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.
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.
lupus; PXK; fine-mapping; B cells; BCR
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.
HIV-1; HLA; human MHC; SNP; viral load
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.
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.
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.
HIV; postpartum; disease progression
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.
This study examined demographic and lifestyle factors that influenced decisions and obstacles to being screened for breast cancer in low-income African Americans in three urban Tennessee cities. As part of the Meharry Community Networks Program (CNP) needs assessment, a 123-item community survey was administered to assess demographic characteristics, health care access and utilization, and screening practices for various cancers in low-income African Americans. For this study, only African American women 40 years and older (n=334) were selected from the Meharry CNP community survey database. There were several predictors of breast cancer screening such as marital status and having health insurance (P< .05). Additionally, there were associations between obstacles to screening and geographic region such as transportation and not having enough information about screenings (P< .05). Educational interventions aimed at improving breast cancer knowledge and screening rates should incorporate information about obstacles and predictors to screening.
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.
Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.
Methotrexate; rheumatoid arthritis; pharmacogenetics
To characterize the clinical features of familial lupus, and determine its influence on damage accrual and survival using data from LUMINA, a longitudinal multiethnic US cohort.
Familial lupus was defined as patients with a first degree relative with SLE. Relative risks were estimated by logistic regression; odds ratios (OR) and their 95% confidence intervals (CI) were the measure of association for familial lupus. Hazard Ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for damage and survival.
Thirty-two of 644 patients had familial and 612 had sporadic lupus; both groups were of comparable age (~ 36 years). Familial lupus patients were in decreasing order of frequency siblings, parents and children. In multivariable analyses, mucosal ulcers (OR=1.92, 95% CI 0.65–5.70), mitral valve prolapse (OR=1.74, 95% CI 0.50–6.10), cerebrovascular disease (OR=4.18, 95% CI 0.98–17.76) and oral contraceptive use (ever/never; OR=2.51, 95% CI 0.88–7.19) were more likely in familial lupus but a history of low platelet count (<150,000/mm3; OR=0.31, 95% CI 0.08–1.17) and pulmonary disease activity (OR=0.39, 95% CI 0.14–1.20) were less likely. However, none of these associations reached statistical significance. Familial lupus was not significantly associated with a shorter time to either damage accrual or death (HR=0.77, 95% CI 0.37–1.59, p = 0.4746 and HR=0.20, 95% CI 0.03–1.47, p = 0.2020, respectively).
Although some clinical differences were observed in patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.
familial lupus; lupus; sporadic lupus; LUMINA; multiethnic cohort
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
The contributing role of stereotype threat (ST) to learning and performance decrements for stigmatized students in highly evaluative situations has been vastly documented and is now widely known by educators and policy makers. However, recent research illustrates that underrepresented and stigmatized students’ academic and career motivations are influenced by ST more broadly, particularly through influences on achievement orientations, sense of belonging, and intrinsic motivation. Such a focus moves conceptualizations of ST effects in education beyond the influence on a student’s performance, skill level, and feelings of self-efficacy per se to experiencing greater belonging uncertainty and lower interest in stereotyped tasks and domains. These negative experiences are associated with important outcomes such as decreased persistence and domain identification, even among students who are high in achievement motivation. In this vein, we present and review support for the Motivational Experience Model of ST, a self-regulatory model framework for integrating research on ST, achievement goals, sense of belonging, and intrinsic motivation to make predictions for how stigmatized students’ motivational experiences are maintained or disrupted, particularly over long periods of time.
stereotype; stereotype threat; motivation; self-regulation; interest; belonging
The Dorsal Mesenchymal Protrusion (DMP) is a prong of mesenchyme derived from the Second Heart Field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular septal defect (AVSD). Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated.
To determine the role of BMP signaling in DMP development.
Methods and Results
Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AVSDs. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/TGFβ signaling was not significantly altered in the AV cushions of SHF-Alk3 mutants.
BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.
DMP; AVSD; Alk3; BMP; ASD
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in RA patients. However such comparison is lacking in African-Americans with RA.
This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry which enrolls self-declared African-Americans with RA. Using tender and swollen joint counts separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient’s assessment of disease activity. The scores were compared using paired t-test, simple agreement and kappa, correlation coefficient and Bland-Altman plots.
Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs. 3.9; p<0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs. 3.9; p<0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.
There was significant discordance between the ESR-based and CRP-based DAS28 which could impact clinical treatment decisions in African-Americans with RA.
DAS28; Rheumatoid Arthritis; African-Americans
Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.
Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon’s rank sum test, chi-square test, and logistic regression analyses.
Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.
CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
The HPTN 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV-infection despite prophylaxis.
HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher’s exact tests were used to evaluate associations between categorical variables.
NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in seven (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8=75% in the NVP arm, 1/17=5.9% in the placebo arm, P=0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral (ARV) treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all four of those infants by 6 months of age (4/4=100%). In contrast, only three (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate ARV treatment developed NVP resistance (P=0.003).
Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.
Nevirapine resistance; prevention of mother-to-child transmission; extended nevirapine; HIV
We evaluated herpes simplex virus type 2 (HSV-2) seropositivity in an HIV clinic–based population with CD4 lymphocytes counts ≥250 cells/μL and no previous knowledge of HSV-2 infection by history of serology. We demonstrate that although the seroprevalence of HSV-2 is higher in this HIV-infected population, predictors of HSV-2 seropositivity are similar to those in the general population.
Assays for detecting levels of antiretroviral drugs in study participants are increasingly popular in preexposure prophylaxis (PrEP) trials, since they provide an objective measure of adherence. Current correlation analyses of drug concentration data are prone to bias. In this article, we formulate the causal estimand of prevention efficacy among drug compliers, those who would have had a threshold level of drug concentration had they been assigned to the drug arm of the trial. The identifiability of the causal estimand is facilitated by exploiting the exclusion restriction; that is, drug noncompliers do not acquire any prevention benefit. In addition, we develop an approach to sensitivity analysis that relaxes the exclusion restriction. Applications to published data from 2 PrEP trials, namely the Preexposure Prophylaxis Initiative (iPrEx) trial and the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial, suggest high efficacy estimates among drug compliers (in the iPrEx trial, odds ratio = 0.097 (95% confidence interval: 0.027, 0.352); in the CAPRISA 004 trial, odds ratio = 0.104 (95% confidence interval: 0.024, 0.447)). In summary, the proposed inferential method provides an unbiased assessment of PrEP efficacy among drug compliers, thus adding to the primary intention-to-treat analysis and correlation analyses of drug concentration data.
causal inference; compliance; exclusion restriction; potential outcome; principal stratification; two-phase sampling
Maternal obesity is associated with high plasma triglyceride, poor vascular function and increased risk for pregnancy complications. In normal weight pregnant women, higher triglyceride is associated with increased small, dense LDL.
In obese pregnancy, increased plasma triglyceride concentrations result in triglyceride enrichment of VLDL-1 particles and formation of small dense LDL via lipoprotein lipase.
Women (n=55) of BMI 18-46 kg/m2 were sampled longitudinally at 12, 26 and 35 weeks’ gestation and 4 months post-natal.
Women were recruited at hospital antenatal appointments and study visits were in a clinical research suite.
Plasma concentrations of lipids, triglyceride-rich lipoproteins, lipoprotein lipase mass, estradiol, steroid hormone binding globulin, insulin, glucose, leptin and adiponectin were determined.
Obese women commenced pregnancy with higher plasma triglyceride, reached the same maximum and then returned to higher post-natal levels than normal weight women. Estradiol response to pregnancy (trimester 1-3 incremental area under the curve) was positively associated with plasma triglyceride response (r2 adjusted 25%, P<0.001). In the third trimester, the proportion of small, dense LDL-III was 2 fold higher in obese women than normal weight women (mean [SD] 40.7[18.8] vs 21.9[10.9] %, P<0.005), and 35% of obese, 14% of overweight and none of the normal weight women displayed an atherogenic LDL subfraction phenotype. The LDL-III mass response to pregnancy was inversely associated with adiponectin response (17%, P=0.013).
Maternal obesity is associated with an atherogenic LDL subfraction phenotype and may provide a mechanistic link to poor vascular function and adverse pregnancy outcome.
pregnancy; lipids; obesity
The vast initial diversity of the antibody repertoire is generated centrally by means of a complex series of V(D)J gene rearrangement events, variation in the site of gene segment joining, and TdT catalyzed N-region addition. Although the diversity is great, close inspection has revealed distinct and unique characteristics in the antibody repertoires expressed by different B cell developmental subsets. In order to illustrate our approach to repertoire analysis, we present an in-depth comparison of V(D)J gene usage, hydrophobicity, length, DH reading frame, and amino acid usage between heavy chain repertoires expressed by immature, transitional, mature, memory IgD+, memory IgD−, and plasmacytes isolated from the blood of a single individual. Our results support the view that in both human and mouse, the H chain repertoires expressed by individual, developmental B cell subsets appear to differ in sequence content. Sequencing of unsorted B cells from the blood is thus likely to yield an incomplete or compressed view of what is actually happening in the immune response of the individual. Our findings support the view that studies designed to correlate repertoire expression with diseases of immune function will likely require deep sequencing of B cells sorted by subset.
human antibody repertoire; CDR-H3; B cells subsets
The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. In a case-control analysis, we investigated whether 33 established and novel single nucleotide polymorphisms (SNP) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis in the general population were risk factors for SLE development among Asians.
Patients in the discovery cohort were enrolled in one of two North American SLE cohorts. Patients in the replication cohort were enrolled in one of four Asian or two North American cohorts. SLE cases met American College of Rheumatology classification criteria. We first genotyped 263 Asian SLE and 357 healthy Asian control individuals for 33 SNPs using Luminex multiplex technology in the discovery phase, and then used Taqman and Immunochip assays to examine 5 SNPs in up to an additional 1496 cases and 993 controls in the Replication phase. SLE patients were compared to healthy controls for association with minor alleles in allelic models. Principal components analysis was used to control for intra-Asian ancestry in an analysis of the replication cohort.
Two genetic variants in the gene VKORC1, rs9934438 and rs9923231, were highly significant in both the discovery and replication cohorts: OR(disc) = 2.45 (p=2×10−9), OR(rep) = 1.53 (p=5×10−6) and OR(disc) = 2.40 (p=6×10−9), OR(rep) = 1.53 (p=5×10−6), respectively. These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: rs9934438 OR(adj) = 1.34 (p=0.0029) and rs9923231 OR(adj) = 1.34 (p=0.0032).
Genetic variants in VKORC1, involved in vitamin K reduction and associated with DVT, are associated with SLE development in Asians. These results suggest intersecting genetic pathways for the development of SLE and thrombosis.
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
The first antiretroviral drug (Truvada) to be used as a pre-exposure prophylaxis (PrEP) in preventing HIV transmission is about to be approved. Behavioral studies suggest that a portion of users may share anti-retroviral drugs with sex partners, family, or friends. Pill sharing will decrease PrEP efficacy and adherence level, and potentially create an environment favorable for the development of drug resistance. We aim to evaluate the potential impact of pill sharing on the PrEP effectiveness and on the rates of drug-resistance development in heterosexual populations.
A transmission dynamic model was used to assess the population-level impact of oral PrEP. The fractions of new HIV infections prevented (CPF), drug resistance prevalence and the proportion of new infections in which drug-resistant HIV is transmitted (TDR) are evaluated over fixed time periods. The influence of different factors on CPF and TDR is studied through simulations, using epidemic parameters representative of the countries in Sub-Saharan Africa.
Without pill sharing, a 70% efficacious PrEP used consistently by 60% of uninfected individuals prevents 52.8% (95% CI 49.4%-56.4%) of all new HIV infections over ten years with drug-resistant HIV transmitted in 2.2% of the new infections. Absolute CPF may vary by 9% if up to 20% of the users share PrEP while the level of TDR and total resistance prevalence may increase by up to 6-fold due to pill sharing in some intervention scenarios.
Pill sharing may increase the PrEP coverage level achieved in the population but it also affects the PrEP efficacy for the users who do not follow the prescribed schedule. More importantly, it creates a pool of untracked users who remain unreached by the effort to avoid sub-optimal PrEP usage by infected people. This increases substantially the potential risk of drug resistance in the population.
HIV; Pill sharing; Pre-exposure prophylaxis
Four clinical trials have shown that oral and topical pre-exposure prophylaxis (PrEP) based on tenofovir may be effective in preventing HIV transmission. The expected reduction in HIV transmission and the projected prevalence of drug resistance due to PrEP use vary significantly across modeling studies as a result of the broad spectrum of assumptions employed. Our goal is to quantify the influence of drug resistance assumptions on the predicted population-level impact of PrEP.
All modeling studies which evaluate the impact of oral or topical PrEP are reviewed and key assumptions regarding mechanisms of generation and spread of drug-resistant HIV are identified. A dynamic model of the HIV epidemic is developed to assess and compare the impact of oral PrEP using resistance assumptions extracted from published studies. The benefits and risks associated with ten years of PrEP use are evaluated under identical epidemic, behavioral and intervention conditions in terms of cumulative fractions of new HIV infections prevented, resistance prevalence among those infected with HIV, and fractions of infections in which resistance is transmitted.
Published models demonstrate enormous variability in resistance-generating assumptions and uncertainty in parameter values. Depending on which resistance parameterization is used, a resistance prevalence between 2% and 44% may be expected if 50% efficacious oral PrEP is used consistently by 50% of the population over ten years. We estimated that resistance may be responsible for up to a 10% reduction or up to a 30% contribution to the fraction of prevented infections predicted in different studies.
Resistance assumptions used in published studies have a strong influence on the projected impact of PrEP. Modelers and virologists should collaborate toward clarifying the set of resistance assumptions biologically relevant to the PrEP products which are already in use or soon to be added to the arsenal against HIV.