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BACKGROUND: Noninvasive methods for surveillance of acute rejection are increasingly used in heart transplantation (HT), including donor-derived cell-free DNA (dd-cfDNA). As other cardiac biomarkers differ by sex, we hypothesized that there may be sex-specific differences in the performance of dd-cfDNA for the detection of acute rejection. The purpose of the current study was to examine patterns of dd-cfDNA seen in quiescence and acute rejection in male and female transplant recipients. METHODS: Patients enrolled in the Genomic Research Alliance for Transplantation who were ≥18 years at the time of HT were included. Rejection was defined by endomyocardial biopsy with acute cellular rejection (ACR) grade ≥2R and/or antibody-mediated rejection ≥ pAMR 1. dd-cfDNA was quantitated using shotgun sequencing. Median dd-cfDNA levels were compared between sexes during quiescence and rejection. The performance of dd-cfDNA by sex was assessed using area under the receiver operator characteristic (AUROC) curve. Allograft injury was defined as dd-cfDNA ≥0.25%. RESULTS: One hundred fifty-one unique patients (49 female, 32%) were included in the analysis with 1,119 available dd-cfDNA measurements. Baseline characteristics including demographics and comorbidities were not significantly different between sexes. During quiescence, there were no significant sex differences in median dd-cfDNA level (0.04% [IQR 0.00, 0.16] in females vs 0.03% [IQR 0.00, 0.12] in males, p = 0.22). There were no significant sex differences in median dd-cfDNA for ACR (0.33% [0.21, 0.36] in females vs 0.32% [0.21, 1.10] in males, p = 0.57). Overall, median dd-cfDNA levels were higher in antibody-mediated rejection (AMR) than ACR but did not significantly differ by sex (0.50% [IQR 0.18, 0.82] in females vs 0.63% [IQR 0.32, 1.95] in males, p = 0.51). Elevated dd-cfDNA detected ACR/AMR with an AUROC of 0.83 in females and 0.89 in males, p-value for comparison = 0.16. CONCLUSIONS: There were no significant sex differences in dd-cfDNA levels during quiescence and rejection. Performance characteristics were similar, suggesting similar diagnostic thresholds can be used in men and women for rejection surveillance.
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Ácidos Nucleicos Libres de Células , Rechazo de Injerto , Trasplante de Corazón , Donantes de Tejidos , Humanos , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Masculino , Femenino , Persona de Mediana Edad , Ácidos Nucleicos Libres de Células/sangre , Factores Sexuales , Adulto , Biomarcadores/sangre , Genómica/métodosRESUMEN
BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185â 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75â 346-337â 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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Ácidos Nucleicos Libres de Células , Insuficiencia Cardíaca , Trasplante de Corazón , Humanos , Femenino , Persona de Mediana Edad , Masculino , ADN Mitocondrial/genética , Ácidos Nucleicos Libres de Células/genética , Estudios Longitudinales , Estudios Prospectivos , Factores Raciales , Volumen Sistólico , Biomarcadores , Rechazo de Injerto/genética , Función Ventricular Izquierda , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/efectos adversos , Donantes de TejidosRESUMEN
Gender-based microaggressions have been associated with persistent disparities between women and men in academia. Little is known about the neural mechanisms underlying those often subtle and unintentional yet detrimental behaviors. Here, we assessed the neural responses to gender-based microaggressions in 28 early career faculty in medicine (N = 16 female, N = 12 male sex) using fMRI. Participants watched 33 videos of situations demonstrating gender-based microaggressions and control situations in academic medicine. Video topics had been previously identified through real-life anecdotes about microaggression from women faculty and were scripted and reenacted using professional actors. Primary voxel-wise analyses comparing group differences in activation elucidated a significant group by condition interaction in a right-lateralized cluster across the frontal (inferior and middle frontal gyri, frontal pole, precentral gyrus, postcentral gyrus) and parietal lobes (supramarginal gyrus, angular gyrus). Whereas women faculty exhibited reduced activation in these regions during the microaggression relative to the control condition, the opposite was true for men. Posthoc analyses showed that these patterns were significantly associated with the degree to which participants reported feeling judged for their gender in academic medicine. Lastly, secondary exploratory ROI analyses showed significant between-group differences in the right dorsolateral prefrontal cortex and inferior frontal gyrus. Women activated these two regions less in the microaggression condition compared to the control condition, whereas men did not. These findings indicate that the observation of gender-based microaggressions results in a specific pattern of neural reactivity in women early career faculty.
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Encéfalo , Microagresión , Humanos , Masculino , Femenino , Encéfalo/diagnóstico por imagen , Emociones/fisiología , Corteza Prefrontal , Lóbulo FrontalRESUMEN
Dr. Hannah Valantine is renowned for her work in transplantation medicine, leadership, and mentoring as well as her efforts to improve scientific workforce diversity. In this interview with Cell, she discusses her research; what Juneteenth means to her; the persistent gender, race, and ethnicity leadership gaps that exist in academic medicine; and the importance of equitable, inclusive, and diverse science.
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Tutoría , Humanos , Femenino , Universidades , Mentores , LiderazgoRESUMEN
An extensive body of research about team science provides empirical evidence that diverse teams outperform homogenous teams in creating more innovative solutions to complex problems. At the core of diverse and inclusive teams is a rich diversity of perspectives, experiences, and backgrounds that invite new questions and broaden the scope of research. Diverse perspectives are especially relevant for biomedicine, which seeks to find solutions for challenging problems affecting the human condition. It is essential that diversity and inclusion in biomedicine is prioritized as a key driver of innovation, both through the people who conduct the research and the science itself. Key questions have been articulated as important drivers for funding research: (1) Who is doing the science and who is building the tools? (2) What science and technology is being done and how? and (3) Who has access to the knowledge and benefits of scientific innovation? I will briefly review the empirical evidence supporting diversity as a powerful enhancer of the quality and outputs of research and clinical care. I offer my own research as a case study of incorporating a framework of diversity, equity, and inclusion into research that uses new emerging genomic tools for earlier and more precise diagnosis of organ transplant rejection. I will demonstrate how these same tools hold great promise for accelerating the discovery of hitherto unexplored mechanisms that drive the poor outcomes for African ancestry organ transplant recipients, which in turn will identify new diagnostics and therapeutic targets that benefit transplant recipients across all ancestries.
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Trasplante de Órganos , Humanos , Estados Unidos , GenómicaRESUMEN
BACKGROUND: Cell-free DNA (cfDNA) is a noninvasive marker of cellular injury. Its significance in pulmonary arterial hypertension (PAH) is unknown. METHODS: Plasma cfDNA was measured in 2 PAH cohorts (A, n=48; B, n=161) and controls (n=48). Data were collected for REVEAL 2.0 (Registry to Evaluate Early and Long-Term PAH Disease Management) scores and outcome determinations. Patients were divided into the following REVEAL risk groups: low (≤6), medium (7-8), and high (≥9). Total cfDNA concentrations were compared among controls and PAH risk groups by 1-way analysis of variance. Log-rank tests compared survival between cfDNA tertiles and REVEAL risk groups. Areas under the receiver operating characteristic curve were estimated from logistic regression models. A sample subset from cohort B (n=96) and controls (n=16) underwent bisulfite sequencing followed by a deconvolution algorithm to map cell-specific cfDNA methylation patterns, with concentrations compared using t tests. RESULTS: In cohort A, median (interquartile range) age was 62 years (47-71), with 75% female, and median (interquartile range) REVEAL 2.0 was 6 (4-9). In cohort B, median (interquartile range) age was 59 years (49-71), with 69% female, and median (interquartile range) REVEAL 2.0 was 7 (6-9). In both cohorts, cfDNA concentrations differed among patients with PAH of varying REVEAL risk and controls (analysis of variance P≤0.002) and were greater in the high-risk compared with the low-risk category (P≤0.002). In cohort B, death or lung transplant occurred in 14 of 54, 23 of 53, and 35 of 54 patients in the lowest, middle, and highest cfDNA tertiles, respectively. cfDNA levels stratified as tertiles (log-rank: P=0.0001) and REVEAL risk groups (log-rank: P<0.0001) each predicted transplant-free survival. The addition of cfDNA to REVEAL improved discrimination (area under the receiver operating characteristic curve, 0.72-0.78; P=0.02). Compared with controls, methylation analysis in patients with PAH revealed increased cfDNA originating from erythrocyte progenitors, neutrophils, monocytes, adipocytes, natural killer cells, vascular endothelium, and cardiac myocytes (Bonferroni adjusted P<0.05). cfDNA concentrations derived from erythrocyte progenitor cells, cardiac myocytes, and vascular endothelium were greater in patients with PAH with high-risk versus low-risk REVEAL scores (P≤0.02). CONCLUSIONS: Circulating cfDNA is elevated in patients with PAH, correlates with disease severity, and predicts worse survival. Results from cfDNA methylation analyses in patients with PAH are consistent with prevailing paradigms of disease pathogenesis.
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Ácidos Nucleicos Libres de Células , Hipertensión Arterial Pulmonar , Anciano , Biomarcadores , Ácidos Nucleicos Libres de Células/genética , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/genética , Curva ROCRESUMEN
BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.
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MicroARN Circulante , Cardiopatías , Trasplante de Corazón , MicroARNs , Anticuerpos , Biomarcadores/metabolismo , Biopsia , Femenino , Rechazo de Injerto/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Respiratory viral infection (RVI) in lung transplant recipients (LTRs) is a risk for chronic lung allograft dysfunction (CLAD). We hypothesize that donor-derived cell-free DNA (%ddcfDNA), at the time of RVI predicts CLAD progression. We followed 39 LTRs with RVI enrolled in the Genomic Research Alliance for Transplantation for 1 year. Plasma %ddcfDNA was measured by shotgun sequencing, with high %ddcfDNA as ≥1% within 7 days of RVI. We examined %ddcfDNA, spirometry, and a composite (progression/failure) of CLAD stage progression, re-transplant, and death from respiratory failure. Fifty-nine RVI episodes, 38 low and 21 high %ddcfDNA were analyzed. High %ddcfDNA subjects had a greater median %FEV1 decline at RVI (-13.83 vs. -1.83, p = .007), day 90 (-7.97 vs. 0.91, p = .04), and 365 (-20.05 vs. 1.09, p = .047), compared to those with low %ddcfDNA and experienced greater progression/failure within 365 days (52.4% vs. 21.6%, p = .01). Elevated %ddcfDNA at RVI was associated with an increased risk of progression/failure adjusting for symptoms and days post-transplant (HR = 1.11, p = .04). No difference in %FEV1 decline was seen at any time point when RVIs were grouped by histopathology result at RVI. %ddcfDNA delineates LTRs with RVI who will recover lung function and who will experience sustained decline, a utility not seen with histopathology.
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Ácidos Nucleicos Libres de Células , Trasplante de Pulmón , Trastornos Respiratorios , Virosis , Humanos , Aloinjertos , Pulmón , Trasplante de Pulmón/efectos adversos , Trasplante HomólogoRESUMEN
Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p = 0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p = 0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p = 0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p = 0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p = 0.01), which may explain the higher levels of early allograft injury.
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Rechazo de Injerto , Trasplante de Corazón , Aloinjertos , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Humanos , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Workplace harassment, particularly sexual harassment, has substantial negative implications for individuals and organizations and for scientific advancement. The National Institutes of Health (NIH) is uniquely positioned to lead the effort to prevent sexual harassment in the scientific community and mitigate its detrimental effects. Recognizing the need for benchmark data, NIH developed and validated the 2019 NIH Workplace Climate and Harassment Survey. The goal was to use best practices in survey design methods to create an instrument for rigorous assessment of harassment incidence and organizational climate predictors of sexual harassment in scientific research environments. This article summarizes the processes used to design and administer the NIH survey and provides brief descriptions of 3 products of the process developed to guide scientific institutions wishing to embark on a data-driven approach to assess and prevent harassment: a document detailing survey development and methods, a survey implementation guide, and the key findings obtained from the survey, including recommendations for interventions targeting the organizational climate at NIH and limitations of the survey. The survey identified that 1 in 5 respondents had experienced sexual harassment in the 12 months preceding their participation in the survey and that women, sexual and gender minorities, younger respondents, trainees/students, and individuals with a disability were more likely to have experienced sexual harassment. Those who had experienced sexual harassment during that period were also more likely to have experienced incivility, bullying, and intimidating behaviors in the workplace. NIH intends to use the survey findings as a quality assurance and quality improvement guide to inform future activities to prevent and address harassment across NIH.
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Acoso Sexual , Minorías Sexuales y de Género , Femenino , Humanos , Incidencia , Acoso Sexual/prevención & control , Encuestas y Cuestionarios , Lugar de TrabajoRESUMEN
BACKGROUND: Acute and chronic forms of lung allograft injury are associated with specific respiratory pathogens. Donor-derived cell free DNA (ddcfDNA) has been shown to be elevated with acute lung allograft injury and predictive of long-term outcomes. We examined the %ddcfDNA values at times of microbial isolation from bronchoalveolar lavage (BAL). METHODS: Two hundred and six BAL samples from 51 Lung Transplant Recipients (LTRs) with concurrently available plasma %ddcfDNA were analyzed along with microbiology and histopathology. Microbial species were grouped into bacterial, fungal, and viral and "higher risk" and "lower risk" cohorts based on historical association with downstream allograft dysfunction. Analyses were performed to determine pathogen category association with %ddcfDNA, independent of inter-subject variability. RESULTS: Presence of microbial isolates in BAL was not associated with elevated %ddcfDNA compared to samples without isolates. However, "higher risk" bacterial and viral microbes showed greater %ddcfDNA values than lower risk species (1.19% vs. 0.65%, p < 0.01), independent of inter-subject variability. Histopathologic abnormalities concurrent with pathogen isolation were associated with higher %ddcfDNA compared to isolation episodes with normal histopathology (medians 1.23% and 0.66%, p = 0.05). Assessments showed no evidence of correlation between histopathology or bronchoscopy indication and presence of higher risk vs. lower risk pathogens. CONCLUSION: %ddcfDNA is higher among cases of microbial isolation with concurrent abnormal histopathology and with isolation of higher risk pathogens known to increase risk of allograft dysfunction. Future studies should assess if %ddcfDNA can be used to stratify pathogens for risk of CLAD and identify pathogen associated injury prior to histopathology.
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Ácidos Nucleicos Libres de Células/análisis , Lesión Pulmonar/metabolismo , Trasplante de Pulmón/efectos adversos , Pulmón/química , Medición de Riesgo/métodos , Donantes de Tejidos , Receptores de Trasplantes , Anciano , Aloinjertos , Broncoscopía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Established in 2019, the Roundtable on Black Men and Black Women in STEM convenes a broad array of stakeholders that focus on the barriers and opportunities encountered by Black men and Black women as they navigate the pathways from K-12 and postsecondary education to careers in science, engineering, and medicine. Through meetings, public workshops, and publications, the Roundtable advances discussions that raise awareness and/or highlight promising practices for increasing the representation, retention, and inclusiveness of Black men and Black women in STEM. In keeping with the charge of the Roundtable, Roundtable leadership and leaders of the COVID-19 action group conducted an informational video in January 2021 to provide an in-depth discussion around common, justified questions in the Black community pertaining to the COVID-19 vaccine. The manuscript addresses selected questions and answers relating to the different types of COVID-19 vaccines and their development, administration, and effectiveness. Discussion focuses on addressing vaccine misconceptions, misinformation, mistrust, and hesitancy; challenges in prioritizing vaccinations in diverse populations and communities; dealing with racism in medicine and public health; optimizing communication and health education; and offering practical strategies and recommendations for improving vaccine acceptance by clinicians, health care workers, and the Black community. This manuscript summarizes the content in the YouTube video ( https://www.youtube.com/watch?v=wdEC9c48A_k ).
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Negro o Afroamericano/psicología , Vacunas contra la COVID-19 , Comunicación en Salud/métodos , COVID-19/etnología , COVID-19/prevención & control , HumanosRESUMEN
We developed genetic-epigenetic tissue mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung transplant recipients, we showed that, at 72 hr after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles, and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring, and cancer screening.