Physician assistant burnout and emotional resilience in emergency medicine

The physician assistant profession has grown from its original emergence as a strategy to improve family practice and rural healthcare. Rising emergency department visits and the plateau of physicians entering the profession has contributed to a growing number of PA positions in emergency medicine. Currently, emergency medicine is the third largest practice setting, employing 13% of certified PAs. Unfortunately, little is known about the factors contributing to their resilience to remain in a high stress work environment. The literature review in this study is composed of past research on burnout, uncertainty intolerance, and resilience in emergency medicine practitioners. In summary, the comprehensive review suggests that emergency medicine practitioners, including PAs, suffer a high degree of burnout. However, the factors contributing to this burnout differ between physicians and PAs. Self-directedness, persistence, and cooperation are associated with resilience among family medicine practitioners, but there is a lack of research on the personality traits that affect emergency medicine and EMPAs. This thesis proposes a longitudinal cohort study that will investigate burnout, stress resilience, and personality trait patterns among emergency medicine PAs compared to the general PA population. The study will match emergency medicine PAs with general population PAs based on demographics. Data on burnout, stress resilience, and personality dimensions will be analyzed using a chi-square test and Pearson correlation coefficient to elucidate any differences. The proposed research is meant to better understand and prevent the burnout syndrome, which is associated with negative patient outcomes, higher healthcare costs, and serious mental health strain

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.National Cancer Institute (U.S.) (Grant R01 DK090311)National Cancer Institute (U.S.) (Grant R24OD017870

Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth

The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumor formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppresses hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis.

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap−/− mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap−/− mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant P30DK034854)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant 1R01DK090311)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant R24OD017870)National Institutes of Health (U.S.) (Grant P30DK034854)National Institutes of Health (U.S.) (Grant 1R01DK090311)National Institutes of Health (U.S.) (Grant 1R01DK105198)National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (Grant 1R01DK105198)National Institutes of Health (U.S.) (Grant R24OD017870)National Institute of General Medical Sciences (NIGMS) (Grant T32GM007753)NHMRC (Grant 1146558)National Cancer Institute (U.S.) (Grant 5P01CA120964)National Cancer Institute (U.S.) (Grant 5P30CA006516