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Little has been published on the demographic composition of the clinical and translational science research workforce within the Clinical and Translational Science Awards (CTSA) Program despite the well-documented need for greater diversity in the biomedical research workforce. Analyses of workforce demographic reveal that women and members of underrepresented groups remain persistently underrepresented in the CTSA hub and training components principal investigators. In contrast, in the CTSA Program career development and training programs, females have greater representation as participants, and non-Whites were better represented in training programs.

Abstract Introduction: Clinical and Translational Science Award (CTSA) Program hubs are well-positioned to advance dissemination and implementation (D&I) research and training capacity nationally, though little is known about what D&I research support and services CTSAs provide. To address this gap, the CTSA Dissemination, Implementation, and Knowledge Transfer Working Group conducted an environmental scan of CTSAs (2017–2018). Methods: Of 67 CTSA institutions, we contacted 43 that previously reported delivering D&I research services. D&I experts from these institutions were emailed a survey assessing D&I resources, services, training, and scientific projects. Responses were categorized and double-coded by study authors using a content analysis approach. Results: Thirty-five of the 43 D&I experts (81.4%) responded. Challenges to CTSAs in developing and supporting D&I science activities were related to inadequate D&I science workforce (45.7%) and lack of understanding of D&I science (25.7%). Services provided included consultation/mentoring programs (68%), pilot funding/grants (50%), and workshops/seminars/conferences (46%). Training and workforce development in D&I were frequently identified as future priorities. Recommendations included increase training to meet demand (68.6%), accessible D&I tools/resources (34.3%), greater visibility/awareness of D&I methods (34.3%), consultation services (22.9%), and expand D&I science workforce (22.9%). Conclusions: CTSAs have tremendous potential to support the advancement and impact of D&I science across the translational continuum. Despite the growing presence of D&I science in CTSAs, continued commitment and prioritization are needed from CTSA and institutional leadership to raise awareness of D&I science and its value, meet training demands, and develop necessary infrastructure for conducting D&I science.

Over the last year, COVID-19 has emerged as a highly transmissible and lethal infection. As we address this global pandemic, its disproportionate impact on Black, Indigenous, and Latinx communities has served to further magnify the health inequities in access and treatment that persist in our communities. These sobering realities should serve as the impetus for reexamination of the root causes of inequities in our health system. An increased commitment to strategic partnerships between academic and nonacademic health systems, industry, local communities, and policy-makers may serve as the foundation. Here, we examine the impact of the recent COVID-19 pandemic on health care inequities and propose a strategic roadmap for integration of clinical and translational research into our understanding of health inequities.

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.

Prior to the COVID pandemic, many CTSAs employed face-to-face interactions to conduct most of their community engagement (CE) activities. During the COVID pandemic, such engagement had to be curtailed and alternatives needed to be formulated. In addition, Community Engaged Research (CEnR) teams refocused their efforts to address this public health crisis. To obtain a general understanding of how CTSAs have conducted CE and CEnR during the COVID pandemic, we invited seven CTSA CE leaders to provide brief field reports of their activities during the pandemic. This included how their approaches to CE and CEnR were modified during the COVID-19 pandemic and key lessons learned. We found that despite numerous challenges, all seven CTSAs CE cores were able to successfully carry out CE and CEnR. We also found that the fundamental principles of meaningful and authentic stakeholder engagement were of paramount importance during the pandemic. Through virtual approaches, all sites had considerable success in maintaining CE in during the COVID pandemic. They also leveraged existing bi-directional community partnerships to carry out meaningful and impactful research. This included both new COVID CEnR and also innovative approaches to sustain prior non-COVID research. These findings suggest that academic-community partnerships must be fostered and sustained over the many years so that when such crises emerge, all partners can build on existing trust and mutual respect. The lessons learned and the new tools and approaches developed would be key in addressing any such future public health emergencies.

Hepatocellular carcinoma (HCC) is a malignant tumor with high recurrence and metastasis rates and poor prognosis. Basement membrane is a ubiquitous extracellular matrix and is a key physical factor in cancer metastasis. Therefore, basement membrane-related genes may be new targets for the diagnosis and treatment of HCC. We systematically analyzed the expression pattern and prognostic value of basement membrane-related genes in HCC using the TCGA-HCC dataset, and constructed a new BMRGI based on WGCNA and machine learning. We used the HCC single-cell RNA-sequencing data in GSE146115 to describe the single-cell map of HCC, analyzed the interaction between different cell types, and explored the expression of model genes in different cell types. BMRGI can accurately predict the prognosis of HCC patients and was validated in the ICGC cohort. In addition, we also explored the underlying molecular mechanisms and tumor immune infiltration in different BMRGI subgroups, and confirmed the differences in response to immunotherapy in different BMRGI subgroups based on the TIDE algorithm. Then, we assessed the sensitivity of HCC patients to common drugs. In conclusion, our study provides a theoretical basis for the selection of immunotherapy and sensitive drugs in HCC patients. Finally, we also considered CTSA as the most critical basement membrane-related gene affecting HCC progression. In vitro experiments showed that the proliferation, migration and invasion abilities of HCC cells were significantly impaired when CTSA was knocked down.

Oral cancer (ORCA) is the most prevalent histological subtype of oral malignancies in which immune modulation is relevant. The goal of this work was to employ Mendelian randomization (MR) to investigate the causal connection between the immune-related proteins MICB, CTSA, MMP9, and ORCA. The Open GWAS database of the Integrative Epidemiology Unit (IEU) was accessed to collect GWAS data for ORCA (ieu-b-4961), MICB (prot-a-1898), CTSA (prot-a-717) and MMP9 (prot-a-1921). From 372,373 samples, the ORCA dataset comprises 7,723,107 single nucleotide polymorphisms (SNPs). MICB, CTSA, and MMP9 all have 10,534,735 SNPs and 3,301 sample sizes. Then, the primary SVMR implementation approaches were weighted mode, simple mode, inverse variance weighted (IVW), weighted median, and MR-Egger. IVW was the most effective technique. A sensitivity study was also carried out to assess the correctness of SVMR data, with special focus devoted to heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO). MVMR was eventually implemented as well. A Mendelian randomization analysis of the three exposure factors in the dataset (ieu-b-94, ebi-a-GCST012237) was also performed to validate the study results. According to the SVMR results, there was a noteworthy causal interaction between ORCA and MICB ( P  = 0.0014), MMP9 ( P  = 0.0343), and CTSA ( P  = 0.0003). Furthermore, odds ratios (ORs) values revealed that MMP9 (OR = 1.0005) was an ORCA risk factor, whereas MICB (OR = 0.9994) and CTSA (OR = 0.9993) were security factors. The robustness of the SVMR findings was confirmed by the p-values of the heterogeneity and horizontal pleiotropy, both of which were greater than 0.05. The MVMR result did not affect any of the safety or hazard features of these three exposure factors. However, the P value for MMP9 was greater than 0.05, implying that MICB and CTSA may have a greater influence on ORCA than MMP9. The validation outcomes in both datasets harmonized with the findings from previous research, thereby solidifying the reliability of results. Our investigation provided a crucial resource for further research on the subject by demonstrating a causal relationship between ORCA and MICB, CTSA, and MMP9.

COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.