Abstract
Background:
Adequate equitable recruitment of underrepresented groups in clinical research and trials is a national problem and remains a daunting challenge to translating research ...discoveries into effective healthcare practices. Engagement, recruitment, and retention (ER&R) training programs for Clinical Research Professionals (CRPs) often focus on policies and regulations. Although some training on the importance of diversity and inclusion in clinical research participation has recently been developed, there remains a need for training that couples critical equity, diversity, and inclusion (EDI) concepts with skill development in effective recruitment and retention strategies, regulations, and best practices.
Approach and methods:
We developed the ER&R Certificate program as a holistic approach to provide Duke University CRPs the opportunity to build competency in gap areas and to increase comfort in championing equitable partnerships with clinical research participants. The thirteen core and elective courses include blended learning elements, such as e-learning and wiki journaling prompts, to facilitate meaningful discussions. Pre- and post-assessments administered to CRP program participants and their managers assessed program impact on CRP skills in ER&R tasks and comfort in equitable, diverse, and inclusive engagement of clinical research participants.
Results and discussion:
Results from the first two cohorts indicate that CRPs perceived growth in their own comfort with program learning objectives, especially those centered on participant partnership and EDI principles, and most managers witnessed growth in competence and responsibility for ER&R-related tasks. Results suggest value in offering CRPs robust training programs that integrate EDI and ER&R training.
Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address ...this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
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Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective ...management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
Abstract
In the decades since the first cannabinoids were identified by scientists, research has focused almost exclusively on the function and capacity of cannabinoids as medicines and intoxicants ...for humans and other vertebrates. Very little is known about the adaptive value of cannabinoid production, though several hypotheses have been proposed including protection from ultraviolet radiation, pathogens, and herbivores. To test the prediction that genotypes with greater concentrations of cannabinoids will have reduced herbivory, a segregating F2 population of Cannabis sativa was leveraged to conduct lab- and field-based bioassays investigating the function of cannabinoids in mediating interactions with chewing herbivores. In the field, foliar cannabinoid concentration was inversely correlated with chewing herbivore damage. On detached leaves, Trichoplusia ni larvae consumed less leaf area and grew less when feeding on leaves with greater concentrations of cannabinoids. Scanning electron and light microscopy were used to characterize variation in glandular trichome morphology. Cannabinoid-free genotypes had trichomes that appeared collapsed. To isolate cannabinoids from confounding factors, artificial insect diet was amended with cannabinoids in a range of physiologically relevant concentrations. Larvae grew less and had lower rates of survival as cannabinoid concentration increased. These results support the hypothesis that cannabinoids function in defense against chewing herbivores.
In Fall 2020, universities saw extensive transmission of SARS-CoV-2 among their populations, threatening health of the university and surrounding communities, and viability of in-person instruction. ...Here we report a case study at the University of Illinois at Urbana-Champaign, where a multimodal "SHIELD: Target, Test, and Tell" program, with other non-pharmaceutical interventions, was employed to keep classrooms and laboratories open. The program included epidemiological modeling and surveillance, fast/frequent testing using a novel low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD, and digital tools for communication and compliance. In Fall 2020, we performed >1,000,000 covidSHIELD tests, positivity rates remained low, we had zero COVID-19-related hospitalizations or deaths amongst our university community, and mortality in the surrounding Champaign County was reduced more than 4-fold relative to expected. This case study shows that fast/frequent testing and other interventions mitigated transmission of SARS-CoV-2 at a large public university.
Dexamethasone levels predict cortisol response after infant cardiopulmonary bypass Crow, Sheri S., MD; Oliver, William C., MD; Kiefer, Jamie A., PA ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
2014, January 2014, 2014-Jan, 2014-01-00, 20140101, Letnik:
147, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Objectives We sought to evaluate whether there is variability in blood dexamethasone levels after a standard 1 mg/kg dose of dexamethasone administered before infant cardiopulmonary bypass. We ...hypothesized that postoperative dexamethasone drug levels are highly variable, and that the infant stress response is related inversely to the amount of dexamethasone measured in the blood. Methods Thirty-two infants (age, ≤365 days) received 1 mg/kg of dexamethasone before cardiopulmonary bypass (CPB) initiation. Blood was analyzed for cortisol, adrenocorticotropin, and interleukin (IL)-6, IL-8, and IL-10 levels after anesthesia induction, after CPB, after intensive care unit (ICU) arrival, and 4, 8, 12, and 24 hours after surgery. Patients were grouped as high dexamethasone (≥15 μg/dL) or low dexamethasone (<15 μg/dL) based on their level at ICU arrival. Results Dexamethasone levels varied significantly between the high (n = 22) and low (n = 10) dexamethasone groups throughout the entire postoperative course and were correlated highly with cortisol response. Patients with high dexamethasone levels had postoperative cortisol levels that were lower than their pre-CPB baseline cortisol levels. Cortisol levels remained low throughout the first 24 postoperative hours even after dexamethasone levels neared zero. There were no significant differences between groups in the duration of mechanical ventilation or ICU length of stay. Conclusions Dexamethasone levels are highly variable at ICU arrival, despite standardized 1 mg/kg dosing before CPB initiation.
Background: Acute exacerbations of interstitial lung disease (AE-ILD) cause severe respiratory failure, and mortality is high despite treatment. Lung transplantation is an effective therapy for ...late-stage interstitial lung disease (ILD), but prior studies on post-transplant outcomes for patients trandsplanted in AE-ILD are conflicting. Methods: We performed a retrospective evaluation of all first-time lung transplant recipients for ILD performed at our institution between May 1, 2005, and April 1, 2019. Patients were stratified according to a published consensus definition into AE-ILD recipients, other inpatients, or outpatients. One-year survival was compared with a Cox proportional hazards model. Subset analysis was performed on those with idiopathic pulmonary fibrosis (IPF). Patients were also assessed for survival free of long-term chronic lung allograft dysfunction (CLAD). Results: We identified 717 first-time lung transplant ILD recipients: 41 inpatients in AE-ILD, 31 other inpatients, and 645 outpatients. One-year survival was 93% for AE-ILD recipients, 61% for other inpatient recipients, and 82% for outpatient recipients. Those transplanted in AE-ILD had a lower hazard of death or retransplantation compared to other inpatients (hazard ratio HR 0.16, 95% confidence interval CI 0.04-0.56) and outpatients (HR 0.29, CI 0.09-1.00). Results were similar among the subset of patients with IPF, but differences were not significant. For those transplanted during AE-ILD, rates of CLAD were not significantly different compared to other inpatients (HR 1.34, CI 0.51-3.54) or to outpatients (HR 1.05, CI 0.52-2.13). Conclusions: With careful selection, patients in AE-ILD can be transplanted and have acceptable 1-year outcomes without increased risk of long-term graft dysfunction.
Objective
Patients with juvenile‐onset systemic lupus erythematosus (JSLE) have increased atherosclerosis risk. This study investigated novel atherosclerosis progression biomarkers in the ...Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial, the largest investigator‐led randomized control trial of atorvastatin versus placebo for atherosclerosis progression in JSLE, using carotid intima‐media thickness (CIMT) as the primary outcome.
Methods
Unsupervised clustering of baseline CIMT and CIMT progression over 36 months was used to stratify patients with JSLE. Disease characteristics, cardiovascular risk scores, and baseline serum metabolome were investigated in CIMT‐stratified patients. Machine learning techniques were used to identify and validate a serum metabolomic signature of CIMT progression.
Results
Baseline CIMT stratified patients with JSLE (N = 151) into three groups with distinct high, intermediate, and low CIMT trajectories irrespective of treatment allocation, despite most patients having low cardiovascular disease risk based on recommended assessment criteria. In the placebo group (n = 60), patients with high versus low CIMT progression had higher total (P = 0.001) and low‐density lipoprotein (LDL) (P = 0.002) cholesterol levels, although within the reference range. Furthermore, a robust baseline metabolomic signature predictive of high CIMT progression was identified in the placebo arm (area under the curve, 80.7%). Patients treated with atorvastatin (n = 61) had reduced LDL cholesterol levels after 36 months, as expected; however, despite this, 36% still had high atherosclerosis progression, which was not predicted by metabolomic biomarkers, suggesting nonlipid drivers of atherosclerosis in JSLE with management implications for this subset of patients.
Conclusion
Significant baseline heterogeneity and distinct subclinical atherosclerosis progression trajectories exist in JSLE. Metabolomic signatures can predict atherosclerosis progression in some patients with JSLE with relevance for clinical trial stratification.
The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk ...factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.
IMPORTANCE: Inhaled nitric oxide (iNO) is commonly administered for selectively inhaled pulmonary vasodilation and prevention of oxidative injury after lung transplant (LT). Inhaled epoprostenol ...(iEPO) has been introduced worldwide as a cost-saving alternative to iNO without high-grade evidence for this indication. OBJECTIVE: To investigate whether the use of iEPO will lead to similar rates of severe/grade 3 primary graft dysfunction (PGD-3) after adult LT when compared with use of iNO. DESIGN, SETTING, AND PARTICIPANTS: This health system–funded, randomized, blinded (to participants, clinicians, data managers, and the statistician), parallel-designed, equivalence clinical trial included 201 adult patients who underwent single or bilateral LT between May 30, 2017, and March 21, 2020. Patients were grouped into 5 strata according to key prognostic clinical features and randomized per stratum to receive either iNO or iEPO at the time of LT via 1:1 treatment allocation. INTERVENTIONS: Treatment with iNO or iEPO initiated in the operating room before lung allograft reperfusion and administered continously until cessation criteria met in the intensive care unit (ICU). MAIN OUTCOMES AND MEASURES: The primary outcome was PGD-3 development at 24, 48, or 72 hours after LT. The primary analysis was for equivalence using a two one-sided test (TOST) procedure (90% CI) with a margin of 19% for between-group PGD-3 risk difference. Secondary outcomes included duration of mechanical ventilation, hospital and ICU lengths of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and in-hospital, 30-day, and 90-day mortality rates. An intention-to-treat analysis was performed for the primary and secondary outcomes, supplemented by per-protocol analysis for the primary outcome. RESULTS: A total of 201 randomized patients met eligibility criteria at the time of LT (129 men 64.2%). In the intention-to-treat population, 103 patients received iEPO and 98 received iNO. The primary outcome occurred in 46 of 103 patients (44.7%) in the iEPO group and 39 of 98 (39.8%) in the iNO group, leading to a risk difference of 4.9% (TOST 90% CI, –6.4% to 16.2%; P = .02 for equivalence). There were no significant between-group differences for secondary outcomes. CONCLUSIONS AND RELEVANCE: Among patients undergoing LT, use of iEPO was associated with similar risks for PGD-3 development and other postoperative outcomes compared with the use of iNO. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03081052
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