The phosphate signal transduction (PHO) pathway, which regulates genes in response to phosphate starvation, is well defined in Saccharomyces cerevisiae. We asked whether the PHO pathway was the same in the distantly related fission yeast Schizosaccharomyces pombe. We screened a deletion collection for mutants aberrant in phosphatase activity, which is primarily a consequence of pho1 ؉ transcription. We identified a novel zinc finger-containing protein (encoded by spbc27b12.11c ؉ ), which we have named pho7 ؉ , that is essential for pho1؉ transcriptional induction during phosphate starvation. Few of the S. cerevisiae genes involved in the PHO pathway appear to be involved in the regulation of the phosphate starvation response in S. pombe. Only the most upstream genes in the PHO pathway in S. cerevisiae (ADO1, DDP1, and PPN1) share a similar role in both yeasts. Because ADO1 and DDP1 regulate ATP and IP 7 levels, we hypothesize that the ancestor of these yeasts must have sensed similar metabolites in response to phosphate starvation but have evolved distinct mechanisms in parallel to sense these metabolites and induce phosphate starvation genes.The cellular homeostasis of inorganic phosphate is required for optimal growth and efficient metabolism. The response of the model organism Saccharomyces cerevisiae to extracellular phosphate starvation is well characterized and mediated by the phosphate signal transduction (PHO) pathway (20,24). To determine whether the PHO pathway is conserved in other Ascomycota fungal species, we screened for PHO pathway mutants in the evolutionarily distantly related Schizosaccharomyces pombe, which last shared a common ancestor with S. cerevisiae more than 1 billion years ago (7).The PHO pathway in S. cerevisiae often is defined by the regulation of PHO5, which encodes a phosphate starvationregulated acid phosphatase (17,20). PHO5 is highly induced during phosphate starvation. ScPho5 activity is detected using a diazo-coupling assay with 1-napthylphosphate (9). Numerous studies have determined that PHO5 transcription is regulated by the specific transcription factors Pho4 and Pho2 and by more general chromatin remodeling complexes, such as SWI/ SNF, SAGA, and INO80 (1, 16, 31). Pho4 localization and activity is regulated by a cyclin/cyclin-dependent kinase complex (Pho81/Pho80/Pho85) (11,12,25). During high extracellular phosphate conditions, the kinase complex is active and phosphorylates Pho4, leading to nuclear exclusion and little transcription of PHO5 (10, 15). During low extracellular phosphate conditions, Pho81 inhibits the kinase complex through a noncovalent interaction with IP 7 (inositol heptakisphosphate) (18,19). Certain isomers of IP 7 increase in abundance in response to phosphate starvation, although how extracellular phosphate concentration leads to these increases is unclear. However, Vip1 is required to phosphorylate IP 6 to form 4-PP-IP 5 or 6-PP-IP 5 , and Ddp1 is required for dephosphorylation back to IP 6 (19). Increases in IP 7 during extracellular phosphate st...

Introduction: Physical examination skills are receiving less attention in curricula and clinical practice, being supplanted by imaging and other technologies. We developed an online module to introduce auscultation of common cardiac murmurs to second-year medical students. Methods: The Murmur Online Learning Experience (MOLE) curriculum focused on nine common, unique, or highly testable cardiac murmurs, chosen collaboratively by the authors. The curriculum consisted of (1) a nine-item multiple-choice pretest containing a clinical vignette, a photo of stethoscope location, and an auditory clip; (2) nine modules each containing a several-minute-long auditory clip and a written description (location, quality, radiation, change with exam maneuvers); and (3) a nine-item multiple-choice posttest, identical to the pretest but randomly ordered. All second-year medical students at the University of Louisville were given access to MOLE during their cardiovascular curriculum and given an incentive to complete the ungraded activity. Results: One hundred forty-seven (91.8%) students voluntarily completed the pretest and posttest. The mean pretest score was 3.76 out of 9 (SD = 1.77). The mean posttest score was 7.14 out of 9 (SD = 1.78). Paired t-test results demonstrated a p value of <.001. Discussion: An online murmur curriculum consisting of repetitive auditory murmurs and narrative description of murmurs improved second-year medical students' ability to correctly identify common cardiac murmurs. This method of learning murmurs via online curriculum is a practical and effective way to hone students' physical exam skills in the modern era.

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Background: Transcatheter aortic valve replacement (TAVR) has increasingly become the treatment of choice for symptomatic, severe aortic stenosis in patients at high surgical risk. While women have better morbidity & mortality outcomes following TAVR, it is unclear if there is gender disparity in utilization. We investigated gender-based utilization trends of TAVR and assessed associations with income quartiles & comorbidities. Methods: The Nationwide Inpatient Sample (NIS) data was queried from January 2012 to December 2016 to identify patients undergoing TAVR using International Classification of Diseases (ICD) procedural codes. Statistical analyses included baseline comparisons by gender, analyzing associations between gender, TAVR utilization, income & co-morbidities, with use of Chi-square test for categorical variables and Wilcoxon rank sum test for age. The associations were also analyzed using a propensity score matched subset & a logistic regression model. Results: We identified 21,859 TAVR patients (46.9% women, n=10,259). Women were older than men (median, IQR: 83, 77-87 vs 82, 76-87) and had higher prevalence of hypertension, diastolic heart failure, and pulmonary hypertension (p<0.001). Conversely diabetes, renal disease, atrial fibrillation, prior coronary angioplasty, and systolic heart failure were more prevalent in men (Table 1). TAVR utilization trend from 2012 to 2016 demonstrated a widening gap between the genders (p= 0.006) (Figure A). Median household income was associated with TAVR utilization in women in the entire cohort (p=0.028). However, in the propensity score matched subset, though heterogeniety was noted, the association was not significant per income quartile per year (Figure B). Combining data from all years, a multivariable logistic regression model confirmed that gender-based utilization did not associate with socio-economic factors such as income after adjustment for comorbidities. Conclusion: These findings showed widening utilization gap of TAVR between men and women, despite knowledge of better long-term outcomes in women. Economic factors were not associated with the gender disparity in TAVR utilization. Therefore, further research into TAVR registries is needed to analyze factors impacting this disparity and measures to correct it.

Objectives To evaluate invasive hemodynamics in assessing MC therapy success as well as evaluate its effectiveness as a predictor of functional outcomes. Background Mitral regurgitation grade is a poor predictor of functional outcomes after a MitraClip. There is a paucity of data on invasive hemodynamics as a predictor of outcomes. Methods Sixty‐nine patients underwent MC between 2015 and 2018 at the University of Minnesota Medical Center and were retrospectively analyzed. Invasive hemodynamics were performed before and after device deployment with transesophageal echocardiographic guidance. Statistical analysis was performed using STATA version 16. Student's t test was used for continuous variables and Pearson's chi‐squared test for categorical variables. Mann‐Whitney test was performed for continuous variables where data were not normally distributed. Logistic and linear regression were used to investigate relationships between variables and outcomes. Results A total of 69 patients were included in the study. The mean age was 83 (75‐87) years and 38 (55%) were male. Eighty‐one percentage had >/= NYHA III symptoms. Eighty‐seven percentage had severe MR. Pulmonary capillary wedge pressure was 20 (15‐24). Overall, there was significant improvement in left atrial pressure including mean left atrial pressure index, MR, and NYHA class after MC (<.001). There was no significant association between invasive hemodynamics (including left atrial mean pressure index or its reduction rate) and functional outcomes (p = NS). MR grade was also not predictive of functional outcomes. Conclusion Left atrial pressure may not be a significant predictor of functional outcomes, and, in isolation, may not be an improvement over MR grade.