Summary There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with a post-transplant therapy that combines immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients), and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment, and offer a potential application of the virome state to predict immunocompetence.

Despite efforts to promote diversity in the biomedical workforce, there remains a lower rate of funding of National Institutes of Health R01 applications submitted by African-American/black (AA/B) scientists relative to white scientists. To identify underlying causes of this funding gap, we analyzed six stages of the application process from 2011 to 2015 and found that disparate outcomes arise at three of the six: decision to discuss, impact score assignment, and a previously unstudied stage, topic choice. Notably, AA/B applicants tend to propose research on topics with lower award rates. These topics include research at the community and population level, as opposed to more fundamental and mechanistic investigations; the latter tend to have higher award rates. Topic choice alone accounts for over 20% of the funding gap after controlling for multiple variables, including the applicant’s prior achievements. Our findings can be used to inform interventions designed to close the funding gap.

Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga–base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.

The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.organ transplantation | cell-free DNA | infection | rejection | diagnosis

Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

It is challenging to monitor the health of transplanted organs, particularly with respect to rejection by the host immune system. Because transplanted organs have genomes that are distinct from the recipient's genome, we used high throughput shotgun sequencing to develop a universal noninvasive approach to monitoring organ health. We analyzed cell-free DNA circulating in the blood of heart transplant recipients and observed significantly increased levels of cell-free DNA from the donor genome at times when an endomyocardial biopsy independently established the presence of acute cellular rejection in these heart transplant recipients. Our results demonstrate that cell-free DNA can be used to detect an organ-specific signature that correlates with rejection, and this measurement can be made on any combination of donor and recipient. This noninvasive test holds promise for replacing the endomyocardial biopsy in heart transplant recipients and may be applicable to other solid organ transplants.next-generation sequencing | noninvasive diagnosis | acute rejection

The US biomedical research workforce does not currently mirror the nation's population demographically, despite numerous attempts to increase diversity. This imbalance is limiting the promise of our biomedical enterprise for building knowledge and improving the nation's health. Beyond ensuring fairness in scientific workforce representation, recruiting and retaining a diverse set of minds and approaches is vital to harnessing the complete intellectual capital of the nation. The complexity inherent in diversifying the research workforce underscores the need for a rigorous scientific approach, consistent with the ways we address the challenges of science discovery and translation to human health. Herein, we identify four cross-cutting diversity challenges ripe for scientific exploration and opportunity: research evidence for diversity's impact on the quality and outputs of science; evidence-based approaches to recruitment and training; individual and institutional barriers to workforce diversity; and a national strategy for eliminating barriers to career transition, with scientifically based approaches for scaling and dissemination. Evidence-based data for each of these challenges should provide an integrated, stepwise approach to programs that enhance diversity rapidly within the biomedical research workforce.diversity | scientific workforce | underrepresentation in science | culture | biomedical research