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Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-gamma synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.

PurposeClinicians and researchers must contextualize a patient’s genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care.MethodsThree of the nation’s leading children’s hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model.ResultsHarmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype–phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications.ConclusionsThe GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.

Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-γ synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.

We describe the implementation of an electronic medical record “hard stop” to decrease inappropriate Clostridioides difficile testing across a 5-hospital health system, effectively reducing the rates of healthcare-facility–onset C. difficile infection. This novel approach included expert consultation with medical director of infection prevention and control for test-order override.

Background: Clostridioides difficile infection (CDI) is the most common healthcare-associated infection (HAI) in the United States. Healthcare facility-onset (HO) CDI reporting is a laboratory-identified (LabID) event and does not rely on symptoms. Inappropriate testing can lead to overdiagnosis in patients who are colonized, especially in those receiving promotility agents. Approximately 45% of HO-CDI cases at our institution occurred in the setting of laxative use in 2019. We assessed the effectiveness of an electronic medical record (EMR) “hard stop” in reducing inappropriate CDI testing and its impact on HO-CDI rates. Methods: We conducted a pre–post quasi-experimental retrospective study comparing test order rates per 1,000 patient days, CDI rate per 1,000 patient days, and standardized infection ratio (SIR) in the preintervention period (January 2018–December 2019) to the intervention period (April 2020–September 2021), at a 5-hospital healthcare system in southeastern Michigan. In February 2020, we implemented a hard stop in Epic that was triggered >3 days after admission for the following criteria: patients <1 year of age; repeated testing within 7 days, and receipt of promotility agents within 48 hours. After discontinuing the promotility agents for at least 48 hours, providers were allowed to place an order if diarrhea persisted. The medical director of infection prevention and control or designee had the ability to override the hard stop when deemed necessary after reviewing the case upon provider request. All orders expired after 24 hours if a specimen was not collected. We retrospectively reviewed the number of overrides after the intervention to determine the positivity rate. Results: Our CDI rates per 1,000 patient days were 3.21 in the preintervention period and 1.48 in the postintervention period, a 54% reduction (Fig. 1). The test order rates were 119.4 in the preintervention period and 87.7 in the postintervention period, a 26.5% reduction (Fig. 2). The SIR decreased from 0.542 in the preintervention period to 0.361 in the postintervention period, a 33% reduction (95% CI, 0.54–0.82; P = .0001). After the intervention, 299 patients had an override. Of these, samples from 218 patients (72.9%) were negative, 50 orders (16.7%) were cancelled, and 28 samples (9%) were positive. Conclusions: Diagnostic stewardship, utilizing an electronic hard stop, was effective in reducing inappropriate C. difficile testing in the setting of promotility agents without delaying diagnosis of HO-CDI. This strategy combined with standard best practices can significantly reduce HO-CDI rates. Funding: None Disclosures: None