Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity.

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.

Building and implementing a quality assurance/quality improvement program for clinical research.

Background: A major goal of the Clinical and Translational Science Award programs is to build and grow clinical and translational research, including the need to ensure that study teams are educated and adhere to best clinical research practices. Objective: One of the primary objectives of the Center for Clinical and Translational Science at the University of Kentucky is to help investigators implement standard operating procedures and provide resources to conduct clinical research that is rigorous, ethical and safe. Methods: The University of Kentucky Center for Clinical and Translational Science sought to establish a Quality Assurance/Quality Improvement program for Principal Investigator (PI) initiated clinical research studies using Center for Clinical and Translational Science services. Initiated in 2011, this program's goal was to improve research design quality and from the start of the project, "find it, fix it", leading to improved PI education, without being viewed as punitive. Results: Since the initiation of our Quality Assurance/Quality Improvement program, PI acceptance has been good and we have expanded its footprint and adjusted our review style to better match the needs of our PIs. This article discusses our experiences with Quality Assurance/Quality Improvement program development and growth. Conclusion: A Quality Assurance/Quality Improvement program can be developed that is efficient, effective, educational and well accepted by all clinical research stakeholders.

Building biorepositories in the midst of a pandemic.

Biospecimen repositories play a vital role in enabling investigation of biologic mechanisms, identification of disease-related biomarkers, advances in diagnostic assays, recognition of microbial evolution, and characterization of new therapeutic targets for intervention. They rely on the complex integration of scientific need, regulatory oversight, quality control in collection, processing and tracking, and linkage to robust phenotype information. The COVID-19 pandemic amplified many of these considerations and illuminated new challenges, all while academic health centers were trying to adapt to unprecedented clinical demands and heightened research constraints not witnessed in over 100 years. The outbreak demanded rapid understanding of SARS-CoV-2 to develop diagnostics and therapeutics, prompting the immediate need for access to high quality, well-characterized COVID-19-associated biospecimens. We surveyed 60 Clinical and Translational Science Award (CTSA) hubs to better understand the strategies and barriers encountered in biobanking before and in response to the COVID-19 pandemic. Feedback revealed a major shift in biorepository model, specimen-acquisition and consent process from a combination of investigator-initiated and institutional protocols to an enterprise-serving strategy. CTSA hubs were well equipped to leverage established capacities and expertise to quickly respond to the scientific needs of this crisis through support of institutional approaches in biorepository management.

Informed consent: Old and new challenges in the context of the COVID-19 pandemic.

In this paper, we address how the COVID-19 pandemic has impacted informed consent for clinical research through examining experiences within Clinical and Translation Science Award (CTSA) institutions. We begin with a brief overview of informed consent and the challenges that existed prior to COVID-19. Then, we discuss how informed consent processes were modified or changed to address the pandemic, consider what lessons were learned, and present research and policy steps to prepare for future research and public health crises. The experiences and challenges for CTSA institutions offer an important perspective for examining what we have learned about informed consent and determining the next steps for improving the consent process.

Creation of an institutional semi-independent data monitoring committee.

BACKGROUND: A major goal of the National Institutes of Health's Clinical and Translational Science Award program is to facilitate clinical research and enhance the transition of basic to clinical research. As such, a number of Clinical and Translational Science Award centers have developed services to facilitate the conduct of clinical research, including support with fulfilling regulatory requirements. METHODS: The University of Kentucky sought to establish an institutional semi-independent monitoring committee to provide oversight for clinical research studies per National Institutes of Health requirements and recommendations. Our semi-independent monitoring committee was initiated in 2010. RESULTS: Since the inception of our semi-independent monitoring committee we have restructured its operations and protocols to improve efficiency. This article discusses our experiences with semi-independent monitoring committee creation and growth. CONCLUSION: This article summarizes our experience in creating and maturing an institutional data monitoring committee.

Impact of language barrier on acute care medical professionals is dependent upon role.

Communication with patients is essential to providing quality medical care. The study was conducted to evaluate the effects of language barriers on health care professionals. It is hypothesized that these language barriers are commonly perceived by health care professionals and they are a source of workplace stress in acute care environments. We designed and distributed a survey tool of staff experiences and attitudes regarding the English-Spanish language barrier among patients in an acute care surgical environment of a tertiary medical center. Responses were anonymous, stratified by professional role and comparisons made using paired t tests. Sixty-one nurses and 36 physicians responded to the survey. Overall, 95% of nurses reported that the language barrier was an impediment to quality care, whereas 88% of physicians responded similarly (P = .0004). More nurses than physicians report experiencing stress (97% vs. 78%) and the degree of stress appears to be greater for nurses (P < .0001). The basis of stress was unique between the two groups. This study demonstrates that acute care hospital medical professionals perceive language barriers as an impediment to quality care delivery and as a source of workplace stress. Nurse and physician perceptions differ; therefore, strategies to address these language barriers should be specific to those professional roles. These barriers create a void in health care quality and safety that has effects on health care professionals.