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Abstract Background Itraconazole is first-line treatment for mild-moderate blastomycosis and consolidation of moderate-severe disease. Itraconazole is metabolized to 3 metabolites, including an active metabolite hydroxy-itraconazole. The sum of itraconazole and hydroxy-itraconazole levels > 1.0 mcg/mL is guideline recommended for treatment of invasive fungal infections; conversely, some experts suggest targeting a parent compound level alone > 1.0 mcg/mL. This study aims to compare clinical outcomes and adverse drug reactions (ADRs) of combined itraconazole and hydroxy-itraconazole levels > 1.0 mcg/mL versus itraconazole parent compound alone > 1.0 mcg/mL in patients with blastomycosis. Methods This study is a single-center, retrospective chart review of patients ≥ 18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole level. The primary outcome was rate of partial or complete treatment response in patients with a combined itraconazole and hydroxy-itraconazole level > 1.0 mcg/mL versus itraconazole parent compound > 1.0 mcg/mL for > 75% of measured levels. ADRs attributable to itraconazole were compared between the groups. Treatment response rates and ADRs were compared between groups using two proportion z-tests. Results Total of 80 patients were included: 36 = combined itraconazole and hydroxy-itraconazole > 1.0, 32 = itraconazole parent alone > 1.0, 12 = 75% of all levels < 1.0. No statistically significant difference was observed between groups for blastomycosis rate of partial or complete treatment response (94.3% combined vs 96.6% parent, p=0.99). Significantly higher mortality was observed in patients failing to achieve itraconazole or itraconazole/hydroxy-itraconazole > 1.0 (2.8% combined vs 0% parent vs 25% neither, p=0.01). There was no significant difference in total ADRs between the three groups (p=0.56). Conclusion This limited evidence supports an itraconazole therapeutic target combining itraconazole and hydroxy-itraconazole > 1.0 for blastomycosis treatment. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.

Abstract Background Beta-lactam therapeutic drug monitoring (BL TDM; drug level testing) can facilitate improved outcomes in critically ill patients. Yet less than 20% of hospitals have implemented BL TDM. The purpose of this study was to characterize provider perceptions and key considerations for successful implementation of BL TDM. Methods This was a sequential mixed methods study from 2020 to 2021 of stakeholders at three academic medical centers with varying degrees of BL TDM implementation - Mayo Clinic (BL TDM not implemented), University of Florida Health Shands (partially implemented), and Royal Brisbane and Women’s Hospital (fully implemented). Stakeholders completed a survey to characterize their knowledge, perceptions, and experience with BL TDM. A diverse group of 30 respondents were then purposively sampled for semi-structured interviews. Results from the two strands were integrated, themes were identified, and findings were situated within implementation science frameworks. Results Among the 138 survey respondents (22% response rate), the majority were physicians (38%) and pharmacists (33%). 71% practiced in critical care and 21% in infectious diseases. The majority of respondents felt BL TDM was relevant to their practice and improved medication effectiveness and safety (Figure 1). Two implementation themes were identified: individual internalization and organizational features. Individuals needed to internalize, make sense of, and agree to BL TDM implementation which was positively influenced by repeated exposure to evidence and expertise. The process of internalization seemed more complex with BL TDM than with other antibiotics (i.e., vancomycin). Organizational considerations relevant to BL TDM implementation included adequate physical and informational infrastructure, access to trained personnel, supportive governance/leadership, and robust process and workflow development. Conclusion We found broad enthusiasm about the relevance and potential benefits of BL TDM among stakeholders. Prior literature suggested the primary barrier to implementation was assay availability, but we identified many more individual and organizational attributes which impacted the scale and spread of BL TDM. Disclosures Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Marc H. Scheetz, PharmD, MSc, Abbvie: Advisor/Consultant|Allecra: Grant/Research Support|Merck: Advisor/Consultant|Nevakar: Advisor/Consultant|Nevakar: Grant/Research Support|Premier Healthcare Solutions: Honoraria|Spero: Advisor/Consultant|SuperTrans Medical: Advisor/Consultant|SuperTrans Medical: Grant/Research Support|Takeda: Advisor/Consultant|Third Pole Therapeutics: Advisor/Consultant.

Abstract Purpose: Mesenchymal stem cells (MSC) have emerged as cellular-based vehicles for the delivery of therapeutic genes in cancer therapy based on their inherent tumor-homing capability. As theranostic gene, the sodium iodide symporter (NIS) represents a successful target for noninvasive radionuclide-based imaging and therapy. In this study, we applied genetically engineered MSCs for tumor-targeted NIS gene transfer in experimental glioblastoma (GBM)—a tumor with an extremely poor prognosis. Experimental Design: A syngeneic, immunocompetent GL261 GBM mouse model was established by subcutaneous and orthotopic implantation. Furthermore, a subcutaneous xenograft U87 model was used. Bone marrow–derived MSCs were stably transfected with a NIS-expressing plasmid driven by the constitutively active cytomegalovirus promoter (NIS-MSC). After multiple or single intravenous injection of NIS-MSCs, tumoral iodide uptake was monitored in vivo using 123I-scintigraphy or 124I-PET. Following validation of functional NIS expression, a therapy trial with 131I was performed on the basis of the most optimal application regime as seen by 124I-PET imaging in the orthotopic approach. Results: A robust tumoral NIS-specific radionuclide accumulation was observed after NIS-MSC and radioiodide application by NIS-mediated in vivo imaging. NIS immunofluorescence staining of GBM and non-target tissues showed tumor-selective MSC homing along with NIS expression. Application of therapeutically effective 131I led to significantly delayed tumor growth and prolonged median survival after NIS-MSC treatment as compared with controls. Conclusions: A strong tumor-selective recruitment of systemically applied MSCs into GBM was found using NIS as reporter gene followed by successful therapeutic application of radioiodide demonstrating the potential use of NIS-based MSCs as therapy vehicles as a new GBM therapy approach.

Background: Consequences of physician burnout include medical errors, higher rate of staff turnover, and decreased patient satisfaction. We examined the prevalence of burnout and identified the contributing factors in gastroenterologists and fellows in training. Methods: We performed 3 separate surveys through the American College of Gastroenterology. (1) A national survey of practicing gastroenterologists in the United States that measured burnout and contributing factors, (2) a survey of gastroenterology fellows in training to determine self-identified burnout, as well as mitigating and exacerbating factors, and (3) a follow-up survey of fellows during the COVID-19 pandemic. Results: One thousand and twenty-one persons responded (9.2% response rate) to the first survey, including 756 individuals who completed the Maslach Burnout Inventory survey. Overall, the prevalence of high burnout was 49.3%. Factors associated with high burnout included female sex, younger age, shorter duration in practice, considering the electronic health record non–user-friendly, 2 or more hours of patient-related work at home per day, 8 or more hours of outpatient time per day, 6 or more inpatient consults per day, taking call with procedures 10 or more times per year, and having children at home. With regard to lifestyle factors, taking 20 days or more of vacation time was associated with a lower rate of burnout. The level of burnout for fellows was observed to be high (42.7% in survey 2 and 35.3% in survey 3). Conclusions: Burnout is high in gastroenterologists and fellows in training. Specific contributing factors were both systems based and personal and provide insight into changes that can be made to address burnout.

AbstractBackgroundA recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.MethodsIn this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment.ResultsThe APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014).ConclusionsPatients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Long-term outcomes of surgical treatment for pediatric developmental dysplasia of the hip (DDH) are not well defined. The purpose of this study was to report long-term radiographic and clinical outcomes, survivorship free of total hip arthroplasty (THA), and predictors of subsequent THA following childhood treatment of DDH. This study was a single-institution retrospective review of hips treated for DDH with closed or open reduction at a minimum 10-year follow-up. 107 patients (119 hips) were included with a mean patient age of 3.3 years at childhood treatment. At mean 30.5 years follow-up, 24 hips had undergone THA (20%). Mean patient age at time of THA was 33.5 years. None of the hips treated with closed reduction alone required THA, whereas 8 hips treated with open reduction (25%) underwent THA. Hips with patient age > 4 years at the time of treatment had lower survivorship at 35 years follow-up (50% vs. 85%; p < 0.001). Additionally, femoral osteotomy (OR 2.0, p < 0.001), and previous treatment elsewhere (27% vs. 16%; p < 0.01) were associated with subsequent THA. Early referral and appropriate intervention may prove important, as age and prior treatment were predictive of subsequent THA.