SHIP inhibition mediates select TREM2-induced microglial functions.

Microglia play a pivotal role in the pathology of Alzheimer's Disease (AD), with the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) central to their neuroprotective functions. The R47H variant of TREM2 has emerged as a significant genetic risk factor for AD, leading to a loss-of-function phenotype in mouse AD models. This study elucidates the roles of TREM2 in human microglia-like HMC3 cells and the regulation of these functions by SH2-containing inositol-5'-phosphatase 1 (SHIP1). Using stable cell lines expressing wild-type TREM2, the R47H variant, and TREM2-deficient lines, we found that functional TREM2 is essential for the phagocytosis of Aß, lysosomal capacity, and mitochondrial activity. Notably, the R47H variant displayed increased phagocytic activity towards apoptotic neurons. Introducing SHIP1, known to modulate TREM2 signaling in other cells, revealed its role as a negative regulator of these TREM2-mediated functions. Moreover, pharmacological inhibition of both SHIP1 and its isoform SHIP2 amplified Aß phagocytosis and lysosomal capacity, independently of TREM2 or SHIP1 expression, suggesting a potential regulatory role for SHIP2 in these functions. The absence of TREM2, combined with the presence of both SHIP isoforms, suppressed mitochondrial activity. However, pan-SHIP1/2 inhibition enhanced mitochondrial function in these cells. In summary, our findings offer a deeper understanding of the relationship between TREM2 variants and SHIP1 in microglial functions, and emphasize the therapeutic potential of targeting the TREM2 and SHIP1 pathways in microglia for neurodegenerative diseases.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study.

BACKGROUND: Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus enzalutamide in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Patients in cohort C of the phase 1b/2 KEYNOTE-365 study, who received ≥4 wk of treatment with abiraterone acetate in the prechemotherapy mCRPC state and experienced treatment failure or became drug-intolerant, were included. INTERVENTION: Pembrolizumab 200 mg intravenously every 3 wk plus enzalutamide 160 mg orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were safety, the confirmed prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) on BICR and overall survival (OS). RESULTS AND LIMITATIONS: A total of 102 patients received pembrolizumab plus enzalutamide. Median follow-up was 51 mo (interquartile range 37-56). The confirmed PSA response rate was 24% (95% confidence interval [CI] 16-33%). The confirmed ORR was 11% (95% CI 2.9-25%; 4/38 patients; two complete responses). Median rPFS was 6.0 mo (95% CI 4.1-6.3). Median OS was 20 mo (95% CI 17-24). Treatment-related adverse events (TRAEs) occurred in 94 patients (92%); grade 3-5 TRAEs occurred in 44 patients (43%). The incidence of treatment-related rash was higher with combination therapy than expected from the safety profile of each drug. One patient (1.0%) died of a TRAE (cause unknown). Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus enzalutamide had limited antitumor activity in patients who received prior abiraterone treatment without previous chemotherapy for mCRPC, with a safety profile consistent with the individual profiles of each agent. PATIENT SUMMARY: Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer. The KEYNOTE-365 trial is registered on ClinicalTrials.gov as NCT02861573.

Targeting doublecortin-like kinase 1 reveals a novel strategy to circumvent chemoresistance and metastasis in ovarian cancer.

Ovarian cancer (OvCa) has a dismal prognosis because of its late-stage diagnosis and the emergence of chemoresistance. Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase known to regulate cancer cell "stemness", epithelial-mesenchymal transition (EMT), and drug resistance. Here we show that DCLK1 is a druggable target that promotes chemoresistance and tumor progression of high-grade serous OvCa (HGSOC). Importantly, high DCLK1 expression significantly correlates with poor overall and progression-free survival in OvCa patients treated with platinum chemotherapy. DCLK1 expression was elevated in a subset of HGSOC cell lines in adherent (2D) and spheroid (3D) cultures, and the expression was further increased in cisplatin-resistant (CPR) spheroids relative to their sensitive controls. Using cisplatin-sensitive and resistant isogenic cell lines, pharmacologic inhibition (DCLK1-IN-1), and genetic manipulation, we demonstrate that DCLK1 inhibition was effective at re-sensitizing cells to cisplatin, reducing cell proliferation, migration, and invasion. Using kinase domain mutants, we demonstrate that DCLK1 kinase activity is critical for mediating CPR. The combination of cisplatin and DCLK1-IN-1 showed a synergistic cytotoxic effect against OvCa cells in 3D conditions. Targeted gene expression profiling revealed that DCLK1 inhibition in CPR OvCa spheroids significantly reduced TGFß signaling, and EMT. We show in vivo efficacy of combined DCLK1 inhibition and cisplatin in significantly reducing tumor metastases. Our study shows that DCLK1 is a relevant target in OvCa and combined targeting of DCLK1 in combination with existing chemotherapy could be a novel therapeutic approach to overcome resistance and prevent OvCa recurrence.

CheckPOINT: a simple tool to measure Surgical Safety Checklist implementation fidelity.

INTRODUCTION: The WHO Surgical Safety Checklist (SSC) is a communication tool that improves teamwork and patient outcomes. SSC effectiveness is dependent on implementation fidelity. Administrative audits fail to capture most aspects of SSC implementation fidelity (ie, team communication and engagement). Existing research tools assess behaviours during checklist performance, but were not designed for routine quality assurance and improvement. We aimed to create a simple tool to assess SSC implementation fidelity, and to test its reliability using video simulations, and usability in clinical practice. METHODS: The Checklist Performance Observation for Improvement (CheckPOINT) tool underwent two rounds of face validity testing with surgical safety experts, clinicians and quality improvement specialists. Four categories were developed: checklist adherence, communication effectiveness, attitude and engagement. We created a 90 min training programme, and four trained raters independently scored 37 video simulations using the tool. We calculated intraclass correlation coefficients (ICC) to assess inter-rater reliability (ICC>0.75 indicating excellent reliability). We then trained two observers, who tested the tool in the operating room. We interviewed the observers to determine tool usability. RESULTS: The CheckPOINT tool had excellent inter-rater reliability across SSC phases. The ICC was 0.83 (95% CI 0.67 to 0.98) for the sign-in, 0.77 (95% CI 0.63 to 0.92) for the time-out and 0.79 (95% CI 0.59 to 0.99) for the sign-out. During field testing, observers reported CheckPOINT was easy to use. In 98 operating room observations, the total median (IQR) score was 25 (23-28), checklist adherence was 7 (6-7), communication effectiveness was 6 (6-7), attitude was 6 (6-7) and engagement was 6 (5-7). CONCLUSIONS: CheckPOINT is a simple and reliable tool to assess SSC implementation fidelity and identify areas of focus for improvement efforts. Although CheckPOINT would benefit from further testing, it offers a low-resource alternative to existing research tools and captures elements of adherence and team behaviours.

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.

Defining re-implementation.

BACKGROUND: The first attempt to implement a new tool or practice does not always lead to the desired outcome. Re-implementation, which we define as the systematic process of reintroducing an intervention in the same environment, often with some degree of modification, offers another chance at implementation with the opportunity to address failures, modify, and ultimately achieve the desired outcomes. This article proposes a definition and taxonomy for re-implementation informed by case examples in the literature. MAIN BODY: We conducted a scoping review of the literature for cases that describe re-implementation in concept or practice. We used an iterative process to identify our search terms, pilot testing synonyms or phrases related to re-implementation. We searched PubMed and CINAHL, including articles that described implementing an intervention in the same environment where it had already been implemented. We excluded articles that were policy-focused or described incremental changes as part of a rapid learning cycle, efforts to spread, or a stalled implementation. We assessed for commonalities among cases and conducted a thematic analysis on the circumstance in which re-implementation occurred. A total of 15 articles representing 11 distinct cases met our inclusion criteria. We identified three types of circumstances where re-implementation occurs: (1) failed implementation, where the intervention is appropriate, but the implementation process is ineffective, failing to result in the intended changes; (2) flawed intervention, where modifications to the intervention itself are required either because the tool or process is ineffective or requires tailoring to the needs and/or context of the setting where it is used; and (3) unsustained intervention, where the initially successful implementation of an intervention fails to be sustained. These three circumstances often co-exist; however, there are unique considerations and strategies for each type that can be applied to re-implementation. CONCLUSIONS: Re-implementation occurs in implementation practice but has not been consistently labeled or described in the literature. Defining and describing re-implementation offers a framework for implementation practitioners embarking on a re-implementation effort and a starting point for further research to bridge the gap between practice and science into this unexplored part of implementation.

What I wish I'd known: How experienced physician managers diagnose, treat and prevent disruptive behaviour.

As health systems continue to consolidate at a rapid pace, many physicians are stepping into roles that involve managing other physicians. While more physicians are thrust into these positions each year, the managerial training they receive is highly variable and often insufficient for dealing with the challenges they will face, notably disruptive behaviour. Broadly defined, disruptive behaviour includes any actions that affect a team's ability to effectively care for patients, and can even threaten patient and provider health. New physician managers--who typically have little prior experience in management roles--need specific supports to address this uniquely daunting challenge.Over our management careers, we have spoken with dozens of new and experienced physician managers to understand how they manage disruptive behaviour in the workplace and to collect their advice for future physician managers. In this paper, we reflect on those conversations and distill them into a three-part approach for diagnosing, treating and preventing disruptive behaviour in the workplace. We describe how the right management approach depends on a thorough assessment of the most likely drivers of the disruptive behaviour. Second, we present strategies for treating the behaviour focusing on the physician leader's communication skills and available institutional resources. Finally, we advocate for system-level changes that institutions or departments can implement both to prevent disruptive behaviour and to better prepare new managers to address it.

Multifunctional Microgel-Based Cream Hydrogels for Postoperative Abdominal Adhesion Prevention.

Postoperative abdominal adhesions are a common problem after surgery and can produce serious complications. Current antiadhesive strategies focus mostly on physical barriers and are unsatisfactory and inefficient. In this study, we designed and synthesized advanced injectable cream-like hydrogels with multiple functionalities, including rapid gelation, self-healing, antioxidation, anti-inflammation, and anti-cell adhesion. The multifunctional hydrogels were facilely formed by the conjugation reaction of epigallocatechin-3-gallate (EGCG) and hyaluronic acid (HA)-based microgels and poly(vinyl alcohol) (PVA) based on the dynamic boronic ester bond. The physicochemical properties of the hydrogels including antioxidative and anti-inflammatory activities were systematically characterized. A mouse cecum-abdominal wall adhesion model was implemented to investigate the efficacy of our microgel-based hydrogels in preventing postoperative abdominal adhesions. The hydrogels, with a high molecular weight HA, significantly decreased the inflammation, oxidative stress, and fibrosis and reduced the abdominal adhesion formation, compared to the commercial Seprafilm group or Injury-only group. Label-free quantitative proteomics analysis demonstrated that S100A8 and S100A9 expressions were associated with adhesion formation; the microgel-containing hydrogels inhibited these expressions. The microgel-containing hydrogels with multifunctionality decreased the formation of postoperative intra-abdominal adhesions in a murine model, demonstrating promise for clinical applications.

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.

Temporal control of PDGFRα regulates the fibroblast-to-myofibroblast transition in wound healing.

Fibroblasts differentiate into myofibroblasts by acquiring new contractile function. This is important for tissue repair, but it also contributes to organ fibrosis. Platelet-derived growth factor (PDGF) promotes tissue repair and fibrosis, but the relationship between PDGF and myofibroblasts is unclear. Using mice with lineage tracing linked to PDGF receptor α (PDGFRα) gene mutations, we examine cell fates during skin wound healing. Elevated PDGFRα signaling increases proliferation but unexpectedly delays the fibroblast-to-myofibroblast transition, suggesting that PDGFRα must be downregulated for myofibroblast differentiation. In contrast, deletion of PDGFRα decreases proliferation and myofibroblast differentiation by reducing serum response factor (SRF) nuclear localization. Consequences of SRF deletion resemble PDGFRα deletion, but deletion of two SRF coactivators, MRTFA and MRTFB, specifically eliminates myofibroblasts. Our findings suggest a scenario where PDGFRα signaling initially supports proliferation of fibroblast progenitors to expand their number during early wound healing but, later, PDGFRα downregulation facilitates fibroblast differentiation into myofibroblasts.

Determining Intestinal Permeability using Lucifer Yellow in an Apical-Out Enteroid Model.

Enteroids are an emerging research tool in the study of inflammatory bowel diseases such as necrotizing enterocolitis (NEC). They are traditionally grown in the basolateral-out (BO) conformation, where the apical surface of the epithelial cell faces the inner lumen. In this model, access to the luminal surface of enteroids for treatment and experimentation is challenging, which limits the ability to study host-pathogen interactions. To circumvent this, a neonatal apical-out (AO) model for necrotizing enterocolitis was created. Since intestinal epithelial cell permeability changes are pathognomonic for NEC, this protocol outlines using lucifer yellow (LY) as a marker of paracellular permeability. LY traverses the intestinal epithelial barrier via all three major paracellular pathways: pore, leak, and unrestricted. Using LY in an AO model allows for a broader study of permeability in NEC. Following IRB approval and parental consent, surgical samples of intestinal tissue were collected from human preterm neonates. Intestinal stem cells were harvested via crypt isolation and used to grow enteroids. Enteroids were grown to maturity and then transformed AO or left in BO conformation. These were either not treated (control) or were treated with lipopolysaccharide (LPS) and subjected to hypoxic conditions for the induction of in vitro NEC. LY was used to assess for permeability. Immunofluorescent staining of the apical protein zonula occludens-1 and basolateral protein ß-catenin confirmed AO conformation. Both AO and BO enteroids treated with LPS and hypoxia demonstrated significantly increased paracellular permeability compared to controls. Both AO and BO enteroids showed increased uptake of LY into the lumen of the treated enteroids compared to controls. The utilization of LY in an AO enteroid model allows for the investigation of all three major pathways of paracellular permeability. It additionally allows for the investigation of host-pathogen interactions and how this may affect permeability compared to the BO enteroid model.

Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening. INTERVENTION: Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m2 IV Q3W, and prednisone 5 mg orally twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS). RESULTS AND LIMITATIONS: Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size. CONCLUSIONS: Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted. PATIENT SUMMARY: We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

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.

Examining health care champions: a mixed-methods study exploring self and peer perspectives of champions.

Background: Champions are widely recognized as playing a key role in the successful implementation of evidence-based interventions within the health care sector; however, little is known about which characteristics and skills enable them to play that role. Furthermore, previous studies have measured only individual champions' responses to personal attributes without incorporating input from other observers. A mixed-methods study was conducted to identify, analyze, and group the behaviors and characteristics of champions who have successfully promoted the adoption of new initiatives within the health care delivery system, taking into consideration self and peer perspectives. Methods: Using a mixed-methods, cross-sectional triangulation design with a convergence model, quantitative data were collected and analyzed from health care champions (n = 30) and their colleagues (n = 58) from 11 countries using a survey. Every champion and a subset of colleagues (n = 14) also participated in in-depth interviews. Descriptive statistics were used to explore the relationship between champion and colleague responses to survey items; chi-squared tests and Kruskal-Wallis tests were used to compare the differences. Thematic content analysis of qualitative data was used to explore champion-like behaviors and features. Characteristics of champions were categorized using the Transformational Leadership Theory framework. Results: Champions exhibited characteristics that facilitated trust and encouraged motivation among their colleagues to adopt innovations, such as being intrinsically motivated, persistent, enthusiastic, and highly effective communicators. Champions were described by their colleagues as empathetic, curious, physically present, approachable, and often soliciting feedback from others. Although there was a high degree of agreement between champion and colleague survey responses, champions were more likely to underrate their skills and abilities to instigate change compared to their colleagues. Conclusion: Both champions and colleagues described key champion-like characteristics, but champions often downplayed the characteristics and behaviors that make champions uniquely effective at facilitating the adoption of evidence-based interventions. Plan language abstract: Health care champions are people who promote the adoption of new initiatives to improve the quality of patient care among their colleagues within health care settings. Champions are often viewed by organizational leaders and researchers as critical for the successful implementation of new ideas; however, little is known about what specific skills or characteristics make them effective at promoting the adoption of new ideas among their colleagues. Most studies on champions' behaviors have only included the perspectives of champions, and not perspectives from others within the organization. The goal of our study was to not only explore champions' perspectives of themselves, but also the views of champions' colleagues to understand why and how champions motivated and influenced their colleagues to try new things. Findings from this study could lead to more accurate identification of health care champions, which in turn could lead to more efficient and effective adoption of new initiatives to improve the quality of patient care.

Targeted Transcriptome and KRAS Mutation Analysis Improve the Diagnostic Performance of EUS-FNA Biopsies in Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, and current diagnostic tests have suboptimal sensitivity. Incorporating standard cytology with targeted transcriptomic and mutation analysis may improve upon the accuracy of diagnostic biopsies, thus reducing the burden of repeat procedures and delays to treatment initiation. EXPERIMENTAL DESIGN: We reviewed the accuracy of 308 endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) diagnostic PDAC biopsies using a large multicenter clinical and biospecimen database, then performed RNA sequencing on 134 EUS-FNA biopsies spanning all stages of disease. We identified a transcriptomic diagnostic gene signature that was validated using external datasets and 60 further diagnostic EUS-FNAs. KRAS digital droplet PCR (ddPCR) analysis was performed and correlated with signature gene expression. RESULTS: The sensitivity of EUS-FNA cytology in diagnosing solid pancreatic masses in our retrospective cohort of 308 patients was 78.6% (95% confidence interval, 73.2%-83.2%). KRAS mutation analysis and our custom transcriptomic signature significantly improved upon the diagnostic accuracy of standard cytology to 91.3% in external validation sets and 91.6% in our validation cohort (n = 60). Exploratory ddPCR analysis of KRAS-mutant allele fraction (MAF%) correlated closely to signature performance and may represent a novel surrogate marker of tumor cellularity in snap-frozen EUS-FNA biopsies. CONCLUSIONS: Our findings support snap-frozen EUS-FNA biopsies as a feasible tissue source for the integrated genomic and transcriptomic analysis of patients presenting with PDAC from all tumor stages, including cases with nondiagnostic cytology. Our transcriptome-derived genetic signature in combination with tissue KRAS mutation analysis significantly improves upon the diagnostic accuracy of current standard procedures, and has potential clinical utility in improving the speed and accuracy of diagnosis for patients presenting with PDAC.