by
Matthew N. Ezewudo;
Sandeep J. Joseph;
Santiago Castillo-Ramirez;
Deborah Dean;
Carlos Del Rio;
Xavier Didelot;
Jo-Anne Dillon;
Richard F. Selden;
William Shafer;
Rosemary S. Turingan;
Magnus Unemo;
Timothy Read
Neisseria gonorrhoeae is the causative agent of gonorrhea, a sexually transmitted infection (STI) of major importance. As a result of antibiotic resistance, there are now limited options for treating patients. We collected draft genome sequence data and associated metadata data on 76 N. gonorrhoeae strains from around the globe and searched for known determinants of antibiotics resistance within the strains. The population structure and evolutionary forces within the pathogen population were analyzed. Our results indicated a cosmopolitan gonoccocal population mainly made up of five subgroups. The estimated ratio of recombination to mutation (r/m = 2.2) from our data set indicates an appreciable level of recombination occurring in the population. Strains with resistance phenotypes to more recent antibiotics (azithromycin and cefixime) were mostly found in two of the five population subgroups.
Objective
Age disassortativity is one hypothesis for HIV disparities between Black and White MSM. We examined differences in age mixing by race and the effect of partner age difference on the association between race and HIV status.
Design
We used data from four studies of MSM. Participants reported information about recent sexual partners, including age, race, and sexual behavior. Two studies were online with a US sample and two focused on MSM in Atlanta.
Methods
We computed concordance correlation coefficients (CCCs) by race across strata of partner type, participant HIV status, condom use, and number of partners. We used Wilcoxon rank-sum tests to compare Black and White MSM on partner age differences across five age groups. Finally, we used logistic regression models using race, age, and partner age difference to determine the odds ratio of HIV-positive serostatus.
Results
Of 48 CCC comparisons, Black MSM were more age-disassortative than White MSM in only two. Furthermore, of 20 comparisons of median partner age, Black and White MSM differed in two age groups. One indicated larger age gaps among the Black MSM (18-19). Prevalent HIV infection was associated with race and age. Including partner age difference in the model resulted in a 2% change in the relative odds of infection among Black MSM.
Conclusions
Partner age disassortativity and partner age differences do not differ by race. Partner age difference offers little predictive value in understanding prevalent HIV infection among Black and White MSM, including diagnosis of HIV-positive status among self-reported HIV-negative individuals.
Research data warehouses integrate research and patient data from one or more sources into a single data model that is designed for research. Typically, institutions update their warehouse by fully reloading it periodically. The alternative is to update the warehouse incrementally with new, changed and/or deleted data. Full reloads avoid having to correct and add to a live system, but they can render the data outdated for clinical trial accrual. They place a substantial burden on source systems, involve intermittent work that is challenging to resource, and may involve tight coordination across IT and informatics units. We have implemented daily incremental updating for our i2b2 data warehouse. Incremental updating requires substantial up-front development, and it can expose provisional data to investigators. However, it may support more use cases, it may be a better fit for academic healthcare IT organizational structures, and ongoing support needs appear to be similar or lower.
Objective
Lung infections are a leading cause of death in HIV-infected individuals. Measuring redox in HIV-infected individuals may identify those with chronic oxidative stress who are at increased risk for lung infection. We sought to estimate the association between HIV infection and oxidative stress in the lung, as reflected by decreased levels of glutathione and cysteine in the epithelial lining fluid.
Methods
Bronchoalveolar lavage (BAL) fluid was collected from healthy HIV-infected subjects and controls. Individuals were excluded if they had evidence of major medical co-morbidities, were malnourished or smoked cigarettes.
Results
We enrolled 22 otherwise healthy HIV and 21 non-HIV subjects. Among the HIV-infected subjects, 72.7% were on anti-retroviral therapy (ART) with a median CD4 count of 438 (279.8–599) and viral load of 0 (0–1.0) log copies/mL. There were no significant differences in median BAL fluid glutathione and cysteine levels between HIV and HIV-uninfected subjects. However, BAL glutathione was significantly higher in HIV-infected subjects on anti-retroviral therapy (ART) compared to those not on ART [367.4 (102–965.3) nM vs. 30.8 (1.0–112.1) nM, p = 0.008]. Further, HIV infection with ART was associated with an OR of 2.02 for increased BAL glutathione when adjusted for age and body mass index, whereas HIV infection without ART was associated with an OR of 2.17 for decreased BAL glutathione.
Conclusion
HIV infection without ART was associated with increased oxidative stress, as reflected by decreased alveolar glutathione levels, in otherwise healthy HIV-infected individuals. Further study needs to be done identify predictors of lung health in HIV and to address the role of ART in improving lung immunity.
Background
Improved tests to diagnose latent TB infection (LTBI) are needed. We sought to evaluate the performance of two commercially available interferon-gamma release assays (IGRAs) compared to the tuberculin skin test (TST) for the diagnosis of LTBI and to identify risk factors for LTBI among HIV-infected individuals in Georgia, a country with high rates of TB.
Methods
HIV-patients were enrolled from the National AIDS Center in Tbilisi, Georgia. After providing informed consent, each participant completed a questionnaire, had blood drawn for QuantiFERON-TB Gold in-Tube (QFT-GIT) and T-SPOT.TB testing and had a TST placed. The TST was read at 48–72 hrs with ≥ 5 mm induration considered positive.
Results
Between 2009–2011, 240 HIV-infected persons (66% male) with a median age of 38 years and a median CD4 count of 255 cells/μl (IQR: 124–412) had diagnostic testing for LTBI performed. 94% had visible evidence of a BCG scar. The TST was positive in 41 (17%) patients; QFT-GIT in 70 (29%); and T-SPOT.TB in 56 (24%). At least one diagnostic test was positive in 109 (45%) patients and only among 13 (5%) patients were all three tests positive. Three (1%) QFT-GIT and 19 (8%) T-SPOT.TB test results were indeterminate. The agreement among all pairs of tests was poor: QFT-GIT vs. T-SPOT.TB (κ = 0.18, 95% CI .07-.30), QFT-GIT vs. TST (κ = 0.29, 95% CI .16-.42), and TST vs. T-SPOT.TB (κ = 0.22, 95% CI .07-.29). Risk factors for LTBI varied by diagnostic test and none showed associations between positive test results and well-known risk factors for TB, such as imprisonment, drug abuse and immunological status.
Conclusions
A high proportion of HIV patients had at least one positive diagnostic test for LTBI; however, there was very poor agreement among all tests. This lack of agreement makes it difficult to know which test is superior and most appropriate for LTBI testing among HIV-infected patients. While further follow-up studies will help determine the predictive ability of different LTBI tests, improved modalities are needed for accurate detection of LTBI and assessment of risk of developing active TB among HIV-infected patients.
Human immunodeficiency virus (HIV) is a manageable chronic disease in the United States, yet the first author's experience on a general infectious diseases (ID) consult service illustrates that certain areas of the United States still experience high rates of acquired immune deficiency syndrome-related complications.
by
Joseph T. King;
Adam J. Gordon;
Melissa F. Perkal;
Stephen Crystal;
Ronnie A. Rosenthal;
Maria C. Rodriguez-Barradas;
Adeel A. Butt;
Cynthia L. Gibert;
David Rimland;
Michael S. Simberkoff;
Amy C. Justice
STUDY DESIGN.: Retrospective analysis of nationwide Veterans Health Administration clinical and administrative data. OBJECTIVE.: Examine the association between HIV infection and the rate of spine surgery for degenerative spine disease. SUMMARY OF BACKGROUND DATA.: Combination antiretroviral therapy has prolonged survival in HIV-infected patients, increasing the prevalence of chronic conditions such as degenerative spine disease that may require spine surgery. METHODS.: We studied all HIV-infected patients under care in the Veterans Health Administration from 1996 to 2008 (n = 40,038) and uninfected comparator patients (n = 79,039) matched on age, sex, race, year, and geographic region. The primary outcome was spine surgery for degenerative spine disease, defined by International Classification of Diseases, Ninth Revision procedure and diagnosis codes. We used a multivariate Poisson regression to model spine surgery rates by HIV infection status, adjusting for factors that might affect suitability for surgery (demographics, year, comorbidities, body mass index, combination antiretroviral therapy, and laboratory values). RESULTS.: Two hundred twenty-eight HIV-infected and 784 uninfected patients underwent spine surgery for degenerative spine disease during 700,731 patient-years of follow-up (1.44 surgeries per 1000 patient-years). The most common procedures were spinal decompression (50%) and decompression and fusion (33%); the most common surgical sites were the lumbosacral (50%) and cervical (40%) spine. Adjusted rates of surgery were lower for HIV-infected patients (0.86 per 1000 patient-years of follow-up) than for uninfected patients (1.41 per 1000 patient-years; incidence rate ratio 0.61, 95% confidence interval: 0.51-0.74, P < 0.001). Among HIV-infected patients, there was a trend toward lower rates of spine surgery in patients with detectable viral load levels (incidence rate ratio 0.76, 95% confidence interval: 0.55-1.05, P = 0.099). CONCLUSION.: In the Veterans Health Administration, HIV-infected patients experience significantly reduced rates of surgery for degenerative spine disease. Possible explanations include disease prevalence, emphasis on treatment of nonspine HIV-related symptoms, surgical referral patterns, impact of HIV on surgery risk-benefit ratio, patient preferences, and surgeon bias.
Synthetic peptide vaccines provide the advantages of safety, stability and low cost. The success of this approach is highly dependent on efficient epitope identification and synthetic strategies for efficacious delivery. In malaria, the Merozoite Surface Protein-9 of Plasmodium vivax (PvMSP9) has been considered a vaccine candidate based on the evidence that specific antibodies were able to inhibit merozoite invasion and recombinant proteins were highly immunogenic in mice and humans. However the identities of linear B-cell epitopes within PvMSP9 as targets of functional antibodies remain undefined. We used several publicly-available algorithms for in silico analyses and prediction of relevant B cell epitopes within PMSP9. We show that the tandem repeat sequence EAAPENAEPVHENA (PvMSP9E795-A808) present at the C-terminal region is a promising target for antibodies, given its high combined score to be a linear epitope and located in a putative intrinsically unstructured region of the native protein. To confirm the predictive value of the computational approach, plasma samples from 545 naturally exposed individuals were screened for IgG reactivity against the recombinant PvMSP9-RIRII729-972 and a synthetic peptide representing the predicted B cell epitope PvMSP9E795-A808. 316 individuals (58%) were responders to the full repetitive region PvMSP9-RIRII, of which 177 (56%) also presented total IgG reactivity against the synthetic peptide, confirming it validity as a B cell epitope. The reactivity indexes of anti-PvMSP9-RIRII and anti-PvMSP9E795-A808 antibodies were correlated. Interestingly, a potential role in the acquisition of protective immunity was associated with the linear epitope, since the IgG1 subclass against PvMSP9E795-A808 was the prevalent subclass and this directly correlated with time elapsed since the last malaria episode; however this was not observed in the antibody responses against the full PvMSP9-RIRII. In conclusion, our findings identified and experimentally confirmed the potential of PvMSP9E795-A808 as an immunogenic linear B cell epitope within the P. vivax malaria vaccine candidate PvMSP9 and support its inclusion in future subunit vaccines.
Background
There are increasing efforts to bring high-throughput systems biology techniques to bear on complex animal model systems, often with a goal of learning about underlying regulatory network structures (e.g., gene regulatory networks). However, complex animal model systems typically have significant limitations on cohort sizes, number of samples, and the ability to perform follow-up and validation experiments. These constraints are particularly problematic for many current network learning approaches, which require large numbers of samples and may predict many more regulatory relationships than actually exist.
Results
Here, we test the idea that by leveraging the accuracy and efficiency of classifiers, we can construct high-quality networks that capture important interactions between variables in datasets with few samples. We start from a previously-developed tree-like Bayesian classifier and generalize its network learning approach to allow for arbitrary depth and complexity of tree-like networks. Using four diverse sample networks, we demonstrate that this approach performs consistently better at low sample sizes than the Sparse Candidate Algorithm, a representative approach for comparison because it is known to generate Bayesian networks with high positive predictive value. We develop and demonstrate a resampling-based approach to enable the identification of a viable root for the learned tree-like network, important for cases where the root of a network is not known a priori. We also develop and demonstrate an integrated resampling-based approach to the reduction of variable space for the learning of the network. Finally, we demonstrate the utility of this approach via the analysis of a transcriptional dataset of a malaria challenge in a non-human primate model system, Macaca mulatta, suggesting the potential to capture indicators of the earliest stages of cellular differentiation during leukopoiesis.
Conclusions
We demonstrate that by starting from effective and efficient approaches for creating classifiers, we can identify interesting tree-like network structures with significant ability to capture the relationships in the training data. This approach represents a promising strategy for inferring networks with high positive predictive value under the constraint of small numbers of samples, meeting a need that will only continue to grow as more high-throughput studies are applied to complex model systems.