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1.  Associations of Non-Hodgkin Lymphoma (NHL) Risk With Autoimmune Conditions According to Putative NHL Loci 
American Journal of Epidemiology  2015;181(6):406-421.
Autoimmune conditions and immune system–related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988–2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).
PMCID: PMC4402340  PMID: 25713336
autoimmune conditions; environment; genetics; interaction; human leukocyte antigen; lymphoma, non-Hodgkin; tumor necrosis factor
2.  The facilitators and barriers associated with implementation of a patient-centered medical home in VHA 
The patient-centered medical home (PCMH) is a team-based, comprehensive model of primary care. When effectively implemented, PCMH is associated with higher patient satisfaction, lower staff burnout, and lower hospitalization for ambulatory care-sensitive conditions. However, less is known about what factors contribute to (or hinder) PCMH implementation.
We explored the associations of specific facilitators and barriers reported by primary care employees with a previously validated, clinic-level measure of PCMH implementation, the Patient Aligned Care Team Implementation Progress Index (Pi2).
We used a 2012 survey of primary care employees in the Veterans Health Administration to perform cross-sectional, respondent-level multinomial regressions. The dependent variable was the Pi2 categorized as high implementation (top decile, 54 clinics, 235 respondents), medium implementation (middle eight deciles, 547 clinics, 4537 respondents), and low implementation (lowest decile, 42 clinics, 297 respondents) among primary care clinics. The independent variables were ordinal survey items rating 19 barriers to patient-centered care and 10 facilitators of PCMH implementation. For facilitators, we explored clinic Pi2 score decile both as a function of respondent-reported availability of facilitators and of rating of facilitator helpfulness.
The availability of five facilitators was associated with higher odds of a respondent’s clinic’s Pi2 scores being in the highest versus lowest decile: teamlet huddles (OR = 3.91), measurement tools (OR = 3.47), regular team meetings (OR = 2.88), information systems (OR = 2.42), and disease registries (OR = 2.01). The helpfulness of four facilitators was associated with higher odds of a respondent’s clinic’s Pi2 scores being in the highest versus lowest decile. Six barriers were associated with significantly higher odds of a respondent’s clinic’s Pi2 scores being in the lowest versus highest decile, with the strongest associations for the difficulty recruiting and retaining providers (OR = 2.37) and non-provider clinicians (OR = 2.17). Results for medium versus low Pi2 score clinics were similar, with fewer, smaller significant associations, all in the expected direction.
A number of specific barriers and facilitators were associated with PCMH implementation, notably recruitment and retention of clinicians, team huddles, and local education. These findings can guide future research, and may help healthcare policy makers and leaders decide where to focus attention and limited resources.
PMCID: PMC4766632  PMID: 26911135
3.  Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) study 
In the Microbicide Trial Network MTN-003 (VOICE) study, a Phase IIB pre-exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting.
We included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face-to-face interviews (FTFI), audio computer-assisted self-interviewing (ACASI) and pharmacy-returned product counts (PC). TFV concentrations <0.31 ng/mL in plasma (oral group) and <8.5 ng/swab in vaginal group were defined as “PK non-adherent.” Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over-reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model.
In this random adherence cohort of VOICE participants assigned to active products, (N=472), PK non-adherence was 69% in the oral group (N=314) and 65% in the vaginal group (N=158). Behaviourally, ≤10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤43%). None of the regression models had an AUC >0.65 for any single or combined behavioural measures. Significant (p<0.05) correlates of over-reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over-reporting.
PK measures indicated similarly low adherence for the oral and vaginal groups. No behavioural measure accurately predicted PK non-adherence. Accurate real-time measures to monitor product adherence are urgently needed.
Trial registration: identifier: NCT00705679
PMCID: PMC4744323  PMID: 26850270
microbicide; pre-exposure prophylaxis; adherence measurement; pharmacokinetic drug detection; HIV
4.  The Role of Altruistic Values in Motivating Underrepresented Minority Students for Biomedicine 
Bioscience  2015;65(2):183-188.
Understanding how cultural values influence undergraduate students’ science research experiences and career interest is important in efforts to broaden participation and to diversify the biomedical research workforce. The results from our prospective longitudinal study demonstrated that underrepresented minority student (URM) research assistants who see the altruistic value of conducting biomedical research feel more psychologically involved with their research over time, which, in turn, enhances their interest in pursuing a scientific research career. These altruistic motives are uniquely influential to URM students and appear to play an important role in influencing their interest in scientific research careers. Furthermore, seeing how research can potentially affect society and help one's community does not replace typical motives for scientific discovery (e.g., passion, curiosity, achievement), which are important for all students. These findings point to simple strategies for educators, training directors, and faculty mentors to improve retention among undergraduate URM students in biomedicine and the related sciences.
PMCID: PMC4731875  PMID: 26834259
science education; research motivation; broadening participation; underrepresented minority students; science interest
5.  World checklist of hornworts and liverworts 
PhytoKeys  2016;1-828.
A working checklist of accepted taxa worldwide is vital in achieving the goal of developing an online flora of all known plants by 2020 as part of the Global Strategy for Plant Conservation. We here present the first-ever worldwide checklist for liverworts (Marchantiophyta) and hornworts (Anthocerotophyta) that includes 7486 species in 398 genera representing 92 families from the two phyla. The checklist has far reaching implications and applications, including providing a valuable tool for taxonomists and systematists, analyzing phytogeographic and diversity patterns, aiding in the assessment of floristic and taxonomic knowledge, and identifying geographical gaps in our understanding of the global liverwort and hornwort flora. The checklist is derived from a working data set centralizing nomenclature, taxonomy and geography on a global scale. Prior to this effort a lack of centralization has been a major impediment for the study and analysis of species richness, conservation and systematic research at both regional and global scales. The success of this checklist, initiated in 2008, has been underpinned by its community approach involving taxonomic specialists working towards a consensus on taxonomy, nomenclature and distribution.
PMCID: PMC4758082  PMID: 26929706
Marchantiophyta; Anthocerophyta; nomenclature; taxonomy
6.  Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA 
Annals of the Rheumatic Diseases  2014;75(1):242-252.
Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.
Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.
The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.
These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
PMCID: PMC4717392  PMID: 25180293
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
7.  The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share 
Kottyan, Leah C. | Zoller, Erin E. | Bene, Jessica | Lu, Xiaoming | Kelly, Jennifer A. | Rupert, Andrew M. | Lessard, Christopher J. | Vaughn, Samuel E. | Marion, Miranda | Weirauch, Matthew T. | Namjou, Bahram | Adler, Adam | Rasmussen, Astrid | Glenn, Stuart | Montgomery, Courtney G. | Hirschfield, Gideon M. | Xie, Gang | Coltescu, Catalina | Amos, Chris | Li, He | Ice, John A. | Nath, Swapan K. | Mariette, Xavier | Bowman, Simon | Rischmueller, Maureen | Lester, Sue | Brun, Johan G. | Gøransson, Lasse G. | Harboe, Erna | Omdal, Roald | Cunninghame-Graham, Deborah S. | Vyse, Tim | Miceli-Richard, Corinne | Brennan, Michael T. | Lessard, James A. | Wahren-Herlenius, Marie | Kvarnström, Marika | Illei, Gabor G. | Witte, Torsten | Jonsson, Roland | Eriksson, Per | Nordmark, Gunnel | Ng, Wan-Fai | Anaya, Juan-Manuel | Rhodus, Nelson L. | Segal, Barbara M. | Merrill, Joan T. | James, Judith A. | Guthridge, Joel M. | Hal Scofield, R. | Alarcon-Riquelme, Marta | Bae, Sang-Cheol | Boackle, Susan A. | Criswell, Lindsey A. | Gilkeson, Gary | Kamen, Diane L. | Jacob, Chaim O. | Kimberly, Robert | Brown, Elizabeth | Edberg, Jeffrey | Alarcón, Graciela S. | Reveille, John D. | Vilá, Luis M. | Petri, Michelle | Ramsey-Goldman, Rosalind | Freedman, Barry I. | Niewold, Timothy | Stevens, Anne M. | Tsao, Betty P. | Ying, Jun | Mayes, Maureen D. | Gorlova, Olga Y. | Wakeland, Ward | Radstake, Timothy | Martin, Ezequiel | Martin, Javier | Siminovitch, Katherine | Moser Sivils, Kathy L. | Gaffney, Patrick M. | Langefeld, Carl D. | Harley, John B. | Kaufman, Kenneth M.
Human Molecular Genetics  2014;24(2):582-596.
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5–TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5–TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10−49; OR = 1.38–1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10−27–10−32, OR = 1.7–1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5–TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5–TNPO3.
PMCID: PMC4275071  PMID: 25205108
8.  Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features 
Cancer Causes & Control  2015;27:81-91.
Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear.
Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders.
Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25–2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75–8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59–168) than Whites (OR 2.04, 95% 0.83–5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21–17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13–9.26).
The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-015-0685-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4703620  PMID: 26596855
Multiple myeloma; Family history; Genetic; Black; African American
9.  Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study 
Genes and immunity  2015;16(2):142-150.
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
PMCID: PMC4371129  PMID: 25569266
Biometrics  2014;70(3):742-750.
Estimating the effectiveness of a new intervention is usually the primary objective for HIV prevention trials. The Cox proportional hazard model is mainly used to estimate effectiveness by assuming that participants share the same risk under the covariates and the risk is always non-zero. In fact, the risk is only non-zero when an exposure event occurs, and participants can have a varying risk to transmit due to varying patterns of exposure events. Therefore, we propose a novel estimate of effectiveness adjusted for the heterogeneity in the magnitude of exposure among the study population, using a latent Poisson process model for the exposure path of each participant. Moreover, our model considers the scenario in which a proportion of participants never experience an exposure event and adopts a zero-inflated distribution for the rate of the exposure process. We employ a Bayesian estimation approach to estimate the exposure-adjusted effectiveness eliciting the priors from the historical information. Simulation studies are carried out to validate the approach and explore the properties of the estimates. An application example is presented from an HIV prevention trial.
PMCID: PMC4239192  PMID: 24845658
Hierarchical models; HIV prevention; Intercourse; Markov chain Monte Carlo; Per-exposure effectiveness; Zero-inflated gamma
PLoS ONE  2015;10(6):e0128857.
Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre-exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges.
ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial.
Between August 2012 and June 2014, 5516 women were screened and 2629 HIV-1 seronegative women between 18–45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22–31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis.
African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention.
PMCID: PMC4489588  PMID: 26061040
Constantly evolving technology and techniques within radiation therapy require practitioners to maintain a continuous approach to professional development and training. Systems of performance appraisal and adoption of regular feedback mechanisms are vital to support this development yet frequently lack structure and rely on informal peer support.
A Radiation Therapy Performance Appraisal Framework (RT-PAF) for radiation therapists in planning and simulation was developed to define expectations of practice and promote a supportive and objective culture of performance and skills appraisal. Evaluation of the framework was conducted via an anonymous online survey tool. Nine peer reviewers and fourteen recipients provided feedback on its effectiveness and the challenges and limitations of the approach.
Findings from the evaluation were positive and suggested that both groups gained benefit from and expressed a strong interest in embedding the approach more routinely. Respondents identified common challenges related to the limited ability to implement suggested development strategies; this was strongly associated with time and rostering issues.
This framework successfully defined expectations for practice and provided a fair and objective feedback process that focussed on skills development. It empowered staff to maintain their skills and reach their professional potential. Management support, particularly in regard to provision of protected time was highlighted as critical to the framework's ongoing success. The demonstrated benefits arising in terms of staff satisfaction and development highlight the importance of this commitment to the modern radiation therapy workforce.
PMCID: PMC4462983  PMID: 26229676
Benchmarking; evaluation; feedback; performance appraisal; radiation therapy
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
PMCID: PMC4069204  PMID: 24782186
HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18 month outcomes.
Randomized, placebo-controlled trial in four African countries. Infant diagnostic HIV testing was done regularly from birth, through 18 months. Kaplan-Meier analysis was used to assess 18 month cumulative infant HIV infection, HIV infection/or death and mortality rates.
Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower, among infants receiving daily NVP from 6 weeks to 6 months 1.1% (95% CI 0.2-1.8%), compared to placebo: 2.4% (95% CI 1.3-2.6%), p=0.049; but not significantly lower thereafter. Eighteen month postnatal infection rates were low: 2.2% [95% CI 1.1-3.3%] versus 3.1% [95% CI 1.9-4.4%], respectively, p=0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18 month postnatal infection rates (0.5%, 95% CI 0.0-1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI 1.9-5.5%); and infants of mothers with CD4 >350/mm3 not receiving ART (4.8%, 95% CI 2.7-6.8%), (p=0.46). There were no differences in adverse events between study arms.
This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age six weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.
PMCID: PMC3945386  PMID: 24189151
nevirapine; infant HIV prophylaxis; PMTCT
Primary leiomyosarcoma (LMS) of the renal vein is a rare tumour and poorly described in the literature. Surgical resection, using open and laparoscopic approaches, is the mainstay of treatment. In this report, we describe a patient with left renal vein LMS, report the first robotic laparoscopic resection for this tumor, and review the typical presentation, imaging, pathology and treatment for this rare clinical entity.
PMCID: PMC4455643  PMID: 26085883
There are limited data on prognostic utility of interferon-gamma (IFN-γ) release assays (IGRAs) for active tuberculosis (TB) among HIV-1 infected individuals.
Samples from a perinatal cohort of HIV-1 infected women in Kenya, obtained during pregnancy were tested using T-SPOT.TB IGRAs to detect Mycobacterium tuberculosis (MTB)-specific IFN-γ responses. IFN-γ (cut-off values>0, ≥6 and ≥10 spot forming cells/well (SFCs/well)) and CD4 cell count (cut-off values<250 and <350 cells/μL) were evaluated for sensitivity and specificity using a time dependent receiver operating characteristic (ROC) curve and positive predictive value (PPV) using Kaplan Meier method for future TB within one year postpartum.
Of 327 women, 9 developed TB within one year postpartum (Incidence rate (IR): 3.5/100 person-years of follow-up (pyfu); 95% confidence interval: 1.6–6.7/100 pyfu). IFN-γ≥6 SFCs/well was associated with an optimal trade-off between sensitivity (78%) and specificity (55%) and PPV of 5.9%. In women with CD4<250 cells/μL, sensitivity and specificity of IFN-γ≥6 SFCs/well were 89% and 63%, respectively and PPV was 19.2%.
Among HIV-1 infected women, IFN-γ response (≥6 SFCs/well) during pregnancy lacked high positive predictive value for postpartum TB but had higher sensitivity and positive predictive value among immunosuppressed women (CD4<250 cells/μL).
PMCID: PMC4339676  PMID: 24200267
TB IGRA; Predictive value; Sensitivity; Specificity; HIV-infected women
Intensity modulated radiotherapy (IMRT) is ideal for anal canal cancer (ACC), delivering high doses to irregular tumour volumes whilst minimising dose to surrounding normal tissues. Establishing achievable dose objectives is a challenge. The purpose of this paper was to utilise data collected in the Assessment of New Radiation Oncology Treatments and Technologies (ANROTAT) project to evaluate the feasibility of ACC IMRT dose planning objectives employed in the Australian situation.
Ten Australian centres were randomly allocated three data sets from 15 non-identifiable computed tomography data sets representing a range of disease stages and gender. Each data set was planned by two different centres, producing 30 plans. All tumour and organ at risk (OAR) contours, prescription and dose constraint details were provided. Dose–volume histograms (DVHs) for each plan were analysed to evaluate the feasibility of dose planning objectives provided.
All dose planning objectives for the bone marrow (BM) and femoral heads were achieved. Median planned doses exceeded one or more objectives for bowel, external genitalia and bladder. This reached statistical significance for bowel V30 (P = 0.04), V45 (P < 0.001), V50 (P < 0.001), external genitalia V20 (P < 0.001) and bladder V35 (P < 0.001), V40 (P = 0.01). Gender was found to be the only significant factor in the likelihood of achieving the bowel V50 (P = 0.03) and BM V30 constraints (P = 0.04).
The dose planning objectives used in the ANROTAT project provide a good starting point for ACC IMRT planning. To facilitate clinical implementation, it is important to prioritise OAR objectives and recognise factors that affect the achievability of these objectives.
PMCID: PMC4462981  PMID: 26229674
Anal canal; anus neoplasms; intensity; modulated; radiation oncology; radiotherapy
PLoS ONE  2015;10(1):e0115528.
Randomized clinical trials of HIV prevention in high-risk populations of women often assume that all participants have similar exposure to HIV. However, a substantial fraction of women enrolled in the trial may have no or low exposure to HIV. Our objective was to estimate the proportion of women exposed to HIV throughout a hypothetical high-risk study population.
A stochastic individual-based model was developed to simulate the sexual behavior and the risk of HIV acquisition for a cohort of sexually active HIV-uninfected women in high HIV prevalence settings. Key behavior and epidemic assumptions in the model were based on published studies on HIV transmission in South Africa. The prevalence of exposure, defined as the proportion of women who have sex with HIV-infected partner, and HIV incidence were evaluated.
Our model projects that in communities with HIV incidence rate of 1 per 100 person years, only 5-6% of women are exposed to HIV annually while in communities with an HIV incidence of 5 per 100 person years 20-25% of women are exposed to HIV. Approximately 70% of the new infections are acquired from partners with asymptomatic HIV.
Mathematical models suggest that a high proportion of women enrolled in HIV prevention trials may be unexposed to HIV even when incidence rates are high. The relationship between HIV exposure and other risk factors should be carefully analyzed when future clinical trials are planned.
PMCID: PMC4287619  PMID: 25569838
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
Genes and immunity  2014;15(5):275-281.
Multiple MHC loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6,400 informative xMHC SNPs. When conditioned on HLA and non-genetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and non-classic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.
PMCID: PMC4111776  PMID: 24784026
HIV-1; HLA; human MHC; SNP; viral load
Members of the P4 subfamily of P-type ATPases are thought to create and maintain lipid asymmetry in biological membranes by flipping specific lipids between membrane leaflets. In Arabidopsis, 7 of the 12 Aminophospholipid ATPase (ALA) family members are expressed in pollen. Here we show that double knockout of ALA6 and ALA7 (ala6/7) results in siliques with a ~2-fold reduction in seed set with a high frequency of empty seed positions near the bottom. Seed set was reduced to near zero when plants were grown under a hot/cold temperature stress. Reciprocal crosses indicate that the ala6/7 reproductive deficiencies are due to a defect related to pollen transmission. In-vitro growth assays provide evidence that ala6/7 pollen tubes are short and slow, with ~2-fold reductions in both maximal growth rate and overall length relative to wild-type. Outcrosses show that when ala6/7 pollen are in competition with wild-type pollen, they have a near 0% success rate in fertilizing ovules near the bottom of the pistil, consistent with ala6/7 pollen having short and slow growth defects. The ala6/7 phenotypes were rescued by the expression of either an ALA6-YFP or GFP-ALA6 fusion protein, which showed localization to both the plasma membrane and highly-mobile endomembrane structures. A mass spectrometry analysis of mature pollen grains revealed significant differences between ala6/7 and wild-type, both in the relative abundance of lipid classes and in the average number of double bonds present in acyl side chains. A change in the properties of the ala6/7 plasma membrane was also indicated by a ~10-fold reduction of labeling by lipophilic FM-dyes relative to wild-type. Together, these results indicate that ALA6 and ALA7 provide redundant activities that function to directly or indirectly change the distribution and abundance of lipids in pollen, and support a model in which ALA6 and ALA7 are critical for pollen fitness under normal and temperature-stress conditions.
PMCID: PMC4404812  PMID: 25954280
pollen; temperature stress tolerance; lipid flippases; phosphatidic acid; phosphatidylinositol
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10−5, false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10−4) and European Americans (OR 3.47, P = 0.024).
TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
PMCID: PMC4269184  PMID: 24578102
The goal of this study was to compare the effectiveness of fish oil, fenofibrate, gemfibrozil, and atorvastatin on reducing triglyceride (TG) levels among a large cohort of HIV-infected patients in clinical care.
Retrospective observational cohort study
The primary endpoint was absolute change in TG levels measured using the last TG value pre-treatment and the first TG value post-treatment. A pre-post quasi-experimental design was used to estimate the change in TG due to initiating fish oil. Linear regression models examined the comparative effectiveness of treatment with fish oil versus gemfibrozil, fenofibrate, or atorvastatin for TG reduction. Models were adjusted for baseline differences in age, sex, race, CD4+ cell count, diabetes, body mass index, protease inhibitor use, and time between TG measures.
A total of 493 patients (mean age 46 years; 95% male) were included (46 receiving gemfibrozil, 80 fenofibrate, 291 atorvastatin, 76 fish oil) with a mean baseline TG of 347 mg/dL. New use of fish oil decreased TG (ΔTG -45 mg/dL 95% Confidence interval (CI):-80 to -11) in the pre-post study. Compared with fish oil (reference), fibrates were more effective (ΔTG -66; 95% CI:-120 to -12) in reducing TG levels, whereas atorvastatin was not (ΔTG -39; 95% CI:-86 to 9).
In HIV-infected patients in routine clinical care, fish oil is less effective than fibrates (but not atorvastatin) at lowering triglyceride values. Fish oil may still represent an attractive alternative for patients with moderately elevated triglycerides particularly among patients who may not want or tolerate fibrates.
PMCID: PMC4112457  PMID: 23892238
fish oil; triglycerides; dyslipidemia; fibrates; HIV
Starting lifelong antiretroviral therapy (ART) in HIV-infected pregnant women may decrease HIV progression and transmission but adherence after delivery may be difficult, especially for asymptomatic women. We evaluated disease progression among HIV-infected women not on ART with CD4+ lymphocyte counts above 200 cells/uL at delivery.
We analysed risk of death, progression to AIDS (stage IV or CD4 < 200 cells/uL), or to CD4+ count < 350 one year after delivery among postpartum women enrolled to a prevention of breastfeeding transmission trial using Kaplan-Meier methods. In the primary analysis, women were censored if ART was initiated.
Among 1285 women who were < WHO stage IV at 6 weeks postpartum, 49 (4.3%) progressed to stage IV/CD4 < 200 cells/uL or death by one year. Progression to CD4 < 200 or death occurred among 16 (4.3%) of 441 women with CD4 count of 350–549 and 10 (1.6%) of 713 with CD4 counts > 550 at delivery. CD4 < 350 by 12 months postpartum occurred among 116 (37.0%) of 350 women with CD4 count 400–549 and 48 (7.4%) of 713 > 550 at delivery.
Progression to AIDS or CD4 count < 350 is uncommon through one year postpartum for women with CD4 counts over 550 at delivery, but occurred in over one third of those with CD4 counts under 550. ART should be continued after delivery or breastfeeding among women with CD4 counts < 550 if follow up and ARV adherence can be maintained.
PMCID: PMC3800257  PMID: 23846568
HIV; postpartum; disease progression
Kidney international  2014;85(5):1030-1038.
The haploid human genome is composed of three billion base pairs, about one percent of which consists of exonic regions, the coding sequence for functional proteins, also now known as the “exome”. The development of next-generation sequencing makes it possible from a technical and economic standpoint to sequence an individual’s exome but at the cost of generating long lists of gene variants that are not straightforward to interpret. Various public consortiums such as the 1000 Genomes Project and the NHLBI Exome Sequencing Project have sequenced the exomes and a subset of entire genomes of over 2500 control individuals with ongoing efforts to further catalogue genetic variation in humans.1 The use of these public databases facilitates the interpretation of these variant lists produced by exome sequencing and, as a result, novel genetic variants linked to disease are being discovered and reported at a record rate. However, the interpretation of these results and their bearing on diagnosis, prognosis, and treatment is becoming ever more complicated. Here, we discuss the application of genetic testing to individuals with focal and segmental glomerulosclerosis (FSGS), taking a historical perspective on gene identification and its clinical implications along with the growing potential of next-generation sequencing.
PMCID: PMC4118212  PMID: 24599252

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