3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), the rate-limiting enzymes of sterol synthesis, undergoes feedback-regulated endoplasmic reticulum degradation in both mammals and yeast. The yeast Hmg2p isozyme is subject to ubiquitin-mediated endoplasmic reticulum degradation by the HRD pathway. We had previously shown that alterations in cellular levels of the 15-carbon sterol pathway intermediate farnesyl pyrophosphate (FPP) cause increased Hmg2p ubiquitination and degradation. We now present evidence that the FPP-derived, 20-carbon molecule geranylgeranyl pyrophosphate (GGPP) is a potent endogenous regulator of Hmg2p degradation. This work was launched by the unexpected observation that GGPP addition directly to living yeast cultures caused high potency and specific stimulation of Hmg2p degradation. This effect of GGPP was not recapitulated by FPP, GGOH, or related isoprenoids. GGPP-caused Hmg2p degradation met all the criteria for the previously characterized endogenous signal. The action of added GGPP did not require production of endogenous sterol molecules, indicating that it did not act by causing the build-up of an endogenous pathway signal. Manipulation of endogenous GGPP by several means showed that naturally made GGPP controls Hmg2p stability. Analysis of the action of GGPP indicated that the molecule works upstream of retrotranslocation and can directly alter the structure of Hmg2p. We propose that GGPP is the FPP-derived regulator of Hmg2p ubiquitination. Intriguingly, the sterol-dependent degradation of mammalian HMGR is similarly stimulated by the addition of GGOH to intact cells, implying that a dependence on 20-carbon geranylgeranyl signals may be a common conserved feature of HMGR regulation that may lead to highly specific therapeutic approaches for modulation of HMGR.

Introduction: There is increasing appreciation of the challenges of providing safe and appropriate care to cancer patients in the emergency department (ED). Our goal here was to assess which patient characteristics are associated with more frequent ED revisits. Methods: This was a retrospective cohort study of all ED visits in California during the 2016 calendar year using data from the California Office of Statewide Health Planning and Development. We defined revisits as a return visit to an ED within seven days of the index visit. For both index and return visits, we assessed various patient characteristics, including age, cancer type, medical comorbidities, and ED disposition. Results: Among 12.9 million ED visits, we identified 73,465 adult cancer patients comprising 103,523 visits that met our inclusion criteria. Cancer patients had a 7-day revisit rate of 17.9% vs 13.2% for non-cancer patients. Cancer patients had a higher rate of admission upon 7-day revisit (36.7% vs 15.6%). Patients with cancers of the small intestine, stomach, and pancreas had the highest rate of 7-day revisits (22-24%). Cancer patients younger than 65 had a higher 7-day revisit rate than the elderly (20.0% vs 16.2%). Conclusion: In a review of all cancer-related ED visits in the state of California, we found a variety of characteristics associated with a higher rate of 7-day ED revisits. Our goal in this study was to inform future research to identify interventions on the index visit that may improve patient outcomes.

Background/aimsTo identify clinical characteristics and factors associated with microcystic macular edema (MME) in patients with primary open-angle glaucoma (POAG).MethodsWe included 315 POAG eyes between 2010 and 2019 with good-quality macular volume scans that had reliable visual fields (VF) available within 6 months in this observational retrospective cohort study. Eyes with retinal pathologies except for epiretinal membrane (ERM) were excluded. The inner nuclear layer was qualitatively assessed for the presence of MME. Global mean deviation (MD) and Visual Field Index (VFI) decay rates, superior and inferior MD rates and pointwise total deviation rates of change were estimated with linear regression. Logistic regression was performed to identify baseline factors associated with the presence of MME and to determine whether MME is associated with progressive VF loss.Results25 out of 315 eyes (7.9%) demonstrated MME. The average (±SD) age and MD in eyes with and without MME was 57.2 (±8.7) versus 62.0 (±9.9) years (p=0.02) and −9.8 (±5.7) versus −4.9 (±5.3) dB (p<0.001), respectively. Worse global MD at baseline (p=0.001) and younger age (p=0.02) were associated with presence of MME. ERM was not associated with the presence of MME (p=0.84) in this cohort. MME was not associated with MD and VFI decay rates (p>0.49).ConclusionsMore severe glaucoma and younger age were associated with MME. MME was not associated with faster global VF decay in this cohort. MME may confound monitoring of glaucoma with full macular thickness.