Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings.

Most literature describing pharmacogenetic implementations are within academic medical centers and use single-gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel-based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

SCID repopulating cells derived from unmobilised adult human peripheral blood.

Severe combined immunodeficient (SCID)-repopulating cells (termed SRC) with lymphohaematopoietic differentiation potential reside at an extremely low frequency in unmobilised adult human peripheral blood. Recently, an ex vivo method of increasing the relative numbers of at least four distinct human stem cell classes, that include CD34+ haematopoietic progenitor cells, in mononuclear cells (MNC) obtained from unmobilised adult human peripheral blood has been described. This process is triggered by a monoclonal antibody (mAb) against the human monomorphic region of the beta chain of HLA-DP, DQ and DR (clone CR3/43). Herein, we assess the ability of human male donor-derived MNC, following ex vivo culturing for 3 hr in haematopoietic-conducive conditions (HCC) (3-hr MNC/HCC), to form SRC in female non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. All 3-hr MNC/HCC-recipient animals exhibited significant levels (> 0.5%) of human cell engraftment in the bone marrow, thymus and spleen when compared to animals receiving MNC cultured in the absence of CR3/43. Phenotypic characterisation of the bone marrow cell populations of engrafted mice demonstrated significant levels of human lymphohaematopoietic cell lineages, comprised of T lymphocytes, monocytes, erythrocytes and megakaryocytes, including platelets. In addition, significant levels of clonogenic human CD34+ cells were also detected by in vitro surrogate assay. The thymi of engrafted animals contained maturating human thymocytes, while the spleen consisted mainly of T lymphocytes. Fluorescence in situ hybridisation (FISH) further identified the presence of human male X and Y chromosomes at engrafted sites, whilst the human origin of the cells was confirmed by a specific PCR assay for the human Cart-1 gene. In conclusion, the conversion of MNC to SRC in response to treatment with CR3/43 for 3 hr could have far-reaching clinical implications especially where time and donor-histocompatibility are limiting factors.

Delayed presentation of left ventricular outflow tract aneurysm after penetrating cardiac trauma.

We report a case of posttraumatic left ventricular outflow tract aneurysm in a patient who had a stab injury to the chest requiring emergency operation 40 years previously. After apparent decades without symptoms, the patient presented with exertional dyspnea. Clinical and echocardiographic assessment revealed aortic regurgitation and left ventricular outflow tract aneurysm. Injuries to the chest wall that penetrate the heart and great vessels are life-threatening and require emergency operative intervention. However, these injuries rarely, as in this case, result in chronic cardiac aneurysm and aortic valvular incompetence.

How long is too long? Association of time delay to successful reperfusion and ventricular function outcome in acute myocardial infarction: the case for thrombolytic therapy before planned angioplasty for acute myocardial infarction.

OBJECTIVES: The purpose of this study was to quantify the effect of time delays to reperfusion on ventricular function after myocardial infarction. This allows one to identify a group of patients in whom a strategy using antecedent pharmacologic reperfusion therapy before planned direct angioplasty may offer significant benefit. BACKGROUND: Direct angioplasty for myocardial infarction is associated with a high rate of successful reperfusion compared with pharmacologic reperfusion. However, there is an inherent time delay to treatment with angioplasty compared with pharmacologic therapy. There currently are insufficient data to determine the consequences of incremental time delays to reperfusion on ventricular function. METHODS: We determined, by logistic regression analysis, the probability of observing a decrement in postmyocardial infarction ventricular function as a function of incremental time delays to reperfusion. RESULTS: Time delays of 30, 60, 90, or 120 minutes to reperfusion increased the likelihood of a worse ventricular function outcome by 1.1-, 1.3-, 1.5-, and 1.7-fold, respectively (P <.02). The upper 95% confidence limits around these odds ratios are as high as 1.3 or 2.7 for 30- and 120-minute delays, respectively. Time from symptom onset to patency remained a significant determinant of ventricular function after adjustment for clinical and procedural factors. CONCLUSIONS: Delay in time to reperfusion, measured in minutes, results in significant loss of ventricular function after myocardial infarction. Interventional strategies designed for treatment of myocardial infarction when "door-to-balloon" time is expected to exceed 60 minutes should strongly consider incorporation of pharmacologic reperfusion therapy into the therapeutic paradigm.

Advancing Antithrombin Therapy in Acute Myocardial Infarction Management: Low Molecular Weight Heparins Plus Fibrinolysis.

Unfractionated heparin (UFH) has been traditionally used as an antithrombotic agent following fibrinolytic therapy for acute myocardial infarction. However, UFH has pharmacokinetic, biophysical, and biological limitations. Although early infarct artery patency has been superior with UFH as compared with placebo, aggregate data has demonstrated only a modest reduction in clinical events. Low molecular weight heparins (LMWHs) are attractive as potential adjunctive therapy to thrombolysis because of their greater bioavailabilty and ease of administration compared with UFH. Initial small trials with LMWHs have demonstrated their apparent safety when used in combination with thrombolytic agents, and a trend toward higher infarct-related artery patency rates. The clinical efficacy of LMWHs compared with UFH is currently being addressed in large-scale randomized clinical trials.