Financing U.S. Graduate Medical Education: A Policy Position Paper of the Alliance for Academic Internal Medicine and the American College of Physicians

In this position paper, the Alliance for Academic Internal Medicine and the American College of Physicians examine the state of graduate medical education (GME) financing in the United States and recent proposals to reform GME funding. They make a series of recommendations to reform the current funding system to better align GME with the needs of the nation's health care workforce. These recommendations include using Medicare GME funds to meet policy goals and to ensure an adequate supply of physicians, a proper specialty mix, and appropriate training sites; spreading the costs of financing GME across the health care system; evaluating the true cost of training a resident and establishing a single per-resident amount; increasing transparency and innovation; and ensuring that primary care residents receive training in well-functioning ambulatory settings that are financially supported for their training roles

Perception of isolated chords: Examining frequency of occurrence, instrumental timbre, acoustic descriptors and musical training

This study investigated the perception of isolated chords using a combination of experimental manipulation and exploratory analysis. Twelve types of chord (five triads and seven tetrads) were presented in two instrumental timbres (piano and organ) to listeners who rated the chords for consonance, pleasantness, stability and relaxation. Listener ratings varied by chord, by timbre, and according to musical expertise, and revealed that musicians distinguished consonance from the other variables in a way that other listeners did not. To further explain the data, a principal component analysis and linear regression examined three potential predictors of the listener ratings. First, each chord’s frequency of occurrence was obtained by counting its appearances in selected works of music. Second, listeners rated their familiarity with the instrumental timbre in which the chord was played. Third, chords were described using a set of acoustic features derived using the Timbre Toolbox and MIR Toolbox. Results of the study indicated that listeners’ ratings of both consonance and stability were influenced by the degree of musical training and knowledge of tonal hierarchy. Listeners’ ratings of pleasantness and relaxation, on the other hand, depended more on the instrumental timbre and other acoustic descriptions of the chord

Roles of the Src tyrosine kinases Lck and Fyn in regulating gammadeltaTCR signal strength.

Lck and Fyn, members of the Src family of tyrosine kinases, are key components of the alphabetaTCR-coupled signaling pathway. While it is generally accepted that both Lck and Fyn positively regulate signal transduction by the alphabetaTCR, recent studies have shown that Lck and Fyn have distinct functions in this signaling pathway, with Lck being a positive regulator and Fyn being a negative regulator of alphabetaTCR signal transduction. To determine whether Lck and Fyn also differentially regulate gammadeltaTCR signal transduction, we analyzed gammadelta T cell development and function in mice with reduced Lck or Fyn expression levels. We found that reducing Lck or Fyn levels altered the strength of the gammadeltaTCR signaling response, with low levels of Lck weakening gammadeltaTCR signal strength and low levels of Fyn augmenting gammadeltaTCR signal strength. These alterations in gammadeltaTCR signal strength had profound effects not only on alphabeta/gammadelta lineage choice, but also on gammadelta thymocyte maturation and gammadelta T cell effector function. These results indicate that the cellular levels of Lck and Fyn play a role in regulating the strength of the gammadeltaTCR signaling response at different stages in the life of the gammadelta T cell

Effect of reducing Lck or Fyn levels on αβ/γδ lineage commitment and γδ T cell development.

<p>A. Dot plots show representative CD4 versus CD8 staining profiles for WT γδTCR Tg, Lck^+/− γδTCR Tg, and Fyn^+/− γδTCR Tg thymocytes. Numbers in the quadrants represent percentage of cells in each quadrant. The mean thymus cell number ± SEM for each genotype are displayed above the respective two-color plot. B. Mean number of DN (DN γδTCR⁺; γδ lineage) and DP (αβ lineage) thymocytes in WT γδTCR Tg, Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice. Data represent at least 6 mice per genotype. C. Mean number of DN γδ T cells in the LNs of WT γδTCR Tg, Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice. Data represent at least 5 mice per genotype. In B and C, the bars represent mean ± SEM. *<i>p≤0.05</i>, #<i>p≤0.001</i>.</p

Percentage of Ki-67⁺ DN γδTCR⁺ thymocytes^a.

<p><i>^a</i>Ki-67 expression marks cells in late G₁ phase through mitosis and is used as marker of active cell cycling.</p><p>**<i>p≤0.01</i>.</p

Effect of reducing Lck or Fyn levels on polyclonal γδ T cell development.

<p>A. Demonstration of the reduction of Lck or Fyn levels in CD4⁺ thymocytes and LN cells from Lck^+/− and Fyn^+/− mice. The MFI of the i.c. levels of Lck and Fyn in CD4⁺ lineage cells from heterozygous mice are expressed as a percentage of the MFI of the i.c. levels of Lck and Fyn in CD4⁺ lineage cells from WT mice. A dashed line marks the expected 50% reduction in WT Lck and Fyn levels. B. Number of DN γδ thymocytes and LN γδ T cells in WT, Lck^+/−, and Fyn^+/− mice. Data represent at least 6 mice per genotype. C. Quantifying the reduction of Lck and Fyn expression levels in DN γδTCR⁺ thymocytes and LN cells from Lck^+/− and Fyn^+/− mice. The MFI of the i.c. levels of Lck and Fyn in γδ lineage cells from heterozygous mice are expressed as a percentage of the MFI of the i.c. levels of Lck and Fyn in γδ lineage cells from WT mice. A dashed line marks the expected 50% reduction in WT Lck and Fyn levels. D. Relative expression levels of Lck and Fyn in WT DN2 (lin⁻ CD25⁺ CD44⁺) thymocytes, where lin⁻ is defined as CD4⁻ CD8⁻ CD11b⁻ TCRβ⁻ TCRγδ⁻ CD19⁻ NK1.1⁻ IA^b− Ly6-G/Ly6-C⁻. E. Quantifying the reduction of Lck and Fyn expression levels in DN2 thymocytes from Lck^+/− and Fyn^+/− mice. The MFI of the i.c. levels of Lck and Fyn in DN2 thymocytes from heterozygous mice are expressed as a percentage of the MFI of the i.c. levels of Lck and Fyn in DN2 thymocytes from WT mice. A dashed line marks the expected 50% reduction in WT Lck and Fyn levels. In A, B, C, and E, the bars represent mean ± SEM. *<i>p≤0.05</i>, **<i>p≤0.01</i>, #<i>p≤0.001</i>.</p

Flow cytometric analysis of the intracellular levels of Lck and Fyn in γδ lineage cells.

<p>A. Histograms show representative staining of the i.c. levels of Lck and Fyn in gated populations of DP thymocytes and of thymic and LN CD4⁺ CD3⁺ and DN γδTCR⁺ cells from WT (B6) mice. Staining of cells from Lck^−/− and Fyn^−/− mice are shown as negative controls for i.c. staining of Lck and Fyn, respectively. B. Comparison of the relative expression levels of Lck and Fyn in gated DN γδTCR⁺ thymocytes and LN cells. C. Quantifying the change in the relative expression levels of Lck and Fyn in DN γδTCR⁺ thymocytes and LN cells and, for comparison, CD4⁺ CD3⁺ thymocytes and LN cells. Lck and Fyn expression levels in immature and mature subsets were normalized to those of DP thymocytes, as this population had, in every experiment, consistently lower levels of Lck and Fyn than any other thymocyte or T cell subset (see A). Data are presented as fold change relative to DP thymocytes (set to 1). Data are representative of at least 6 independent experiments. Bars represent mean ± SEM. *<i>p≤0.05</i>, **<i>p≤0.01</i>, #<i>p≤0.001</i>.</p

Phenotypic analysis of γδ lineage cells from Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice.

<p>A. Comparison of CD5 and TCRγδ surface levels on DN γδ thymocytes from WT γδTCR Tg, Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice. MFIs of CD5 and TCRγδ surface levels on DN γδ thymocytes from heterozygous mice are presented as a percentage of the MFIs of CD5 and TCRγδ surface levels on DN γδ thymocytes from WT γδTCR Tg mice. Data represent at least 6 mice per genotype. B. Percentage of CD24⁺ and CD44⁺ γδ T cells in WT γδTCR Tg, Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice. Data represent at least 3 mice per genotype. C. Comparison of CD5 and TCRγδ surface levels on DN γδ T cells from the LNs of WT γδTCR Tg, Lck^+/− γδTCR Tg and Fyn^+/− γδTCR Tg mice. MFIs of CD5 and TCRγδ surface levels on peripheral DN γδ T cells from heterozygous mice are presented as a percentage of the MFIs of CD5 and TCRγδ surface levels on peripheral DN γδ T cells from WT γδTCR Tg mice. Data represent at least 5 mice per genotype. In A, B, and C, the bars represent mean ± SEM. *<i>p≤0.05</i>, **<i>p≤0.01</i>, #<i>p≤0.001</i>.</p