Recent Publications by CFE Educators

Medical devices are of increasing importance in cardiovascular disease and have made important contributions to patient care. These devices continue to evolve with increasing complexity. FDA regulation of medical devices involves increased stringency for higher risk and novel devices. However, there are some current opportunities to strengthen the FDA's pre-approval regulatory process and improve post-marketing surveillance. This article reviews FDA regulation of cardiovascular devices and offers suggestions for strengthening the process while focusing on examples relevant to cardiac electrophysiologists.

Proteolysis is a critical post-translational modification for regulation of cellular processes. Our lab has previously developed a technique for specifically labeling unmodified protein N termini, the α-aminome, using the engineered enzyme, subtiligase. Here we present a database, called the DegraBase (http://wellslab.ucsf.edu/degrabase/), which compiles 8090 unique N termini from 3206 proteins directly identified in subtiligase-based positive enrichment mass spectrometry experiments in healthy and apoptotic human cell lines. We include both previously published and unpublished data in our analysis, resulting in a total of 2144 unique α-amines identified in healthy cells, and 6990 in cells undergoing apoptosis. The N termini derive from three general categories of proteolysis with respect to cleavage location and functional role: translational N-terminal methionine processing (∼10% of total proteolysis), sites close to the translational N terminus that likely represent removal of transit or signal peptides (∼25% of total), and finally, other endoproteolytic cuts (∼65% of total). Induction of apoptosis causes relatively little change in the first two proteolytic categories, but dramatic changes are seen in endoproteolysis. For example, we observed 1706 putative apoptotic caspase cuts, more than double the total annotated sites in the CASBAH and MEROPS databases. In the endoproteolysis category, there are a total of nearly 3000 noncaspase nontryptic cleavages that are not currently reported in the MEROPS database. These studies significantly increase the annotation for all categories of proteolysis in human cells and allow public access for investigators to explore interesting proteolytic events in healthy and apoptotic human cells.

BACKGROUND

Health care providers often tell women to wait until the next menses to begin hormonal contraception. The intent is to avoid contraceptive use during an undetected pregnancy. An alternative is to start hormonal contraception immediately with back-up birth control for the first seven days. Immediate initiation was introduced with combined oral contraceptives (COCs), and has expanded to other hormonal contraceptives. At the time of the initial review, how immediate start compared to conventional menses-dependent start was unclear regarding effectiveness, continuation, and acceptability. The immediate-start approach may improve women's access to, and continuation of, hormonal contraception.

OBJECTIVES

This review examined randomized controlled trials (RCTs) of immediate-start hormonal contraception for differences in effectiveness, continuation, and acceptability.

SEARCH METHODS

In August 2012, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP for trials of immediate-start hormonal contraceptives. We contacted researchers to find other studies. Earlier searches also included EMBASE.

SELECTION CRITERIA

We included RCTs that compared immediate start to conventional start of hormonal contraception. Also included were trials that compared immediate start of different hormonal contraceptive methods with each other.

DATA COLLECTION AND ANALYSIS

Data were abstracted by two authors and entered into RevMan. The Peto odds ratio (OR) with 95% confidence interval (CI) was calculated.

MAIN RESULTS

Five studies were included. No new eligible studies have been found since the review was initially conducted. Method discontinuation was similar between groups in all trials. Bleeding patterns and side effects were similar in trials that compared immediate with conventional start. In a study of depot medroxyprogesterone acetate (DMPA), immediate start of DMPA showed fewer pregnancies than a 'bridge' method before DMPA (OR 0.36; 95% CI 0.16 to 0.84). Further, more women in the immediate-DMPA group were very satisfied versus those with a 'bridge' method (OR 1.99; 95% CI 1.05 to 3.77). A trial of two immediate-start methods showed the vaginal ring group had less prolonged bleeding (OR 0.42; 95% CI 0.20 to 0.89) and less frequent bleeding (OR 0.23; 95% CI 0.05 to 1.03) than COC users. The ring group also reported fewer side effects. Also, more immediate ring users were very satisfied than immediate COC users (OR 2.88; 95% CI 1.59 to 5.22).

AUTHORS' CONCLUSIONS

We found limited evidence that immediate start of hormonal contraception reduces unintended pregnancies or increases method continuation. However, the pregnancy rate was lower with immediate start of DMPA versus another method. Some differences were associated with contraceptive type rather than initiation method, i.e., immediate ring versus immediate COC. More studies are needed of immediate versus conventional start of the same hormonal contraceptive.

BACKGROUND AND OBJECTIVES

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare tumors. Aims of this study were to describe and to compare demographic, clinical, pathologic, and survival characteristics of malignant PHEO and PGL.

METHODS

Patients were identified in SEER, 1988-2009. Analyses included chi-square, ANOVA, Kaplan-Meier, and Cox proportional hazard regression.

RESULTS

Gender distribution and mean age were similar for PHEO and PGL. Surgery was performed in 74.3% of PHEO and 78.9% of PGL; external beam radiation was administered in 8.0% of PHEO and 28.1% of PGL (P 0.001). Compared to PGL, PHEO were larger (mean size 7.7 vs. 4.5 cm PGL, P = 0.001) and more were SEER-staged as localized (17.3% vs. 49.6%, respectively, P 0.001). PGLs were more often located in the trunk than in the head/neck (53.8% vs. 38.0%, P 0.001). PHEO had lower overall and disease-specific survival than PGL (54.0% and 73.5% vs. 73.3% and 80.5% for PGL, respectively, P 0.001 and P = 0.118). Independent factors associated with mortality for PHEO included not undergoing surgery and metastases at diagnosis; for PGL, these were age 61-75 years, size ≥5 cm, and presenting with metastases.

CONCLUSIONS

Malignant PHEO has a more aggressive course than malignant PGL; long-term survival has not improved over the last two decades. Multi-institutional efforts should be pursued to seek novel treatments.

OBJECTIVE

To report a novel cell surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels.

METHODS

Four patients with encephalitis of unclear etiology and antibodies with a similar pattern of neuropil brain immunostaining were selected for autoantigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-base experiments with Kv4.2 and several dipeptidyl-peptidase-like protein-6 (DPPX) plasmid constructs, and comparative brain immunostaining of wild-type and DPPX-null mice.

RESULTS

Immunoprecipitation studies identified DPPX as the target autoantigen. A cell-based assay confirmed that all 4 patients, but not 210 controls, had DPPX antibodies. Symptoms included agitation, confusion, myoclonus, tremor, and seizures (1 case with prominent startle response). All patients had pleocytosis, and 3 had severe prodromal diarrhea of unknown etiology. Given that DPPX tunes up the Kv4.2 potassium channels (involved in somatodendritic signal integration and attenuation of dendritic back-propagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX), and Kv4.2. Patients' antibodies were found to be specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to a demonstration of a robust expression of DPPX in the myenteric plexus, which strongly reacted with patients' antibodies. The course of neuropsychiatric symptoms was prolonged and often associated with relapses during decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 was lost to follow-up).

INTERPRETATION

Antibodies to DPPX are associated with a protracted encephalitis characterized by central nervous system hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy.

OBJECTIVE

Mitral annular calcification (MAC) is a degenerative process of the mitral annulus associated with cardiac disease and stroke. Although thought to be more prevalent in type 2 diabetes (T2DM), MAC remains poorly characterized in this population, due to confounding by renal and cardiac disease. Our goal was to study the risk factors for MAC in a sample of T2DM subjects without renal and cardiac disease.

METHODS

The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of diabetic individuals without clinical cardiovascular or renal disease. We quantified and analyzed MAC Agatston scores in baseline cardiac CTs from 1753 individuals. Logistic and tobit regression were used to assess MAC's relationship with risk factors and coronary artery calcium (CAC).

RESULTS

MAC was present in 12.0% of subjects, with a median Agatston score of 72.3 [Interquartile range (22.2-256.9)]. Older age, female gender, Caucasian race, and longer diabetes duration were independently associated with both the presence and extent MAC even after controlling for CAC; however, hypertension, hyperlipidemia, tobacco use, CRP levels, and other comorbidities were not associated. CAC was strongly associated with MAC [OR of 4.0 (95% CI 2.4-6.6)] in multivariable models.

CONCLUSIONS

Age, female gender, Caucasian race, and diabetes duration were associated with the presence and extent of MAC in T2DM subjects, independent of CAC, which was also strongly associated with MAC. These data suggest that additional mechanisms for MAC formation in diabetics may exist which are distinct from those related to generalized atherosclerosis and deserve further investigation.

OBJECTIVE

To determine whether fingolimod, an oral sphingosine-1-phosphate receptor modulator approved for treatment of multiple sclerosis (MS), generally leads to increased retinal tissue volume.

METHODS

In this longitudinal observational study, we compared changes in macular volume on spectral-domain optical coherence tomography (OCT) between consecutive patients with MS who initiated fingolimod and a matched reference cohort of patients with MS never exposed to the drug. The primary reference cohort was matched based on time interval between OCT examinations. A secondary reference cohort was matched based on age and disease duration. Change in macular volume within each group was analyzed using the paired t test. Change in macular volume between groups was examined using multiple linear regression.

RESULTS

Macular volume increased by a mean of 0.025 mm3 (95% confidence interval [CI] +0.017 to +0.033, p 0.001) in the 30 patients with MS who initiated fingolimod over a mean follow-up time of 5 months (SD 3). Macular volume did not significantly change over a mean follow-up time of 6 months (SD 4) in a comparison group of 30 patients with MS never treated with fingolimod (mean change of -0.003 mm3, 95% CI -0.009 to +0.004, p = 0.47). Overall, 74% of eyes in the fingolimod-treated group exhibited an increase in macular volume vs. 37% of eyes in the comparison group.

CONCLUSION

Initiation of fingolimod in MS is associated with a modest, relatively rapid increase in macular volume.

SETTING

A total of 663 human immunodeficiency virus (HIV) care and treatment sites in nine tuberculosis (TB) affected African countries, serving over 900,000 persons living with HIV.

OBJECTIVE

To determine the implementation of infection control (IC) measures and whether program and facility characteristics were associated with implementation of these measures.

DESIGN

A survey was conducted to assess the presence of a TB IC plan, triage practices for TB suspects, location of sputum collection and availability of particulate respirators. The association of facility characteristics with IC measures was examined using bivariate and multivariate methods.

RESULTS

Forty-seven per cent (range across countries [RAC] 2-77%) of sites had written TB IC plans; 60% (RAC 5-93%) practiced triage; of those with access to microscopy, 83% (RAC 59-91%) performed sputum collection outdoors and 13% (RAC 0-36%) in ventilated indoor rooms; 16% (RAC 1-87%) had particulate respirators available. Sites providing anti-tuberculosis treatment were more likely to have written IC plans (54% vs. 12%, P 0.0001) and particulate respirators (18% vs. 8%, P = 0.0126), and to perform TB triage (65% vs. 40%, P = 0.0001) than those without anti-tuberculosis treatment services.

CONCLUSIONS

To protect HIV-infected patients and health care workers, there is an urgent need to scale up IC practices at HIV care and treatment sites, particularly at sites without anti-tuberculosis treatment services.