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th warfarin users.BACKGROUND The patient-centered medical home (PCMH) model is intended to improve primary care, but evidence of its effects on provider well-being is mixed. Investigating the relationships between specific PCMH components and provider burnout and potential attrition may help improve the efficacy of the care model. OBJECTIVE We analyzed provider attitudes toward specific components of PCMH in the Veterans Health Administration (VA) and their relation to emotional exhaustion (EE)-a central component of burnout-and intent to remain in VA primary care. [https://www.selleckchem.com/products/Etopophos.html find more] DESIGN Logistic regression analysis of a cross-sectional survey. SUBJECTS 116 providers (physicians; nurse practitioners; physician assistants) in 21 practices between September 2015 and January 2016 in one VA region. MAIN MEASURES Outcomes burnout as measured with the emotional exhaustion (EE) subscale of the Maslach Burnout Inventory and intent to remain in VA primary care for the next 2&nbsp;years; predictors difficulties with components of PCMH, demographic characteristics. KEY RESULTS Forty percent of providers reported high EE (≥ 27 points) and 63% reported an intent to remain in VA primary care for the next 2&nbsp;years. Providers reporting high difficultly with PCMH elements were more likely to report high EE, for example, coordinating with specialists (odds ratio [OR] 8.32, 95% confidence interval [CI] 3.58-19.33), responding to EHR alerts (OR 6.88; 95% CI 1.93-24.43), and managing unscheduled visits (OR 7.53, 95% CI 2.01-28.23). Providers who reported high EE were also 87% less likely to intend to remain in VA primary care. CONCLUSIONS To reduce EE and turnover in PCMH, primary care providers may need additional support and training to address challenges with specific aspects of the model.BACKGROUND The use of marijuana for medical purposes is increasing in parallel with expanding legalization and decreased public perception of harm. Despite this increase in use, it is unclear which medical conditions patients are attempting to treat with marijuana and whether they are communicating with medical providers about their use. OBJECTIVE To understand the medical reasons for marijuana use, forms of marijuana used for medical purposes, and disclosure of use to physicians. DESIGN National, probability-based online survey. SETTING The USA, 2017. PARTICIPANTS 16,280 US adults. MAIN MEASURE Proportion of US adults who agreed with a statement. KEY RESULTS A total of 9003 participants completed the survey (55% response rate). Five hundred ninety-one (7% of US adults) reported using marijuana for medical purposes. The most common medical reasons for marijuana use were anxiety (49%), insomnia (47%), chronic pain (42%), and depression (39%). The most common forms of use for all medical conditions were smoking and edibles, followed by vaping, concentrate, and topical. We found women were more likely to use marijuana for posttraumatic stress disorder, sleep, anxiety, and migraines. link2 We did not find substantial variation in medical reasons for marijuana use by race. Among those using marijuana for medical purposes, 21% did not have a doctor. Among those with doctors, 33% did not inform them, 28% reported their doctor was neutral on their use, 32% reported their doctor was supportive, and 8% reported their doctor was not supportive. Those who lived in states where medical marijuana was illegal were less likely to disclose use to their doctor. LIMITATION The online format of the survey may have caused selection bias. Wording of the questions may have affected interpretation. Doctors were not queried directly, rather participants were asked about their perception of doctor attitudes. CONCLUSION Americans are using marijuana to treat medical conditions despite lack of evidence of efficacy.BACKGROUND A comprehensive picture of how the US population engages in specialty care use is lacking, even though redesign models focused on specialty care are becoming more popular. OBJECTIVE To describe the type of provider, primary care or specialist, most often seen by individuals, to test associations between type of provider most often seen and insurance coverage, and to test associations between the number of generalist and specialist visits and insurance coverage. DESIGN Cross-sectional analysis of 2013-2016 Medicaid Expenditure Panel Survey. link3 Logistic and negative binomial models were used in multivariate regression modeling. PARTICIPANTS Depending on the analysis, the study samples include between 71,402 and 79,518 US residents. MAIN MEASURES Individuals' provider type most often seen, primary care visits, and specialist visits were reported. KEY RESULTS More than half of the sample (55%) predominantly visited primary care providers (or generalists), and 36% predominantly visited specialists. Among iamong Medicare enrollees, public payers are uniquely positioned to promote specialty care redesign and champion improved coordination between specialists.BACKGROUND Orphan drugs offer important therapeutic options to patients suffering from rare conditions, but are typically considerably more expensive than non-orphan drugs, leading to questions about their cost-effectiveness. OBJECTIVE To compare the value of orphan and non-orphan drugs approved by the FDA from 1999 through 2015. DESIGN We searched the PubMed database to identify estimates of incremental health gains (measured in quality-adjusted life-years, or QALYs) and incremental costs that were associated with orphan and non-orphan drugs compared with preexisting care. We excluded pharmaceutical industry-funded studies from the dataset. When a drug was approved for multiple indications, we considered each drug-indication pair separately. We then compared incremental QALY gains, incremental costs, and incremental cost-effectiveness ratios for orphan and non-orphan drugs using the Mann-Whitney U (MWU) test (to compare median values of the different distributions) and the Kolmogorov-Smirnov (KS) test (to compare the shape of different distributions). RESULTS We identified estimates for 49 orphan drug-indication pairs, and for 169 non-orphan drug-indication pairs. We found that orphan drug-indication pairs offered larger median incremental health gains than non-orphan drug-indication pairs (0.25 vs. 0.05 QALYs; MWU p = 0.0093, KS p = 0.02), but were associated with substantially higher costs ($47,652 vs. $2870; MWU p  less then  0.001, KS p  less then  0.001) and less favorable cost-effectiveness ($276,288 vs. $100,360 per QALY gained; MWU p = 0.0068, KS p = 0.009). CONCLUSIONS Our study suggests that orphan drugs often offer larger health gains than non-orphan drugs, but due to their substantially higher costs they tend to be less cost-effective than non-orphan drugs. Our findings highlight the challenge faced by health care payers to provide patients appropriate access to orphan drugs while achieving value from drug spending.BACKGROUND Gastrokine 1 (GKN1) is a stomach-specific tumor suppressor that is secreted into extracellular space as an exosomal cargo protein. The objective of this study was to investigate the uptake and tumor-suppressive pathways of exosome-associated GKN1 protein in gastric epithelial cells. METHODS Immunofluorescent and Western blot analysis were used to investigate gastric-specific uptake of HFE-145-derived exosomes. Binding affinity of HFE-145 derived exosomes with integrin proteins was examined using protein microarray chip. Tumor suppressor activities of exosome-carrying GKN1 protein were analyzed using transwell co-culture, MTT assay, BrdU incorporation, immunoprecipitation, and Western blot analysis. RESULTS HFE-145-derived exosomes were internalized only into HFE-145 gastric epithelial cells and gastric cancer cells. Gastric-specific uptake of stomach-derived exosomes required integrin α6 and αX proteins. Clathrin and macropinocytosis increased the uptake of exosomes into gastric epithelial cells, whereas caveolin inhibited the uptake of exosomes. Transwell co-culture of AGS cells with HFE-145 cells markedly inhibited viability and proliferation of AGS cells. Following uptake of HFE-145-derived exosomes in recipient cells, GKN1 protein bound to HRas and inhibited the binding of HRas to b-Raf and c-Raf which subsequently downregulated HRas/Raf/MEK/ERK signaling pathways in AGS, MKN1 cells, and MKN1-derived xenograft tumor tissues. In addition, exosomal GKN1 protein suppressed both migration and invasion of gastric cancer cells by inhibiting epithelial-mesenchymal transition. CONCLUSIONS Gastric-specific uptake of exosomes derived from gastric epithelial cells requires integrin α6 and αX proteins in both gastric epithelial cells and exosomes. Exosomal GKN1 protein inhibits gastric carcinogenesis by downregulating HRas/Raf/MEK/ERK signaling pathways.BACKGROUND The majority of GISTs express mutationally activated KIT. Imatinib and sunitinib are approved KIT-inhibiting therapies. Their efficacy is usually hampered by the acquired multiple secondary drug-resistance KIT mutations. The most problematic resistance subset is GISTs with acquisition of secondary mutations in the KIT activation loop. Here, we establish the spectrum of activity of dasatinib against a comprehensive collection of clinically relevant KIT mutants associated with drug-sensitive and drug-resistant GIST. METHODS The cellular and in vitro activities of tyrosine kinase inhibitors (TKIs) against mutant KIT were assessed using a panel of engineered and GIST-derived cell lines. The in vivo activities of dasatinib were determined using TKI-resistant xenograft models. RESULTS In engineered and GIST-derived cell lines, dasatinib potently inhibited KIT with primary mutations in exon 11 or 9 and a range of secondary imatinib-resistant mutations in exons 13 and 14, encoding the ATP-binding pocket, and in exons 17 and 18, encoding the activation loop, with the exception of a substitution at codon T670. Our data show that dasatinib is more potent than imatinib or sunitinib at inhibiting the activity of drug-resistant KIT mutants. Dasatinib also induces regression in GIST-derived xenograft models containing these secondary mutations. A major determinant of the efficacy of dasatinib for the treatment of advanced GIST is the activity of this inhibitor against KIT mutants. CONCLUSION Dasatinib shows efficacy in cancer models, inhibiting a wide range of oncogenic primary and drug-resistant KIT mutants. These results have implications for the further development of dasatinib precision therapy in GIST patients.BACKGROUND Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption. METHODS Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed. RESULTS Conjugated BA levels in the BP-limb were significantly higher than that of the control group.