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1.  Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus 
Clinical immunology (Orlando, Fla.)  2015;161(2):157-162.
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
doi:10.1016/j.clim.2015.09.007
PMCID: PMC4658308  PMID: 26385092
systemic lupus erythematosus; leptin pathway; gene polymorphisms
2.  Closing the Communal Gap: The Importance of Communal Affordances in Science Career Motivation 
To remain competitive in the global economy, the United States (and other countries) is trying to broaden participation in science, technology, engineering, and mathematics (STEM) by graduating an additional 1 million people in STEM fields by 2018. Although communion (working with, helping, and caring for others) is a basic human need, STEM careers are often (mis)perceived as being uncommunal. Across three naturalistic studies we found greater support for the communal affordance hypothesis, that perceiving STEM careers as affording greater communion is associated with greater STEM career interest, than two alternative hypotheses derived from goal congruity theory. Importantly, these findings held regardless of major (Study 1), college enrollment (Study 2), and gender (Studies 1–3). For undergraduate research assistants, mid-semester beliefs that STEM affords communion predicted end of the semester STEM motivation (Study 3). Our data highlight the importance of educational and workplace motivational interventions targeting communal affordances beliefs about STEM.
doi:10.1111/jasp.12327
PMCID: PMC4717480  PMID: 26806983
goal congruity theory; communion; science, technology, engineering, and mathematics (STEM); motivation
3.  To Grab and To Hold: Cultivating communal goals to overcome cultural and structural barriers in first generation college students' science interest 
Homogeneity within science limits creativity and discovery, and can feed into a perpetuating cycle of underrepresentation. From enhancing social justice to alleviating health and economic disadvantages, broadening participation in science is imperative. We focus here on first-generation students (FGS) and identify factors which grab and hold science interest among this underrepresented group. Might the culture and norms within science unintentionally limit FGS' participation? We argue that two distinct aspects of communal goals contribute to FGS' underrepresentation at different stages of the STEM pipeline: cultural perceptions of science as uncommunal (little emphasis on prosocial behavior and collaboration) and the uncommunal structure of STEM graduate education and training. Across 2 studies we investigated factors that catch (Study 1) and hold (Study 2) FGS' science interest. In Study 1, we find only when FGS believe that working in science will allow them to fulfill prosocial communal purpose goals are they more intrinsically interested in science. Yet, later in the pipeline science education devalues prosocial communal goals creating a structural mobility barrier among FGS. Study 2 found that FGS generally want to stay close to home instead of relocating to pursue a graduate education. For FGS (versus continuing-generation students), higher prosocial communal goal orientation significantly predicted lower residential mobility. We discuss implications for interventions to counteract the uncommunal science education and training culture to help improve access to FGS and other similarly situated underrepresented populations.
doi:10.1037/tps0000046
PMCID: PMC4718605  PMID: 26807431
first-generation students; communal goals; intrinsic motivation; residential mobility
4.  Temporal trends in conduit urinary diversion with concomitant cystectomy for benign indications: a population-based analysis 
Urology  2016;98:70-74.
Objectives
To describe national trends in cystectomy at the time of urinary diversion for benign indications. Multiple practice patterns exist regarding the necessity of concomitant cystectomy with urinary diversion for benign end-stage lower urinary tract dysfunction. Beyond single institution reports, limited data is available to describe how concurrent cystectomy is employed on a national level.
Methods
A representative sample of patients undergoing urinary diversion for benign indications with or without concurrent cystectomy was identified from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample from 1998–2011. Using multivariate logistic regression models, we identified hospital and patient-level characteristics associated with concomitant cystectomy with urinary diversion.
Results
There was an increase in the proportion of concomitant cystectomy at the time of urinary diversion from 20% to 35% (p<0.001) between 1998 and 2011. The increase in simultaneous cystectomy over time occurred at teaching hospitals (vs. community hospitals), in older patients, in male patients, in the Medicare population (vs. private insurance and Medicaid), and in those with certain diagnoses.
Conclusions
There has been an overall increase in the use of cystectomy at the time of urinary diversion for benign indications on a national level, though the indications driving this clinical decision appear inconsistent.
doi:10.1016/j.urology.2016.06.035
PMCID: PMC5116247  PMID: 27374730
cystectomy; urinary diversion; ileal conduit; national trends; neurogenic bladder
5.  Estimating Efficacy in a Randomized Trial With Product Nonadherence: Application of Multiple Methods to a Trial of Preexposure Prophylaxis for HIV Prevention 
American Journal of Epidemiology  2015;182(10):848-856.
Antiretroviral preexposure prophylaxis (PrEP) for persons at high risk of human immunodeficiency virus infection is a promising new prevention strategy. Six randomized trials of oral PrEP were recently conducted and demonstrated efficacy estimates ranging from 75% to no effect, with nonadherence likely resulting in attenuated estimates of the protective effect of PrEP. In 1 of these trials, the Partners PrEP Study (Kenya and Uganda, 2008–2011), participants (4,747 serodiscordant heterosexual couples) were randomized to receipt of tenofovir (TDF), coformulated TDF/emtricitabine (FTC), or placebo. Intention-to-treat analyses found efficacy estimates of 67% for TDF and 75% for TDF/FTC. We applied multiple methods to data from that trial to estimate the efficacy of PrEP with high adherence, including principal stratification and inverse-probability-of-censoring (IPC) weights. Results were further from the null when correcting for nonadherence: 1) among the strata with an estimated 100% probability of high adherence (TDF hazard ratio (HR) = 0.19, 95% confidence interval (CI): 0.07, 0.56; TDF/FTC HR = 0.12, 95% CI: 0.03, 0.52); 2) with IPC weights used to approximate a continuously adherent population (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.15, 95% CI: 0.04, 0.52); and 3) in per-protocol analysis (TDF HR = 0.18, 95% CI: 0.06, 0.53; TDF/FTC HR = 0.16, 95% CI: 0.05, 0.53). Our results suggest that the efficacy of PrEP with high adherence is over 80%.
doi:10.1093/aje/kwv202
PMCID: PMC4634306  PMID: 26487343
HIV; HIV prevention; intention-to-treat analysis; medication adherence; randomized controlled trials
6.  Pharmacodynamic activity of Dapivirine and Maraviroc single entity and combination topical gels for HIV-1 prevention 
Pharmaceutical research  2015;32(11):3768-3781.
Purpose
Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission.
Methods
0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety.
Results
The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm2/min1/2), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm2/min1/2). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe.
Conclusions
The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.
doi:10.1007/s11095-015-1738-7
PMCID: PMC4600024  PMID: 26078001
HIV prevention; pre-exposure prophylaxis; rectal microbicides; antiretroviral drugs; drug combinations
7.  From Bench to Bedside: A communal utility value intervention to enhance students’ biomedical science motivation 
Journal of educational psychology  2015;107(4):1116-1135.
Motivating students to pursue science careers is a top priority among many science educators. We add to the growing literature by examining the impact of a utility value intervention to enhance student’s perceptions that biomedical science affords important utility work values. Using an expectancy-value perspective we identify and test two types of utility value: communal (other-oriented) and agentic (self-oriented). The culture of science is replete with examples emphasizing high levels of agentic value, but communal values are often (stereotyped as) absent from science. However, people in general want an occupation that has communal utility. We predicted and found that an intervention emphasizing the communal utility value of biomedical research increased students’ motivation for biomedical science (Studies 1–3). We refined whether different types of communal utility value (working with, helping, and forming relationships with others) might be more or less important, demonstrating that helping others was an especially important predictor of student motivation (Study 2). Adding agentic utility value to biomedical research did not further increase student motivation (Study 3). Furthermore, the communal value intervention indirectly impacted students’ motivation because students believed that biomedical research was communal and thus subsequently more important (Studies 1–3). This is key, because enhancing student communal value beliefs about biomedical research (Studies 1–3) and science (Study 4) was associated both with momentary increases in motivation in experimental settings (Studies 1–3) and increased motivation over time among students highly identified with biomedicine (Study 4). We discuss recommendations for science educators, practitioners, and faculty mentors who want to broaden participation in science.
doi:10.1037/edu0000033
PMCID: PMC4657866  PMID: 26617417
STEM education; motivation; utility value; communion; psychological intervention
8.  Phylogeographic Analysis of Blastomyces dermatitidis and Blastomyces gilchristii Reveals an Association with North American Freshwater Drainage Basins 
PLoS ONE  2016;11(7):e0159396.
Blastomyces dermatitidis and Blastomyces gilchristii are dimorphic fungal pathogens that cause serious pulmonary and systemic infections in humans. Although their natural habitat is in the environment, little is known about their specific ecologic niche(s). Here, we analyzed 25 microsatellite loci from 169 strains collected from various regions throughout their known endemic range in North America, representing the largest and most geographically diverse collection of isolates studied to date. Genetic analysis of multilocus microsatellite data divided the strains into four populations of B. dermatitidis and four populations of B. gilchristii. B. dermatitidis isolates were recovered from areas throughout North America, while the B. gilchristii strains were restricted to Canada and some northern US states. Furthermore, the populations of both species were associated with major freshwater drainage basins. The four B. dermatitidis populations were partitioned among (1) the Nelson River drainage basin, (2) the St. Lawrence River and northeast Atlantic Ocean Seaboard drainage basins, (3) the Mississippi River System drainage basin, and (4) the Gulf of Mexico Seaboard and southeast Atlantic Ocean Seaboard drainage basins. A similar partitioning of the B. gilchristii populations was observed among the more northerly drainage basins only. These associations suggest that the ecologic niche where the sexual reproduction, growth, and dispersal of B. dermatitidis and B. gilchristii occur is intimately linked to freshwater systems. For most populations, sexual reproduction was rare enough to produce significant linkage disequilibrium among loci but frequent enough that mating-type idiomorphic ratios were not skewed from 1:1. Furthermore, the evolutionary divergence of B. dermatitidis and B. gilchristii was estimated at 1.9 MYA during the Pleistocene epoch. We suggest that repeated glaciations during the Pleistocene period and resulting biotic refugia may have provided the impetus for speciation as theorized for other species associated with temperate freshwater systems.
doi:10.1371/journal.pone.0159396
PMCID: PMC4948877  PMID: 27428521
9.  Clinical associations of anti-Smith antibodies in PROFILE: a multi-ethnic lupus cohort 
Clinical rheumatology  2015;34(7):1217-1223.
The aim of this study was to determine the association of anti-Sm antibodies with clinical manifestations, comorbidities, and disease damage in a large multi-ethnic SLE cohort. SLE patients (per American College of Rheumatology criteria), age ≥16 years, disease duration ≤10 years at enrollment, and defined ethnicity (African American, Hispanic or Caucasian), from a longitudinal US cohort were studied. Socioeconomic-demographic features, cumulative clinical manifestations, comorbidities, and disease damage (as per the Systemic Lupus International Collaborating Clinics Damage Index [SDI]) were determined. The association of anti-Sm antibodies with clinical features was examined using multivariable logistic regression analyses adjusting for age, gender, ethnicity, disease duration, level of education, health insurance, and smoking. A total of 2322 SLE patients were studied. The mean (standard deviation, SD) age at diagnosis was 34.4 (12.8) years and the mean (SD) disease duration was 9.0(7.9)years; 2127 (91.6 %) were women. Anti-Sm antibodies were present in 579 (24.9 %) patients. In the multivariable analysis, anti-Sm antibodies were significantly associated with serositis, renal involvement, psychosis, vasculitis, Raynaud's phenomenon, hemolytic anemia, leukopenia, lymphopenia, and arterial hypertension. No significant association was found for damage accrual. In this cohort of SLE patients, anti-Sm antibodies were associated with several clinical features including serious manifestations such as renal, neurologic, and hematologic disorders as well as vasculitis.
doi:10.1007/s10067-015-2941-y
PMCID: PMC4475431  PMID: 25896533
Anti-Smith antibodies; Clinical manifestations; Disease damage; Systemic lupus erythematosus
10.  Underactive bladder in women: is there any evidence? 
Current opinion in urology  2016;26(4):309-314.
Purpose of review
Underactive bladder (UAB) is a clinical symptom complex only recently gaining recognition as a clinical diagnosis. Lack of consensus agreement on a definition of UAB has limited its recognition and diagnosis in clinical practice. The purposes of this review are to: present existing definitions of UAB, review recent data regarding clinical and urodynamic diagnosis of the condition, and examine up-to-date hypotheses regarding its pathophysiology, with a focus on women.
Recent findings
The process to develop a consensus definition for UAB as a clinical symptom complex is ongoing. Symptoms associated with UAB, such as weak stream, straining to void, and history of urinary retention are well correlated to detrusor underactivity on urodynamics, which frequently develops in elderly women. In addition to aging, UAB may be the end stage of a variety of contributing pathologic conditions such as diabetes and ischemic disease. In some women, UAB may result from a progression from overactive bladder to UAB.
Summary
Existing evidence supports UAB in women as a symptom complex with a clinical and pathophysiologic profile distinguishable from other lower urinary tract-associated clinical conditions. Consensus definitions of clinical and urodynamic diagnostic parameters will be essential to more widespread recognition of UAB.
doi:10.1097/MOU.0000000000000280
PMCID: PMC4893010  PMID: 26927630
definition; detrusor underactivity; diagnosis; pathophysiology; underactive bladder; women
11.  Nasal saline or intranasal corticosteroids to treat allergic rhinitis in children 
Clinical Question
In pediatric populations, is nasal saline irrigation as effective as intranasal corticosteroids at relieving allergic rhinitis symptoms?
Answer
No. Intranasal steroids are more effective than nasal saline alone to reduce symptoms of allergic rhinitis (AR) in children. Combination therapy further improves symptom reduction.
Level of Evidence for the Answer
B
Search Terms
Allergic Rhinitis, Nasal Saline, Nasal corticosteroids, children younger than age 18.
Date Search Was Conducted
August and September 2014, October 2015.
Inclusion Criteria
Meta-analyses, randomized controlled trials, systematic reviews, cohort studies, nasal spray, hypertonic saline solution, nasal lavage, rhinitis, intranasal administration, nasal saline, human, English language.
Exclusion Criteria
Antihistamines, Adults, Articles older than 2008
PMCID: PMC4918463  PMID: 27328556
12.  Perceptions and Experiences with the VOICE Adherence Strengthening Program (VASP) in the MTN-003 Trial 
AIDS and behavior  2015;19(5):770-783.
The VOICE Adherence Strengthening Program (VASP) was implemented in May 2011 to improve adherence counseling in VOICE (MTN-003), a multisite placebo-controlled trial of daily oral or vaginal tenofovir-based Pre-Exposure Prophylaxis (PrEP). Anonymous baseline (N = 82) and final follow-up (N = 75) surveys were administered to counselors and pharmacists at 15 VOICE sites, and baseline (N = 18) and final (N = 26) qualitative in-depth interviews were conducted with purposively selected counseling staff at 13 VOICE sites. Qualitative interviews with VOICE participants (N = 38) were also analyzed for segments related to counseling. Behavioral and biological measures of product use collected in the 6 months prior to VASP implementation were compared to those collected during the 6 months following implementation. Results show that the majority of staff preferred VASP and thought that participants preferred VASP over the previous education and counseling strategy, although there was no evidence to suggest that participants noticed modifications in the counseling approach. No meaningful changes were observed in pre/post levels of reported use or drug detection. Interpretation of results is complicated by mid-trial implementation of VASP and its proximity to early closure of oral and vaginal tenofovir study arms because of futility.
doi:10.1007/s10461-014-0945-2
PMCID: PMC4416998  PMID: 25384907
PrEP; Microbicides; Adherence; Intervention; Counseling staff; HIV prevention trial
13.  An update on the use of transdermal oxybutynin in the management of overactive bladder disorder 
Antimuscarinic medications are used to treat nonneurogenic overactive bladder refractory to nonpharmacologic therapy. Side effects such as dry mouth, constipation, blurred vision, dizziness, and impaired cognition limit the tolerability of therapy and are largely responsible for high discontinuation rates. Oxybutynin is a potent muscarinic receptor antagonist whose primary metabolite after first-pass hepatic metabolism is considered largely responsible for its associated anticholinergic side effects. Transdermal administration of medications bypasses hepatic processing. Specifically with oxybutynin, whose low molecular weight permits transdermal administration, bioavailability of the parent drug with oral administration is less than 10%, whereas with transdermal delivery is a minimum of 80%. The result has been an improved side effect profile in multiple clinical trials with maintained efficacy relative to placebo; however, the drug may still be discontinued by patients due to anticholinergic side effects and application site reactions. Transdermal oxybutynin is available as a patch that is changed every 3–4 days, a gel available in individual sachets, or via a metered-dose pump that is applied daily. The transdermal patch was briefly available as an over-the-counter medication for adult women, although at this time all transdermal formulations are available by prescription only.
doi:10.1177/1756287215626312
PMCID: PMC4772360  PMID: 27034721
overactive bladder; oxybutynin; transdermal; cost; efficacy; pharmacology
14.  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).
doi:10.1093/aje/kwu290
PMCID: PMC4402340  PMID: 25713336
autoimmune conditions; environment; genetics; interaction; human leukocyte antigen; lymphoma, non-Hodgkin; tumor necrosis factor
15.  The facilitators and barriers associated with implementation of a patient-centered medical home in VHA 
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/s13012-016-0386-6
PMCID: PMC4766632  PMID: 26911135
16.  Divergent adherence estimates with pharmacokinetic and behavioural measures in the MTN-003 (VOICE) study 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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: ClinicalTrials.gov identifier: NCT00705679
doi:10.7448/IAS.19.1.20642
PMCID: PMC4744323  PMID: 26850270
microbicide; pre-exposure prophylaxis; adherence measurement; pharmacokinetic drug detection; HIV
17.  The Role of Altruistic Values in Motivating Underrepresented Minority Students for Biomedicine 
Bioscience  2014;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.
doi:10.1093/biosci/biu199
PMCID: PMC4731875  PMID: 26834259
science education; research motivation; broadening participation; underrepresented minority students; science interest
18.  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.
doi:10.1093/biosci/biu199
PMCID: PMC4731875  PMID: 26834259
science education; research motivation; broadening participation; underrepresented minority students; science interest
19.  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.
doi:10.3897/phytokeys.59.6261
PMCID: PMC4758082  PMID: 26929706
Marchantiophyta; Anthocerophyta; nomenclature; taxonomy
20.  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.
Objectives
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/annrheumdis-2014-205584
PMCID: PMC4717392  PMID: 25180293
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
21.  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.
doi:10.1093/hmg/ddu455
PMCID: PMC4275071  PMID: 25205108
22.  Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features 
Cancer Causes & Control  2015;27:81-91.
Purpose
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1007/s10552-015-0685-2
PMCID: PMC4703620  PMID: 26596855
Multiple myeloma; Family history; Genetic; Black; African American
23.  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
doi:10.1038/gene.2014.73
PMCID: PMC4371129  PMID: 25569266
Biometrics  2014;70(3):742-750.
Summary
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.
doi:10.1111/biom.12183
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.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0128857
PMCID: PMC4489588  PMID: 26061040

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