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BACKGROUND. Features of consumptive coagulopathy and thromboinflammation are prominent in cerebral malaria (CM). We hypothesized that thrombogenic autoantibodies contribute to a procoagulant state in CM. METHODS. Plasma from children with uncomplicated malaria (UM) (n = 124) and CM (n = 136) was analyzed by ELISA for a panel of 8 autoantibodies including anti-platelet factor 4/polyanion (anti-PF4/P), anti-phospholipid, anti-phosphatidylserine, anti-myeloperoxidase, anti-proteinase 3, anti-dsDNA, anti-[beta]-2- glycoprotein I, and anti-cardiolipin. Plasma samples from individuals with nonmalarial coma (NMC) (n = 49) and healthy controls (HCs) (n = 56) were assayed for comparison. Associations with clinical and immune biomarkers were determined using univariate and logistic regression analyses. RESULTS. Median anti-PF4/P and anti-PS IgG levels were elevated in individuals with malaria infection relative to levels in HCs (P < 0.001) and patients with NMC (PF4/P: P < 0.001). Anti-PF4/P IgG levels were elevated in children with CM (median = 0.27, IQR: 0.19-0.41) compared with those with UM (median = 0.19, IQR: 0.14-0.22, P < 0.0001). Anti-PS IgG levels did not differ between patients with UM and those with CM (P = 0.39). When patients with CM were stratified by malaria retinopathy (Ret) status, the levels of anti-PF4/P IgG correlated negatively with the peripheral platelet count in patients with [Ret.sup.+] CM (Spearman's rho [[R.sub.s]] = 0.201, P = 0.04) and associated positively with mortality (OR = 15.2, 95% CI: 1.02-275, P = 0.048). Plasma from patients with CM induced greater platelet activation in an ex vivo assay relative to plasma from patients with UM (P = 0.02), and the observed platelet activation was associated with anti-PF4/P IgG levels ([R.sub.s]= 0.293, P = 0.035). CONCLUSIONS. Thrombosis mediated by elevated anti-PF4/P autoantibodies may be one mechanism contributing to the clinical complications of CM., Introduction Immunothrombosis is a host defense mechanism where the innate and adaptive immune systems work in conjunction with the hemostatic system (platelets and endothelial cells) to control infection (1). Although [...]

Youth referred to mentoring programs vary considerably in the range and severity of difficulties (i.e., behavioral, internalizing, social and academic) and environmental challenges they face. However, their patterns of risk and corresponding consequences for mentoring have rarely been investigated. This study draws on data for youth participants in 30 mentoring programs (n = 2,165, 55.1% females) to examine patterns of presenting challenges. Four profiles emerged using three-step latent profile analyses. Profiles with more intensive symptoms were associated with more environmental stressors. Moreover, there were significant differences between profiles in youth-perceived relationship attributes, including closeness, youth-centeredness, growth focus and mentor-mentee relational health. The profile with the highest externalizing and social challenge indicators scored the lowest across these four relational indices. The results highlight variability of youth risk at baseline, and its differential impact on mentoring relationship outcomes. Implications for mentoring programs are discussed.

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.

The National Institutes of Health (NIH) established the Building University Infrastructure Leading to Diversity (BUILD) initiative to increase engagement and retention of undergraduates from diverse backgrounds in biomedical research. Portland State University, in partnership with ten other academic institutions, received a BUILD award and developed the BUILD EXITO (Enhancing Cross-Disciplinary Infrastructure and Training at Oregon) project. The EXITO program offers a three-year research and mentorship experience for undergraduates in biomedical, behavioral, social science, clinical,and bioengineering disciplines. The BUILD initiative also emphasizes enhancing research capacity and infrastructure through institutional change and faculty development. A key piece of EXITO's program to enhance research capacity is offering faculty an opportunity to apply for up to $50,000 of funding to carry out a one-year pilot study. We conducted two separate RFAs for this purpose, closely modeled on NIH's Small Grant Program (R03),over two years. Principal Investigators of pilot projects were encouraged to include EXITO students, or other undergraduate students, on their research teams. Students then worked on these research projects as part of EXITO's intensive mentored research program. This paper reports on methods to conduct and implement a pilot project program intended to train primarily junior faculty members to write and submit an NIH proposal and fund successful applicants to gather pilot project data to aid in applying for future proposals. We provided a step-by-step rigorous submission and review process. We provided proposal writing and revising workshops, technical support, and helped pilot project Principal Investigators (PIs)with biosketches, IRB applications, IUCUC documents, budgets, and other proposal sections.We secured at least three external (not at any BUILD EXITO institution) reviewers for each proposal. PIs revised proposals before resubmitting and receiving their final scores.Across two RFAs, we provided funds to twenty PIs to conduct pilot projects; these projects included at least 21 students working on them who received mentoring in research methods and in disseminating results. This paper describes important lessons learned, including the importance of: allotting sufficient time to recruit reviewers; recruiting reviewers through a variety of sources and methods; and assisting PIs in engaging with research administration staff at Portland State University and partner institutions. Challenges included: finding an optimal timeline that was neither too compressed nor too stretched out; encouraging applicants from distant partner institutions to apply and keeping them engaged and retained through the entire process; and assisting PIs from partner institutions to efficiently utilize Portland State University's sponsored projects department if similar resources were not available at their home institutions. Our goal is to provide guidance and insights to faculty and research-administration staff at other institutions interested in replicating or adapting EXITO's program to enhance institutional research capacity.

BackgroundAlthough inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment per risk stratification models remains unclear.Research questionAre inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes?Study design and methodsWe conducted secondary analyses of Long-term Oxygen Treatment Trial (LOTT) data. The trial enrolled patients with COPD with moderate resting or exertional hypoxemia between 2009 and 2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary composite outcome was time to death or first hospitalization for COPD. Additional outcomes included individual components of the composite outcome and time to first exacerbation. We generated multivariable Cox proportional hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for time to event outcomes. We adjusted models a priori for potential confounders, clustered by site.ResultsThe trial enrolled 738 patients (73.4% men; mean age, 68.8 years). Of the patients, 571 (77.4%) were low risk for future exacerbations. Of the patients, 233 (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During a 2.3-year median follow-up, 332 patients (44.9%) experienced the composite outcome. We found no difference in time to composite outcome or death among patients reporting regimens aligning with recommendations compared with undertreated patients. Among patients at low risk, potential overtreatment was associated with higher exacerbation risk (hazard ratio, 1.42; 95% CI, 1.09-1.87), whereas inhaled corticosteroid treatment was associated with 64% higher risk of pneumonia (incidence rate ratio, 1.64; 95% CI, 1.01-2.66).InterpretationAmong patients with COPD with moderate hypoxemia, we found no difference in clinical outcomes between inhaled regimens aligning with the 2017 GOLD strategy compared with those that were undertreated. These findings suggest the need to reevaluate the effectiveness of risk stratification model-based inhaled treatment strategies.