STAT1 modulates tissue wasting or overgrowth downstream from PDGFRß.

Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRß. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRß signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb+/D849V mice with Stat1 knockout (Stat1-/-Pdgfrb+/D849V ) are rescued from autoinflammation and have improved life span compared with Stat1+/-Pdgfrb+/D849V mice. Furthermore, PDGFRß-STAT1 signaling suppresses PDGFRß itself. Thus, Stat1-/-Pdgfrb+/D849V fibroblasts exhibit increased PDGFRß signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1+/-Pdgfrb+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRß signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.

KRCC1, a modulator of the DNA damage response.

The lysine-rich coiled-coil 1 (KRCC1) protein is overexpressed in multiple malignancies, including ovarian cancer, and overexpression correlates with poor overall survival. Despite a potential role in cancer progression, the biology of KRCC1 remains elusive. Here, we characterize the biology of KRCC1 and define its role in the DNA damage response and in cell cycle progression. We demonstrate that KRCC1 associates with the checkpoint kinase 1 (CHK1) upon DNA damage and regulates the CHK1-mediated checkpoint. KRCC1 facilitates RAD51 recombinase foci formation and augments homologous recombination repair. Furthermore, KRCC1 is required for proper S-phase progression and subsequent mitotic entry. Our findings uncover a novel component of the DNA damage response and a potential link between cell cycle, associated damage response and DNA repair.

FGF1 supports glycolytic metabolism through the estrogen receptor in endocrine-resistant and obesity-associated breast cancer.

BACKGROUND: Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. METHODS: We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. RESULTS: FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. CONCLUSIONS: Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.

Associations between gynecologic clinician type and routine female sexual dysfunction screening.

BACKGROUND: Female sexual dysfunction (FSD) is a common problem in the United States; however, only 14% to 40% of women are screened by their health care clinicians. There are few data on how differences in clinician type affects screening rates. AIM: This study aimed to assess differences in FSD screening rates among gynecology clinician types, identify factors associated with screening, and compare screening rates of FSD against conditions with established screening recommendations. METHODS: Data were collected by retrospective chart review of annual visits at an urban tertiary care center. Screening rates for FSD, depression, cervical cancer, and breast cancer were calculated and compared. Multivariable logistic regression modeling was utilized to assess the correlation between various patient characteristics and FSD screening rates. OUTCOMES: Study outcome measures included percentages of women who were screened for FSD, depression, cervical cancer, and breast cancer. RESULTS: FSD screening rate was significantly higher among resident-level clinicians vs nonresident clinicians (59% vs 31%; P < .001). When the nonresident clinicians were subanalyzed, certified nursing midwives were the second most likely to screen for FSD (odds ratio [OR], 0.41), followed by nurse practitioners (OR, 0.29) and attending physicians (OR, 0.22). According to multivariable logistic regression techniques, 5 factors were associated with an increased likelihood of a patient being screened for FSD at an annual examination: patient seen by a resident physician rather than an attending physician, patient history of FSD, patient age ≥40 years, patient report of being sexually active at the time of visit, and patient history of cervical procedures. CLINICAL IMPLICATIONS: There is an opportunity to improve FSD screening rates by clinicians. Future research may assess what factors, such as increased sexual function education or greater incentives to document FSD screening, may result in higher screening rates. From this, targeted and effective interventions might be crafted to improve future screening rates. STRENGTHS AND LIMITATIONS: This study is one of the first to compare FSD screening rates among clinician types in the same specialty. Study limitations include the inherent limitations of a retrospective design, including selection biases. CONCLUSION: Residents were more likely to screen for FSD at annual well-woman visits than attending clinicians, nurse practitioners, and certified nurse midwives. Understanding the reasons for varied FSD screening rates among clinician types may aid in the development of strategies to improve screening for this important aspect of women's health.

Improving communication and teamwork during labor: A feasibility, acceptability, and safety study.

BACKGROUND: TeamBirth was designed to promote best practices in shared decision making (SDM) among care teams for people giving birth. Although leading health organizations recommend SDM to address gaps in quality of care, these recommendations are not consistently implemented in labor and delivery. METHODS: We conducted a mixed-methods trial of TeamBirth among eligible laboring patients and all clinicians (nurses, midwives, and obstetricians) at four high-volume hospitals during April 2018 to September 2019. We used patient and clinician surveys, abstracted clinical data, and administrative claims to evaluate the feasibility, acceptability, and safety of TeamBirth. RESULTS: A total of 2,669 patients (approximately 28% of eligible delivery volume) and 375 clinicians (78% response rate) responded to surveys on their experiences with TeamBirth. Among patients surveyed, 89% reported experiencing at least one structured full care team conversation ("huddle") during labor and 77% reported experiencing multiple huddles. There was a significant relationship between the number of reported huddles and patient acceptability (P < 0.001), suggestive of a dose response. Among clinicians surveyed, 90% would recommend TeamBirth for use in other labor and delivery units. There were no significant changes in maternal and newborn safety measures. CONCLUSIONS: Implementing a care process that aims to improve communication and teamwork during labor with high fidelity is feasible. The process is acceptable to patients and clinicians and shows no negative effects on patient safety. Future work should evaluate the effectiveness of TeamBirth in improving care experience and health outcomes.

A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.

BACKGROUND: Retrospective analyses of randomized trials suggest that Black men with metastatic castration-resistant prostate cancer (mCRPC) have longer survival than White men. The authors conducted a prospective study of abiraterone acetate plus prednisone to explore outcomes by race. METHODS: This race-stratified, multicenter study estimated radiographic progression-free survival (rPFS) in Black and White men with mCRPC. Secondary end points included prostate-specific antigen (PSA) kinetics, overall survival (OS), and safety. Exploratory analysis included genome-wide genotyping to identify single nucleotide polymorphisms associated with progression in a model incorporating genetic ancestry. One hundred patients self-identified as White (n = 50) or Black (n = 50) were enrolled. Eligibility criteria were modified to facilitate the enrollment of individual Black patients. RESULTS: The median rPFS for Black and White patients was 16.6 and 16.8 months, respectively; their times to PSA progression (TTP) were 16.6 and 11.5 months, respectively; and their OS was 35.9 and 35.7 months, respectively. Estimated rates of PSA decline by ≥50% in Black and White patients were 74% and 66%, respectively; and PSA declines to <0.2 ng/mL were 26% and 10%, respectively. Rates of grade 3 and 4 hypertension, hypokalemia, and hyperglycemia were higher in Black men. CONCLUSIONS: Multicenter prospective studies by race are feasible in men with mCRPC but require less restrictive eligibility. Despite higher comorbidity rates, Black patients demonstrated rPFS and OS similar to those of White patients and trended toward greater TTP and PSA declines, consistent with retrospective reports. Importantly, Black men may have higher side-effect rates than White men. This exploratory genome-wide analysis of TTP identified a possible candidate marker of ancestry-dependent treatment outcomes.

The design of "TeamBirth": A care process to improve communication and teamwork during labor.

BACKGROUND: Despite evidence that communication and teamwork are critical to patient safety, few care processes have been intentionally designed for this purpose in labor and delivery. The purpose of this project was to design an intrapartum care process that aims to improve communication and teamwork between clinicians and patients. METHODS: We followed the "Double-Diamond" design method with four sequential steps: Discover, Define, Develop, and Deliver. In Discover, we searched professional guidelines and peer-reviewed literature to delineate the challenges to quality of intrapartum care and to uncover options for solutions. In Define, we convened an interdisciplinary group of experts to focus the problem scope and prioritize solution features. In Develop, we created initial prototype solutions. In Deliver, we engaged clinicians and patients in rapid cycle testing to iteratively produce a care process called "TeamBirth" that aims to improve team communication. RESULTS: We designed TeamBirth, an intrapartum care process composed of brief team meetings ("huddles") between clinicians and patients. Huddles are navigated by a shared planning board placed in the labor and delivery room in view of the patient and their care team. The board promotes transparent and reliable communication and contains four areas to be acknowledged or discussed: (a) the names of the team members, starting with the patient; (b) the patient's preferences; (c) the care plan for the patient, baby, and labor progress; and (d) when the next team huddle is anticipated. DISCUSSION: We identified an opportunity to improve the safety and dignity of childbirth care through an intrapartum care process that promotes reliable and structured communication and teamwork. Future work should evaluate the acceptability and feasibility of implementation and potential impact on safety and experience of care.

The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer.

BACKGROUND: Women with colorectal cancer (CRC) have a significant survival advantage over men. Sex influences on the tumour microenvironment (TME) are not well characterised, despite the importance of immune response in CRC. We hypothesised that sex-divergent immune responses could contribute to survival. METHODS: Using a murine model of metastatic CRC, we examined T cells, macrophages, and cytokines locally and systemically. TME and serum cytokines were measured by multiplex bead-based arrays, while FCA was used to identify cells and phenotypes. IHC provided spatial confirmation of T cell infiltration. RESULTS: Females had increased survival and T cell infiltration. CD8, CD4 and Th2 populations correlated with longer survival. Males had increased serum levels of chemokines and inflammation-associated cytokines. Within the TME, males had lower cytokine levels than females, and a shallower cytokine gradient to the periphery. Female tumours had elevated IL-10+ macrophages, which correlated with survival. CONCLUSIONS: These data demonstrate survival-associated differences in the immune response of males and females to metastatic CRC. Females showed changes in cytokine production accompanied by increased immune cell populations, biased toward Th2-axis phenotypes. Key differences in the immune response to CRC correlated with survival in this model. These differences support a multi-faceted shift across the TME.

PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis.

Adipose tissue is distributed in depots throughout the body with specialized roles in energy storage and thermogenesis. PDGFRα is a marker of adipocyte precursors, and increased PDGFRα activity causes adipose tissue fibrosis in adult mice. However, the function of PDGFRα during adipose tissue organogenesis is unknown. Here, by analyzing mice with juxtamembrane or kinase domain point mutations that increase PDGFRα activity (V561D or D842V), we found that PDGFRα activation inhibits embryonic white adipose tissue organogenesis in a tissue-autonomous manner. By lineage tracing analysis, we also found that collagen-expressing precursor fibroblasts differentiate into white adipocytes in the embryo. PDGFRα inhibited the formation of adipocytes from these precursors while favoring the formation of stromal fibroblasts. This imbalance between adipocytes and stromal cells was accompanied by overexpression of the cell fate regulator Zfp521. PDGFRα activation also inhibited the formation of juvenile beige adipocytes in the inguinal fat pad. Our data highlight the importance of balancing stromal versus adipogenic cell expansion during white adipose tissue development, with PDGFRα activity coordinating this crucial process in the embryo.

World Health Organization Surgical Safety Checklist Modification: Do Changes Emphasize Communication and Teamwork?

BACKGROUND: The World Health Organization's (WHO) surgical safety checklist is meant to be customized to facilitate local implementation, encourage full-team participation, and promote a culture of safety. Although it has been globally adopted, little is known about the extent of checklist modification and the type of changes made. METHODS: Nonsubspecialty surgical checklists were obtained through online search and targeted hospital requests. A detailed coding scheme was created to capture modifications to checklist content and formatting. Descriptive statistics were performed. RESULTS: Of 155 checklists analyzed, all were modified. Compared with the WHO checklist, those in our sample contained more lines of text (median: 63 [interquartile range: 50-73] versus 56) and items (36 [interquartile range: 30-43] versus 28). A median of 13 new items were added. Items most frequently added included implants/special equipment (added by 84%), deep vein thrombosis prophylaxis/anticoagulation (added by 75%), and positioning (added by 63%). Checklists removed a median of 5 WHO items. The most frequently removed item was the pulse oximeter check (removed in 75%), followed by 4 items (each removed in 39%-48%) that comprise part of the WHO Checklist's "Anticipated Critical Events" section, which is intended for exchanging critical information. The surgeon was not explicitly mentioned in the checklist in 12%; the anesthesiologist/certified registered nurse anesthetist in 14%, the circulator in 10%, and the surgical tech/scrub in 79%. CONCLUSIONS: Checklists are highly modified but often enlarged with items that may not prompt discussion or teamwork. Of concern is the frequent removal of items from the WHO's "Anticipated Critical Events" section.

Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.

Multisource Evaluation of Surgeon Behavior Is Associated With Malpractice Claims.

OBJECTIVE: We merged direct, multisource, and systematic assessments of surgeon behavior with malpractice claims, to analyze the relationship between surgeon 360-degree reviews and malpractice history. BACKGROUND: Previous work suggests that malpractice claims are associated with a poor physician-patient relationship, which is likely related to behaviors captured by 360-degree review. We hypothesize that 360-degree review results are associated with malpractice claims. METHODS: Surgeons from 4 academic medical centers covered by a common malpractice carrier underwent 360-degree review in 2012 to 2013 (n = 385). Matched, de-identified reviews and malpractice claims data were available for 264 surgeons from 2000 to 2015. We analyzed 23 questions, highlighting positive and negative behaviors within the domains of education, excellence, humility, openness, respect, service, and teamwork. Regression analysis with robust standard error was used to assess the potential association between 360-degree review results and malpractice claims. RESULTS: The range of claims among the 264 surgeons was 0 to 8, with 48.1% of surgeons having at least 1 claim. Multiple positive and negative behaviors were significantly associated with the risk of having malpractice claims (P < 0.05). Surgeons in the bottom decile for several items had an increased likelihood of having at least 1 claim. CONCLUSION: Surgeon behavior, as assessed by 360-degree review, is associated with malpractice claims. These findings highlight the importance of teamwork and communication in exposure to malpractice. Although the nature of malpractice claims is complex and multifactorial, the identification and modification of negative physician behaviors may mitigate malpractice risk and ultimately result in the improved quality of patient care.

A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking.

The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition. Mechanistically, this disrupted motility results from aberrant degradation of Miro2, a mitochondrial GTPase that links mitochondria to microtubules. Rescue experiments demonstrate that this Miro2 degradation involves the KEAP1-cullin-3 E3 ubiquitin ligase and the proteasome. These data are consistent with a model in which an intact complex of PGAM5-KEAP1-Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. These data further provide a mechanistic explanation for how age-dependent declines in Nrf2 expression impact mitochondrial motility and induce functional deficits commonly linked to neurodegeneration.

Development and Feasibility Testing of a Device Briefing Tool and Training to Improve Patient Safety During Introduction of New Devices in Operating Rooms: Best Practices and Lessons Learned.

BACKGROUND: Introducing new surgical devices into the operating room (OR) can serve as a critical opportunity to address patient safety. The effectiveness of OR briefings to improve communication, teamwork, and safety has not been evaluated in this setting. METHODS: Ariadne Labs and Johnson and Johnson (J&J) collaborated to develop and assess an intervention including a Device Briefing Tool (DBT) and novel multidisciplinary team training for clinicians (surgeons and nurses) around the introduction of a new device in the OR. J&J sales representatives trained clinicians to use the DBT, a communication tool to improve patient safety when a new device is used for the first time. Surveys were administered to representatives (n = 10), surgeons (n = 15), and nurses (n = 30) at the baseline, after trainings, and after using the DBT in an operation at six different Thai hospitals. RESULTS: Familiarity with the Surgical Safety Checklist (SURGICAL SAFETY CHECKLIST) varied but increased post-training. Regarding trainings, 90% of representatives felt they very much or completely met all learning objectives but 50% felt only slightly prepared to train clinicians on using DBT. Post-training, clinician confidence in using a new device rose from 47 to 85%. Regarding the DBT, 90% of clinicians felt confident using it and reported they were very likely to use it in the future. Overall, over 90% of all clinicians and representatives felt safe having surgery in their hospitals. CONCLUSIONS: There is high acceptability and feasibility of the multidisciplinary trainings and the DBT among representatives and clinicians, albeit in a limited number of participants from a small number of institutions.

Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer.

Renal cell carcinoma (RCC) is a common and devastating disease characterized by a hypoxic microenvironment, epithelial-mesenchymal transition and potent resistance to therapy evidencing the presence of cancer stem cells (CSCs). Various CSC markers have been studied in RCC, but overall there is limited data on their role and most markers studied have been relatively nonspecific. Doublecortin-like kinase 1 (DCLK1) is a validated CSC marker in the gastrointestinal tract and evidence for an equivalent role in other cancers is accumulating. We used bioinformatics, immunohistochemistry, flow cytometry, spheroid self-renewal and chemoresistance assays in combination with overexpression and siRNA-knockdown to study the stem cell-supportive role of DCLK1 alternative splice variants (DCLK1 ASVs) in RCC. To target tumor cells expressing DCLK1 ASVs directly, we developed a novel monoclonal antibody (CBT-15) and delivered it systemically to RCC tumor xenografts. DCLK1 ASVs were overexpressed, enriched together with CSC markers and predictive of overall and recurrence-free survival in RCC patients. In vitro, DCLK1 ASVs were able to directly stimulate essential molecular and functional characteristics of renal CSCs including expression of aldehyde dehydrogenase, self-renewal and resistance to FDA-approved receptor tyrosine kinase and mTOR inhibitors, while targeted downregulation of DCLK1 reversed these characteristics. Finally, targeting DCLK1 ASV-positive cells with the novel CBT-15 monoclonal antibody blocked RCC tumorigenesis in vivo. These findings establish DCLK1 as a CSC marker with implications for therapy, disease progression and survival in RCC and demonstrate the therapeutic value of DCLK1-targeted monoclonal antibodies against renal CSCs.

An evidence-based intraoperative communication tool for emergency general surgery: a pilot study.

BACKGROUND: Emergency general surgery (EGS) is characterized by high rates of morbidity and mortality. Though checklists and associated communication-based huddle strategies have improved outcomes, these tools have never been specifically examined in EGS. We hypothesized that use of an evidence-based communication tool aimed to trigger intraoperative discussion could improve communication in the EGS operating room (OR). MATERIALS AND METHODS: We designed a set of discussion prompts based on modifiable factors identified from previously published studies aimed to encourage all team members to speak up and to centralize awareness of patient disposition and intraoperative transfusion practices. This tool was pilot-tested using OR human patient simulators and was then rolled out to EGS ORs at an academic medical center. The perceived effect of our tool's implementation was evaluated through mixed-methodologic presurvey and postsurvey analysis. RESULTS: Preimplementation and postimplementation survey-based data revealed that providers reported the EGS-focused discussion prompts as improving team communication in EGS. A trend toward shared awareness of intraoperative events was observed; however, nurses described cultural impedance of discussion initiation. Providers described a need for further reinforcement of the tool and its indications during implementation. CONCLUSIONS: Use of a discussion-based communication tool is perceived as supporting team communication in the EGS OR and led to a trend toward improving a shared understanding of intraoperative events. Analyses suggest the need for enhanced reinforcement of use during implementation and improvement of team-based education regarding EGS. Furthermore work is needed to understand the full impact of this evidence-based tool on OR team dynamics and EGS patient outcomes.

Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes.

The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications.