Laura Musselwhite

Chagas disease: "the new HIV/AIDS of the Americas".

Endemic Chagas disease has emerged as an important health disparity in the Americas. As a result, we face a situation in both Latin America and the US that bears a resemblance to the early years of the HIV/AIDS pandemic.

Shared monocyte subset phenotypes in HIV-1 infection and in uninfected subjects with acute coronary syndrome

The mechanisms responsible for increased cardiovascular risk associated with HIV-1 infection are incompletely defined. Using flow cytometry, in the present study, we examined activation phenotypes of monocyte subpopulations in patients with HIV-1 infection or acute coronary syndrome to find common cellular profiles. Nonclassic (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocytes are proportionally increased and express high levels of tissue factor and CD62P in HIV-1 infection. These proportions are related to viremia, T-cell activation, and plasma levels of IL-6. In vitro exposure of whole blood samples from uninfected control donors to lipopolysaccharide increased surface tissue factor expression on all monocyte subsets, but exposure to HIV-1 resulted in activation only of nonclassic monocytes. Remarkably, the profile of monocyte activation in uncontrolled HIV-1 disease mirrors that of acute coronary syndrome in uninfected persons. Therefore, drivers of immune activation and inflammation in HIV-1 disease may alter monocyte subpopulations and activation phenotype, contributing to a pro-atherothrombotic state that may drive cardiovascular risk in HIV-1 infection.

Alemtuzumab in the Treatment of Refractory Acute Rejection and Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Despite substantial improvements in early survival after lung transplantation, refractory acute rejection (RAR) and bronchiolitis obliterans syndrome (BOS) remain major contributors to transplant‐related morbidity and mortality. We have utilized alemtuzumab, a humanized anti‐CD52 antibody which results in potent lymphocyte depletion, in consecutive patients with RAR (n = 12) or BOS (n = 10). All patients failed conventional treatment with methylprednisolone and antithymocyte globulin and received strict infection prophylaxis. Alemtuzumab significantly improved histological rejection scores in RAR. Total rejection grade/biopsy was 1.98 ± 0.25 preceding alemtuzumab versus 0.33 ± 0.14 posttreatment, p‐value <0.0001 (with a similar number of biopsies/patient per respective time interval). Freedom from BOS was observed in 65% of RAR patients 2 years after alemtuzumab treatment. Although there was no statistically significant change in forced expiratory volume in 1 second (FEV1) before and after alemtuzumab treatment in patients with BOS, a stabilization or improvement in BOS grade occurred in 70% of patients. Patient survival 2 years after alemtuzumab for BOS was 69%. Despite a dramatic decline in CD4 counts in alemtuzumab‐treated patients, only one patient developed a lethal infection. Thus, we provide the first evidence that alemtuzumab is a potentially useful therapy in lung transplant recipients with RAR or BOS.

Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in Hiv

Objective:HIV infection is associated with coagulation abnormalities and significantly increased risk of venous thrombosis. It has been shown that higher plasma levels of coagulation and inflammatory biomarkers predicted mortality in HIV. We investigated the relationship between venous thrombosis and HIV-related characteristics, traditional risk factors of hypercoagulability, and pre-event levels of biomarkers. Design:A retrospective case–control study of 23 HIV-infected individuals who experienced an incident venous thromboembolic event while enrolled in National Institutes of Health studies from 1995 to 2010 and 69 age-matched and sex-matched HIV-infected individuals without known venous thromboembolism (VTE). Methods:Biomarkers of inflammation, endothelial dysfunction, coagulation, tissue fibrosis, and cytomegalovirus (CMV) reactivation were assessed by ELISA-based assays and PCR using plasma obtained prior to the event. Results:VTE events were related to nadir CD4 cell count, lifetime history of multiple opportunistic infections, CMV disease, CMV viremia, immunological AIDS, active infection, and provocation (i.e., recent hospitalization, surgery, or trauma). VTE events were independently associated with increased plasma levels of P-selectin (P = 0.002), D-dimer (P = 0.01), and hyaluronic acid (P = 0.009) in a multivariate analysis. No significant differences in antiretroviral or interleukin-2 exposures, plasma HIV viremia, or other traditional risk factors were observed. Conclusion:Severe immunodeficiency, active infection, and provocation are associated with venous thromboembolic disease in HIV. Biomarkers of endothelial dysfunction, coagulation, and tissue fibrosis may help identify HIV-infected patients at elevated risk of VTE.

Adaptations across Clinical Sites of an Integrated Treatment Model for Persons with HIV and Substance Abuse

Substance use disorders are common among people living with HIV (PLWHA), and PLWHA with untreated substance use are less likely to receive antiretroviral therapy (ART) or achieve viral suppression when ART is prescribed. Integrated behavioral and medical interventions are one approach used to treat complex chronic illnesses, including HIV and substance abuse (SA). As the potential benefit for integrated HIV-substance abuse treatment is recognized, the number of providers attempting to integrate care is growing. Integrated care models can range from coordinated to colocated to fully integrated models. Providers need a better understanding of these implementation options for HIV-substance abuse treatment and how they impact providers of different disciplines. Between April and November 2006, interviews exploring the process of implementing an integrated HIV-substance abuse intervention were completed with clinic staff at three diverse HIV clinics in North Carolina. Key differences in implementation between sites were found. The degree of integrated care between sites ranged from colocated to integrated, and clinic staff perceived each integrated model to have advantages and disadvantages. Recommendations for implementing HIV-SA integrated care are made.

Racial/Ethnic Disparities in Cervical Cancer Screening and Outcomes

Invasive cervical cancer disproportionately affects women without sufficient access to care, with higher rates among minority groups in higher-income countries and women in low-resource regions of the world. Many elements contribute to racial/ethnic disparities in the cervical cancer continuum - from screening and diagnosis to treatment and outcome. Sociodemographic factors, access to healthcare, income and education level, and disease stage at diagnosis are closely linked to such inequities. Despite the identification of such elements, racial/ethnic disparities persist, and are widening in several minority subgroups, particularly in older women, who are ineligible for human papillomavirus (HPV) vaccination and are underscreened. Recent studies suggest that racial/ethnic differences in HPV infection exist and may also have a role in observed differences in cervical cancer. In this review, we provide an overview of the current literature on racial disparities in cervical cancer screening, incidence, treatment and outcome to inform future strategies to reduce persistent inequities.

IL-10, IL-15, IL-17, and GMCSF levels in cervical cancer tissue of Tanzanian women infected with HPV16/18 vs. non-HPV16/18 genotypes

BackgroundDespite comparable screening rates for precancerous lesions, higher incidence and mortality related to cervical cancer in minority women persists. Recent evidence suggests that minority women with precancerous cervical lesions harbor a wider range of human papillomavirus (HPV) genotypes, many of these distinct from HPV16/18, those most commonly found in Caucasian women. The goal of the analysis was to determine if inflammatory cytokines and chemokines varied by HPV 16/18 versus other genotypes in cervical cancer tissues from Tanzanian women.MethodsHPV genotypes and concentrations of chemokines and cytokines were measured from homogenized fresh tumor tissue of thirty-one women with invasive cervical cancer (ICC). Risk factors for cervical cancer including age, parity, hormonal contraceptive use and cigarette smoking were obtained by questionnaire. Generalized linear models were used to evaluate differences between chemokines/cytokine levels in women infected with HPV16/18 and those infected with other HPV genotypes.ResultsAfter adjusting for age, parity and hormonal contraceptives, IL-17 was found significantly more frequently in invasive cervical cancer samples of women infected with HPV16/18 compared to women infected with other HPV genotypes (p = 0.033). In contrast, higher levels for granular macrophage colony-stimulating factor (p = 0.004), IL-10 (p = 0.037), and IL-15 (p = 0.041) were found in ICC tissues of women infected with genotypes other than HPV16/18 when compared to those of women infected with HPV16/18.ConclusionsWhile the small sample size limits inference, our data suggest that infection with different HPV genotypes is associated with distinct pro-inflammatory cytokine expression profiles; whether this explains some of the racial differences observed in cervical cancer is still unclear. Future studies are needed to confirm these findings.

First Universities Allied for Essential Medicines (UAEM) Neglected Diseases and Innovation Symposium

Universities Allied for Essential Medicines organized its first Neglected Diseases and Innovation Symposium to address expanding roles of public sector research institutions in innovation in research and development of biomedical technologies for treatment of diseases, particularly neglected tropical diseases. Universities and other public research institutions are increasingly integrated into the pharmaceutical innovation system. Academic entities now routinely undertake robust high-throughput screening and medicinal chemistry research programs to identify lead compounds for small molecule drugs and novel drug targets. Furthermore, product development partnerships are emerging between academic institutions, non-profit entities, and biotechnology and pharmaceutical companies to create diagnostics, therapies, and vaccines for diseases of the poor. With not for profit mission statements, open access publishing standards, open source platforms for data sharing and collaboration, and a shift in focus to more translational research, universities and other public research institutions are well-placed to accelerate development of medical technologies, particularly for neglected tropical diseases.

Abstract IA09: IL-17 and GMCSF may be novel markers for detection of ICC

Ethnic/Racial differences in invasive cervical cancer incidence and mortality Despite major reductions in incidence and mortality over the last decade, an estimated half million cases of invasive cancers of the uterine cervix (ICC) continue to be diagnosed annually worldwide with 12,340 of these cases occurring in the United States. The highest incidence is in Hispanic and African American and lowest in European American women 1,2. Liquid-based cytology screening rates, whether self-reported or estimated from insurance claims data, accounted for most of the overall decline in incidence and mortality, but are comparable among African Americans, Hispanics and European Americans and thus fail to explain the racial/ethnic disparity in ICC incidence and mortality 3-5. Ethnic/race differences in HPV distribution in Africa and the US Reasons for continued racial/ethnic disparities in ICC incidence and mortality are still unclear, although published data in the last few years suggest that among women with cancerous lesions, women of African descent may harbor human papillomavirus (HPV) genotypes distinct from those found in women of European descent 6-8 and may be more likely to be infected with genotypes not covered by the vaccine. Among Tanzanian women, we previously found that HPV 35, 45, and 31, in addition to HPV 16 and 18, were the genotypes more frequently found in ICC cases 9. Among African Americans with CIN in North Carolina, we also found that HPV 35, 45, and 31, in addition to HPV 16 and 18 were the most common genotypes. Data suggesting that HPV 35, 45, and 31 were common genotypes in women of African descent were recently confirmed using cervical scrapes obtained from Haiti and oral lavage in the US. While HPV genotypes 45, 58 and 68 are part of the nonavalent vaccine currently in Phase III clinical trials, HPV35 is not. The singular importance of high-risk HPV 68, 35 and 58, as well as co-infections with multiple HPV types remains unclear, these findings support that some of the racial differences seen in high-grade CIN, and perhaps ICC, may be due to the different genotypes inherent to different ethnic groups. Together, these intriguing findings raise the question of what the population attributable risk of HPV 35 is, and whether it ultimately is worth adding HPV 35 to the vaccine to reduce disparities in cervical cancer incidence and mortality. Differences in immune response to HPV genotypes may explain race/ethnic differences A key question is whether race/ethnic differences observed are the consequence of a higher propensity for infection with specific HPV type variants in different race/ethnic groups. If so, this may suggest differences in immunological response to HPV or co-infections. It is known that infection with high risk HPV genotypes initiate a local Th2 inflammatory response at an early stage, which fosters an immunosuppressive microenvironment that contributes to tumor progression 10. Paradkar et al. 11, summarized recent data on cytokine dysregulation in cervical cancer, raising the possibility of using distinct inflammatory cytokines as biomarkers to assist in the early diagnosis of HPV-infected women at high risk of developing cancer. The goal of the present analysis is to determine if cytokines/chemokine expression differs in HPV-infected women with high risk HPV16 and/or 18 genotypes compared to women with other genotypes. Methods The MilliPLex MAP Human Cytokine/Chemokine immune assay kit (Millipore Corporation, Billerica, MA) was used to measure 30 chemokines and cytokines in flash-frozen ICC tissue specimens obtained from 40 women recruited from Kilimanjaro Christian Medical Center, Tanzania. Results In these African women, 65% (95% confidence limits, 55%-87%) of ICC tissue samples harbored HPV16 and 18. Among the 30 cytokines and chemokines measured in homogenized cervical cancer tissues, pro-inflammatory cytokine/chemokine levels differed by HPV16/18 status. In general, pro-inflammatory cytokines/chemokine levels were higher in women infected with HPV 16/18 compared to those infected with other HPV genotypes. After adjusting for age, parity and cigarette smoking, 4 cytokines remained significantly differentially expressed in ICC harboring HPV 16/18 vs. ICC without HPV16/18: IL-10 (p=0.037), IL-15 (p=0.041), IL-17 (p=0.0006), and GMCSF (p=0.0036),. To adjust for multiple comparisons, a bonferroni correction was applied and IL-17 remained significant (p=0.05). Conclusion These findings are consistent with IL-17 increased expression being associated with cervical cancer cell growth in tissue 11. Increased levels of IL-10, one of the best-studied Th2 type cytokines which has a general immunosuppressive function 12, have been associated with high-grade cervical lesions 13-15. Furthermore, Scott et. al., [9], reported that significantly increased levels of MIP-1a, TNF, IL-12 and IL-10 cytokines were associated with a reduced likelihood of HPV clearance among women with incident HPV infections, but without cervical intraepithelial neoplasia (CIN). While the small sample size limits inference, our data support further evaluation of, IL-17 and perhaps GMCSF as novel biomarkers of HPV16/18 related ICC. Citation Format: Cathrine Hoyo, Adriana Vidal, John Bartlett, Olala Oneko, Laura Musselwhite, Rachel Maguire, Joseph Obure, Pendo Mlay, Susan Murphy. IL-17 and GMCSF may be novel markers for detection of ICC. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA09.

Societal Impact Of Extending Market Exclusivity For Conventional Drugs

without prior written permission from the Publisher. All rights reserved. or mechanical, including photocopying or by information storage or retrieval systems, may be reproduced, displayed, or transmitted in any form or by any means, electronic States copyright law (Title 17, U.S. Code), no part of by Project HOPE The People-to-People Health Foundation. As provided by United Suite 600, Bethesda, MD 20814-6133. Copyright