Publications

Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease.

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.

BACKGROUND

Understanding normal volume asymmetry is essential for accurate assessment of limb volume changes following breast cancer (BC) treatment in which lymphatic function is disrupted. The purposes of this study were to evaluate for differences in dominant and nondominant limb volumes and to evaluate for interactions between the effects of dominance and side of cancer on limb volume.

METHODS AND RESULTS

This study evaluated preoperative limb volumes of 397 women enrolled in a prospective, longitudinal study of neuropathic pain and lymphedema. Volume was calculated from circumference. Limb resistance was measured with bioimpedance. Women were dichotomized into two groups: those whose cancer was on their dominant side and those whose cancer was on their nondominant side. Analyses of variance were used to evaluate for differences. In 47%, BC occurred on the side of the dominant limb. Except for the 30 to 40 centimeter (cm) limb volume segment, a main effect of dominance was found for all measures. The volume of the dominant limb was significantly greater than that of the nondominant limb. No main effects were found for side of cancer. A statistically significant interaction was found only at the 0 to 10 cm limb volume segment.

CONCLUSIONS

Prior to BC treatment, the dominant limb demonstrated lower bioimpedance resistance (-2.09%) and greater total limb volume (1.12%) than the nondominant limb. Segmental volume differences were greatest at the proximal forearm segment (2.31%) and least at the proximal arm segment (0.21%). This study provides evidence that preoperative volume assessment is important due to normal variability associated with limb dominance.

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

OBJECTIVE

To determine whether earlier initiation of antiretroviral therapy (ART) is associated with better economic outcomes.

DESIGN

Prospective cohort study of HIV-positive patients on ART in rural Uganda.

METHODS

Patients initiating ART at a regional referral clinic in Uganda were enrolled in the Uganda AIDS Rural Treatment Outcomes study starting in 2005. Data on labor force participation and asset ownership were collected on a yearly basis, and CD4 cell counts were collected at pre-ART baseline. We fitted multivariable regression models to assess whether economic outcomes at baseline and in the 6 years following ART initiation varied by baseline CD4 cell count.

RESULTS

Five hundred and five individuals, followed up to 6 years, formed the estimation sample. Participants initiating ART at CD4 cell count at least 200 cells/μl were 13 percentage points more likely to be working at baseline (P < 0.01, 95% confidence interval 0.06-0.21) than those initiating below this threshold. Those in the latter group achieved similar labor force participation rates within 1 year of initiating ART (P < 0.01 on the time indicators). Both groups had similar asset scores at baseline and demonstrated similar increases in asset scores over the 6 years of follow-up.

CONCLUSION

ART helps participants initiating therapy at CD4 cell count below 200 cells/μl rejoin the labor force, though the findings for participants initiating with higher CD4 cell counts suggests that pretreatment declines in labor supply may be prevented altogether with earlier therapy. Baseline similarities in asset scores for those with early and advanced disease suggest that mechanisms other than morbidity may help drive the relationship between HIV infection and economic outcomes.

OBJECTIVE

To identify factors associated with contraceptive nonuse and use of less effective methods among obese women in the US.

STUDY DESIGN

We analyzed data from sexually active obese women (body mass index >30 kg/m²) age 20-44 using the 2006-2010 National Survey of Family Growth. We conducted multinomial logistic regression to assess associations between current contraceptive use and demographic, reproductive and health services factors. Specifically, we compared contraceptive nonusers, behavioral method users (withdrawal and fertility awareness) and barrier method users (condoms) to prescription method users (pill, patch, ring, injection, implant and intrauterine device).

RESULTS

Of 1345 obese respondents, 21.5% used no method, 10.3% behavioral methods, 20.8% barrier methods and 47.4% prescription methods. Only 42.4% of respondents overall and 20.4% of nonprescription method users reported discussing contraception with a provider in the past year. Similar to findings in the general population, behavioral method users were more likely to have previously discontinued a contraceptive method due to dissatisfaction [adjusted RR (aRR), 1.93; 95% confidence interval (CI), 1.09-3.44], and nonusers were more likely to perceive difficulty becoming pregnant (aRR, 3.86; 95% CI, 2.04-7.29), compared to prescription method users. Respondents using nonprescription methods were significantly less likely to have discussed contraception with a healthcare provider (nonusers: aRR, 0.16; 95% CI, 0.10-0.27; behavioral methods: aRR, 0.13; 95% CI, 0.06-0.25, barrier methods: aRR, 0.15; 95% CI, 0.09-0.25) than prescription method users.

CONCLUSIONS

Obese women who discuss contraception with a provider are more likely to use effective contraception and may be less likely to experience unintended pregnancy; however, over half report no recent discussion of contraception with a provider.

IMPLICATIONS

Efforts are needed to increase contraceptive counseling for obese women, who face increased risks of morbidity from unintended pregnancy.