Identifying Symptoms Prior to Pancreatic Ductal Adenocarcinoma Diagnosis in Real-World Care Settings: Natural Language Processing Approach.

BACKGROUND: Pancreatic cancer is the third leading cause of cancer deaths in the United States. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, accounting for up to 90% of all cases. Patient-reported symptoms are often the triggers of cancer diagnosis and therefore, understanding the PDAC-associated symptoms and the timing of symptom onset could facilitate early detection of PDAC. OBJECTIVE: This paper aims to develop a natural language processing (NLP) algorithm to capture symptoms associated with PDAC from clinical notes within a large integrated health care system. METHODS: We used unstructured data within 2 years prior to PDAC diagnosis between 2010 and 2019 and among matched patients without PDAC to identify 17 PDAC-related symptoms. Related terms and phrases were first compiled from publicly available resources and then recursively reviewed and enriched with input from clinicians and chart review. A computerized NLP algorithm was iteratively developed and fine-trained via multiple rounds of chart review followed by adjudication. Finally, the developed algorithm was applied to the validation data set to assess performance and to the study implementation notes. RESULTS: A total of 408,147 and 709,789 notes were retrieved from 2611 patients with PDAC and 10,085 matched patients without PDAC, respectively. In descending order, the symptom distribution of the study implementation notes ranged from 4.98% for abdominal or epigastric pain to 0.05% for upper extremity deep vein thrombosis in the PDAC group, and from 1.75% for back pain to 0.01% for pale stool in the non-PDAC group. Validation of the NLP algorithm against adjudicated chart review results of 1000 notes showed that precision ranged from 98.9% (jaundice) to 84% (upper extremity deep vein thrombosis), recall ranged from 98.1% (weight loss) to 82.8% (epigastric bloating), and F1-scores ranged from 0.97 (jaundice) to 0.86 (depression). CONCLUSIONS: The developed and validated NLP algorithm could be used for the early detection of PDAC.

Stomach Cancer Prediction Model (SCoPM): An approach to risk stratification in a diverse U.S. population.

BACKGROUND AND AIMS: Population-based screening for gastric cancer (GC) in low prevalence nations is not recommended. The objective of this study was to develop a risk-prediction model to identify high-risk patients who could potentially benefit from targeted screening in a racial/ethnically diverse regional US population. METHODS: We performed a retrospective cohort study from Kaiser Permanente Southern California from January 2008-June 2018 among individuals age ≥50 years. Patients with prior GC or follow-up <30 days were excluded. Censoring occurred at GC, death, age 85 years, disenrollment, end of 5-year follow-up, or study conclusion. Cross-validated LASSO regression models were developed to identify the strongest of 20 candidate predictors (clinical, demographic, and laboratory parameters). Records from 12 of the medical service areas were used for training/initial validation while records from a separate medical service area were used for testing. RESULTS: 1,844,643 individuals formed the study cohort (1,555,392 training and validation, 289,251 testing). Mean age was 61.9 years with 53.3% female. GC incidence was 2.1 (95% CI 2.0-2.2) cases per 10,000 person-years (pyr). Higher incidence was seen with family history: 4.8/10,000 pyr, history of gastric ulcer: 5.3/10,000 pyr, H. pylori: 3.6/10,000 pyr and anemia: 5.3/10,000 pyr. The final model included age, gender, race/ethnicity, smoking, proton-pump inhibitor, family history of gastric cancer, history of gastric ulcer, H. pylori infection, and baseline hemoglobin. The means and standard deviations (SD) of c-index in validation and testing datasets were 0.75 (SD 0.03) and 0.76 (SD 0.02), respectively. CONCLUSIONS: This prediction model may serve as an aid for pre-endoscopic assessment of GC risk for identification of a high-risk population that could benefit from targeted screening.

Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.

Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients' overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8 + T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-ß-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8 + T cells activation. Mechanistically, these CAFs downregulated components of the TGF-ß pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer. Statement of Significance: Here we uncovered the pro-tumor roles of the synaptic protein NGL-1 in the tumor microenvironment of pancreatic cancer, defining a new target that simultaneously modulates tumor cell, fibroblast, and immune cell functions. This study reports a new pathway where NGL-1 controls TGF-ß, AP-1 transcription factor members and NFAT1, modulating the immunosuppressive microenvironment in pancreatic cancer. Our findings highlight NGL-1 as a new stromal immunomodulator in pancreatic cancer.

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts.

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDR's potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

Association of endoscopic biopsy sampling methods with detection of precursor lesions of gastric cancer.

BACKGROUND AND AIMS: The yield of various endoscopic biopsy sampling methods for detection of precursor lesions of noncardia gastric cancer in a real-world setting remains unclear. Our objective was to evaluate the association of endoscopic biopsy sampling methods with detection of gastric intestinal metaplasia (GIM) and gastric dysplasia (GD). METHODS: We conducted a case-control study of adult patients who underwent EGD with biopsy sampling between 2010 and 2021 in a racially and ethnically diverse U.S. healthcare system. Cases were patients with histopathologic findings of GIM and/or GD. Control subjects were matched 1:1 by age, procedure date, and medical center. We compared the detection of GIM and GD using 4 different biopsy sampling methods: unspecified, specified stomach location, 2+2, and the Sydney protocol. Additionally, we assessed trends in use of sampling methods (Cochrane-Armitage) and identified patient and endoscopist factors associated with their use (logistic regression). RESULTS: We identified 20,938 GIM and 455 GD matched pairs. A greater proportion of GIM cases were detected using 2+2 (31.3% vs 25.3%, P < .0001) and the Sydney protocol (9.1% vs 1.0%, P < .0001) compared with control subjects. Similarly, a greater proportion of GD cases were detected using the Sydney protocol (15.6% vs .4%, P < .0001). We observed an increasing trend in the use of the Sydney protocol during the study period (3.8%-16.1% in cases, P < .0001; 1%-1.1% in control subjects, P = .005). Male and Asian American patients were more likely to undergo 2+2 or the Sydney protocol, whereas female and Hispanic endoscopists were more likely to perform sampling using these protocols. CONCLUSIONS: The application of the Sydney protocol is associated with an increased detection of precursor lesions of gastric cancer in routine clinical practice.

Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6).

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

Machine learning versus regression for prediction of sporadic pancreatic cancer.

BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed. RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively. CONCLUSIONS: The three models complement each other, but each has unique contributions.

Derivation and External Validation of Machine Learning-Based Model for Detection of Pancreatic Cancer.

INTRODUCTION: There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. METHODS: This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. RESULTS: The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. DISCUSSION: Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.

Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating selected features of TGFß inhibition.

BACKGROUND: Less than 11% of pancreatic cancer patients survive 5-years post-diagnosis. The unique biology of pancreatic cancer includes a significant expansion of its desmoplastic tumor microenvironment, wherein cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix are key components. CAF functions are both tumor-supportive and tumor-suppressive, while normal fibroblastic cells are solely tumor-suppressive. Knowing that CAF-eliminating drugs are ineffective and can accelerate cancer progression, therapies that "normalize" CAF function are highly pursued. Eribulin is a well-tolerated anti-microtubule drug used to treat a plethora of neoplasias, including advanced/metastatic cancers. Importantly, eribulin can inhibit epithelial to mesenchymal transition via a mechanism akin to blocking pathways induced by transforming growth factor-beta (TGFß). Notably, canonical TGFß signaling also plays a pivotal role in CAF activation, which is necessary for the development and maintenance of desmoplasia. Hence, we hypothesized that eribulin could modulate, and perhaps "normalize" CAF function. METHODS: To test this premise, we used a well-established in vivo-mimetic fibroblastic cell-derived extracellular matrix (CDM) system and gauged the effects of eribulin on human pancreatic CAFs and cancer cells. This pathophysiologic fibroblast/matrix functional unit was also used to query eribulin effects on CDM-regulated pancreatic cancer cell survival and invasive spread. RESULTS: Demonstrated that intact CAF CDMs modestly restricted eribulin from obstructing pancreatic cancer cell growth. Nonetheless, eribulin-treated CAFs generated CDMs that limited nutrient-deprived pancreatic cancer cell survival, similar to reported tumor-suppressive CDMs generated by TGFß-deficient CAFs. CONCLUSIONS: Data from this study support the central proposed premise suggesting that eribulin could be used as a CAF/matrix-normalizing drug.

NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress.

It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEVs). The tumor-supportive CAFs possess a distinct phenotypic profile, compared to normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α5ß1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Further, we show that NetG1 expression in CAFs is required for the pro-survival properties of sEVs. Additionally, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5ß1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5ß1 were detected in sEVs collected from plasma of PDAC patients, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor-stroma interactions and pathogenic stroma detection.

Laboratory monitoring to reduce adverse drug-related events: a mixed methods study.

BACKGROUND: Therapy with angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) requires laboratory monitoring to avoid hyperkalemia and acute kidney failure. OBJECTIVE: To assess the frequency of recommended annual serum potassium and creatinine monitoring and determine potential factors associated with care gaps among adults dispensed an ACEI or ARB. METHODS: This mixed-methods study integrated findings from a retrospective cohort study and individual patient interviews. Adults aged 21 years and over within Kaiser Permanente Southern California with at least 180 treatment days of an ACEI and/or ARB in 2015 were included. Patients invited for qualitative interviews included those who did and did not complete the recommended laboratory tests. We assessed the proportion of patients completing both recommended laboratory tests, factors associated with not receiving laboratory monitoring, and patients' insights into barriers and facilitators of recommended monitoring. RESULTS: Of 437,544 patients who received an ACEI or ARB, 9.0% did not receive both a serum potassium and creatinine laboratory test during treatment (defined as a care gap). Lower risk of a care gap was observed for patients with increasing age (rate ratio [RR] per 10-year increase = 0.78, 95% CI = 0.77-0.79); diabetes mellitus (RR = 0.62, 95% CI = 0.60-0.64); hypertension (RR = 0.71, 95% CI = 0.71-0.74); Charlson Comorbidity Index score of at least 2 (RR = 0.62, 95% CI = 0.60-0.64); those who changed medication classes (RR = 0.53, 95% CI = 0.51-0.56); and patients with a cardiologist (RR = 0.81, 95% CI = 0.73-0.90) or nephrologist (RR = 0.60, 95% CI = 0.52-0.69) as their prescribing provider. Twenty-five patients completed the qualitative interviews. Patients often lacked knowledge about the need for laboratory monitoring, cited logistical barriers to accessing the laboratory, and deemed the reminders they received through an outpatient safety program as a facilitator to completing tests. CONCLUSIONS: Given the large patient population on ACEI and ARB medications, monitoring and support strategies such as electronic clinical surveillance could be important in addressing care gaps and potentially reducing adverse drug effects. DISCLOSURES: This project was supported by grant number R01HS024437 from the Agency for Healthcare Research and Quality. The funder had no role in the design of the study; collection, analyses, or interpretation of the data, or decision to submit this manuscript for publication. Harrison, Reynolds, Hahn, Munoz-Plaza, Yi, Fischer, Luong, Sim, Brettler, Handler, and Mittman are employees of the Southern California Permanente Medical Group. Danworth was employed by the Southern California Permanente Medical Group at the time of this study. Singh was partially supported by the Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (CIN13-413). Reynolds reports grants from Novartis, Amgen Inc., and Vital Strategies, Resolve to Save Lives, unrelated to this work. Yi reports grants from Novartis unrelated to this work. Kanter has nothing to disclose.

Clinical and Imaging Predictors of Pancreatic Cancer in Patients Hospitalized for Acute Pancreatitis.

Background and Aims: Identifying factors associated with increased short-term risk of pancreatic cancer in the setting of acute pancreatitis (AP) can inform clinical care decisions and expedite cancer diagnosis. Methods: A retrospective cohort study of patients hospitalized for AP between 2007 and 2017 in an integrated health-care system in Southern California. AP cases were identified by diagnosis code with laboratory confirmation. Multivariable Cox proportional hazards regression model was used to assess risk of pancreatic cancer within 3 years of AP, adjusting for patient demographics, clinical parameters (body mass index, AP etiology, chronic pancreatitis, diabetes) and radiographic imaging features. Results: Among 9,490 patients hospitalized with AP, the mean (standard deviation) age was 55.8 (17.8) years, 55% were women, and 42% were Hispanic. Majority of AP cases were biliary (64%), 12% were alcohol-related, 5% were hypertriglyceridemia-induced, and 19% were other/unknown etiology. Ninety-five (1%) patients were diagnosed with pancreatic cancer within 3 years of AP (4.2 cases/1000 person-years). Risk factors for pancreatic cancer were age ≥65 years (hazard risk [HR]: 2.5, 95% confidence interval [CI]: 1.2-5.3), male sex (HR: 1.9, 95% CI: 1.2-2.8), Asian/Pacific Islander race (HR: 2.0, 95% CI: 1.1-3.6), and underweight body mass index (HR: 2.6, 95% CI: 1.1-6.5). In addition, other/unknown AP etiology (HR: 2.0, 95% CI: 1.3-3.1) and dilatation of the main pancreatic duct (HR: 6.6, 95% CI: 4.2-10.5) were independently associated with increased risk of pancreatic cancer. Conclusion: In addition to older age, the lack of well-established etiology, underweight body habitus, and main pancreatic duct dilatation were independently associated with increased short-term risk of pancreatic cancer among patients hospitalized for AP.

Draft Genome Sequence of the Multidrug-Resistant Strain Pseudomonas aeruginosa PA291, Isolated from Cystic Fibrosis Sputum.

Here, we report the genome sequence of PA291, a nonmucoid, multidrug-resistant strain of Pseudomonas aeruginosa isolated from cystic fibrosis sputum. Short reads were de novo assembled into 190 contigs and scaffold assembled to a length of 6.26 Mbp. PhiSpy predicts that PA291 is free of prophages.

Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit natural killer cell-mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.See related commentary by Sherman, p. 230.This article is highlighted in the In This Issue feature, p. 211.

Severity of Diabetic Retinopathy and the Risk of Future Cerebrovascular Disease, Cardiovascular Disease, and All-Cause Mortality.

PURPOSE: To determine the relationship between the severity of diabetic retinopathy and the future risk of cerebrovascular accident (CVA), myocardial infarction (MI), congestive heart failure (CHF), and all-cause mortality in patients with type 2 diabetes mellitus. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with type 2 diabetes who underwent diabetic retinopathy screening via fundus photography. METHODS: The relationship between retinopathy status and the 5-year risk of first-time CVA, MI, CHF, and all-cause mortality was investigated using multivariate Cox proportional hazards regressions that controlled for age, gender, race or ethnicity, hemoglobin A1c, duration of diabetes, high-density lipoprotein level, low-density lipoprotein level, history of hypertension, systolic blood pressure, diastolic blood pressure, tobacco use, statin use, body mass index, urine microalbumin-to-creatinine ratio, and estimated glomerular filtration rate. MAIN OUTCOME MEASURES: Five-year risk of first-time CVA, MI, CHF, and all-cause mortality. RESULTS: Seventy-seven thousand three hundred seventy-six patients were included in this study. The average age was 59.8 years with 53.6% male, 31.2% non-Hispanic White, and 41.4% Hispanic patients. Diabetic retinopathy was significantly associated with all outcomes on multivariate analysis. Compared with patients with no retinopathy, those with minimal nonproliferative diabetic retinopathy (NPDR) had a higher risk of CVA (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.18-1.46), MI (HR, 1.30; 95% CI, 1.15-1.46), CHF (HR, 1.29; 95% CI, 1.19-1.40), and death (HR, 1.15; 95% CI, 1.05-1.25). Similarly, patients with moderate to severe NPDR had a higher risk of each outcome (CVA: HR, 1.56; 95% CI, 1.29-1.89; MI: HR, 1.92; 95% CI, 1.57-2.34; CHF: HR, 1.90; 95% CI, 1.66-2.18, and death: HR, 1.55; 95% CI, 1.32-1.82), as did patients with proliferative diabetic retinopathy (CVA: HR, 2.53; 95% CI, 1.84-3.48; MI: HR, 1.89; 95% CI, 1.26-2.83; CHF: HR, 1.96; 95% CI, 1.47-2.59; and death: HR, 1.87; 95% CI, 1.36-2.56). CONCLUSIONS: Diabetic retinopathy is significantly associated with future risk of CVA, MI, CHF, and death, with higher degrees of retinopathy appearing to carry a heightened risk for each outcome. Retinal information may provide valuable insights into patients' risk of future vascular disease and death.

Racial and Ethnic Differences in Myopia Progression in a Large, Diverse Cohort of Pediatric Patients.

Purpose: The purpose of this study was to characterize the differences in myopic progression in children by race/ethnicity and age. Methods: Patients enrolled in Kaiser Permanente Southern California between 2011 and 2016 and between the ages of 4 and 11 years old with a documented refraction between -6 and -1 diopters (Ds) were included in this retrospective cohort study. Patients with a history of amblyopia, strabismus, retinopathy of prematurity, or prior ocular surgery were excluded from analyses. Patients' race/ethnicity and language information were used to create the following groups for analysis: white, Black, Hispanic, South Asian, East/Southeast Asian, Other Asian, and other/unknown. A growth curve analysis using linear mixed-effects modeling was used to trace longitudinal progression of spherical equivalents over time, modeled by race/ethnicity. Analyses adjusted for potential confounders, including body mass index (BMI), screen time, and physical activity. Results: There were 11,595 patients who met the inclusion criteria. Patients were 53% girls, 55% Latino, 15% white, 9% black, 9% East/Southeast Asian, and 2% South Asian. Mean age (standard deviation [SD]) at the time of initial refraction was 8.9 years (1.6 years). Patients had an average (SD) of 3.4 (1.5) refractions, including the baseline measurement, during the study period. A three-way interaction model that assessed the effects of age at baseline, time since baseline, and race/ethnicity found that children of East/Southeast Asian descent showed significantly faster myopia progression across time (P < 0.001). East/Southeast Asian patients who presented with myopia between 6 to < 8 years progressed similarly to white patients in the same age group and significantly faster compared with white patients in other age groups. Conclusions: Myopia progression differed significantly between East/Southeast Asian and white patients depending on the patients' age.

Engineering clinically-relevant human fibroblastic cell-derived extracellular matrices.

Three-dimensional (3D) culturing models, replicating in vivo tissue microenvironments that incorporate native extracellular matrix (ECM), have revolutionized the cell biology field. Fibroblastic cells generate lattices of interstitial ECM proteins. Cell interactions with ECMs and with molecules sequestered/stored within these are crucial for tissue development and homeostasis maintenance. Hence, ECMs provide cells with biochemical and biomechanical cues to support and locally control cell function. Further, dynamic changes in ECMs, and in cell-ECM interactions, partake in growth, development, and temporary occurrences such as acute wound healing. Notably, dysregulation in ECMs and fibroblasts could be important triggers and modulators of pathological events such as developmental defects, and diseases associated with fibrosis and chronic inflammation such as cancer. Studying the type of fibroblastic cells producing these matrices and how alterations to these cells enable changes in ECMs are of paramount importance. This chapter provides a step-by-step method for producing multilayered (e.g., 3D) fibroblastic cell-derived matrices (fCDM). Methods also include means to assess ECM topography and other cellular traits, indicative of fibroblastic functional statuses, like naïve/normal vs. inflammatory and/or myofibroblastic. For these, protocols include indications for isolating normal and diseased fibroblasts (i.e., cancer-associated fibroblasts known as CAFs). Protocols also include means for conducting microscopy assessments, querying whether fibroblasts present with fCDM-dependent normal or CAF phenotypes. These are supported by discrete semi-quantitative digital imaging analyses, providing some imaging processing advice. Additionally, protocols include descriptions for effective fCDM decellularization, which renders cellular debris-free patho/physiological in vivo-like scaffolds, suitable as 3D substrates for subsequent cell culturing.

Disparities in Stage at Diagnosis in an Equal-access Integrated Delivery System: A Retrospective Cohort Study of 7244 Patients With Bladder Cancer.

BACKGROUND: Disparities in bladder cancer survival by race/ethnicity and gender are likely related to differences in diagnosis. We assessed disparities in stage at diagnosis and potential contributing factors within a large, integrated delivery system. PATIENTS AND METHODS: We conducted a retrospective cohort study of 7244 patients with bladder cancer age ≥ 21 years diagnosed from January 2001 to June 2015 within Kaiser Permanente Southern California. Bivariate analyses compared stage at diagnosis - as well as comorbidities, health plan membership length, and health care utilization prior to diagnosis - by race/ethnicity, gender, and age. Multivariable generalized linear mixed models with urologist as a random effect were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for diagnosis of muscle-invasive bladder cancer (MIBC) versus non-muscle-invasive bladder cancer. RESULTS: In multivariable analyses, stage at diagnosis varied significantly by race/ethnicity (P < .001). Non-Hispanic black patients had significantly higher odds of being diagnosed with MIBC than non-Hispanic white patients (OR, 1.33; 95% CI, 1.05-1.67), whereas Asian patients had significantly lower odds (OR, 0.67; 95% CI, 0.49-0.91). Women were significantly more likely to be diagnosed with MIBC than men (OR, 1.40; 95% CI, 1.22-1.61). Non-Hispanic black women had the highest proportion (39%) of MIBC diagnoses. Among Hispanic and Asian patients, a greater proportion of diagnoses occurred at younger ages. CONCLUSIONS: Health care coverage within an equal-access system did not eliminate disparities in stage at diagnosis by race/ethnicity or gender. Studies are needed to identify etiologic factors and aspects of care delivery (eg, patient-physician interactions) that may affect the diagnostic process to inform efforts to improve health equity.

Follow-up of Abnormal Estimated GFR Results Within a Large Integrated Health Care Delivery System: A Mixed-Methods Study.

BACKGROUND: Timely follow-up of abnormal laboratory results is important for high-quality care. We sought to identify risk factors, facilitators, and barriers to timely follow-up of an abnormal estimated glomerular filtration rate (eGFR) for the diagnosis of chronic kidney disease. STUDY DESIGN: Mixed-methods study: retrospective electronic health record (EHR) analyses, physician interviews. SETTING & PARTICIPANTS: Large integrated health care delivery system. Quantitative analyses included 244,540 patients 21 years or older with incident abnormal eGFRs from January 1, 2010, to December 31, 2015, ordered by 7,164 providers. Qualitative analyses included 15 physician interviews. EXPOSURES: Patient-, physician-, and system-level factors. OUTCOME: Timely follow-up of incident abnormal eGFRs, defined as repeat eGFR obtained within 60 to 150 days, follow-up testing before 60 days that indicated normal kidney function, or diagnosis before 60 days of chronic kidney disease or kidney cancer. ANALYTICAL APPROACH: Multivariable robust Poisson regression models accounting for clustering within provider were used to estimate risk ratios (RRs) and 95% CIs for lack of timely follow-up. Team coding was used to identify themes from physician interviews. RESULTS: 58% of patients lacked timely follow-up of their incident abnormal eGFRs (ie, had a care gap). An abnormal creatinine result flag in the EHR was associated with better follow-up (RR for care gap, 0.65; 95% CI, 0.64-0.66). Patient online portal use and physician panel size were weakly associated with follow-up. Patients seen by providers behind on managing their EHR message box were at higher risk for care gaps. Physician interviews identified system-level (eg, panel size and assistance in managing laboratory results) and provider-level (eg, proficiency using EHR tools) factors that influence laboratory result management. LIMITATIONS: Unable to capture intentional delays in follow-up testing. CONCLUSIONS: Timely follow-up of abnormal results remains challenging in an EHR-based integrated health care delivery system. Strategies improving provider EHR message box management and leveraging health information technology (eg, flagging abnormal eGFR results), making organizational/staffing changes (eg, increasing the role of nurses in managing laboratory results), and boosting patient engagement through better patient portals may improve test follow-up.

Care Quality and Variability in the Use of Intravesical Therapy for Initial Treatment of Nonmuscle Invasive Bladder Cancer Within a Large, Diverse Integrated Delivery System.

OBJECTIVES: To examine treatment variability, disparities, and quality among newly diagnosed nonmuscle invasive bladder cancer (NMIBC) patients, and to identify factors associated with treatment use in a large, diverse integrated delivery system. METHODS: Retrospective cohort study of 5386 NMIBC patients diagnosed between January 2001 and June 2015 within Kaiser Permanente Southern California. Electronic health data were used to identify treatment outcomes and patient, provider, and tumor characteristics. Outcomes were use of (1) postoperative intravesical chemotherapy, (2) induction Bacille Calmette-Guérin (BCG) immunotherapy, and (3) any intravesical therapy. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using generalized linear mixed models with a binary outcome and urologist as a random effect. RESULTS: From 2001 to 2015, 41% of newly diagnosed NMIBC patients were treated with intravesical therapy. Postoperative chemotherapy use increased significantly over this period (OR per-year = 1.16, 95% CI: 1.07-1.25). BCG use was strongly associated with tumor characteristics: patients with high-grade or carcinoma in situ tumors were more likely to receive BCG (OR = 10.10, 95% CI: 8.39-12.16). Few treatment differences were found by sex or race/ethnicity, but were observed by age. Wide treatment variability across urologists was observed, with some urologists never using intravesical therapy as part of initial treatment while others almost always used it. Differences across urologists accounted for more variability in postoperative chemotherapy (intraclass correlation coefficient = 0.52) than BCG immunotherapy (intraclass correlation coefficient = 0.11) use. CONCLUSION: Substantial variability in initial treatment of NMIBC was observed across urologists, accounting for tumor, patient, and provider characteristics. Results suggest a considerable opportunity for quality improvement programs to reduce unwanted treatment variability and improve care for patients.