H. Valantine

National Institutes of Health addresses the science of diversity

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.

Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma.

Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100u2009bp nuclear genomic cfDNA (p 10−5, Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10−5) and microbial cfDNA (71.3x, p 10−5). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.

From the NIH: A Systems Approach to Increasing the Diversity of the Biomedical Research Workforce

The National Institutes of Health presents a systems approach to developing and sustaining a diverse biomedical workforce through interventions that promote successful transitions from training to career independence.

Teaching Corporate in College

By applying the strengths of corporate models for effective teamwork, academic scientists can drive transdisciplinary research and accelerate biomedical translation. By applying the strengths of corporate models for effective teamwork, academic scientists can drive transdisciplinary research and accelerate biomedical translation.

Towards Equity in Health: Researchers Take Stock.

For the 2016 end-of-the-year editorial, the PLOS Medicine editors asked 7 global health leaders to discuss developments relevant to the equitable provision of medical care to all populations. The result is a collection of expert views on ethical trial design, research during outbreaks, high-burden infectious diseases, diversity in research and protection of migrants.

Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

BACKGROUNDnObservational studies suggest that cell-free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury.nnnMETHODSnGenetically modified pig donor hearts were heterotopically transplanted into baboons (n = 7). Cell-free DNA was extracted from pre-transplant and post-transplant baboon plasma samples for shotgun sequencing. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads.nnnRESULTSnThe xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels.nnnCONCLUSIONnCross-species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

Pulled in Too Many Directions: The Causes and Consequences of Work-Work Conflict:

Previous research has documented the influence of overwork and inflexible hours on work-life conflict for working professionals. In this paper, we build on this literature and explore the novel theoretical concept of work-work conflict, a form of inter-role conflict analogous to work-life conflict. Drawing on 48 in-depth interviews with 42 physicians and survey data of 60 faculty at a prominent west-coast academic medical center, we find that work-work conflict is fueled by institutional structural characteristics. Institutional incentives, the extent of recognition for various work activities, and financial rewards are misaligned, causing physicians to experience competing demands across multiple organizational missions (research, teaching, clinical care, and administration/service). Other industries may face similar conditions leading to work-work conflict. We conclude that work-life interventions are necessary but not sufficient to increase employee satisfaction, and that mechanisms to alleviate work-work conflict must be incorporated in practical solutions to address burnout.

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis

BACKGROUNDnAntibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.nnnMETHODSnWe adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs.nnnRESULTSnCompared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.nnnCONCLUSIONnDiagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.

Advancing the Progress of Mentoring for Diversity in AIDS Research: Warming the Mentoring Climate

There is no doubt that in 2016, after many years of attempts to diversify the U.S. biomedical workforce, we are not yet there. Currently, the nation’s biomedical workforce of researchers, physicians, and public health professionals does not mirror our nation’s demographic diversity. A workforce lacking in diversity is especially troubling for disease areas such as HIV/AIDS that disproportionately affect underserved populations. For example, according to the U.S. Centers for Disease Control and Prevention, the greatest number of new HIV infections among gay, bisexual, and other men who have sex with men (MSM) occurred in young black/African American MSM 13–24xa0years old. By race, blacks/African Americans face the most severe burden of HIV.