Donor-Advised Funds and the Shifting Charitable Landscape: Why Congress Must Respond

In recent years, donor-advised funds (DAFs), historically a relatively minor part of American philanthropy, have taken on an outsized importance. The dramatic growth of donor-advised funds has been driven not only by the inherent attractiveness of DAFs, but also by the profit margins of the financial services industry and the donors’ financial advisors. As more and more money rushes into DAFs – as of 2013, roughly 7% of all charitable gifts from individuals – the operating nonprofits that supposedly are the beneficiaries of donor-advised funds are losing out. At a time of higher demand for services and reduced funding, nonprofits are looking to individual donors for financial support, but increasingly donors are diverting their gifts into DAFs. This might be acceptable if DAFs were inspiring increased charitable giving, but there is little evidence to support that claim. And, because there is no mandated spend-down requirement, far more money is flowing into donor-advised funds than is flowing out into the charitable community. Wise public policy demands that Congress act to mandate an account-by-account spend-down of donor-advised funds within 15 to 20 years of the date of donation, and to prohibit private foundations from meeting their 5% distribution requirement through grants to DAFs

The Impact of State Dependent Coverage Expansions on Young Adult Insurance Status: Further Analysis

Outlines how state initiatives to expand dependent coverage affected young adults' rates of uninsurance and of employer-sponsored coverage. Considers differential time effects and implications for national reform provisions to expand coverage to age 26

Dependent Coverage Expansions: Estimating the Impact of Current State Policies

Presents preliminary findings on common provisions in state regulations of dependent health coverage and discusses the analytic approach to estimating the impact of state policy changes on young adults

The Newtonian Limit for Asymptotically Flat Solutions of the Vlasov-Einstein System

It is shown that there exist families of asymptotically flat solutions of the Einstein equations coupled to the Vlasov equation describing a collisionless gas which have a Newtonian limit. These are sufficiently general to confirm that for this matter model as many families of this type exist as would be expected on the basis of physical intuition. A central role in the proof is played by energy estimates in unweighted Sobolev spaces for a wave equation satisfied by the second fundamental form of a maximal foliation.Comment: 24 pages, plain TE

Magnetic Resonance Imaging as a Predictor of Pathologic Response in Patients Treated with Neoadjuvant Systemic Treatment for Operable Breast Cancer (TBCRC 017)

Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer has prompted interest in whether patients with pCR can be identified preoperatively and potentially spared the morbidity of surgery. This multicenter retrospective study was performed to estimate the accuracy of preoperative MRI in predicting pCR in the breast

Consumer Bankruptcy Update

Materials from the Consumer Bankruptcy Update presentations held by UK/CLE in December 2000

CHD7 and Runx1 interaction provides a braking mechanism for hematopoietic differentiation.

Hematopoietic stem and progenitor cell (HSPC) formation and lineage differentiation involve gene expression programs orchestrated by transcription factors and epigenetic regulators. Genetic disruption of the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7) expanded phenotypic HSPCs, erythroid, and myeloid lineages in zebrafish and mouse embryos. CHD7 acts to suppress hematopoietic differentiation. Binding motifs for RUNX and other hematopoietic transcription factors are enriched at sites occupied by CHD7, and decreased RUNX1 occupancy correlated with loss of CHD7 localization. CHD7 physically interacts with RUNX1 and suppresses RUNX1-induced expansion of HSPCs during development through modulation of RUNX1 activity. Consequently, the RUNX1:CHD7 axis provides proper timing and function of HSPCs as they emerge during hematopoietic development or mature in adults, representing a distinct and evolutionarily conserved control mechanism to ensure accurate hematopoietic lineage differentiation.Bloodwise, CRUK, MRC, Wellcome Trust, NIH, Leukemia and Lymphoma Societ

A Deep Catalogue of Protein-Coding Variation in 983,578 Individuals

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser

The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. We found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mammalian target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E–binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in <i>RUNX1</i>, <i>GATA2</i>, and <i>DDX41</i>

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted