of medicine in America. During the March 2020 lockdown, elective cases were canceled to conserve hospital beds/resources resulting in financial losses for health systems and delayed surgical care. Ambulatory percutaneous nephrolithotomy (aPCNL) has been shown to be safe and could be a strategy to ensure patients receive care that has been delayed, conserve hospital resources, and maximize cost-effectiveness. We aimed to compare the safety and cost-effectiveness of patients undergoing aPCNL against standard PCNL (sPCNL). Materials and Methods: Ninty-eight patients underwent PCNL at Indiana University Methodist Hospital, a tertiary referral center, by three expert surgeons from January 2020 to September 2020. The primary outcome of the study was to compare the 30-day rates of emergency department (ED) visits, readmissions, and complications between sPCNL and aPCNL. Secondary outcomes included cost analysis and stone-free rates (SFRs). Propensity score matching was performed to ensure the groups were balanced. Statistical analyses were performed using SAS 9.4 using independent t-tests for continuous variables and chi-square analyses for categorical variables. Results: Ninety-eight patients underwent PCNL during the study period (sPCNL = 75 and aPCNL = 23). After propensity score matching, 42 patients were available for comparison (sPCNL = 19 and aPCNL = 23). We found no difference in 30-day ED visits, readmissions, or complications between the two groups. aPCNL resulted in cost savings of $5327 ± 442 per case. SFRs were higher for aPCNL compared with sPCNL. Conclusions: aPCNL appears safe to perform and does not have a higher rate of ED visits or readmissions compared with sPCNL. aPCNL may also be cost-effective compared with sPCNL. [ABSTRACT FROM AUTHOR]

Introduction: Although holmium laser enucleation of the prostate (HoLEP) is a highly effective surgery, there is a variable recovery period where patients may experience hematuria, dysuria, or urinary incontinence (UI). Despite preoperative consultation, there is a paucity of literature examining the effectiveness of physician-patient communication in preparing the patient for the postoperative recovery period. We sought to examine recovery expectations as a patient-reported outcome (PRO) metric for HoLEP. Methods: With institutional review board approval, we queried our electronic medical record and retrospective clinical registry to identify 50 consecutive patients that underwent HoLEP from November 2019 to March 2020 by two endourologists. Patients were provided questionnaires via Twistle© ≥6 months postoperatively. Patient demographics and perioperative course was examined in the context of responses. Our primary objective was determining whether patients felt they had a reasonable understanding of the recovery process. Results: We observed a 92% (46/50) response rate, with an average patient age of 69.4 years (range 55-88). Overall, 91.3% (42/46) felt they had a reasonable understanding of the recovery. Additionally, 97.8% (45/46) were aware of temporary UI, with 87% having ≥1 episodes of UI after catheter removal. We found 47.8% (22/46) of patients expected UI to resolve within 30 days, while 8.6% expected >90 days of UI. All patients were aware of the risk of hematuria, with 93.5% (43/46) expecting resolution within 30 days (<7 days: 47.8%; 7-14 days: 28.3%; 15-30 days: 17.4%). Conclusions: Although surgical technique continues to improve HoLEP, ensuring adequate physician-patient communication to optimize expectations is crucial. We report patient understanding of HoLEP recovery and areas for future improvement. [ABSTRACT FROM AUTHOR]

Objectives: To determine if patients were obtaining opioids after HoLEP from other sources - despite our opioid-free postoperative pathway - we utilized a national prescription drug monitoring program (PDMP) to review all patients who underwent HoLEP at our institution.Methods: We performed a retrospective review of all HoLEPs completed by two fellowship-trained surgeons. We utilized a national PDMP to determine the true rate of postoperative opioid use. The primary outcome was filling of an opioid prescription within 31 postoperative days. Student t-tests and chi-square tests were used to compare continuous and categorical variables, respectively.Results: From July 2018-July 2020, 284 men underwent HoLEP. Despite our opioid-free pathway, 35 men (12.4%) received postoperative opioids. Unfortunately, 41.2% of opioids were prescribed by our inpatient physician assistant on his own accord. To prevent confounding, these patients were excluded from primary analyses. Thus, only 7.4% of patients received postoperative opioids. On univariate analysis, surgeon experience, chronic opioid use, any opioid exposure, benzodiazepine use, and chronic pain were associated with postoperative opioid use. On multivariate analysis, only preoperative opioid exposure (OR 41.9, P = 0.0383) was identified as a significant variable.Conclusion: 92.6% of patients did not obtain postoperative opioids on our opioid-free post-HoLEP pathway, but 7.4% of patients did obtain opioids from outside sources. Proper education of the surgical team is key to prevent inappropriate opioid prescribing. On multivariate analysis, we identified that any preoperative opioid exposure was associated with an increased risk of obtaining postoperative opioids. [ABSTRACT FROM AUTHOR]

Purpose: To perform a global survey to identify contemporary practice patterns of transurethral therapies for benign prostatic hypertrophy. Methods: A REDCap survey was distributed to the ~ 3500 members of the Endourological Society. Surgeons completed demographic information and then selected the BPH therapies they perform 10 cases/year. There were four categories of BPH therapies: ablation, enucleation, resection/vaporization, and MIST (minimally invasive surgical technique). Within each category, there were subcategories to account for different energy modalities. All statistical analyses were performed using SAS 9.4. Results: A total of 175 surgeons responded to our survey. Prostate resection/vaporization remained the most commonly utilized technique (51.9%, n = 147/283) followed by enucleation (22.6%, n = 64/283). Bipolar TURP (bTURP) was the most common modality for prostate resection (69.4%, n = 102/147). Holmium laser enucleation (HoLEP) was the most common modality for enucleation (46.9%, n = 30/64). Urolift® was performed more often than Rezūm™ (55.9% vs. 44.1%, n = 19/34 vs. 15/34, respectively). Among surgeons performing ablation, country of practice was a significantly associated with length of stay (LOS), p < 0.0001. For surgeons performing enucleation, academic institution and completion of a fellowship were associated with postoperative day (POD) 1 catheter removal (p = 0.0240 and p = 0.020, respectively). Conclusions: In this contemporary, global survey of the Endourology Society, resection/vaporization techniques were the most commonly performed. Rates of MISTs remained relatively low at 12.1%. Academic institution and fellowship status were associated with shorter catheterization times and LOS for certain surgical categories. [ABSTRACT FROM AUTHOR]

Objective: To determine the true failure rate of opioid free ureteroscopy (OF-URS) and rates of new-persistent opioid use utilizing a national prescription drug monitoring program.Material and Methods: We identified 239 patients utilizing our retrospective stone database who underwent OF-URS from Februrary 2018-March 2020. In Feb 2018, we initiated a OF-URS pathway (diclofenac, tamsulosin, acetaminophen, pyridium and oxybutynin). Patients who had a contraindication to NSAIDs were excluded from primary analyses. A prescription drug monitoring program was then utilized to determine the number of patients who failed OF-URS (defined as receipt of an opioid within 31 days of surgery) as well as rates of new-persistent opioid use (defined as receipt of opioid 91-180 days after surgery). All statistical analyses were performed using SAS 9.4. Tests were 2-sided and statistical significance was set at P<0.05.Results: We found a OF-URS failure rate of 16.6% and 14.0% in the total and opioid naïve cohorts, respectively. Rates of new-persistent opioid use were 0.9% and 1.2%, respectively (lower than published expected rate of ~6% after URS with postoperative opioids). 91% of patients obtained opioid from alternative sources. Uni/multivariate analyses were performed for both cohorts. In the total cohort, benzodiazepine users had a lower risk of OF-URS failure on multivariate analysis. No variables were associated with OF-URS failure in the opioid naïve cohort.Conclusion: The true failure rate of OF-URS is higher than previously thought at 16.6% and 14.0%. However, efforts to reduce opioid prescriptions with OF-URS pathways have successfully reduced new-persistent opioid use. [ABSTRACT FROM AUTHOR]

We present a patient with acute myeloid leukemia and prolonged, severe neutropenia who developed fulminant Clostridioides difficile infection refractory to medical therapy and was high‐risk for surgical intervention. He was treated with fecal microbiota transplantation (FMT) for life‐saving cure. The patient had subsequent clinical improvement, however, developed multidrug‐resistant Pseudomonas aeruginosa bacteremia 2 days post‐procedure. We describe subsequent investigation of this event that found this bacteremia was not related to the donor stool administered during FMT. This case adds to the literature that FMT could be considered in heavily immunocompromised patients with fulminant Clostridioides difficile infection where maximal medical therapy has been ineffective and surgery may carry an excessively high mortality risk. [ABSTRACT FROM AUTHOR]

A quiz is presented related to the diagnosis of Fevers and Night Sweats of a 35-year-old Man.

An otherwise healthy 7-year-old boy was diagnosed with malignant large cell calcifying Sertoli cell tumor (LCCSCT) of the testis. He underwent attempted partial orchiectomy with conversion to radical orchiectomy due to suspected malignancy on intraoperative frozen section. There was no lymph node or visceral metastases. To our knowledge, this is the first report of malignant LCCSCT in the prepubertal population. LCCSCT of the testis is an extremely rare neoplasm, with low malignant potential. Malignant cases are exclusively reported previously in the adult population. We report the first case of malignant LCCSCT in a pediatric patient. We review the literatures and discuss the clinical, pathologic features and treatments of malignant LCCSCT. [ABSTRACT FROM AUTHOR]

Introduction: Holmium laser enucleation of the prostate (HoLEP) has evidenced-based advantages in treating benign prostatic hyperplasia (BPH) relative to other interventions. Unfortunately, the adoption of HoLEP has remained relatively low in Medicare and the National Surgical Quality Improvement Program populations. HoLEPs role as an inpatient surgical intervention is changing as advancements in the technique and systems have demonstrated the feasibility of same-day discharge. Thus, our objective was to evaluate national HoLEP trends in ambulatory surgery settings from 2016 to 2019. Materials and Methods: The Nationwide Ambulatory Surgery Sample (NASS) is the largest national all-payer database of ambulatory surgical encounters, managed by the Agency for Healthcare Research and Quality. A cross-sectional retrospective analysis of the 2016 and 2019 NASS was performed. Rates of BPH surgeries were calculated and stratified by age, census region, and primary payer to compare across time points for trends. Chi-squared tests and two-sample t-tests were completed for categorical and continuous variables, respectively. Results: The total number of ambulatory BPH surgeries fell 20% between 2016 (n = 124,538) and 2019 (n = 100,593). In 2016, HoLEP lagged behind photoselective vaporization of the prostate (PVP) and transurethral resection of prostate (TURP) with 4.7% of surgeries but rose to the second most common procedure in 2019 with 8.3% of total surgeries. TURP was the most common intervention (62.6% in 2016, 90.7% in 2019). Simple prostatectomy was the most expensive intervention. By U.S. census region, more HoLEPs were carried out in the South (43.1% in 2016, 37.5% in 2019) and Midwest (26.8% in 2016, 31.7% in 2019). Conclusions: Overall, HoLEP uptake is increasing. HoLEP has replaced greenlight PVP as the second most frequently used intervention. The rate of ambulatory HoLEPs has nearly doubled despite a general decrease in the number of surgeries. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Prostatic urethral lift (PUL) accounts for approximately one-quarter of all surgical benign prostatic hyperplasia (BPH) procedures performed in the U.S.1 Within five years of a patient's PUL procedure, approximately 1/7 patients will require surgical BPH retreatment.2 We aimed to highlight the evidence of surgical BPH retreatment modalities after PUL, with a focus on safety, short-term efficacy, durability, and relative costs. METHODS: A literature review was performed using PubMed, and an exhaustive review of miscellaneous online resources was completed. The search was limited to English, human studies. Citations of relevant studies were reviewed. RESULTS: No study has examined the efficacy, safety, or durability of transurethral resection of the prostate (TURP) or repeat PUL in the post-PUL setting. Recently, groups have examined laser enucleation (n=81), water vapor thermal therapy (WVTT) (n=5), robotic simple prostatectomy (SP) (n=2), and prostatic artery embolization (PAE) (n=1) in the post-PUL setting. Holmium enucleation of the prostate (HoLEP) after PUL appears to be safe and has similar functional outcomes to HoLEP controls. Other treatment modalities examined appear safe but have limited efficacy evidence supporting their use. Photo-selective vaporization of the prostate (PVP) and robotic waterjet treatment (RWT) have no safety or efficacy studies to support their use in the post-PUL setting. CONCLUSIONS: Despite increasing numbers of patients expected to require surgical retreatment after PUL in North America, there is currently limited evidence and a lack of recommendations guiding the evaluation and management of these patients. HoLEP is associated with the strongest evidence to support its use in the post-PUL setting. [ABSTRACT FROM AUTHOR]

To compare anesthetic parameters using a novel prone single transverse chest roll technique (STR) to the standard thoraco-pelvic dual transverse roll technique (DTR). A retrospective review of 441 patients who underwent PCNL between 2018 and 2022 was performed. A total of 4 surgeons were included—surgeon 1 utilized the STR technique while surgeons 2, 3, and 4 used the DTR technique. Anesthetic parameters including end-tidal CO 2 (ETCO 2), mean arterial pressure (MAP), peak airway pressure (P peak), plateau airway pressure (P plat), positive end-expiratory pressure (PEEP), oxygen saturation (SpO 2), and tidal volume (TV) were compared between both groups at 0 (supine), 15-, 30-, and 60-minute post-intubation intervals. Mixed effects regression models with interaction and pairwise comparisons were made between both groups (P <.05). A total of 581 PCNLs were performed with 199 using STR and 382 using DTR. Surgery duration, ASA class, and age were similar amongst the STR and DTR groups. Estimated blood loss (59cc vs 83cc, P =.007) and length of stay (77 hrs vs 163 hrs, P = <.001) was significantly lower in the STR group. There was a significantly lower P peak , P plat and TV in the STR compared to DTR group at 0, 15, 30, and 60 minutes (P <.001). Usage of a single transverse chest roll during prone PCNL appears to be a safe positioning method. STR patients had lower P peak and P plat at all time points, which has been shown to be predictive of lower blood loss. [ABSTRACT FROM AUTHOR]

A series of nitrosyl tris(5,10,15-aryl)corrolate complexes of iron(III) Fe(Ar3C)(NO) with different substituents on the aryl groups have been prepared, and certain spectroscopic and reaction properties were compared. The cyclic voltammetric analysis of the various Fe(Ar3C)(NO) complexes demonstrated that both the one-electron oxidation and one-electron reduction potentials respond in systematic and nearly identical trends relative to the electron-donor properties of the substituents. A similar pattern was seen in the nitrosyl stretching frequency, νNO, which modestly decreased with the stronger donor substituents. Flash photolysis of Fe(Ar3C)(NO) solutions in toluene leads to NO dissociation followed by rapid [NO]-dependent decay of the transients formed (presumably Fe(Ar3C)) to regenerate the original spectra. As was seen in an earlier flash photolysis study of Fe(TNPC)(NO) (TNPC3- = 5,10,15-tris(4-nitro-phenyl)corrolate; Joseph, C.; Ford, P. C. J. Am. Chem. Soc. 21)05, 127, 6737–6743), the second-order rate constants, kNO, are all much faster ((1–9) ⊗ 108 M-1 s-1 at 298 K) than those for analogous iron(III) complexes of porphyrins. However, on a more microscopic level there is no obvious pattern in these rates with respect to the donor properties of the aryl ring substituents. The high reactivity of the ferric triarylcorrolates with NO data is interpreted in terms of the strongly electron-donating character of the Ar3C3- ligand and the quartet electronic configuration of the Fe(Ar3C) intermediate. [ABSTRACT FROM AUTHOR]

Background The Infectious Diseases Society of America (IDSA) developed the Core Antimicrobial Stewardship (AS) Curriculum to meet the increasing demand for infectious diseases (ID) providers with AS expertise. Notable diversity in implementation approaches has been observed among ID fellowship programs using the curriculum. We sought to describe individual approaches and develop a curriculum implementation roadmap. Methods We surveyed ID fellowship programs that had previously implemented the IDSA Core AS curriculum. The survey included questions regarding program characteristics, curriculum participants and presentation format, resources and barriers, and implementation strategies. Commonly reported program features were summarized in the context of the self-reported implementation strategies. Implementation guides were developed based on the most common characteristics observed. Results Of 159 programs that had purchased the curriculum, 37 responded, and 34 (21%) were included in the analysis. The curriculum was primarily taught by AS physicians (85%) and AS pharmacists (47%). The most common conference structure was a longitudinal conference series (32%), and eLearning was the most common presentation format. Limited AS faculty time (76%) and limited first-year fellow availability (62%) were frequently reported as barriers, and dedicated AS curricular time was a resource available to most programs (67%); implementation guides were created for these 3 program features. Conclusions Programs reported a variety of implementation barriers and resources, with several common themes emerging, allowing for the development of tailored curriculum planners for 3 commonly observed program characteristics. This work will equip fellowship programs with curriculum implementation strategies and guide future enhancements of the IDSA Core and Advanced AS curricula. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to compare holmium laser enucleation of the prostate (HoLEP) outcomes in patients with and without neurologic diseases (ND). Methods: A prospectively maintained database of patients undergoing HoLEP from January 2021 to April 2022 was reviewed. The following NDs were included: diabetes-related neuropathy/neurogenic bladder, Parkinson’s disease, dementia, cerebrovascular accident, multiple sclerosis, traumatic brain injury, transient ischemic attack, brain/spinal tumors, myasthenia gravis, spinal cord injury, and other. Statistical analysis was performed using t-tests, Chi-squared, and binomial tests (p<0.05). Results: A total of 118 ND patients were identified with 135 different neurologic diseases. ND patients were more likely to have indwelling catheters (57% vs. 39%, p=0.012) and urinary tract infections (UTIs) preoperatively (32% vs. 19%, p=0.002). Postoperatively, ND patients were more likely to fail initial trial of void (20% vs. 8.1%, p<0.001) and experience an episode of acute urinary retention (16% vs. 8.5%, p=0.024). Within 90 days postoperative, the overall complication rate was higher in the ND group (26% vs. 13%, p=0.001). Within the ND group, 30/118 (25%) had ≥1 UTI within 90 days preoperative, which decreased to 10/118 (8.7%) 90 days postoperative (p<0.001). At last followup (mean 6.7 months [ND] vs. 5.4 months [nonND], p=0.03), four patients (4.4%) in the ND group required persistent catheter/clean intermittent catheterization compared to none in the non-ND group (p=0.002). Conclusions: Patients with ND undergoing HoLEP are more likely to experience postoperative retention and higher complication rates compared to non-ND patients. While UTI rates are higher in this population, HoLEP significantly reduced three-month UTI and catheterization rates. [ABSTRACT FROM AUTHOR]

Background: Holmium laser enucleation of the prostate (HoLEP) is a highly effective and durable minimally invasive surgery for benign prostatic hyperplasia. Historically, alternative treatments for large glands (≥175 cc) are associated with prolonged length of stay (LOS) and postoperative catheterization. However, advances in laser technology combined with surgical technique optimization have early evidence supporting same-day discharge. We look to examine contemporary same-day discharge outcomes for large glands. Materials and Methods: With Institutional Review Board (IRB) approval we queried our electronic medical record and retrospective clinical registry to examine perioperative outcomes of large gland (≥175 cc) prostates that underwent HoLEP with consideration for same-day discharge. Results: From December 10, 2019 to September 29, 2020 we identified 55 patients with a preoperative prostate size ≥175 cc (39 CT, 12 MRI, 4 transrectal ultrasound), of which 45 were scheduled for same-day discharge and 10 for admission. Mean preoperative prostate size was 229.9 cc (range 175–535 cc) and 36 (65.5%) were in urinary retention. Mean preoperative prostate-specific antigen (PSA) was 8.58 ng/mL, American Urological Association Symptom Score (AUASS) 22.3, and Qmax 8.8 mL/second. At 3 months postoperative follow-up mean AUASS was 6.7, PSA 0.87 ng/mL and Qmax 20.4 mL/second. All comer same-day discharge rate was 70% (38/55). Of patients planned for same-day discharge 38/45 (84%) were effective. Average LOS for all patients was 11.8 hours with catheterization of 21.2 hours. When compared with 2010 published large gland outcomes, our current LOS represents a 220% reduction. Looking specifically at patients planned for same-day discharge, average LOS and catheter duration was 8.8 and 17.0 hours, whereas LOS and catheter duration for patients planned for admission was 25.7 and 39.4 hours, respectively. Conclusions: We report the first outcomes of preoperatively planned same-day discharge for HoLEP in large glands (≥175 cc). A combination of technologic advances and optimization of technique have allowed for a safe adoption of same-day discharge, providing additional advantages over alternative large gland treatments. [ABSTRACT FROM AUTHOR]

Background Antimicrobial stewardship programs (ASPs) often utilize Infectious Diseases fellows (IDFs) to cover pre-authorization processes during evening and weekend hours. IDFs often provide ASP coverage in addition to their inpatient consult roles. In response to increasing consult volume, we worked with our fellowship program to relieve IDFs of evening and weekend coverage (a decrease in fellow coverage by 26 hours per week) starting in October 2017. Members of the ASP assumed the majority of these evening and weekend hours. Additional post-prescriptive activities and a rotation in Infection Control and Antimicrobial Stewardship were implemented in response. We sought to analyze the impact of this intervention. Methods Intervention and medication data were extracted from the electronic medical record during 1 July 2017 through 30 September of 2017 (IDF Coverage) and the same 3 months of 2018 (ASP Coverage). Comparisons between the two periods were performed using descriptive statistics of the number of interventions, number of weekend interventions, types of interventions, and days of therapy (DOT; per 1000 patient-days). Results Comparing July-September of 2017 and 2018, total ASP interventions increased 16% (1192 to 1391); weekend ASP interventions increased 75% (139 to 243). The most common interventions were "Choice of Therapy" (41% in both years), "De-Escalation" (17% in 2017, 16% in 2018), and "Dose/Interval Optimization" (10% in both years). The most intervened agents were piperacillin–tazobactam, cefepime, vancomycin, meropenem, and ceftazidime. Comparing the same time periods, total antibiotic DOT decreased 4% (714.1 to 684.9). There was a 28% decrease in piperacillin–tazobactam (41.47 to 29.85), 19% decrease in meropenem (28.08 to 22.61), and 7% decrease in vancomycin (125.09 to 116.17) use. Ceftazidime was unchanged (18.13 to 18.08). Cefepime increased by 9% (56.78 to 61.97). Conclusion Relieving IDFs of evening and weekend ASP coverage during busy inpatient consult rotations may help decrease burnout. The assumption of these hours by dedicated members of ASP led to an increase in documented total and weekend ASP interventions. In addition, the change was associated with a relative decrease in piperacillin–tazobactam, meropenem, and vancomycin use. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Advanced Practice Providers (APPs), including nurse practitioners (NPs) and physician assistants (PAs), increasingly provide patient care in inpatient settings at academic medical centers. However, little is known about their medical education. We sought to describe current APP educational experiences at our institution and to implement and evaluate an educational intervention aimed at decreasing inappropriate antimicrobial use for asymptomatic bacteriuria (ASB) amongst this group. Methods 33 inpatient-based APPs participated in the educational intervention consisting of in-person sessions and an online video reviewing diagnosis and management of ASB. Pre- and post-intervention surveys assessed knowledge before and after the intervention. Surveys also assessed APP's educational background, opportunities, and barriers. Results 17 APPs completed the pre-intervention survey. 59% estimated less than 10 hours of antimicrobial education during their training. 88% reported that the majority of their current learning is independent. All APPs reported desiring more educational opportunities. 76% felt current opportunities are designed for medical students or housestaff. Commonly reported barriers included patient care, rounding obligations, and lack of protected time. 8 APPs attended the in-person sessions and there were 21 views of the online video. 10 APPs completed the post-intervention survey. All reported interest in similar sessions in the future. 70% planned to prescribe fewer antimicrobials for ASB; however, the same number also reported "Attending or fellow decision" as the main barrier to decreasing prescriptions. Mean knowledge scores significantly increased after the intervention from 2.5 to 4.125 (P < 0.05). Conclusion APPs within an academic medical center have unique educational backgrounds and needs. APPs identified current educational opportunities as student/resident directed and incompatible with their work schedules. More APPs utilized the video session than attended in-person lectures. This intervention improved immediate knowledge acquisition; however, retention and impact on clinical outcomes are still being evaluated. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background: Outcomes of holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia has been well studied. As comfort with the procedure has improved, the number of concurrent surgeries performed with HoLEP has increased. Technology and technique optimization have safely transitioned HoLEP toward same-day catheter removal and discharge. We aim to assess the success and safety of transitioning toward a same-day care pathway for patients undergoing concurrent surgeries with HoLEP. Materials and Methods: With institutional review board approvals, we queried the electronic medical record and retrospective clinical registry to examine perioperative characteristics and outcomes of patients who underwent HoLEP performed by two endourologists at two centers between July 1, 2016, and June 1, 2021, in which ≥1 concurrent surgical procedure was performed. Results: There were 188 patients with an average age of 72.3 years, who underwent HoLEP with ≥1 concurrent surgical procedure within the study period. In total, 221 non-HoLEP procedures were performed with 30/188 (16.0%) undergoing ≥3 total procedures in a single operation. The four-most common concurrent procedures were cystolitholapaxy 86/221 (38.9%), ureteroscopy 57/221 (25.8%), transurethral resection of bladder tumor 14/221 (6.3%), and percutaneous nephrolithotomy 14/221 (6.3%). Postoperatively, 3 (1.6%) patients required transfusion. After transitioning to a same-day care path, the proportion of patients who had successful same-day catheter removal and same-day discharge increased (all p < 0.05). Median length of stay decreased (from 23 hours 11 minutes to 3 hours 49 minutes, p = 0.008). Our 90-day readmission rate for urology complication was 7.9%, and only 3.6% of patients undergoing concurrent stone surgery required an additional stone surgery within 90 days. The overall Clavien–Dindo ≥3b rate was 4.8% (9-3b, 0-4, 0-5). Conclusions: Advances in HoLEP technique and technology allow for safe same-day discharge for concurrent surgery performed at the time of HoLEP. Few patients were readmitted within 90 days and no patients experienced Clavien–Dindo ≥4 complications. [ABSTRACT FROM AUTHOR]

Introduction: Intradetrusor onabotulinumtoxinA (OTA) injection is a well-established treatment option for refractory overactive bladder; however, its use at the time of holmium laser enucleation of the prostate (HoLEP) for men with bladder outlet obstruction (BOO) and severe storage symptoms has not been previously reported. Materials and Methods: We retrospectively identified men with BOO and severe storage symptoms who underwent treatment with 200 U of intradetrusor OTA (Botox®) at the time of HoLEP. Patients were propensity score matched to a cohort of HoLEP-only patients based on age, Michigan Incontinence Symptom Index (M-ISI) score, preoperative urinary retention, urge incontinence, and prostate size. Perioperative, postoperative, and patient-reported outcomes were examined between groups. Results: We identified 82 men who underwent HoLEP, including 41 patients in the OTA group and 41 patients in the control group. There was no difference in operative times (59 minutes OTA vs 55 minutes control, p = 0.2), rates of same-day trial of void (TOV) (92% OTA vs 94% control, p = 0.7), or rates of same-day discharge (88% OTA vs 85% control, p = 0.6) between groups. There was no difference in temporary postoperative urinary retention (7% OTA vs 2% control, p = 0.3) between groups. Patients who received OTA injections had a significant reduction in their incontinence scores at 3-month follow-up (M-ISI −8, interquartile range [IQR]: −13 to 0, p < 0.001), whereas control patients did not (M-ISI −5, IQR: −8 to −1, p = 0.2). There was no difference in rates of 90-day complications between groups (OTA 10% vs control 5%, p = 0.7). Conclusions: Intradetrusor OTA at the time of HoLEP is safe and is associated with improved urinary incontinence scores and AUA Symptom Score. Rates of same-day discharge and same-day TOV after HoLEP were not affected by OTA. These findings support the role of OTA as an adjunct to surgical intervention in men with incontinence in the presence of BOO. [ABSTRACT FROM AUTHOR]

This study compared the effects of a conventional approach and a progressive approach to discrete trial teaching when teaching tact relations to 12 children diagnosed with autism spectrum disorder (ASD). The conventional approach was informed by best practice guidelines for teaching receptive and expressive language (Green Focus on Autism and Other Developmental Disabilities, 16(2), 72–85, 2001; Grow & Leblanc Behavior Analysis in Practice, 6(1), 56–75, 2013) and other relevant research (e.g., Graff & Karsten Behavior Analysis in Practice, 5(2), 37–48, 2012; León & Rosales Journal of Behavioral Education, 27(1), 81–100, 2018; Majdalany et al. Journal of Applied Behavior Analysis, 47(3), 657–662, 2014). The progressive approach was informed by guidelines outlined by Leaf, Cihon, Leaf, et al. International Electronic Journal of Elementary Education, 9(2), 361–372, (2016a) and Leaf, Leaf, McEachin, et al. Journal of Autism & Developmental Disorders, 46(2), 720–731, (2016c). In this study, highly vocal-verbal participants diagnosed with ASD were randomly assigned to the conventional or progressive condition and received 20 sessions of intervention. Following intervention, statistical analysis was used to evaluate and compare the effects of each condition. Although both were effective in teaching the participants tact relations, there was a statistically significant difference in the number of tact relations learned in the progressive condition when compared to the conventional condition. [ABSTRACT FROM AUTHOR]

Shock wave lithotripsy (SWL) is an effective and commonly applied clinical treatment for human kidney stones. Yet the success of SWL is counterbalanced by the risk of retained fragments causing recurrent stone formation, which may require retreatment. This study has applied GeoBioMed experimental and analytical approaches to determine the size frequency distribution, fracture patterns, and reactive surface area of SWL-derived particles within the context of their original crystal growth structure (crystalline architecture) as revealed by confocal autofluorescence (CAF) and super-resolution autofluorescence (SRAF) microscopy. Multiple calcium oxalate (CaOx) stones were removed from a Mayo Clinic patient using standard percutaneous nephrolithotomy (PCNL) and shock pulse lithotripsy (SPL). This produced approximately 4–12 mm-diameter PCNL-derived fragments that were experimentally treated ex vivo with SWL to form hundreds of smaller particles. Fractures propagated through the crystalline architecture of PCNL-derived fragments in a variety of geometric orientations to form rectangular, pointed, concentrically spalled, and irregular SWL-derived particles. Size frequency distributions ranged from fine silt (4–8 μm) to very fine pebbles (2–4 mm), according to the Wentworth grain size scale, with a mean size of fine sand (125–250 μm). Importantly, these SWL-derived particles are smaller than the 3–4 mm-diameter detection limit of clinical computed tomography (CT) techniques and can be retained on internal kidney membrane surfaces. This creates clinically undetectable crystallization seed points with extremely high reactive surface areas, which dramatically enhance the multiple events of crystallization and dissolution (diagenetic phase transitions) that may lead to the high rates of CaOx kidney stone recurrence after SWL treatment. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) regulate cellular processes such as differentiation and apoptosis and are targeted by anticancer therapeutics in development and in the clinic. HDAC8 is a metal-dependent class I HDAC and is proposed to use a general acid-base catalytic pair in the mechanism of amide bond hydrolysis. Here, we report site-directed mutagenesis and enzymological measurements to elucidate the catalytic mechanism of HDAC8. Specifically, we focus on the catalytic function of Y306 and the histidine-aspartate dyads H142-D176 and H143-D183. Additionally, we report X-ray crystal structures of four representative HDAC8 mutants: D176N, D176N/Y306F, D176A/Y306F, and H142A/Y306F. These structures provide a useful framework for understanding enzymological measurements. The pH dependence of kcat/KM for wild-type Co(II)-HDAC8 is bell-shaped with two pKa values of 7.4 and 10.0. The upper pKa reflects the ionization of the metal-bound water molecule and shifts to 9.1 in Zn(II)-HDAC8. The H142A mutant has activity 230-fold lower than that of wild-type HDAC8, but the pKa1 value is not altered. Y306F HDAC8 is 150-fold less active than the wild-type enzyme; crystal structures show that Y306 hydrogen bonds with the zinc-bound substrate carbonyl, poised for transition state stabilization. The H143A and H142A/H143A mutants exhibit activity that is >80000-fold lower than that of wild-type HDAC8; the buried D176N and D176A mutants have significant catalytic effects, with more subtle effects caused by D183N and D183A. These enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization. [ABSTRACT FROM AUTHOR]

Background Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact. Methods ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows' knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation ("pre-curriculum") and compared to first-year fellows who complete the curriculum the following year ("post-curriculum"). Results Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a "formal" curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows' confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P  = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning. Conclusions Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors. [ABSTRACT FROM AUTHOR]

Professional societies serve many functions that benefit constituents; however, few professional societies have undertaken the development and dissemination of formal, national curricula to train the future workforce while simultaneously addressing significant healthcare needs. The Infectious Diseases Society of America (IDSA) has developed 2 curricula for the specific purpose of training the next generation of clinicians to ensure the future infectious diseases (ID) workforce is optimally trained to lead antimicrobial stewardship programs and equipped to meet the challenges of multidrug resistance, patient safety, and healthcare quality improvement. A core curriculum was developed to provide a foundation in antimicrobial stewardship for all ID fellows, regardless of career path. An advanced curriculum was developed for ID fellows specifically pursuing a career in antimicrobial stewardship. Both curricula will be broadly available in the summer of 2021 through the IDSA website. [ABSTRACT FROM AUTHOR]

A series of novel, highly potent, selective, and ATP-competitivemammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepinescaffold have been identified. Lead optimization resulted in the discoveryof inhibitors with low nanomolar activity and greater than 1000-foldselectivity over the closely related PI3K kinases. Compound 28(XL388) inhibited cellular phosphorylation of mTOR complex1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates.Furthermore, this compound displayed good pharmacokinetics and oralexposure in multiple species with moderate bioavailability. Oral administrationof compound 28to athymic nude mice implanted with humantumor xenografts afforded significant and dose-dependent antitumoractivity. [ABSTRACT FROM AUTHOR]

Abstract: We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials. [Copyright &y& Elsevier]

The phosphoinositide 3-kinases (PI3Ks) have been linkedto an extraordinarilydiversified group of cellular functions making these enzymes compellingtargets for the treatment of disease. A large body of evidence haslinked PI3Kγ to the modulation of autoimmune and inflammatoryprocesses making it an intriguing target for drug discovery. Our high-throughputscreening (HTS) campaign revealed two hits that were nominated forfurther optimization studies. The in vitro activity of the first HTShit, designated as the sulfonylpiperazine scaffold, was optimizedutilizing structure-based design. However, nonoptimal pharmacokineticproperties precluded this series from further studies. An overlayof the X-ray structures of the sulfonylpiperazine scaffold and thesecond HTS hit within their complexes with PI3Kγ revealed ahigh degree of overlap. This feature was utilized to design a seriesof hybrid analogues including advanced leads such as 31with desirable potency, selectivity, and oral bioavailability. [ABSTRACT FROM AUTHOR]

[Display omitted] • Missense mutations in HDAC8 can cause Cornelia de Lange Syndrome. • HDAC8 mutations I45T, E66D, D176G, and G320R HDAC8 result in loss of function. • Crystallographic and computational approaches yield models of these mutants. • Structural analysis reveals a molecular basis for compromised catalysis. Cornelia de Lange Syndrome (CdLS) and associated spectrum disorders are characterized by one or more congenital anomalies including distinctive facial features, upper limb abnormalities, intellectual disability, and other symptoms. The molecular genetic basis of CdLS is linked to defects in cohesin, a protein complex that functions in sister chromatid cohesion, chromatin organization, and transcriptional regulation. Histone deacetylase 8 (HDAC8) plays an important role in cohesin function by catalyzing the deacetylation of SMC3, which is required for efficient recycling of the cohesin complex. Missense mutations in HDAC8 have been identified in children diagnosed with CdLS spectrum disorders, and here we outline structure-function relationships for four of these mutations. Specifically, we report the 1.50 Å-resolution structure of the I45T HDAC8–suberoylanilide hydroxamic acid complex, the 1.84 Å-resolution structure of E66D/Y306F HDAC8 complexed with a peptide assay substrate, and the 2.40 Å-resolution structure of G320R HDAC8 complexed with the inhibitor M344. Additionally, we present a computationally generated model of D176G HDAC8. These structures illuminate new structure-function relationships for HDAC8 and highlight the importance of long-range interactions in the protein scaffold that can influence catalytic function. [ABSTRACT FROM AUTHOR]