Are Physician Assistants Able to Correctly Identify Prescribing Errors? A Cross-Sectional Study.

PURPOSE: (1) To describe how often physician assistant (PA) students correctly identify prescribing errors and (2) examine between-cohort differences on ability to correctly identify prescribing errors. METHODS: This was a cross-sectional study of 2 cohorts of PA students at one institution. Students were presented with 3 hypothetical prescriptions, 2 of which contained a prescribing error. For each prescription, students were asked to (1) identify whether an error occurred and (2) indicate the type of error. A simple Poisson regression model analyzed the data. RESULTS: We received responses from 130 students (72.6% response rate). Approximately 12% (12.3%, n = 16) correctly identified whether all 3 prescriptions were correct. The median number of correctly identified prescriptions was 1 (interquartile range = 1). There was not a statistically significant between-cohort difference identifying the correct number of prescriptions (ß = 0.27, P = .10). CONCLUSION: Physician assistant students' prescribing error identification was similar to previous research in medical and nursing students. Efforts to improve prescribing training are critical to ensure patient safety.

Adaptation and factor structure of three psychometric instruments measuring behavioral aspects of medication prescribing in physician assistants.

OBJECTIVES: (1) Present the factor structure of two psychometric instruments for self-efficacy and one for outcome expectations of medication prescribing; (2) evaluate the reliability of the scales, and (3) present preliminary evidence of validity. METHODS: Physician assistants (PA) and PA students completed a survey evaluating three psychometric instruments: (1) Self-Efficacy in Prescribing (SEP), (2) Self-Efficacy in Prescribing-Geriatric (SEPG), and (3) Outcomes Expectations of Prescribing Errors (OEP). Students also evaluated 3 hypothetical prescriptions, two of which contained a prescribing error. Students were instructed to identify (1) if an error occurred and (2) what type of error. The data were analyzed using parallel analysis with a varimax rotation, Cronbach's α, Pearson and Spearman correlations. RESULTS: One hundred eighty five (n = 185) respondents completed the survey (response rate = 63.8%). The parallel analysis found that the SEP had one 7-item factor with α = 0.94 (M = 5.7 (SD = 1.9) out of 10). The SEPG also had one 7-item factor with α = 0.95 (M = 5.5 (1.9). The OEP had one 6-item factor with α = 0.89 (M = 3.5 (SD = 0.8) out of 5). The SEP and SEPG, were correlated to the OEP each other (both p < 0.01). Actively practicing PAs had the highest composite mean SEP and SEPG scores. First-year PA students had the highest mean scores for the OEP. There was a weak association between the mean SEPG score and the number of correctly identified prescriptions (rs = 0.18, p = 0.04). CONCLUSION: The SEP, SEPG, and OEP show preliminary evidence of reliability and structural, construct, and known-group validities using simulated prescriptions. These tools may be able to be used by educators and implementation scientists as one method to show the effectiveness of future interventions to reduce incidence of prescribing errors.

A miniaturized screening platform to identify novel regulators of extracellular matrix alignment.

Extracellular matrix alignment contributes to metastasis in a number of cancers and is a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Cancer-associated fibroblasts (CAF) play a critical role in this process, particularly via matrix production and modulation of key signaling pathways controlling cell adhesion and contractility. Stroma normalization, as opposed to elimination, is a highly sought strategy, and screening for drugs that effectively alter extracellular matrix (ECM) alignment is a practical way to identify novel CAF-normalizing targets that modulate ECM organization. To meet this need, we developed a novel high-throughput screening platform in which fibroblast-derived matrices were produced in 384-well plates, imaged with automated confocal microscopy, and analyzed using a customized MATLAB script. This platform is a technical advance because it miniaturizes the assay, eliminates costly and time-consuming experimental steps, and streamlines data acquisition and analysis to enable high-throughput screening applications. As a proof of concept, this platform was used to screen a kinase inhibitor library to identify modulators of matrix alignment. A number of novel potential regulators were identified, including several receptor tyrosine kinases (c-MET, tropomyosin receptor kinase 1 (NTRK1), HER2/ERBB2) and the serine/threonine kinases protein kinase A, C, and G (PKA, PKC, and PKG). The expression of these regulators was analyzed in publicly available patient datasets to examine the association between stromal gene expression and patient outcomes.

Transparency of racial participation reporting in randomized controlled trials of minimally invasive surgical techniques.

BACKGROUND: Enrolment of racial/ethnic minorities in randomized controlled trials (RCTs) has historically been poor, despite efforts at improving access to RCTs. Under-representation of racial/ethnic minorities limits the external validity and generalizability of trials. Our objective was to determine to what extent are published RCTs of minimally invasive surgical techniques reporting the racial composition of their study cohorts and to describe the racial composition of patients enrolled in these trials, where data were available. METHODS: EMBASE (OvidSP®), MEDLINE (OvidSP®), and Cochrane (Wiley®) databases were systematically searched from inception to December 22, 2017 to identify all RCTs comparing minimally invasive and classical surgical techniques. The Mann-Kendall trend test was used to evaluate reporting trends over the study period. Predictors of racial reporting were evaluated using logistic regression analyses. RESULTS: Our search strategy yielded 9,321 references of which 496 RCTs met our inclusion/exclusion criteria. Racial information was reported in 20 (4.03%) studies. There was no significant improvement in racial reporting over the study period (p for trend = 0.31). Of the 17 different patient populations accounting for the 20 RCTs, 14 (82.4%) originated from the USA. Multicenter RCTs had significantly increased likelihood of reporting racial composition of the patient cohort (odds ratio 5.10, p = 0.025). White/Caucasian patients accounted for 84.5% of the pooled patient population, with Black/African American, Asian and Latin/Hispanic patients accounting for 7.9%, 1.2%, and 2.1%, respectively. CONCLUSIONS: Among RCTs assessing minimally invasive surgical techniques over the past 30 years, data on included patients' race is poorly reported. In addition to important efforts to improve access to clinical trials for racial and ethnic minorities, efforts aimed at improving reporting and transparency of surgical RCTs are sorely needed.

Women as Authors of Randomized Controlled Trials of Minimally Invasive Surgery: Systematic Review and Meta-Analysis of 3 Decades of Trials.

BACKGROUND: Female authorship opportunities have lagged behind those of their male counterparts, with gender disparities most prominent in surgical specialties. Our objective was to determine trends of female first, last, and first or last authorships across time and surgical specialties and whether female first or last authorship was associated with journal impact factor. STUDY DESIGN: A systematic review of EMBASE (OvidSP), MEDLINE (OvidSP), and Cochrane (Wiley) databases from inception to December 22, 2017 was performed to identify all randomized controlled trials evaluating minimally invasive surgery vs classical surgical techniques. The primary end point was female first, last, and first or last authorship, with gender determined via an online search strategy and verified via Genderize.io. Secondary end point was journal impact factor, recorded from Clarivate Analytics InCites. RESULTS: There were 9,321 articles identified and 489 met our inclusion/exclusion criteria. Sixty-eight (13.9%) first and 60 (12.3%) last female authors were identified. A positive linear trend for female first (R2 = 0.35, Cochran-Armitage test for trend, p < 0.001), last (R2 = 0.30, p < 0.001), and first or last authorships (R2 = 0.40, p < 0.001) over time was identified. This trend was observed across surgical specialties except for orthopaedics. The highest calculated percentages of female first, last, and first or last authorships by the year 2017 were seen in obstetrics and gynecology (33.8%, 32.0%, and 43.8%, respectively), all significantly lower than the corresponding percentage of the female obstetrics and gynecology workforce in 2017 (57.0%). Neither female first nor last authorship positions were associated with journal impact factor. CONCLUSIONS: A significant increase in female first and last authorship in randomized controlled trials of minimally invasive surgical techniques in the last 3 decades has been observed, but continued efforts to bridge this gender gap are sorely needed.

Pten regulates collagen fibrillogenesis by fibroblasts through SPARC.

Collagen deposition contributes to both high mammographic density and breast cancer progression. Low stromal PTEN expression has been observed in as many as half of breast tumors and is associated with increases in collagen deposition, however the mechanism connecting PTEN loss to increased collagen deposition remains unclear. Here, we demonstrate that Pten knockout in fibroblasts using an Fsp-Cre;PtenloxP/loxP mouse model increases collagen fiber number and fiber size within the mammary gland. Pten knockout additionally upregulated Sparc transcription in fibroblasts and promoted collagen shuttling out of the cell. Interestingly, SPARC mRNA expression was observed to be significantly elevated in the tumor stroma as compared to the normal breast in several patient cohorts. While SPARC knockdown via shRNA did not affect collagen shuttling, it notably decreased assembly of exogenous collagen. In addition, SPARC knockdown decreased fibronectin assembly and alignment of the extracellular matrix in an in vitro fibroblast-derived matrix model. Overall, these data indicate upregulation of SPARC is a mechanism by which PTEN regulates collagen deposition in the mammary gland stroma.

Barriers to Accurate Fluid Measurement in Perioperative Patients: A Mixed Methods Approach.

BACKGROUND: Surgeons depend on fluid intake and output (I/O) measurements for assessment of resuscitation and fluid balance during the perioperative period. Frequently, these measurements are taken by Registered Nurses (RNs) and/or Patient Care Technicians (PCTs). There is variability in the accuracy and consistency of these measurements across nursing units. The goal of this study is to establish what barriers exist in obtaining accurate fluid measurements and potential solutions. MATERIALS AND METHODS: A mixed-method, sequential study design was utilized. First, a survey was conducted at a tertiary care institution of 8 nonintensive care nursing units assessing the perceptions of RNs (n = 85) and PCTs (n = 38) regarding fluid intake and output measurements for surgical patients. Four focus groups were then conducted to expand upon the results of the survey. Fourteen participants (10 RNs and 4 PCTs) were interviewed, and transcripts were analyzed by three reviewers. Qualitative data were manually coded by reviewers using a hierarchical methodology. RESULTS: Survey response rate was 40.6%. The strongest barriers in the survey were patient load and staff time limitations. About half (49%) of the respondents acknowledged that fluid measurements were inaccurate half of the time. PCTs spend more time collecting and charting I/Os and have higher patient loads (P < 0.001) than RNs. PCTs noted more difficulty with complex patients (P = 0.017) and devices for outputs (P = 0.004). PCT's (94%) handwrite data prior to electronic entry. One-third of nurses reported direct electronic entry (P < 0.001). Overall, 71% would prefer to chart in patient's rooms. Most (80%) of respondents received <5 h of fluids-related training at the time they were hired. Cronbach's alpha for three focus group reviewers was 0.84 (95% CI 0.693-0.923). Themes included understaffing, lack of training, a high percentage of traveling nurses, and poor communication regarding new orders. Recommended solutions to improve I/Os included in-room kiosks for electronic entry and relief of staffing burdens. CONCLUSIONS: Fluid I/O measurement accuracy and efficiency may be improved by increased staffing, educational programs, and computer access, streamlining of order sets, simplicity of EMR data entry, and a standardized process for measuring, recording, and charting I/Os.

In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness.

BACKGROUND: In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. METHODS: We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. RESULTS: We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. CONCLUSIONS: As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.

Malnutrition, frailty, and sarcopenia in pancreatic cancer patients: assessments and interventions for the pancreatic surgeon.

The objective of this article is to review the available literature examining the impact of malnutrition, frailty, and sarcopenia on surgical morbidity among pancreatic cancer patients. We examine definitions used to diagnose and quantify these conditions and review the differences between them with regards to preoperative assessment and postoperative outcomes. The most relevant scoring systems are summarized. Lastly, we summarize current knowledge regarding effectiveness of specific interventions aimed at malnutrition, frailty, and sarcopenia for patients undergoing pancreatic cancer surgery.

Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland.

The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten-/- fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.

PEG-peptide hydrogels reveal differential effects of matrix microenvironmental cues on melanoma drug sensitivity.

Metastatic melanoma is highly drug resistant, though the exact mechanisms of this resistance are not completely understood. One method to study melanoma drug responsiveness in vitro is through the use of multicellular spheroids, which have been found to exhibit decreased drug sensitivity compared to traditional 2D culture on various substrates. Because it is unclear whether dimensionality, cell-matrix interactions, and/or cell-cell contacts may influence melanoma drug responsiveness, we utilized a synthetic PEG-based hydrogel to compare the responses of cells cultured on top of or encapsulated within matrices with the same adhesive ligand density, polymer density, and material properties. We found that depending on the stage of progression at which the melanoma cells were derived, the cells responded differently to PLX4032 treatment, a commercially available melanoma drug. In particular, early stage WM35 cells were insensitive to dimensionality (i.e., 2D versus 3D culture), while metastatic A375 cells exhibited decreased responsiveness in 3D compared to 2D. To further understand the role of the microenvironment in early stage melanoma cells, we tested single WM35 cells and multicellular WM35 spheroids in 3D. The results revealed that the spheroids were similarly sensitive to PLX4032 treatment compared to single cell encapsulations. Collectively, this study implicates the role that 3D microenvironments (i.e., dimensionality) may play in observed melanoma drug responsiveness, and the potential lack of influence of cell-matrix interactions over cell-cell contacts in early stages of melanoma resistance to PLX4032-induced apoptosis.

Multifunctional bioscaffolds for 3D culture of melanoma cells reveal increased MMP activity and migration with BRAF kinase inhibition.

Matrix metalloproteinases (MMPs) are important for many different types of cancer-related processes, including metastasis. Understanding the functional impact of changes in MMP activity during cancer treatment is an important facet not typically evaluated as part of preclinical research. With MMP activity being a critical component of the metastatic cascade, we designed a 3D hydrogel system to probe whether pharmacological inhibition affected human melanoma cell proteolytic activity; metastatic melanoma is a highly aggressive and drug-resistant form of skin cancer. The relationship between MMP activity and drug treatment is unknown, and therefore we used an in situ fluorogenic MMP sensor peptide to determine how drug treatment affects melanoma cell MMP activity in three dimensions. We encapsulated melanoma cells from varying stages of progression within PEG-based hydrogels to examine the relationship between drug treatment and MMP activity. From these results, a metastatic melanoma cell line (A375) and two inhibitors that inhibit RAF (PLX4032 and sorafenib) were studied further to determine whether changes in MMP activity led to a functional change in cell behavior. A375 cells exhibited increased MMP activity despite an overall decrease in metabolic activity with PLX4032 treatment. The changes in proteolytic activity correlated with increased cell elongation and increased single-cell migration. In contrast, sorafenib did not alter MMP activity or cell motility, showing that the changes induced by PLX4032 were not a universal response to small-molecule inhibition. Therefore, we argue the importance of studying MMP activity with drug treatment and its possible implications for unwanted side effects.