Publications

INTRODUCTION

People with α1-antitrypsin deficiency are at increased risk for the development of chronic obstructive pulmonary disease. Previous retrospective epidemiologic studies have found that exposure to occupational dust among those with α1-antitrypsin deficiency is a risk factor at the group level for poorer lung function, but on an individual clinical basis, a causal attribution can be difficult to establish.

CASE PRESENTATION

We describe the case of a 68-year-old Caucasian man with a 25 pack-year smoking history who presented with new-onset dyspnea on exertion in the setting of workplace dust exposure. During his evaluation, he was found to have α1-antitrypsin deficiency with evidence of development of pulmonary emphysema. Workplace spirometric monitoring over 10 years of surveillance for an on-the-job respirator fit program demonstrated a sharp downward slope in forced expiratory volume in one second, or FEV1, during his periods of most significant dust exposure, which was attenuated after discontinuation of his workplace exposure.

CONCLUSION

Patients with α1-antitrypsin disease should be assessed for occupational exposures and closely monitored for work-accelerated progression of lung function decline. More generally, this case report supports the biological plausibility of occupationally associated chronic obstructive pulmonary disease, underscoring that work-associated pulmonary disease can be multi-factorial.

BACKGROUND

Recombinant factor VIIa (rFVIIa), a hemostatic agent approved for hemophilia, is increasingly used for off-label indications.

PURPOSE

To evaluate the benefits and harms of rFVIIa use for 5 off-label, in-hospital indications: intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy.

DATA SOURCES

Ten databases (including PubMed, EMBASE, and the Cochrane Library) queried from inception through December 2010. Articles published in English were analyzed.

STUDY SELECTION

Two reviewers independently screened titles and abstracts to identify clinical use of rFVIIa for the selected indications and identified all randomized, controlled trials (RCTs) and observational studies for full-text review.

DATA EXTRACTION

Two reviewers independently assessed study characteristics and rated study quality and indication-wide strength of evidence.

DATA SYNTHESIS

16 RCTs, 26 comparative observational studies, and 22 noncomparative observational studies met inclusion criteria. Identified comparators were limited to placebo (RCTs) or usual care (observational studies). For intracranial hemorrhage, mortality was not improved with rFVIIa use across a range of doses. Arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], 0.03 [95% CI, 0.01 to 0.06]) and high-dose rFVIIa use (RD, 0.06 [CI, 0.01 to 0.11]). For adult cardiac surgery, there was no mortality difference, but there was an increased risk for thromboembolism (RD, 0.05 [CI, 0.01 to 0.10]) with rFVIIa. For body trauma, there were no differences in mortality or thromboembolism, but there was a reduced risk for the acute respiratory distress syndrome (RD, -0.05 [CI, -0.02 to -0.08]). Mortality was higher in observational studies than in RCTs.

LIMITATIONS

The amount and strength of evidence were low for most outcomes and indications. Publication bias could not be excluded.

CONCLUSION

Limited available evidence for 5 off-label indications suggests no mortality reduction with rFVIIa use. For some indications, it increases thromboembolism.

BACKGROUND

Recombinant factor VIIa (rFVIIa) is approved for treatment of bleeding in patients who have hemophilia with inhibitors but has been applied to a wide range of off-label indications.

OBJECTIVE

To estimate patterns of off-label rFVIIa use in U.S. hospitals.

DESIGN

Retrospective database analysis.

SETTING

Data were extracted from the Premier Perspectives database (Premier, Charlotte, North Carolina), which contains discharge records from a sample of academic and nonacademic U.S. hospitals.

PATIENTS

12 644 hospitalizations for patients who received rFVIIa during a hospital stay.

MEASUREMENTS

Hospital diagnoses and patient dispositions from 1 January 2000 to 31 December 2008. Statistical weights for each hospital were used to provide national estimates of rFVIIa use.

RESULTS

From 2000 to 2008, off-label use of rFVIIa in hospitals increased more than 140-fold, such that in 2008, 97% (95% CI, 96% to 98%) of 18 311 in-hospital uses were off-label. In contrast, in-hospital use for hemophilia increased less than 4-fold and accounted for 2.7% (CI, 1.9% to 3.5%) of use in 2008. Adult and pediatric cardiovascular surgery (29% [CI, 21% to 33%]), body and brain trauma (29% [CI, 19% to 38%]), and intracranial hemorrhage (11% [CI, 7.7% to 14%]) were the most common indications for rFVIIa use. Across all indications, in-hospital mortality was 27% (CI, 19% to 34%) and 43% (CI, 26% to 59%) of patients were discharged to home.

LIMITATION

Accuracy and completeness of the discharge diagnoses and patient medication records in the database sample cannot be verified.

CONCLUSION

Off-label use of rFVIIa in the hospital setting far exceeds use for approved indications. These patterns raise concern about the application of rFVIIa to conditions for which strong supporting evidence is lacking.

Sphingosine kinase (SphK) exhibits two isoforms, SphK1 and SphK2. Both forms catalyze the synthesis of sphingosine 1-phosphate (S1P), a sphingolipid involved in ischemic preconditioning (IPC). Since the ratio of SphK1:SphK2 changes dramatically with aging, it is important to assess the role of SphK2 in IR injury and IPC. Langendorff mouse hearts were subjected to IR (30 min equilibration, 50 min global ischemia, and 40 min reperfusion). IPC consisted of 2 min of ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), ± dP/dtmax, and heart rate between SphK2 null (KO) and wild-type (WT) hearts. In KO hearts, SphK2 activity was undetectable, and SphK1 activity was unchanged compared to WT. Total SphK activity was reduced by 53%. SphK2 KO hearts subjected to IR exhibited significantly more cardiac damage (37 ± 1% infarct size) compared with WT (28 ± 1% infarct size); postischemic recovery of LVDP was lower in KO hearts. IPC exerted cardioprotection in WT hearts. The protective effect of IPC against IR was diminished in KO hearts which had much higher infarction sizes (35 ± 2%) compared to the IPC/IR group in control hearts (12 ± 1%). Western analysis revealed that KO hearts had substantial levels of phosphorylated p38 which could predispose the heart to IR injury. Thus, deletion of the SphK2 gene sensitizes the myocardium to IR injury and diminishes the protective effect of IPC.

The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism, lower expression on the cell surface, and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV, and with levels of HLA-C messenger RNA transcripts and cell-surface expression, but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.

BACKGROUND

The objective of this study was to assess the effect of timing of postpartum levonorgestrel-releasing intrauterine device (IUD) insertion on breast-feeding continuation.

STUDY DESIGN

Women interested in using a levonorgestrel IUD postpartum were randomized to immediate postplacental insertion (postplacental group) or insertion 6-8 weeks after vaginal delivery (delayed group). Duration and exclusivity of breast-feeding were assessed at 6-8 weeks, 3 months, and 6 months postpartum. Only women who received an IUD were included in this analysis.

RESULTS

Breast-feeding was initiated by 32 (64%) of 50 of women receiving a postplacental IUD and 27 (58.7%) of 46 of women receiving a delayed IUD (p=.59). More women in the delayed group compared with the postplacental group continued to breast-feed at 6-8 weeks (16/46 vs. 15/50, p=.62), 3 months (13/46 vs. 7/50, p=.13), and 6 months postpartum (11/46 vs. 3/50, p=.02). The results did not differ when only women who initiated breast-feeding or only primiparous women with no prior breast-feeding experience were analyzed.

CONCLUSIONS

Immediate postplacental insertion of the levonorgestrel IUD is associated with shorter duration of breast-feeding and less exclusive breast-feeding. Further studies on the effects of early initiation of progestin-only methods on women's lactation experience are needed.