An FBN1 deep intronic variant is associated with pseudoexon formation and a variable Marfan phenotype in a five generation family.

Exome sequencing of genes associated with heritable thoracic aortic disease (HTAD) failed to identify a pathogenic variant in a large family with Marfan syndrome (MFS). A genome-wide linkage analysis for thoracic aortic disease identified a peak at 15q21.1, and genome sequencing identified a novel deep intronic FBN1 variant that segregated with thoracic aortic disease in the family (LOD score 2.7) and was predicted to alter splicing. RT-PCR and bulk RNA sequencing of RNA harvested from fibroblasts explanted from the affected proband revealed an insertion of a pseudoexon between exons 13 and 14 of the FBN1 transcript, predicted to lead to nonsense mediated decay (NMD). Treating the fibroblasts with an NMD inhibitor, cycloheximide, greatly improved the detection of the pseudoexon-containing transcript. Family members with the FBN1 variant had later onset aortic events and fewer MFS systemic features than typical for individuals with haploinsufficiency of FBN1. Variable penetrance of the phenotype and negative genetic testing in MFS families should raise the possibility of deep intronic FBN1 variants and the need for additional molecular studies.

Pharmacological thromboembolic prophylaxis for medical patients in a tertiary care, teaching community hospital: room for improvement.

Venous Thrombembolism (VTE) is a potentially lethal complication in hospitalized patients. Studies indicate that pharmacological prophylaxis may reduce the incidence of VTE. However, the use of VTE prophylaxis remains unclear. We aimed to retrospectively assess whether medically ill hospitalized patients with established risk factors receive pharmacological VTE prophylaxis in our 912-bed community-based tertiary care teaching hospital between 1997 and 2003. We randomly selected a sample of 350 medically ill (non surgical) hospitalized patients with risk factors for VTE. A total of 164 of 321 patients (51.1%) received pharmacological VTE prophylaxis. Patients with a platelet count of greater than or equal to 278 K/cu mm, a weight of 146 to 184 lbs, or a weight > or = 185 lbs were found more likely to receive prophylaxis. Patients with cancer as well as other diagnoses (compared to MI patients) were less likely to receive prophylaxis. We conclude that there continues to be a significant underutilization of VTE prophylaxis in this patient population. Strategies for identifying patients at risk for VTE and implementing appropriate protocols to ensure that these patients receive prophylaxis are necessary.

Comprehensive hospital care improvement strategies reduce time to treatment in ST-elevation acute myocardial infarction.

BACKGROUND: Delay in treatment of patients with ST-elevation acute myocardial infarction (STEMI) has an adverse effect on patient outcomes. Limited data are available on the effectiveness of hospital care improvement strategies (HCIS) to reduce time to reperfusion by percutaneous coronary intervention (PCI). This study evaluated the combined effect of HCIS implementation to reduce door-to-balloon time in patients with STEMI. METHODS: Retrospective chart review was done for 95 consecutive patients with STEMI who underwent PCI at Charleston Area Medical Center. Patients with non-STEMI and patients transferred from other medical centers were excluded. Door-to-balloon time was defined as time from emergency department arrival to first PCI balloon inflation. A program of 3 HCIS was implemented: 1) a fast-track catheterization laboratory protocol, 2) feedback to cardiologists on their treatment times, and 3) a weekday 24-hour inhouse catheterization laboratory team. Patients were separated into groups before (n = 46), during (n = 18), and after (n = 31) HCIS implementation. RESULTS: Mean age was 60.3 +/- 13 years and 74% were male. The majority (64%) arrived by ambulance; 29% had a prehospital electrocardiogram done. Most patients presented during the day (68%) on weekdays (75%). Symptom onset-to-door time was 289 +/- 393 minutes. No significant differences were found between the groups for these variables. Door-to-PCI time in minutes was reduced in the group after versus the group before HCIS implementation (94.3 +/- 37 vs 133.5 +/- 53; P < 0.0001). CONCLUSION: Implementation of HCIS shortened door-to-PCI time for patients with STEMI by 39.2 +/- 10 minutes. Thus, HCIS may be effective in improving patient outcomes.