A retrospective cost analysis of the frequency and cost of transfusion premedications.

BACKGROUND: Acetaminophen and diphenhydramine are routinely administered to prevent febrile non-hemolytic and allergic blood transfusion reactions despite multiple randomized controlled trials demonstrating that this practice lacks efficacy. As a result, patients are exposed to the adverse effects of these medications and their financial burdens with no expected benefit. The aim of this study was to quantify the frequency and cost of transfusion premedications in patients with acute myeloid leukemia (AML). STUDY DESIGN AND METHODS: This was a retrospective study of patients with AML admitted to Vanderbilt University Medical Center (VUMC) for induction chemotherapy between January 2008 and December 2016. Data were collected on the number of platelet and packed red blood cell (PRBC) transfusions each patient received during the initial inpatient encounter for AML, as well as on the administration of premedications prior to each transfusion. RESULTS: During the 9-year study period, 948 AML patients received a total of 19,820 transfusions. Of these, 30% were preceded by oral diphenhydramine, 8% by intravenous diphenhydramine, and 39% by oral acetaminophen. The percentage of patients that received a transfusion preceded by a premedication increased over the study period (p = 0.03), as did the percentage of transfusions preceded by a premedication (p = 0.02). The total unadjusted cost of pre-transfusion medications to the institution during the study period was $50,309.77, or $52.67 per patient with AML. The cost of premedications per patient did not increase over the study period (p = .45). CONCLUSIONS: Routine transfusion premedication administration is common in AML patients and not well-supported by available evidence.

Wnt/ß-catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration.

The Wnt/ß-catenin pathway is an evolutionarily conserved set of signals with critical roles in embryonic and neonatal development across species. In mammals the pathway is quiescent in many organs. It is reactivated in response to injury and is reported to play complex and contrasting roles in promoting regeneration and fibrosis. We review the current understanding of the role of the Wnt/ß-catenin pathway in injury of various mammalian organs and discuss the current advances and potential of Wnt inhibitory therapeutics toward promoting tissue regeneration and reducing fibrosis.-Bastakoty, D., Young, P. P. Wnt/ß-catenin pathway in tissue injury: roles in pathology and therapeutic opportunities for regeneration.

Inhibition of Wnt/ß-catenin pathway promotes regenerative repair of cutaneous and cartilage injury.

Wound healing in mammals is a fibrotic process. The mechanisms driving fibrotic (as opposed to regenerative) repair are poorly understood. Herein we report that therapeutic Wnt inhibition with topical application of small-molecule Wnt inhibitors can reduce fibrosis and promote regenerative cutaneous wound repair. In the naturally stented model of ear punch injury, we found that Wnt/ß-catenin pathway is activated most notably in the dermis of the wound bed early (d 2) after injury and subsides to baseline levels by d10. Topical application of either of 2 mechanistically distinct small-molecule Wnt pathway inhibitors (a tankyrase inhibitor, XAV-939, and the U.S. Food and Drug Administration-approved casein kinase activator, pyrvinium) in C57Bl/6J mice resulted in significantly increased rates of wound closure (72.3 ± 14.7% with XAV-939; and 52.1 ± 20.9% with pyrvinium) compared with contralateral controls (38.1 ± 23.0 and 40.4.± 16.7%, respectively). Histologically, Wnt inhibition reduced fibrosis as measured by α-smooth muscle actin positive myofibroblasts and collagen type I α1 synthesis. Wnt inhibition also restored skin architecture including adnexal structures in ear wounds and dermal-epidermal junction with rete pegs in excisional wounds. Additionally, in ear punch injury Wnt inhibitor treatment enabled regeneration of auricular cartilage. Our study shows that pharmacologic Wnt inhibition holds therapeutic utility for regenerative repair of cutaneous wounds.

Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice.

Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS has both, a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA class II haplotypes such as DR2/DQ6, DR3/DQ2, and DR4/DQ8 show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP(91-110) induced experimental autoimmune encephalomyelitis (EAE), while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL-17. Further, we have observed that myelin-specific antibodies play an important role in PLP(91-110) induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS.

Resilience of clinical text de-identified with "hiding in plain sight" to hostile reidentification attacks by human readers.

OBJECTIVE: Effective, scalable de-identification of personally identifying information (PII) for information-rich clinical text is critical to support secondary use, but no method is 100% effective. The hiding-in-plain-sight (HIPS) approach attempts to solve this "residual PII problem." HIPS replaces PII tagged by a de-identification system with realistic but fictitious (resynthesized) content, making it harder to detect remaining unredacted PII. MATERIALS AND METHODS: Using 2000 representative clinical documents from 2 healthcare settings (4000 total), we used a novel method to generate 2 de-identified 100-document corpora (200 documents total) in which PII tagged by a typical automated machine-learned tagger was replaced by HIPS-resynthesized content. Four readers conducted aggressive reidentification attacks to isolate leaked PII: 2 readers from within the originating institution and 2 external readers. RESULTS: Overall, mean recall of leaked PII was 26.8% and mean precision was 37.2%. Mean recall was 9% (mean precision = 37%) for patient ages, 32% (mean precision = 26%) for dates, 25% (mean precision = 37%) for doctor names, 45% (mean precision = 55%) for organization names, and 23% (mean precision = 57%) for patient names. Recall was 32% (precision = 40%) for internal and 22% (precision =33%) for external readers. DISCUSSION AND CONCLUSIONS: Approximately 70% of leaked PII "hiding" in a corpus de-identified with HIPS resynthesis is resilient to detection by human readers in a realistic, aggressive reidentification attack scenario-more than double the rate reported in previous studies but less than the rate reported for an attack assisted by machine learning methods.

Temporary, Systemic Inhibition of the WNT/ß-Catenin Pathway promotes Regenerative Cardiac Repair following Myocardial Infarct.

AIMS: The WNT/ß-catenin pathway is temporarily activated in the heart following myocardial infarction (MI). Despite data from genetic models indicating both positive and negative roles for the WNT pathway depending on the model used, the effect of therapeutic inhibition of WNT pathway on post-injury outcome and the cellular mediators involved are not completely understood. Using a newly available, small molecule, GNF-6231, which averts WNT pathway activation by blocking secretion of all WNT ligands, we sought to investigate whether therapeutic inhibition of the WNT pathway temporarily after infarct can mitigate post injury cardiac dysfunction and fibrosis and the cellular mechanisms responsible for the effects. METHODS AND RESULTS: Pharmacologic inhibition of the WNT pathway by post-MI intravenous injection of GNF-6231 in C57Bl/6 mice significantly reduced the decline in cardiac function (Fractional Shortening at day 30: 38.71 ± 4.13% in GNF-6231 treated vs. 34.89 ± 4.86% in vehicle-treated), prevented adverse cardiac remodeling, and reduced infarct size (9.07 ± 3.98% vs. 17.18 ± 4.97%). WNT inhibition augmented proliferation of interstitial cells, particularly in the distal myocardium, inhibited apoptosis of cardiomyocytes, and reduced myofibroblast proliferation in the peri-infarct region. In vitro studies showed that WNT inhibition increased proliferation of Sca1+ cardiac progenitors, improved survival of cardiomyocytes, and inhibited collagen I synthesis by cardiac myofibroblasts. CONCLUSION: Systemic, temporary pharmacologic inhibition of the WNT pathway using an orally bioavailable drug immediately following MI resulted in improved function, reduced adverse remodeling and reduced infarct size in mice. Therapeutic WNT inhibition affected multiple aspects of infarct repair: it promoted proliferation of cardiac progenitors and other interstitial cells, inhibited myofibroblast proliferation, improved cardiomyocyte survival, and reduced collagen I gene expression by myofibroblasts. Our data point to a promising role for WNT inhibitory therapeutics as a new class of drugs to drive post-MI repair and prevent heart failure.

Human mesenchymal stromal cells: identifying assays to predict potency for therapeutic selection.

Multipotent mesenchymal stromal cells (MSCs) have the potential to repair and regenerate damaged tissues, making them attractive candidates for cell-based therapies. To maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used. Our goal was to identify feasible and reproducible in vitro assays to predict MSC potency. We generated cell lines from 10 normal human bone marrow samples and used the International Society for Cellular Therapy's minimal criteria to define them as MSCs: plastic adherence, appropriate surface marker expression, and trilineage differentiation. Each MSC line was further characterized by its growth, proliferation, and viability as determined by cell count, bromodeoxyuridine incorporation, and cellular ATP levels, respectively. To determine whether these tests reliably predict the therapeutic aptitude of the MSCs, several lines were implanted in vivo to examine their capacity to engraft and form granulation tissue in a well-established murine wound model using polyvinyl alcohol sponges. Long-term engraftment of MSCs in the sponges was quantified through the presence of the human-specific Alu gene in sponge sections. Sections were also stained for proliferating cells, vascularity, and granulation tissue formation to determine successful engraftment and repair. We found that high performance in a combination of the in vitro tests accurately predicted which lines functioned well in vivo. These findings suggest that reliable and reproducible in vitro assays may be used to measure the functional potential of MSCs for therapeutic use.