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1.  GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV) Seropositive Women with or at Risk for HIV Infection 
PLoS ONE  2014;9(12):e114467.
Background
GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US.
Results
438 hepatitis C virus (HCV) seropositive women, including 306 HIV-infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co-infected. Among HIV-infected women, the only significant difference between GBV-negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes.
Conclusions
Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype.
doi:10.1371/journal.pone.0114467
PMCID: PMC4262414  PMID: 25493916
2.  Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis 
Objective: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC.
Study design: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects.
Results: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2 (rs5743704, Pro631His) increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations.
Condensation: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense.
Conclusion: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC.
doi:10.3389/fmicb.2014.00483
PMCID: PMC4172055  PMID: 25295030
RVVC; genetic variation; pattern recognition receptors; cytokines
3.  Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS) 
PLoS ONE  2014;9(6):e99109.
Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the MAGI-3 gene and one SNP (rs8031627) in the SMAD3 gene were associated with HR-HPV clearance (p<10−6). A variant (rs1633038) in HLA-G were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.
doi:10.1371/journal.pone.0099109
PMCID: PMC4053382  PMID: 24918582
4.  Novel PCR-Based Methods Enhance Characterization of Vaginal Microbiota in a Bacterial Vaginosis Patient before and after Treatment 
Applied and Environmental Microbiology  2013;79(13):4181-4185.
Deep characterization, even by next-generation sequencing, of the vaginal microbiota in healthy women or posttreatment bacterial vaginosis patients is limited by the dominance of lactobacilli. To improve detection, we offer two approaches: quantitative PCR (qPCR) using phylogenetic branch-inclusive primers and sequencing of broad-spectrum amplicons generated with oligomers that block amplification of lactobacilli.
doi:10.1128/AEM.01160-13
PMCID: PMC3697572  PMID: 23624483
5.  Longitudinal Analysis of Vaginal Microbiome Dynamics in Women with Recurrent Bacterial Vaginosis: Recognition of the Conversion Process 
PLoS ONE  2013;8(12):e82599.
Bacterial vaginosis (BV) affects ∼30% of women of reproductive age, has a high rate of recurrence, and is associated with miscarriage, preterm birth, and increased risk of acquiring other sexually transmitted infections, including HIV-1. Little is known of the daily changes in the vaginal bacterial composition as it progresses from treatment to recurrence, or whether any of these might be useful in its prediction or an understanding of its causes. We used phylogenetic branch-inclusive quantitative PCR (PB-qPCR) and Lactobacillus blocked/unblocked qPCR (Lb-qPCR) to characterize longitudinal changes in the vaginal microbiota in sequential vaginal self-swabs from five women with recurrent BV, from diagnosis through remission to recurrence. Both patients with acute BV samples dominated by G. vaginalis recurred during the study with similar profiles, whereas the three patients with acute BV samples dominated by other anaerobes did not recur or recurred to an intermediate Nugent score. L. iners dominated remission phases, with intermittent days of abnormal microbial profiles typically associated with menses. The exception was a newly discovered phenomenon, a sustained period of abnormal profiles, termed conversion, which preceded symptomatic acute BV. Species known to have antagonistic activity towards Lactobacillus were detected in pre-conversion samples, possibly contributing to the decline in Lactobacillus. Lb-qPCR scores define two categories of response in the initial post-treatment visit samples; scores <5 may correspond with poor response to treatment or rapid recurrence, whereas scores >8 may predict delayed or no recurrence. Amsel criteria or Nugent scores did not have this potential predictive capability. Larger studies are warranted to evaluate the prognostic potential of detecting conversion and poor Lb-qPCR scores at the post-treatment visit of recurrent BV patients.
doi:10.1371/journal.pone.0082599
PMCID: PMC3869700  PMID: 24376552
6.  Factors involved in patient choice of oral or vaginal treatment for vulvovaginal candidiasis 
Vulvovaginal candidiasis (VVC) is an extremely common cause of vaginal symptoms in women. Multiple antifungal products are available by either the oral or vaginal route, although no new drugs have become available for two decades. Given the therapeutic equivalence of the antimycotic agents and their routes of administration, the specific drug and formulation selected is entirely arbitrary in relation to final treatment outcome. Nevertheless, multiple factors affecting preference, both practitioner-dependent and patient-dependent, impact on selection of a specific drug and route of administration.
doi:10.2147/PPA.S38984
PMCID: PMC3869914  PMID: 24368881
antifungal drugs; antimycotics; Candida vaginitis; vulvovaginal candidiasis
7.  Subjective health status and health-related quality of life among women with Recurrent Vulvovaginal Candidosis (RVVC) in Europe and the USA 
Background
Recurrent vulvovaginal candidosis (RVVC) is a chronic condition causing discomfort and pain. Health status and health-related quality of life (HRQoL) in RVVC were never previously described using validated questionnaires. The objective of this study is to describe subjective health status and HRQoL and estimate health state utilities among women with RVVC.
Methods
A cross-sectional online survey was conducted among women who reported having suffered four or more yeast infections over the past 12 months, in five European countries (France, Germany, Italy, Spain and the UK) and the USA. Index scores were derived from the EQ-5D, a questionnaire providing a single index value for health status. The SF-36 questionnaire was used for HRQoL assessment. Information on disease severity, treatment patterns and productivity was also collected.
Results
12,834 members of online research panels were contacted. Among them, 620 women with RVVC (5%) were selected to complete the full questionnaire. The mean EQ-5D index score was 0.70 (95% confidence interval: [0.67, 0.72]) and the difference between women with a yeast infection at the time of questionnaire completion and other respondents was 0.05 (p = 0.47). The EQ-5D index score increased significantly with the time since last infection (p < 0.001). 68% of women reported depression/anxiety problems during acute episode, and 54% outside episodes, compared to less than 20% in general population (p < 0.001). All SF-36 domain scores were significantly below general population norms. Mental health domains were the most affected. The impact on productivity was estimated at 33 lost work hours per year on average, corresponding to estimated costs between €266/year and €1,130/year depending on the country.
Conclusions
Subjective health status and HRQoL during and in between acute inflammatory episodes in women with RVVC are significantly worse than in the general population, despite the use of antifungal therapy. The average index score in women with RVVC is comparable to other diseases such as asthma or COPD and worse than diseases such as headache/migraine according to US and UK catalogs of index scores. The survey also revealed a significant loss of productivity associated with RVVC.
doi:10.1186/1477-7525-11-169
PMCID: PMC3815627  PMID: 24119427
8.  THE INFLUENCE OF HLA CLASS I ALLELES AND THEIR POPULATION FREQUENCIES ON HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 CONTROL AMONG AFRICAN AMERICANS 
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
doi:10.1016/j.humimm.2011.01.003
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
9.  Listeriosis in Human Pregnancy: a systematic review 
Journal of perinatal medicine  2011;39(3):227-236.
Listeria is commonly found in processed and prepared foods and listeriosis is associated with high morbidity and mortality. Preventative measures are well prescribed and monitoring and voluntary recall of contaminated products has resulted in a 44% reduction in the prevalence of perinatal listeriosis in the USA. Pregnant women are at high risk for listeriosis, but symptoms are non-specific and diagnosis is difficult. The intracellular life-cycle of Listeria protects the bacterium from host innate and adaptive immune responses. Antibiotic treatment requires agents able to penetrate, distribute, and remain stable within host cells. Prolonged use of high-dose ampicillin can significantly improve neonatal outcome.
doi:10.1515/JPM.2011.035
PMCID: PMC3593057  PMID: 21517700
Listeriosis; Listeria monocytogenes; infection; foodborne; pregnancy; newborn; neonate; Epidemics
10.  Trichomonas vaginalis Genital Infections: Progress and Challenges 
Trichomonas vaginalis (TV) infection is the most prevalent curable sexually transmitted infection in the United States and worldwide. Most TV infections are asymptomatic, and the accurate diagnosis of this infection has been limited by lack of sufficiently sensitive and specific diagnostic tests, particularly for men. To provide updates for the 2010 Centers for Disease Control and Prevention’s Sexually Transmitted Diseases Treatment Guidelines, a PubMed search was conducted of all TV literature published from 9 January 2004 through 24 September 2008. Approximately 175 pertinent abstracts and articles were reviewed and discussed with national experts. This article describes advances in TV diagnostics which have led to an improved understanding of the epidemiology of this pathogen, as well as potential biologic and epidemiological interactions between TV and human immunodeficiency virus (HIV). New data on treatment outcomes, metronidazole-resistant TV, management of nitroimidazole-allergic patients, frequency of recurrent TV infection following treatment, and screening considerations for TV in certain populations are also presented.
doi:10.1093/cid/cir705
PMCID: PMC3897282  PMID: 22080269
11.  A framework for human microbiome research 
Methé, Barbara A. | Nelson, Karen E. | Pop, Mihai | Creasy, Heather H. | Giglio, Michelle G. | Huttenhower, Curtis | Gevers, Dirk | Petrosino, Joseph F. | Abubucker, Sahar | Badger, Jonathan H. | Chinwalla, Asif T. | Earl, Ashlee M. | FitzGerald, Michael G. | Fulton, Robert S. | Hallsworth-Pepin, Kymberlie | Lobos, Elizabeth A. | Madupu, Ramana | Magrini, Vincent | Martin, John C. | Mitreva, Makedonka | Muzny, Donna M. | Sodergren, Erica J. | Versalovic, James | Wollam, Aye M. | Worley, Kim C. | Wortman, Jennifer R. | Young, Sarah K. | Zeng, Qiandong | Aagaard, Kjersti M. | Abolude, Olukemi O. | Allen-Vercoe, Emma | Alm, Eric J. | Alvarado, Lucia | Andersen, Gary L. | Anderson, Scott | Appelbaum, Elizabeth | Arachchi, Harindra M. | Armitage, Gary | Arze, Cesar A. | Ayvaz, Tulin | Baker, Carl C. | Begg, Lisa | Belachew, Tsegahiwot | Bhonagiri, Veena | Bihan, Monika | Blaser, Martin J. | Bloom, Toby | Vivien Bonazzi, J. | Brooks, Paul | Buck, Gregory A. | Buhay, Christian J. | Busam, Dana A. | Campbell, Joseph L. | Canon, Shane R. | Cantarel, Brandi L. | Chain, Patrick S. | Chen, I-Min A. | Chen, Lei | Chhibba, Shaila | Chu, Ken | Ciulla, Dawn M. | Clemente, Jose C. | Clifton, Sandra W. | Conlan, Sean | Crabtree, Jonathan | Cutting, Mary A. | Davidovics, Noam J. | Davis, Catherine C. | DeSantis, Todd Z. | Deal, Carolyn | Delehaunty, Kimberley D. | Dewhirst, Floyd E. | Deych, Elena | Ding, Yan | Dooling, David J. | Dugan, Shannon P. | Dunne, Wm. Michael | Durkin, A. Scott | Edgar, Robert C. | Erlich, Rachel L. | Farmer, Candace N. | Farrell, Ruth M. | Faust, Karoline | Feldgarden, Michael | Felix, Victor M. | Fisher, Sheila | Fodor, Anthony A. | Forney, Larry | Foster, Leslie | Di Francesco, Valentina | Friedman, Jonathan | Friedrich, Dennis C. | Fronick, Catrina C. | Fulton, Lucinda L. | Gao, Hongyu | Garcia, Nathalia | Giannoukos, Georgia | Giblin, Christina | Giovanni, Maria Y. | Goldberg, Jonathan M. | Goll, Johannes | Gonzalez, Antonio | Griggs, Allison | Gujja, Sharvari | Haas, Brian J. | Hamilton, Holli A. | Harris, Emily L. | Hepburn, Theresa A. | Herter, Brandi | Hoffmann, Diane E. | Holder, Michael E. | Howarth, Clinton | Huang, Katherine H. | Huse, Susan M. | Izard, Jacques | Jansson, Janet K. | Jiang, Huaiyang | Jordan, Catherine | Joshi, Vandita | Katancik, James A. | Keitel, Wendy A. | Kelley, Scott T. | Kells, Cristyn | Kinder-Haake, Susan | King, Nicholas B. | Knight, Rob | Knights, Dan | Kong, Heidi H. | Koren, Omry | Koren, Sergey | Kota, Karthik C. | Kovar, Christie L. | Kyrpides, Nikos C. | La Rosa, Patricio S. | Lee, Sandra L. | Lemon, Katherine P. | Lennon, Niall | Lewis, Cecil M. | Lewis, Lora | Ley, Ruth E. | Li, Kelvin | Liolios, Konstantinos | Liu, Bo | Liu, Yue | Lo, Chien-Chi | Lozupone, Catherine A. | Lunsford, R. Dwayne | Madden, Tessa | Mahurkar, Anup A. | Mannon, Peter J. | Mardis, Elaine R. | Markowitz, Victor M. | Mavrommatis, Konstantinos | McCorrison, Jamison M. | McDonald, Daniel | McEwen, Jean | McGuire, Amy L. | McInnes, Pamela | Mehta, Teena | Mihindukulasuriya, Kathie A. | Miller, Jason R. | Minx, Patrick J. | Newsham, Irene | Nusbaum, Chad | O’Laughlin, Michelle | Orvis, Joshua | Pagani, Ioanna | Palaniappan, Krishna | Patel, Shital M. | Pearson, Matthew | Peterson, Jane | Podar, Mircea | Pohl, Craig | Pollard, Katherine S. | Priest, Margaret E. | Proctor, Lita M. | Qin, Xiang | Raes, Jeroen | Ravel, Jacques | Reid, Jeffrey G. | Rho, Mina | Rhodes, Rosamond | Riehle, Kevin P. | Rivera, Maria C. | Rodriguez-Mueller, Beltran | Rogers, Yu-Hui | Ross, Matthew C. | Russ, Carsten | Sanka, Ravi K. | Pamela Sankar, J. | Sathirapongsasuti, Fah | Schloss, Jeffery A. | Schloss, Patrick D. | Schmidt, Thomas M. | Scholz, Matthew | Schriml, Lynn | Schubert, Alyxandria M. | Segata, Nicola | Segre, Julia A. | Shannon, William D. | Sharp, Richard R. | Sharpton, Thomas J. | Shenoy, Narmada | Sheth, Nihar U. | Simone, Gina A. | Singh, Indresh | Smillie, Chris S. | Sobel, Jack D. | Sommer, Daniel D. | Spicer, Paul | Sutton, Granger G. | Sykes, Sean M. | Tabbaa, Diana G. | Thiagarajan, Mathangi | Tomlinson, Chad M. | Torralba, Manolito | Treangen, Todd J. | Truty, Rebecca M. | Vishnivetskaya, Tatiana A. | Walker, Jason | Wang, Lu | Wang, Zhengyuan | Ward, Doyle V. | Warren, Wesley | Watson, Mark A. | Wellington, Christopher | Wetterstrand, Kris A. | White, James R. | Wilczek-Boney, Katarzyna | Wu, Yuan Qing | Wylie, Kristine M. | Wylie, Todd | Yandava, Chandri | Ye, Liang | Ye, Yuzhen | Yooseph, Shibu | Youmans, Bonnie P. | Zhang, Lan | Zhou, Yanjiao | Zhu, Yiming | Zoloth, Laurie | Zucker, Jeremy D. | Birren, Bruce W. | Gibbs, Richard A. | Highlander, Sarah K. | Weinstock, George M. | Wilson, Richard K. | White, Owen
Nature  2012;486(7402):215-221.
A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.
doi:10.1038/nature11209
PMCID: PMC3377744  PMID: 22699610
12.  Validation Data-Based Adjustments for Outcome Misclassification in Logistic Regression:An Illustration 
Epidemiology (Cambridge, Mass.)  2011;22(4):589-597.
Misclassification of binary outcome variables is a known source of potentially serious bias when estimating adjusted odds ratios. Although researchers have described frequentist and Bayesian methods for dealing with the problem, these methods have seldom fully bridged the gap between statistical research and epidemiologic practice. In particular, there have been few real-world applications of readily grasped and computationally accessible methods that make direct use of internal validation data to adjust for differential outcome misclassification in logistic regression. In this paper, we illustrate likelihood-based methods for this purpose that can be implemented using standard statistical software. Using main study and internal validation data from the HIV Epidemiology Research Study, we demonstrate how misclassification rates can depend on the values of subject-specific covariates, and illustrate the importance of accounting for this dependence. Simulation studies confirm the effectiveness of the maximum likelihood approach. We emphasize clear exposition of the likelihood function itself, to permit the reader to easily assimilate appended computer code that facilitates sensitivity analyses as well as the efficient handling of main/external and main/internal validation-study data. These methods are readily applicable under random cross-sectional sampling, and we discuss the extent to which the main/internal analysis remains appropriate under outcome-dependent (case-control) sampling.
doi:10.1097/EDE.0b013e3182117c85
PMCID: PMC3454464  PMID: 21487295
13.  Varicella Zoster Virus (Chickenpox) Infection in Pregnancy 
Congenital varicella syndrome, maternal varicella zoster virus pneumonia and neonatal varicella infection are associated with serious feto-maternal morbidity and not infrequently with mortality. Vaccination against Varicella zoster virus can prevent the disease and outbreak control limits the exposure of pregnant women to the infectious agent. Maternal varicella zoster immune globulin (VZIG) administration before rash development, with or without antivirals medications can modify progression of the disease.
doi:10.1111/j.1471-0528.2011.02983.x
PMCID: PMC3155623  PMID: 21585641
Varicella; Zoster; Virus; Chickenpox; Infection; Pregnancy
14.  Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis 
The purpose of this study was to determine whether the administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation reduces the risk of preterm birth and late miscarriage. We conducted a systematic review and metaanalysis of randomized controlled trials of the early administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation. Five trials that comprised 2346 women were included. Clindamycin that was administered at <22 weeks of gestation was associated with a significantly reduced risk of preterm birth at <37 weeks of gestation and late miscarriage. There were no overall differences in the risk of preterm birth at <33 weeks of gestation, low birthweight, very low birthweight, admission to neonatal intensive care unit, stillbirth, peripartum infection, and adverse effects. Clindamycin in early pregnancy in women with abnormal vaginal flora reduces the risk of spontaneous preterm birth at <37 weeks of gestation and late miscarriage. There is evidence to justify further randomized controlled trials of clindamycin for the prevention of preterm birth. However, a deeper understanding of the vaginal microbiome, mucosal immunity, and the biology of bacterial vaginosis will be needed to inform the design of such trials.
doi:10.1016/j.ajog.2011.03.047
PMCID: PMC3217181  PMID: 22071048
antibiotic; bacterial vaginosis; clindamycin; late miscarriage; preterm birth
15.  Effect of pH on In Vitro Susceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use 
The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH, C. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90 for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0.
doi:10.1128/AAC.05025-11
PMCID: PMC3294902  PMID: 22232293
16.  Lack of Association of Herpes Simplex Virus Type 2 Seropositivity With the Progression of HIV Infection in the HERS Cohort 
American Journal of Epidemiology  2011;173(7):837-844.
Many studies have chronicled the “epidemiologic synergy” between human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). HIV adversely affects the natural history of HSV-2 and results in more frequent and severe HSV-2 reactivation. Few longitudinal studies, however, have examined whether HSV-2 is associated with increased HIV plasma viral loads or decreased CD4 counts. The authors estimated the effect of HSV-2 seropositivity on HIV RNA viral load and on CD4 count over time among 777 HIV-seropositive US women not receiving suppressive HSV-2 therapy in the HIV Epidemiology Research Study (1993–2000). Linear mixed models were used to assess the effect of HSV-2 on log HIV viral load and CD4 count/mm3 prior to widespread initiation of highly active antiretroviral therapy. Coinfection with HSV-2 was not associated with HIV RNA plasma viral loads during study follow-up. There was a statistically significant association between HSV-2 seropositivity and CD4 count over time, but this difference was small and counterintuitive at an increase of 8 cells/mm3 (95% confidence interval: 2, 14) per year among HSV-2-seropositive women compared with HSV-2-seronegative women. These data do not support a clinically meaningful effect of baseline HSV-2 seropositivity on the trajectories of HIV plasma viral loads or CD4 counts.
doi:10.1093/aje/kwq432
PMCID: PMC3105280  PMID: 21372062
CD4 lymphocyte count; herpes simplex; herpesvirus 2, human; HIV; viral load
17.  The vaginal microbiome: New information about genital tract flora using molecular based techniques 
Vaginal microbiome studies provide information which may change the way we define vaginal flora. Normal flora appears dominated by one or two species of Lactobacillus. Significant numbers of healthy women lack appreciable numbers of vaginal lactobacilli. Bacterial vaginosis (BV) is not a single entity, but different bacterial communities or profiles of greater microbial diversity than is evident from cultivation-dependent studies. BV should be considered a syndrome of variable composition which results in different symptoms, phenotypical outcomes, and responses to different antibiotic regimens. This information may help to elucidate the link between BV and infection-related adverse outcomes of pregnancy.
doi:10.1111/j.1471-0528.2010.02840.x
PMCID: PMC3055920  PMID: 21251190
18.  Current Debate on the Use of Antibiotic Prophylaxis for Cesarean Section 
Cesarean delivery is frequently complicated by surgical site infections (SSIs), endometritis and urinary tract infection. Most SSIs occur after discharge from hospital, and are increasingly being used as performance indicators. Worldwide, the rate of cesarean delivery is increasing. Evidence-based guidelines recommended the use of prophylactic antibiotics prior to surgical incision. An exception is made for cesarean delivery, where narrow-range antibiotics are administered post umbilical cord clamping because of putative neonatal benefit. However, recent evidence supports the use of pre-incision, broad-spectrum antibiotics which result in less maternal morbidity with no disadvantage to the neonate.
doi:10.1111/j.1471-0528.2010.02729.x
PMCID: PMC3059069  PMID: 21159119
19.  Parvovirus B19 Infection in Human Pregnancy 
Human parvovirus B19 infection is widespread. Approximately 30-50% of pregnant women are non-immune and vertical transmission is common following maternal infection in pregnancy. Fetal infection may be associated with a normal outcome but fetal death may also occur without ultrasound evidence of infections sequelae. B19 infection should be considered in any case of non-immune hydrops. Diagnosis is mainly through serology and PCR. Surveillance requires sequential ultrasound and Doppler screening for signs of fetal anemia, heart failure, and hydrops. Immunoglobulins antiviral and vaccination are not yet available but intrauterine transfusion in selected cases can be lifesaving.
doi:10.1111/j.1471-0528.2010.02749.x
PMCID: PMC3059196  PMID: 21040396
20.  Association between Semen Exposure and Incident Bacterial Vaginosis 
Objective. To identify correlates of incident bacterial vaginosis (BV) diagnosed with Nugent scoring among high-risk women. Study Design. We conducted both cohort and case-crossover analyses, stratified by HIV infection status, based on 871 HIV-infected and 439 HIV-uninfected participants in the HIV Epidemiology Research Study, conducted in 4 US sites in 1993–2000. Results. BV incidence was 21% and 19% among HIV-infected and -uninfected women, respectively. Fewer correlates of BV were found with case-crossover than with cohort design. Reporting frequent coitus (regardless of consistency of condom use) was correlated with BV in cohort analyses but not in case-crossover analyses. The sole correlate of BV in both types of analyses was the detection of spermatozoa on Gram stain, which is a marker of semen exposure. Conclusion. The inconsistent association between condom use and BV in prior studies could be from reporting bias. We found evidence of a relationship between semen exposure and incident BV.
doi:10.1155/2011/842652
PMCID: PMC3235572  PMID: 22190844
22.  Bacterial Vaginosis and the Natural History of Human Papillomavirus 
Objective. To evaluate associations between common vaginal infections and human papillomavirus (HPV). Study Design. Data from up to 15 visits on 756 HIV-infected women and 380 high-risk HIV-uninfected women enrolled in the HIV Epidemiology Research Study (HERS) were evaluated for associations of bacterial vaginosis, trichomoniasis, and vaginal Candida colonization with prevalent HPV, incident HPV, and clearance of HPV in multivariate analysis. Results. Bacterial vaginosis (BV) was associated with increased odds for prevalent (aOR = 1.14, 95% CI: 1.04, 1.26) and incident (aOR = 1.24, 95% CI: 1.04, 1.47) HPV and with delayed clearance of infection (aHR = 0.84, 95% CI: 0.72, 0.97). Whereas BV at the preceding or current visit was associated with incident HPV, in an alternate model for the outcome of incident BV, HPV at the current, but not preceding, visit was associated with incident BV. Conclusion. These findings underscore the importance of prevention and successful treatment of bacterial vaginosis.
doi:10.1155/2011/319460
PMCID: PMC3159014  PMID: 21869857
23.  Septic Shock Due to Candidemia: Outcomes and Predictors of Shock Development 
Background
The present report describes the outcomes of a cohort of patients with Candida induced septic shock.
Methods
Retrospective analysis of individuals who had at least one positive blood culture for Candida species ≥ 48 h after ICU admission. Data from patients that developed septic shock within 48 hr of the positive blood culture were compared to non-shock candidemic patients. Patients with a concomitant bacteremia and/or endocarditis were excluded.
Results
Fifteen patients with Candida induced septic shock were studied and compared to 35 candidemic patients without shock. Overall mortality was 76% (87 % among those who had shock). A high proportion of non-albicans Candida species causing fungemia (74%) was observed. All patients with shock were receiving antibiotics but not antifungal treatment at the time of shock development, eight were on parenteral nutrition, six on steroids and nine had a cancer history. High dose fluconazole was the most common initial treatment provided. Four patients died before receiving any antifungal treatment. Time in ICU before the development of candidemia was identified as a predictor of shock development (higher chance if fungemia developed < 7 days after ICU admission).
Conclusions
Septic shock due to invasive candidiasis is a near fatal condition. No conventional risk factors were identified to predict shock development other than time (shorter) spent in ICU before the development of candidemia. We encourage clinicians to consider the initiation of appropriate empiric antifungal treatment in high-risk patients who develop septic shock while on antimicrobial treatment.
Keywords
Septic shock; Candidemia; Outcome; Predictor
doi:10.4021/jocmr536w
PMCID: PMC3140925  PMID: 21811532
24.  Human Leukocyte Antigen Class I Supertypes and HIV-1 Control in African Americans▿  
Journal of Virology  2009;84(5):2610-2617.
The role of human leukocyte antigen (HLA) class I supertypes in controlling human immunodeficiency virus type 1 (HIV-1) infection in African Americans has not been established. We examined the effects of the HLA-A and HLA-B alleles and supertypes on the outcomes of HIV-1 clade B infection among 338 African American women and adolescents. HLA-B58 and -B62 supertypes (B58s and B62s) were associated with favorable HIV-1 disease control (proportional odds ratio [POR] of 0.33 and 95% confidence interval [95% CI] of 0.21 to 0.52 for the former and POR of 0.26 and 95% CI of 0.09 to 0.73 for the latter); B7s and B44s were associated with unfavorable disease control (POR of 2.39 and 95% CI of 1.54 to 3.73 for the former and POR of 1.63 and 95% CI of 1.08 to 2.47 for the latter). In general, individual alleles within specific B supertypes exerted relatively homogeneous effects. A notable exception was B27s, whose protective influence (POR, 0.58; 95% CI, 0.35 to 0.94) was masked by the opposing effect of its member allele B*1510. The associations of most B supertypes (e.g., B58s and B7s) were largely explained either by well-known effects of constituent B alleles or by effects of previously unimplicated B alleles aggregated into a particular supertype (e.g., B44s and B62s). A higher frequency of HLA-B genotypic supertypes correlated with a higher mean viral load (VL) and lower mean CD4 count (Pearson's r = 0.63 and 0.62, respectively; P = 0.03). Among the genotypic supertypes, B58s and its member allele B*57 contributed disproportionately to the explainable VL variation. The study demonstrated the dominant role of HLA-B supertypes in HIV-1 clade B-infected African Americans and further dissected the contributions of individual class I alleles and their population frequencies to the supertype effects.
doi:10.1128/JVI.01962-09
PMCID: PMC2820922  PMID: 20032191
25.  Guidelines for the treatment of bacterial vaginosis: focus on tinidazole 
Bacterial vaginosis (BV) is a complex vaginal infection most commonly associated with women of child-bearing age. Risk factors for BV are numerous. There are currently multiple clinical and laboratory tests for diagnosis of BV, including the most commonly used diagnostic methods: Amsel’s criteria or Nugent’s Gram stain scale. The mainstay of BV therapy is metronidazole, but tinidazole as well as a few other agents have also been used successfully. Tinidazole is the second nitroimidazole antiprotozoal agent and a structural derivative of metronidazole. With a favorable pharmacokinetic profile and reduced side effects, tinidazole is an alternative agent for BV treatment. There are minimal head-to-head comparative data to establish tinidazole’s superiority to metronidazole or other therapeutic agents. Available data suggest tinidazole has a role in special populations particularly for refractory or relapsing BV.
PMCID: PMC2710380  PMID: 19707258
bacterial vaginosis; vaginosis; tinidazole; Gardnerella

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