Association Between Antithrombotic Medication Use After Bioprosthetic Aortic Valve Replacement and Outcomes in the Veterans Health Administration System

IMPORTANCE: The recommendations about antithrombotic medication use after bioprosthetic aortic valve replacement (bAVR) vary. OBJECTIVES: To describe the post-bAVR antithrombotic medication practice across the Veterans Health Administration (VHA) and to assess the association between antithrombotic strategies and post-bAVR outcomes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study. Multivariable modeling with propensity scores was conducted to adjust for differences in patient characteristics across the 3 most common antithrombotic medication strategies (aspirin plus warfarin sodium, aspirin only, and dual antiplatelets). Text mining of notes was used to identify the patients with bAVR (fiscal years 2005-2015). MAIN OUTCOMES AND MEASURES: This study used VHA and non-VHA outpatient pharmacy data and text notes to classify the following antithrombotic medications prescribed within 1 week after discharge from the bAVR hospitalization: aspirin plus warfarin, aspirin only, dual antiplatelets, no antithrombotics, other only, and warfarin only. The 90-day outcomes included all-cause mortality, thromboembolism risk, and bleeding events. Outcomes were identified using primary diagnosis codes from emergency department visits or hospital admissions. RESULTS: The cohort included 9060 veterans with bAVR at 47 facilities (mean [SD] age, 69.3 [8.8] years; 98.6% male). The number of bAVR procedures per year increased from 610 in fiscal year 2005 to 1072 in fiscal year 2015. The most commonly prescribed antithrombotic strategy was aspirin only (4240 [46.8%]), followed by aspirin plus warfarin (1638 [18.1%]), no antithrombotics (1451 [16.0%]), dual antiplatelets (1010 [11.1%]), warfarin only (439 [4.8%]), and other only (282 [3.1%]). Facility variation in antithrombotic prescription patterns was observed. During the 90-day post-bAVR period, adverse events were uncommon, including all-cause mortality in 127 (1.4%), thromboembolism risk in 142 (1.6%), and bleeding events in 149 (1.6%). No differences in 90-day mortality or thromboembolism were identified across the 3 antithrombotic medication groups in either the unadjusted or adjusted models. Patients receiving the combination of aspirin plus warfarin had higher odds of bleeding than patients receiving aspirin only in the unadjusted analysis (odds ratio, 2.58; 95% CI, 1.71-3.89) and after full risk adjustment (adjusted odds ratio, 1.92; 95% CI, 1.17-3.14). CONCLUSIONS AND RELEVANCE: These data demonstrate that bAVR procedures are increasingly being performed in VHA facilities and that aspirin only was the most commonly used antithrombotic medication strategy after bAVR. The risk-adjusted results suggest that the combination of aspirin plus warfarin does not improve either all-cause mortality or thromboembolism risk but increases the risk of bleeding events compared with aspirin only

A Tmprss2-CreERT2 Knock-In Mouse Model for Cancer Genetic Studies on Prostate and Colon.

Fusion between TMPRSS2 and ERG, placing ERG under the control of the TMPRSS2 promoter, is the most frequent genetic alteration in prostate cancer, present in 40-50% of cases. The fusion event is an early, if not initiating, event in prostate cancer, implicating the TMPRSS2-positive prostate epithelial cell as the cancer cell of origin in fusion-positive prostate cancer. To introduce genetic alterations into Tmprss2-positive cells in mice in a temporal-specific manner, we generated a Tmprss2-CreERT2 knock-in mouse. We found robust tamoxifen-dependent Cre activation in the prostate luminal cells but not basal epithelial cells, as well as epithelial cells of the bladder and gastrointestinal (GI) tract. The knock-in allele on the Tmprss2 locus does not noticeably impact prostate, bladder, or gastrointestinal function. Deletion of Pten in Tmprss2-positive cells of adult mice generated neoplasia only in the prostate, while deletion of Apc in these cells generated neoplasia only in the GI tract. These results suggest that this new Tmprss2-CreERT2 mouse model will be a useful resource for genetic studies on prostate and colon

Prostate specific activity of <i>Tmprss2-CreER</i>^<i>T2</i> mice.

<p>(a) H&E and YFP IHC of anterior prostate, dorsolateral prostate, ventral prostate in TY mice. Scale bar represents 100 μM. (b) IF stain of basal cell marker P63 with endogenous YFP and DAPI fluorescence in TY mice. Scale bar represents 20 μM. (c) IF stain of luminal cell marker Ck8 with endogenous YFP and DAPI fluorescence in TY mice. Scale bar represents 20 μM. (d) Quantitative RT-PCR analysis of basal (<i>Ck5</i>, <i>Ck14</i>, <i>P63</i>) and luminal (<i>Ck8</i>, <i>Ck18</i>) marker expression in YFP+ and YFP- epithelial cells. Basal cell markers are strongly expressed YFP- cells; luminal cell markers strongly expressed in YFP+ cells. Expression was normalized to Actin. Results are shown as mean ± SD. (e) Comparison <i>of Tmprss2-CreER</i>^<i>T2</i> with <i>Nkx3</i>.<i>1-CreER</i>^<i>T2</i> driven conversion of membrane tdTomato (mT) to membrane EGFP (mG) of the anterior prostate. Scale bar represents 50 μM. (f) Same as in (e) but in periurethral proximal prostate. These cells are tightly packed with scant cytoplasm. The white line in the <i>Nkx3</i>.<i>1-CreER</i>^<i>T2</i> mouse separates the anterior prostate from periurethral prostate. Scale bar represents 50 μM.</p

Tissue distribution of <i>Tmprss2-CreER</i>^<i>T2</i> mediated recombination.

<p>(a) RNA-seq-based expression of <i>Tmprss2</i> mRNA in human tissues from the Genotype-Tissue Expression (GTEx) project. (b) MOE430-based expression of <i>Tmprss2</i> mRNA in mouse tissues from BioGPS. (c) Table of recombination efficiency, based on YFP IHC, in tissues of TY mice after tamoxifen administration. (d) H&E and YFP IHC of bladder and colon in TY mice. Scale bars represent 100 μM.</p

Generation of the <i>Tmprss2-CreER</i>^<i>T2</i> knock-in mouse.

<p>(a) Schematic of targeting strategy. A cassette including an adenovirus splice acceptor (SA), followed by PGK-driven neomycin selection cassette flanked by FRT recombination sites, followed by the CreER^T2-IRES-nlsEGFP was used to replace exon 2 of mouse Tmprss2. The cassette is flanked by 3.5kb 5’ and 5kb 3’ homology arms. 5’ and 3’ Southern probes as was as HindIII (H) and EcoRI (E) sites and genotyping PCR primers (universal F1, wild-type specific R1, and knock-in specific R2) are depicted. The final transcript includes the non-coding exon 1 of Tmprss2 spliced into the CreER^T2-IRES-nlsEGFP gene. (b) Southern blot using 3’ probe and HindIII digestion. WT mice give a 7.5 kb band and the targeted mice (regardless of neomycin cassette) give a 8.2 kb band. (c) Southern blot using 5’ probe and EcoRI digestion. WT mice give a 9.5 kb band; the targeted mice with neomycin cassette (T) give a 9.9 kb band, while the mice with excised neomycin cassette (E) give a 9.5 kb band. (d) Genotype determination of wild-type and heterozygous mice by PCR. Wild-type fragment is 300-bp and mutant is 380-bp.</p

Tissue specific tumorigenesis of Apc deletion.

<p>(a) Characterization of Cre-mediated recombination in Tam-treated <i>Tmprss2CreER</i>^{<i>T2/ T2</i>}<i>; Apc</i>^{<i>LoxP/LoxP</i>} (TA) mice. Genomic DNA isolated from the indicated organs of a Tam-treated mouse were analyzed by PCR. The positions of the <i>Apc</i> floxed 498bp, and recombined 568bp DNA segments are indicated. (b) Gross pathology of colon of TA and wild-type mice following tamoxifen administration showing macroscopic colon polyps in tamoxifen treated mice. (c) H&E and β-catenin, Ki67 stain of TA and wild-type mouse colon. (d) H&E and β-catenin, Ki67 stain of TA and wild-type mouse prostate. Scale bars represent 100 μM.</p

Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance.

Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance

The effects of a high-energy diet on hippocampal-dependent discrimination performance and blood-brain barrier integrity differ for diet-induced obese and diet-resistant rats.

Rats that consume high-energy (HE) diets (i.e., diets high in saturated fats and sugar) show impaired hippocampal-dependent learning and memory (e.g., [1]). To further investigate this effect, we trained rats given restricted access to low-fat lab chow on hippocampal-dependent serial feature-negative (FN) and hippocampal-independent simple discrimination problems. When training was completed, Group Chow received ad libitum lab chow. The remaining rats received ad libitum HE diet. Performance on both discrimination problems was tested following 7, 14, 21 and 28 days of HE diet exposure. FN, but not simple discrimination, was abolished initially for all rats, and then re-emerged for Group Chow. For rats fed HE diet, those that weighed the least and had lowest amount of body fat (HE-diet resistant (HE-DR) rats), performed like Group Chow on both discrimination problems. However, HE diet-induced obese (HE-DIO) rats (i.e., rats that weighed the most weight and had the most body fat) performed like Group Chow on the simple discrimination problem, but were impaired throughout testing on the FN problem. Subsequent assessment of blood-brain barrier (BBB) permeability revealed that concentrations of an exogenously administered dye were elevated in the hippocampus, but not in the striatum or prefrontal cortex for HE-DIO rats relative to the HE-DR and Chow groups. The results indicate that the adverse consequences of HE diet on hippocampal-dependent cognitive functioning are associated with detrimental effects on the BBB and that both of these outcomes vary with sensitivity to HE diet-induced increases in weight and adiposity