Quantifying the Financial Value of Clinical Specialty Choice and Its Association With Competitiveness of Admissions.

Background The factors influencing medical student clinical specialty choice have important implications for the future composition of the US physician workforce. The objective of this study was to determine the career net present values (NPVs) of US medical students' clinical specialty choices and identify any relationships between a specialty's NPV and competitiveness of admissions as measured by the US Medical Licensing Examination (USMLE) Step 1 scores. Methodology NPVs were calculated using the results of the 2019 Doximity Physician Compensation report, a survey of 90,000 physicians. Mean USMLE Step 1 scores for matched US allopathic seniors in the 2018 National Resident Matching Program were used as a measure of clinical specialties' competitiveness of admissions. We calculated a composite measure of NPV and annual work-hours by dividing each specialty's NPV by the reported average number of hours worked per year. Results In our analysis, orthopedic surgery had the highest NPV ($10,308,868), whereas family medicine had the lowest NPV ($5,274,546). Dermatology and plastic surgery had the highest mean USMLE Step 1 scores (249 for both), whereas family medicine had the lowest (220). Clinical specialties' NPVs were positively associated with mean USMLE Step 1 scores (Pearson's r = 0.82; p < 0.001). Conclusions In this study, we describe associations suggesting that medical students respond to financial incentives in choosing clinical specialties and that these decisions are mediated by USMLE Step 1 scores. This underscores the importance of titrating and aligning incentives to improve the allocation of medical students into clinical specialties.

Variability in asthma quality and costs in children with different Medicaid insurance plans in Maricopa County.

OBJECTIVE: To describe the variation in asthma quality and costs among children with different Medicaid insurance plans. METHODS: We used 2013 data from the Center for Health Information and Research, which houses a database that includes individuals who have Medicaid insurance in Arizona. We analyzed children ages 2-17 years-old who lived in Maricopa County, Arizona. Asthma medication ratio (AMR, a measure of appropriate asthma medication use), outpatient follow-up within 2 weeks after asthma-related hospitalization (a measure of continuity of care), asthma-related hospitalizations, and all emergency department (ED) visits were the primary quality metrics. Direct costs were reported in 2013 $US dollars. We used one-way analysis of variance to compare the health plans for AMR and per member cost (total, ER, and hospital), and the chi-squared test for the outpatient follow-up measure. We used coefficient of variation to identify variation of each measure across all individuals in the study. RESULTS: In 2013, 90,652 children in Maricopa County were identified as having asthma. The average patient-weighted AMR for children with persistent asthma was 0.35, well short of the goal of ≥0.70, and only 36% of hospitalized asthma patients had outpatient follow-up within 2 weeks of hospitalization. AMR, total costs, and ED costs varied significantly (p <.0001) when comparing health plans while hospital costs and outpatient follow-up showed no significant variation. CONCLUSIONS: Targeting appropriate medication use for asthma may help reduce variation, improve outcomes, and increase healthcare value for children with asthma and Medicaid insurance in the US.

Science of health care delivery as a first step to advance undergraduate medical education: A multi-institutional collaboration.

Physicians must possess knowledge and skills to address the gaps facing the US health care system. Educators advocate for reform in undergraduate medical education (UME) to align competencies with the Triple Aim. In 2014, five medical schools and one state university began collaborating on these curricular gaps. The authors report a framework for the Science of Health Care Delivery (SHCD) using six domains and highlight curricular examples from each school. They describe three challenges and strategies for success in implementing SHCD curricula. This collaboration highlights the importance of multi-institutional partnerships to accelerate innovation and adaptation of curricula.

Teamwork in health care.

It is becoming increasingly clear that maintaining and improving the health of the population, and doing so in a financially sustainable manner, requires the coordination of acute medical care with long-term care, and social support services, that is, team-based care. Despite a growing body of evidence on the benefits of team-based care, the health care ecosystem remains "resistant" to a broader implementation of such care models. This resistance is a function of both system-wide and organizational barriers, which result primarily from fragmentation in reimbursement for health care services, regulatory restrictions, and the siloed nature of health professional education. To promote the broader adoption of team-based care models, the health care system must transition to pay for value reimbursement, as well as break down the educational silos and move toward team-based and value-based education of health professionals.

Phenotypic assays for ß-amyloid in mouse embryonic stem cell-derived neurons.

Given the complex nature of Alzheimer's disease (AD), a cell-based model that recapitulates the physiological properties of the target neuronal population would be extremely valuable for discovering improved drug candidates and chemical probes to uncover disease mechanisms. We established phenotypic neuronal assays for the biogenesis and synaptic action of amyloid ß peptide (Aß) based on embryonic stem cell-derived neurons (ESNs). ESNs enriched with pyramidal neurons were robust, scalable, and amenable to a small-molecule screening assay, overcoming the apparent limitations of neuronal models derived from human pluripotent cells. Small-molecule screening of clinical compounds identified four compounds capable of reducing Aß levels in ESNs derived from the Tg2576 mouse model of AD. Our approach is therefore highly suitable for phenotypic screening in AD drug discovery and has the potential to identify therapeutic candidates with improved efficacy and safety potential.

Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3.

Amyloid ß-peptide (Aß) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aß levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aß levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aß-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aß-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aß biogenesis.

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism.

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg2+ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP2 closely correlates with 42-residue amyloid beta-peptide (Abeta42) levels. Our data suggest that PIP2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Abeta42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP2 may offer a therapeutic approach in Alzheimer's disease.

Got RIP? Presenilin-dependent intramembrane proteolysis in growth factor receptor signaling.

A number of cell surface growth factor receptors are subject to presenilin-dependent regulated intramembrane proteolysis (PS-RIP) after ligand binding and/or ectodomain cleavage. PS-RIP is mediated by a highly conserved multi-component membrane-bound protease, termed gamma-secretase, responsible for generating Alzheimer's disease (AD)-associated Abeta peptide from its membrane-bound beta-amyloid precursor protein (APP), as well as for cleaving a number of other type-I membrane receptors. PS-RIP is a conserved cellular process by which cells transmit signals from one compartment to another, including the liberation of membrane-bound transcription factors. Recent studies indicate that PS-RIP also mediates the proteolytic inactivation of heteromeric receptor complexes by removing the transmembrane domains required for receptor-receptor interaction. Thus, PS-RIP appears to regulate diverse cellular pathways either by generating soluble effectors from membrane-bound precursors, or by removing the transmembrane domain of a membrane-tethered signaling component.

Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor.

The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent gamma-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including beta-amyloid precursor protein (APP) and Notch. A small fraction of intracellular domains derived from both APP and Notch translocates to and appears to function in the nucleus, suggesting a generic role for gamma-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75NTR) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75NTR is a multifunctional type I membrane protein that promotes neurotrophin-induced neuronal survival and differentiation by forming a heteromeric co-receptor complex with the Trk receptors. Mass spectrometric analysis revealed that gamma-secretase-mediated cleavage of p75NTR occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid beta-peptide 40 (Abeta40) cleavage of APP and is topologically distinct from the major TM cleavage site of Notch 1. Size exclusion chromatography and co-immunoprecipitation analyses revealed that TrkA forms a molecular complex together with either full-length p75 or membrane-tethered C-terminal fragments. The p75-ICD was not recruited into the TrkA-containing high molecular weight complex, indicating that gamma-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that gamma-secretase-mediated p75NTR proteolysis plays a role in the formation/disassembly of the p75-TrkA receptor complex by regulating the availability of the p75 TM domain that is required for this interaction.

Gene transfer of the Caenorhabditis elegans n-3 fatty acid desaturase inhibits neuronal apoptosis.

Previous studies have shown that n-3 polyunsaturated fatty acids (PUFAs) can exert an antiapoptotic effect on neurons. The present study was designed to investigate whether the Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase (an enzyme that converts n-6 PUFAs to corresponding n-3 PUFAs) can be expressed functionally in rat cortical neurons and whether its expression can change the ratio of n-6 : n-3 fatty acids in the cell membrane and exert an effect on neuronal apoptosis. Infection of primary rat cortical cultures with Ad-fat-1 resulted in high expression of the fat-1 gene. Lipid analysis indicated a decrease in the ratio of n-6 : n-3 PUFAs from 5.9 : 1 in control cells, to 1.45 : 1 in cells expressing the n-3 fatty acid desaturase. Accordingly, the levels of prostaglandin E2, an eicosanoid derived from n-6 PUFA, were significantly lower in cells infected with Ad-fat-1 when compared with control cells. Finally, there was a significant inhibition of growth factor withdrawal-induced apoptotic cell death in neurons expressing the fat-1 gene. These results demonstrate that expression of the fat-1 gene can inhibit apoptotic cell death in neurons and suggest that the change in the n-6 : n-3 fatty acid ratio may play a key role in this protective effect.

Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells.

BACKGROUND: Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) has been found in breast cancer. However, whether or not decreased levels of functional M6P/IGF2R directly contribute to the process of carcinogenesis needs to be further verified by functional studies. METHODS: In this study, using viral and ribozyme strategies we reduced the expression of M6P/IGF2R in human breast cancer cells and then examined the effect on growth and apoptosis of these cells. RESULTS: Our results showed that infection of MCF-7 cells with the adenovirus carrying a ribozyme targeted against the M6P/IGF2R mRNA dramatically reduced the level of transcripts and the functional activity of M6P/IGF2R in these cells. Accordingly, cells treated with a ribozyme exhibited a higher growth rate and a lower apoptotic index than control cells (infected with a control vector). Furthermore, decreased expression of M6P/IGF2R enhanced IGF-II-induced proliferation and reduced cell susceptibility to TNF-induced apoptosis. CONCLUSIONS: These results suggest that M6P/IGF2R functions as a growth suppressor and its loss or mutation may contribute to development and progression of cancer. This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth.