Role of CTSA institutes and academic medical centers in facilitating preapproval access to investigational agents and devices during the COVID-19 pandemic.

INTRODUCTION: With no approved treatments for COVID-19 initially available, the Food and Drug Administration utilized multiple preapproval pathways to provide access to investigational agents and/or medical devices: Expanded Access, Emergency Use Authorizations, and Clinical Trials. Regulatory units within an Academic Medical Center (AMC), including those part of the Clinical and Translational Science Award (CTSA) consortium, have provided support for clinicians in navigating these options prior to the pandemic. As such, they were positioned to be a resource for accessing therapies during the COVID-19 public health emergency. METHODS: A small survey and a follow-on poll of the national Investigational New Drug (IND)/Investigational Device Exemption (IDE) Workgroup were conducted in October and December 2020 to determine whether CTSA regulatory units assisted in facilitating access to COVID-19 therapies and the extent of pandemic-related challenges these units faced. RESULTS: Fifteen survey and 21 poll responses were received, which provided insights into the demands placed on these regulatory support units due to the pandemic and the changes required to provide critical support during this and future crises. Key changes and lessons learned included the importance of regulatory knowledge to support the institutional response, the critical need for electronic submission capacity for Food and Drug Administration (FDA) documents, and the nimble reallocation of regulatory and legal resources to support patient access to investigational agents and/or medical devices during the pandemic. CONCLUSION: AMC- and CTSA-based regulatory units played a meaningful role in the COVID-19 pandemic but further unit modifications are needed for enabling more robust regulatory support in the future.

Oil Red O-positive lipid in peritoneal fluid from a horse with a rectal tear.

A 4-year-old Quarter Horse mare was presented to the Texas A&M University Veterinary Medical Teaching Hospital for evaluation of a rectal tear. On initial evaluation, rectal palpation and colonoscopy revealed a grade IIIb rectal tear. Analysis of peritoneal fluid revealed a modified transudate. Preliminary supportive care included fluid therapy and mineral oil administration via nasogastric tube. Approximately 48 hours after presentation, a second abdominocentesis was performed, and cytologic examination of the fluid revealed a marked suppurative exudate. Round clear nonrefractile material observed within neutrophils and macrophages and in the background stained bright pink to red with Oil Red O, confirming the material as lipid, likely from leakage of mineral oil through the rectal tear. The condition of the mare deteriorated and euthanasia was elected due to the poor prognosis. At necropsy, gross and histologic findings included peritoneal effusion and a full-thickness rectal tear with transmural necrotizing pyogranulomatous colitis and fibrinous peritonitis. To the authors' knowledge, this is the first reported case of Oil Red O-positive lipid vacuoles in the peritoneal fluid of a horse from presumed leakage of mineral oil through a transmural rectal perforation. The frequency of this occurrence in horses is unknown, but it is important for cytopathologists to be familiar with the appearance and significance of lipid-type droplets in phagocytic cells in cytologic fluid analysis specimens.

BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice.

In mice heterozygous for p53 (Trp53(+/-)), the incidence of mammary tumors varies among strains, with C57BL/6 being resistant and BALB/c being susceptible. Mammary tumor phenotypes were examined in female Trp53(+/-) F1 mice (C57BL/6 x BALB/c;n = 19) and N2 backcross mice [(C57BL/6 x BALB/c) x BALB/c] (n = 224). Susceptibility to mammary tumors segregated as a dominant phenotype in F1 females, but a higher frequency and shorter latency in N2 mice indicated a contribution from recessive-acting modifiers. Segregation of the hypomorphic BALB/c alleles for DNA-dependent protein kinase catalytic subunit (Prkdc) and p16(INK4A) (Cdkn2a) was analyzed in the N2 mice. The time to first tumor (considering all tumor types) was significantly different among the four genotype combinations (P = 0.01). Cdkn2a had a strong effect (P = 0.008) but was restricted to Prkdc(B/B) mice (P = 0.001), indicating a strong interaction between the loci. Differences in mammary tumor occurrence among genotypes for Prkdc and Cdkn2a in N2 mice were not statistically significant. This study indicates that BALB/c Prkdc and Cdkn2a alleles do modify tumor incidence in Trp53(+/-) mice and highlights the complexity of gene interaction effects in determining cancer phenotypes but discounts these alleles as major recessive loci contributing to spontaneous mammary tumor susceptibility.