Publications

BACKGROUND

Although inappropriate shocks are known to be an important consequence of implantable cardioverter-defibrillators (ICDs), the subjective experience of pain intensity perceived by those receiving inappropriate versus appropriate shocks has not previously been examined.

METHODS

One hundred ICD patients underwent a standardized interview by an investigator blinded to the clinical history. Patients with a previous ICD shock were asked to describe the intensity of the associated pain on a standard 0-10 scale (10 being the worst pain they had ever experienced). Medical charts were then examined for any history of inappropriate and/or appropriate ICD discharges.

RESULTS

Thirty-five of the 100 patients had a record of at least one ICD shock, and 17 had experienced at least one inappropriate shock. Those with a history of an inappropriate shock described a significantly higher median pain scale (9, interquartile range [IQR] 8-10) compared to those with a history of only appropriate shocks (median 4, IQR 2-8, P = 0.0011). In multivariable analysis, a history of an inappropriate shock was the only predictor statistically significantly associated with an increase in shock pain: the pain scale for those with inappropriate shocks was higher by 2.8 points on average after multivariable adjustment (95% confidence interval 0.29-5, P = 0.030). Eighteen patients had considered having their device deactivated, and a history of an inappropriate shock was the only factor independently associated with this consideration.

CONCLUSIONS

Compared to those who have received only appropriate shocks, inappropriate ICD shocks are associated with a recollection of greater pain and consideration of device inactivation.

OBJECTIVE

Disease activity and medication use can complicate pregnancies in patients with systemic lupus erythematosus (SLE). We therefore examined contraceptive counseling and use among women in the University of California, San Francisco Lupus Outcomes Study.

METHODS

In 2008, we queried participants regarding their pregnancy intentions, contraceptive use, and receipt of contraceptive counseling. Premenopausal women age <45 years who were sexually active with men were considered at risk of pregnancy. We compared self-reported rates of contraceptive counseling and use stratified by treatment with teratogenic medications and by history of thrombosis or antiphospholipid antibodies (aPL), using chi-square tests. We used logistic regression models to examine predictors of contraceptive counseling and use.

RESULTS

Among 206 women, 86 were at risk for unplanned pregnancy. Most (59%) had not received contraceptive counseling in the last year, 22% reported inconsistent contraceptive use, and 53% depended solely on barrier methods. Intrauterine device contraceptives (IUDs) were used by 13%. Women using potentially teratogenic medications were no more likely to have received contraceptive counseling, to have used contraception consistently, or to have used more effective contraceptives. A history of thrombosis or aPL did not account for low rates of hormonal methods. Four women with a history of thrombosis or aPL were using estrogen-containing contraceptives.

CONCLUSION

Most women at risk for unplanned pregnancy reported no contraceptive counseling in the past year, despite common use of potentially teratogenic medications. Many relied upon contraceptive methods with high failure rates; few used IUDs. Some were inappropriately using estrogen-containing contraceptives. These findings suggest the need to improve the provision of contraceptive services to women with SLE.

OBJECTIVE

There is a need to identify clinical characteristics and/or biomarkers that can predict treatment outcome in lupus nephritis. To this end, we utilized data from the Aspreva Lupus Management Study to identify possible baseline and early predictors of renal response to mycophenolate mofetil (MMF) or intravenous (IV) cyclophosphamide (CYC).

METHODS

Patients with class III-V lupus nephritis were randomized to MMF or IV CYC. We assessed predictors of renal response, including baseline demographic, clinical, laboratory, and histologic characteristics, as well as early clinical and laboratory data, obtained within the first 2 months of therapy. Odds ratios (ORs) and 95% confidence intervals for renal response were calculated for each putative predictor.

RESULTS

Normalization of C3, C4, or both by week 8 was strongly predictive of renal response at week 24 (ORs 2.5, 2.6, and 2.9, respectively; P < 0.05). Reduction in proteinuria by ≥25% by week 8 was predictive of renal response at week 24 (OR 3.2, P < 0.05). Reduction in anti-double-stranded DNA (anti-dsDNA) by week 8 was not predictive of renal response. Only 3 baseline characteristics (C4 level, time since diagnosis of lupus nephritis, and estimated glomerular filtration rate [GFR]) were predictive of renal response; the remaining characteristics (age, age at lupus nephritis onset, time since diagnosis of systemic lupus erythematosus, sex, histopathologic class, anti-dsDNA antibody level, C3 level, level of proteinuria, and use of angiotensin-converting enzyme inhibitors, statins, or hydroxychloroquine) were not.

CONCLUSION

This study demonstrates that baseline C4 level, time since diagnosis of lupus nephritis, baseline estimated GFR, early normalization of complement, and reduction in proteinuria independently predict renal response to therapy at 6 months.

A comprehensive understanding of evidence related to treatments for a disease is critical for planning effective clinical care, and for designing future trials. However, it is often difficult to comprehend the available evidence because of the complex combination of interventions across trials, in addition to the limited search and retrieval tools available in databases such as ClinicalTrials.gov. Here we demonstrate the use of networks to visualize and quantitatively analyze the co-occurrence of drug interventions across trials on depression in ClinicalTrials.gov. The analysis identified general co-occurrence patterns of interventions across all depression trials, and specific co-occurrence patterns related to antidepressants and natural supplements. These results led to insights about the current state of depression trials, and to a graph-theoretic measure to categorize interventions for a disease. We conclude by discussing the opportunities and challenges of generalizing our approach to analyze comparative interventional studies for any disease.

Application of the widely used immunosuppressant (ISS) cyclosporine (CsA) is severely limited by a number of serious side-effects such as kidney and neurotoxicity. As we have shown before, CsA exhibits metabolic toxicity in brain-models. The macrolide ISSs sirolimus (SRL) and everolimus (RAD) are capable of modulating these CsA-induced effects. It was our aim to study the age-dependent metabolic changes in the rat brain after ISS-treatment and the possible role of the blood-brain-barrier in modulation of CsA metabolic toxicity. Young and adult rats were treated orally with one ISS alone or in combination with CsA for six days. Metabolic changes were assessed by nuclear magnetic resonance (NMR) spectroscopy of brain extracts as toxicodynamic endpoints. Brain P-glycoprotein (P-gp) and ISS concentrations were determined as pharmacokinetic endpoints. Young rats were more susceptible to CsA-induced inhibition of the Krebs cycle (glutamate: 78% of controls, glutamine: 82%, GABA: 71% in young vs. 85%, 89%, 92% in adult rats). Increased glycolysis after CsA-treatment was sufficient to maintain the energy state at control levels in adult brains, but not in the young rat brains (phosphocreatine: 35%). Tissue concentrations of CsA and SRL within the brain of young rats were three-fold higher, while concentrations of P-gp were three-fold higher in adult rat brains. Our results suggest that age-dependent differences in the blood-brain barrier led to increased ISS brain concentrations and hence inhibition of brain energy metabolism.