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 (TGFβ). Notably, canonical TGFβ 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.
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.
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 TGFβ-deficient CAFs.
Data from this study support the central proposed premise suggesting that eribulin could be used as a CAF/matrix-normalizing drug.
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.
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.
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.
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.
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).
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).
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.
The application of the Sydney protocol is associated with an increased detection of precursor lesions of gastric cancer in routine clinical practice.
Myopia prevalence and risk factors in children Theophanous, Christos; Modjtahedi, Bobeck S; Batech, Michael ...
Clinical ophthalmology (Auckland, N.Z.),
01/2018, Volume:
12
Journal Article
Peer reviewed
Open access
To evaluate the prevalence and risk factors for pediatric myopia in a contemporary American cohort.
A cross-sectional study of pediatric patients enrolled in the Kaiser Permanente Southern California ...health plan was done. Eligible patients were 5- to 19-years old between January 1, 2008, through December 31, 2013, and received an ophthalmologic or optometric refraction. Electronic medical records were reviewed for demographic data, refraction results, and exercise data. Prevalence and relative risks of myopia (defined as ≤-1.0 diopter) were characterized. Age, sex, race/ethnicity, median neighborhood income, and minutes of exercise per day were examined as risk factors.
There were 60,789 patients who met the inclusion criteria, of which 41.9% had myopia. Myopia was more common in older children (14.8% in 5- to 7-year olds, 59.0% in 17- to 19-year olds). Asian/Pacific Islander patients (OR 1.64, CI 1.58-1.70) had an increased rate of myopia compared to White patients as did African Americans to a lesser extent (OR 1.08, CI 1.03-1.13). Median neighborhood household income of $25,000-40,000 was associated with lower rates of myopia (OR 0.90, CI 0.83-0.97) compared to median neighborhood household incomes less than $25,000. Having at least 60 min of daily exercise was associated with lower prevalence of myopia (OR 0.87, CI 0.85-0.89).
Myopia was common in this large and diverse Southern Californian pediatric cohort. The prevalence of myopia increases with age. Asian children are at highest risk for myopia. Exercise is associated with a lower rate of myopia and represents an important potentially modifiable risk factor that may be a target for future public health efforts.
Deoxyribonucleic acid (DNA) of the human immunodeficiency virus (HIV) provides the most sensitive measurement of residual infection in patients on effective combination antiretroviral therapy (cART). ...Droplet digital PCR (ddPCR) has recently been shown to provide highly accurate quantification of DNA copy number, but its application to quantification of HIV DNA, or other equally rare targets, has not been reported. This paper demonstrates and analyzes the application of ddPCR to measure the frequency of total HIV DNA (pol copies per million cells), and episomal 2-LTR (long terminal repeat) circles in cells isolated from infected patients. Analysis of over 300 clinical samples, including over 150 clinical samples assayed in triplicate by ddPCR and by real-time PCR (qPCR), demonstrates a significant increase in precision, with an average 5-fold decrease in the coefficient of variation of pol copy numbers and a >20-fold accuracy improvement for 2-LTR circles. Additional benefits of the ddPCR assay over qPCR include absolute quantification without reliance on an external standard and relative insensitivity to mismatches in primer and probe sequences. These features make digital PCR an attractive alternative for measurement of HIV DNA in clinical specimens. The improved sensitivity and precision of measurement of these rare events should facilitate measurements to characterize the latent HIV reservoir and interventions to eradicate it.
The purpose of this study was to characterize the differences in myopic progression in children by race/ethnicity and age.
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.
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.
Myopia progression differed significantly between East/Southeast Asian and white patients depending on the patients' age.
Vaccine hesitancy poses one of the largest threats to global health. Informing people about the collective benefit of vaccination has great potential in increasing vaccination intentions. This ...research investigates the potential for engaging experiences in immersive virtual reality (VR) to strengthen participants' understanding of community immunity, and therefore, their intention to get vaccinated. In a pre-registered lab-in-the-field intervention study, participants were recruited in a public park (tested: Formula: see text, analyzed: Formula: see text). They were randomly assigned to experience the collective benefit of community immunity in a gamified immersive virtual reality environment (Formula: see text of sample), or to receive the same information via text and images (Formula: see text of sample). Before and after the intervention, participants indicated their intention to take up a hypothetical vaccine for a new COVID-19 strain (0-100 scale) and belief in vaccination as a collective responsibility (1-7 scale). The study employs a crossover design (participants later received a second treatment), but the primary outcome is the effect of the first treatment on vaccination intention. After the VR treatment, for participants with less-than-maximal vaccination intention, intention increases by 9.3 points (95% CI: 7.0 to Formula: see text). The text-and-image treatment raises vaccination intention by 3.3 points (difference in effects: 5.8, 95% CI: 2.0 to Formula: see text). The VR treatment also increases collective responsibility by 0.82 points (95% CI: 0.37 to Formula: see text). The results suggest that VR interventions are an effective tool for boosting vaccination intention, and that they can be applied "in the wild"-providing a complementary method for vaccine advocacy.
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
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
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
by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.
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Background Direct oral anticoagulants (DOACs) are widely used in patients with nonvalvular atrial fibrillation for stroke prevention. However, long-term adherence to DOACs and clinical outcomes in ...real-world clinical practice is not well understood. This study evaluated long-term medication adherence patterns to DOAC therapy and clinical outcomes in a large US integrated health care system. Methods and Results We included adult patients with nonvalvular atrial fibrillation who newly initiated DOACs between 2012 and 2018 in Kaiser Permanente Southern California. Long-term (3.5 years) adherence trajectories to DOAC were investigated using monthly proportion of days covered and group-based trajectory models. Factors associated with long-term adherence trajectories were investigated. Multivariable Poisson regression analyses were used to investigate thromboembolism and major bleeding events associated with long-term adherence trajectories. Of 18 920 patients newly initiating DOACs, we identified 3 DOAC adherence trajectories: consistently adherent (85.2%), early discontinuation within 6 months (10.6%), and gradually declining adherence (4.2%). Predictors such as lower CHA
DS
-VASc (0-1 versus ≥5) and previous injurious falls were associated with both early discontinuation and gradually declining adherence trajectories. Early discontinuation of DOAC therapy was associated with a higher risk of thromboembolism (rate ratio, 1.40; 95% CI, 1.05-1.86) especially after 12 months from DOAC initiation but a lower risk of major bleed compared with consistent adherence (rate ratio, 0.48; 95% CI, 0.30-0.75), specifically during the first 12 months following DOAC initiation. A gradual decline in adherence to DOACs was not statistically significantly associated with thromboembolism outcomes compared with consistent adherence. Conclusions Although a large proportion of patients with nonvalvular atrial fibrillation were adherent to DOAC therapy over 3.5 years, early discontinuation of DOAC was associated a higher risk of thromboembolic events. Future tailored interventions for early discontinuers may improve clinical outcomes.
Most patients with diabetes have little or no retinopathy on initial examination. Tracking the long-term outcomes of these patients may increase our understanding of how to best provide follow-up ...treatment.
To assess how many patients with minimal or no retinopathy require retinal intervention within 2 years of retinal evaluation.
This retrospective cohort study assessed patients who underwent screening for diabetic retinopathy within a telemedicine program at Kaiser Permanente Southern California and had minimal or no retinopathy on fundus photographs.
Retinal interventions performed within 2 years of photographs.
Patients with minimal or no retinopathy on initial screening photographs taken in 2012 had their medical records searched for Current Procedural Terminology codes for intravitreal injections, retinal lasers, or pars plana vitrectomy. The medical records of patients identified as having received these interventions within 2 years of retinal evaluation were then manually reviewed for further characterization.
Diabetic retinopathy screening photographs were taken for 116 134 patients (mean SD age, 58 12.8 years; 54 582 47.0% female; 46 453 40.0% Latino). Of these patients, 79 445, including 69 634 patients without retinopathy and 9811 patients with minimal retinopathy, had 2 years of follow-up. Eleven patients without baseline retinopathy required treatment of diabetic retinopathy in the following 2 years (1 of 12 660 or 0.000079 patients per year), and 11 patients with minimal retinopathy required intervention during the same period (1 of 1784 or 0.000561 patients per year). In addition, retinal interventions were performed for conditions not directly related to diabetic eye disease in 44 patients without baseline retinopathy (1 of 3165 or 0.000316 patients per year) and 5 patients with minimal retinopathy at baseline (1 of 3924 or 0.000255 patients per year).
These findings suggest that it is rare for patients with minimal or no baseline retinopathy to require retinal interventions in the 2 years after retinal evaluation. It appears that extending the recommended follow-up interval for low-risk patients may be reasonable as long as this does not lead to worse follow-up in later years, because most are unlikely to have vision-threatening disease that necessitates treatment.
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