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1.  Habitual alcohol consumption associated with reduced semen quality and changes in reproductive hormones; a cross-sectional study among 1221 young Danish men 
BMJ Open  2014;4(9):e005462.
Objective
Study associations between three measures of alcohol consumption (recent, typical/habitual, binging), semen quality and serum reproductive hormones.
Design
Cross-sectional population based study.
Setting and participants
1221 young Danish men, aged 18–28 years were recruited when they attended a compulsory medical examination to determine their fitness for military service from 2008 to 2012. Total alcohol consumption: (1) in the week preceding (habitual/typical) the visit (recent alcohol intake), (2) in a typical week and (3) frequency of ‘binge drinking’ (consuming more than 5 units/day)) in the past 30 days was estimated.
Main outcome measures
Semen quality (volume, sperm concentration, total sperm count, and percentages of motile and morphologically normal spermatozoa) and serum concentration of reproductive hormones (follicle-stimulating hormone, luteinising hormone, testosterone, sex hormone binding globulin, oestradiol, free testosterone and inhibin B).
Results
Sperm concentration, total sperm count and percentage of spermatozoa with normal morphology were negatively associated with increasing habitual alcohol intake. This association was observed in men reporting at least 5 units in a typical week but was most pronounced for men with a typical intake of more than 25 units/week. Men with a typical weekly intake above 40 units had a 33% (95% CI 11% to 59%) reduction in sperm concentration compared to men with an intake of 1–5 units/week. A significant increase in serum free testosterone with increasing alcohol consumption the week preceding the visit was found. Binging was not independently associated with semen quality.
Conclusions
Our study suggests that even modest habitual alcohol consumption of more than 5 units per week had adverse effects on semen quality although most pronounced associations were seen in men who consumed more than 25 units per week. Alcohol consumption was also linked to changes in testosterone and SHBG levels. Young men should be advised to avoid habitual alcohol intake.
doi:10.1136/bmjopen-2014-005462
PMCID: PMC4185337  PMID: 25277121
EPIDEMIOLOGY; PUBLIC HEALTH; REPRODUCTIVE MEDICINE
2.  Urinary Bisphenol A Levels in Young Men: Association with Reproductive Hormones and Semen Quality 
Environmental Health Perspectives  2014;122(5):478-484.
Background: Few human studies have examined bisphenol A (BPA) exposure in relation to semen quality and reproductive hormones in men, and results are divergent.
Objectives: We examined associations between urinary BPA concentration and reproductive hormones, as well as semen quality, in young men from the general population.
Methods: Our study population consisted of 308 young men from the general population. Urinary BPA concentration was measured by isotope dilution TurboFlow-liquid chromatography–tandem mass spectrometry. We used multiple linear regression analysis to estimate associations between BPA concentration and reproductive hormones and semen quality, adjusting for confounding factors.
Results: We found that 98% of the men had detectable urinary levels of BPA. Median (5th–95th percentiles) BPA concentration was 3.25 ng/mL (0.59–14.89 ng/mL). Men with BPA concentrations above the lowest quartile had higher concentrations of serum testosterone, luteinizing hormone (LH), estradiol, and free testosterone compared with the lowest quartile (ptrend ≤ 0.02). Men in the highest quartile of BPA excretion had on average 18% higher total testosterone (95% CI: 8, 28%), 22% higher LH (95% CI: 6, 39%), and 13% higher estradiol (95% CI: 4, 24%) compared with lowest quartile. Men in the highest quartile of BPA also had significantly lower percentage progressive motile spermatozoa compared with men in the lowest quartile (–6.7 percentage points, 95% CI: –11.76, –1.63). BPA was not associated with other semen parameters. Adjusting for dietary patterns did not influence the results.
Conclusions: The pattern of associations between BPA and reproductive hormones could indicate an antiandrogenic or antiestrogenic effect, or both, of BPA on the hypothalamic–pituitary–gonadal hormone feedback system, possibly through a competitive inhibition at the receptor level. However, additional research is needed to confirm our findings and to further test the suggested potential mechanisms.
Citation: Lassen TH, Frederiksen H, Jensen TK, Petersen JH, Joensen UN, Main KM, Skakkebaek NE, Juul A, Jørgensen N, Andersson AM. 2014. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environ Health Perspect 122:478–484; http://dx.doi.org/10.1289/ehp.1307309
doi:10.1289/ehp.1307309
PMCID: PMC4014766  PMID: 24786630
3.  Characterization of a Recombinant Adeno-Associated Virus Type 2 Reference Standard Material 
Human Gene Therapy  2010;21(10):1273-1285.
Here, the AAV Reference Standard Working Group presents the results of their international collaboration to produce and characterize a recombinant AAV serotype 2 Reference Standard Material. The purpose of this material is to provide a universal standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors.
Abstract
A recombinant adeno-associated virus serotype 2 Reference Standard Material (rAAV2 RSM) has been produced and characterized with the purpose of providing a reference standard for particle titer, vector genome titer, and infectious titer for AAV2 gene transfer vectors. Production and purification of the reference material were carried out by helper virus–free transient transfection and chromatographic purification. The purified bulk material was vialed, confirmed negative for microbial contamination, and then distributed for characterization along with standard assay protocols and assay reagents to 16 laboratories worldwide. Using statistical transformation and modeling of the raw data, mean titers and confidence intervals were determined for capsid particles ({X}, 9.18 × 1011 particles/ml; 95% confidence interval [CI], 7.89 × 1011 to 1.05 × 1012 particles/ml), vector genomes ({X}, 3.28 × 1010 vector genomes/ml; 95% CI, 2.70 × 1010 to 4.75 × 1010 vector genomes/ml), transducing units ({X}, 5.09 × 108 transducing units/ml; 95% CI, 2.00 × 108 to 9.60 × 108 transducing units/ml), and infectious units ({X}, 4.37 × 109 TCID50 IU/ml; 95% CI, 2.06 × 109 to 9.26 × 109 TCID50 IU/ml). Further analysis confirmed the identity of the reference material as AAV2 and the purity relative to nonvector proteins as greater than 94%. One obvious trend in the quantitative data was the degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This relatively poor degree of interlaboratory precision and accuracy was apparent even though attempts were made to standardize the assays by providing detailed protocols and common reagents. This is the first time that such variation between laboratories has been thoroughly documented and the findings emphasize the need in the field for universal reference standards. The rAAV2 RSM has been deposited with the American Type Culture Collection and is available to the scientific community to calibrate laboratory-specific internal titer standards. Anticipated uses of the rAAV2 RSM are discussed.
doi:10.1089/hum.2009.223
PMCID: PMC2957240  PMID: 20486768
4.  The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge 
Nucleic Acids Research  2007;36(Database issue):D913-D918.
PharmGKB is a knowledge base that captures the relationships between drugs, diseases/phenotypes and genes involved in pharmacokinetics (PK) and pharmacodynamics (PD). This information includes literature annotations, primary data sets, PK and PD pathways, and expert-generated summaries of PK/PD relationships between drugs, diseases/phenotypes and genes. PharmGKB's website is designed to effectively disseminate knowledge to meet the needs of our users. PharmGKB currently has literature annotations documenting the relationship of over 500 drugs, 450 diseases and 600 variant genes. In order to meet the needs of whole genome studies, PharmGKB has added new functionalities, including browsing the variant display by chromosome and cytogenetic locations, allowing the user to view variants not located within a gene. We have developed new infrastructure for handling whole genome data, including increased methods for quality control and tools for comparison across other data sources, such as dbSNP, JSNP and HapMap data. PharmGKB has also added functionality to accept, store, display and query high throughput SNP array data. These changes allow us to capture more structured information on phenotypes for better cataloging and comparison of data. PharmGKB is available at www.pharmgkb.org
doi:10.1093/nar/gkm1009
PMCID: PMC2238877  PMID: 18032438
5.  Glucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice 
Nature Communications  2014;5:4924.
DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to impaired energy homeostasis, catabolism, suppression of IGF-1/mTOR signalling, suppression of mitochondrial biogenesis and tissue atrophy. A glucose-enriched diet reverts these defects by activating glycolysis, mitochondrial biogenesis and oxidative glucose metabolism. The beneficial effects of glucose substitution on mitochondrial function and glucose metabolism are blocked by mTOR inhibition but mimicked by IGF-1 application. Together, these results provide the first experimental evidence that telomere dysfunction enhances the requirement of glucose substitution for the maintenance of energy homeostasis and IGF-1/mTOR-dependent mitochondrial biogenesis in ageing tissues.
Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al. show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.
doi:10.1038/ncomms5924
PMCID: PMC4199114  PMID: 25233189
6.  Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood–brain barrier and infection by HIV: Implications for NeuroAIDS 
Cellular immunology  2010;267(2):109-123.
The prevalence of human immunodeficiency virus 1 (HIV) associated neurocognitive disorders resulting from infection of the central nervous system (CNS) by HIV continues to increase despite the success of combination antiretroviral therapy. Although monocytes are known to transport HIV across the blood–brain barrier (BBB) into the CNS, there are few specific markers that identify monocyte subpopulations susceptible to HIV infection and/or capable of infiltrating the CNS. We cultured human peripheral blood monocytes and characterized the expression of the phenotypic markers CD14, CD16, CD11b, Mac387, CD163, CD44v6 and CD166 during monocyte/macrophage (Mo/Mac) maturation/differentiation. We determined that a CD14+CD16+CD11b+Mac387+ Mo/Mac subpopulation preferentially transmigrates across our in vitro BBB model in response to CCL2. Genes associated with Mo/Mac subpopulations that transmigrate across the BBB and/or are infected by HIV were identified by cDNA microarray analyses. Our findings contribute to the understanding of monocyte maturation, infection and transmigration into the brain during the pathogenesis of NeuroAIDS.
doi:10.1016/j.cellimm.2010.12.004
PMCID: PMC4335637  PMID: 21292246
NeuroAIDS; Monocytes/macrophages; Transmigration; Maturation/differentiation; Blood; brain barrier; CCL2; CD14; CD16
7.  Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma 
Vithana, Eranga N | Khor, Chiea-Chuen | Qiao, Chunyan | Nongpiur, Monisha E | George, Ronnie | Chen, Li-Jia | Do, Tan | Abu-Amero, Khaled | Huang, Chor Kai | Low, Sancy | Tajudin, Liza-Sharmini A | Perera, Shamira A | Cheng, Ching-Yu | Xu, Liang | Jia, Hongyan | Ho, Ching-Lin | Sim, Kar Seng | Wu, Ren-Yi | Tham, Clement C Y | Chew, Paul T K | Su, Daniel H | Oen, Francis T | Sarangapani, Sripriya | Soumittra, Nagaswamy | Osman, Essam A | Wong, Hon-Tym | Tang, Guangxian | Fan, Sujie | Meng, Hailin | Huong, Dao T L | Wang, Hua | Feng, Bo | Baskaran, Mani | Shantha, Balekudaru | Ramprasad, Vedam L | Kumaramanickavel, Govindasamy | Iyengar, Sudha K | How, Alicia C | Lee, Kelvin Y | Sivakumaran, Theru A | Yong, Victor H K | Ting, Serena M L | Li, Yang | Wang, Ya-Xing | Tay, Wan-Ting | Sim, Xueling | Lavanya, Raghavan | Cornes, Belinda K | Zheng, Ying-Feng | Wong, Tina T | Loon, Seng-Chee | Yong, Vernon K Y | Waseem, Naushin | Yaakub, Azhany | Chia, Kee-Seng | Allingham, R Rand | Hauser, Michael A | Lam, Dennis S C | Hibberd, Martin L | Bhattacharya, Shomi S | Zhang, Mingzhi | Teo, Yik Ying | Tan, Donald T | Jonas, Jost B | Tai, E-Shyong | Saw, Seang-Mei | Hon, Do Nhu | Al-Obeidan, Saleh A | Liu, Jianjun | Chau, Tran Nguyen Bich | Simmons, Cameron P | Bei, Jin-Xin | Zeng, Yi-Xin | Foster, Paul J | Vijaya, Lingam | Wong, Tien-Yin | Pang, Chi-Pui | Wang, Ningli | Aung, Tin
Nature genetics  2012;44(10):1142-1146.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.
doi:10.1038/ng.2390
PMCID: PMC4333205  PMID: 22922875
9.  Membrane tethering by the atlastin GTPase depends on GTP hydrolysis but not on forming the cross-over configuration 
Molecular Biology of the Cell  2014;25(24):3942-3953.
The atlastin GTPase couples nucleotide hydrolysis to formation of a trans cross-over dimer to catalyze homotypic endoplasmic reticulum membrane fusion. Assays that separate tethering from fusion reveal that stable trans contact for tethering depends on GTP hydrolysis. In contrast, cross-over formation is required only for the fusion step.
The membrane-anchored atlastin GTPase couples nucleotide hydrolysis to the catalysis of homotypic membrane fusion to form a branched endoplasmic reticulum network. Trans dimerization between atlastins anchored in opposing membranes, accompanied by a cross-over conformational change, is thought to draw the membranes together for fusion. Previous studies on the conformational coupling of atlastin to its GTP hydrolysis cycle have been carried out largely on atlastins lacking a membrane anchor. Consequently, whether fusion involves a discrete tethering step and, if so, the potential role of GTP hydrolysis and cross-over in tethering remain unknown. In this study, we used membrane-anchored atlastins in assays that separate tethering from fusion to dissect the requirements for each. We found that tethering depended on GTP hydrolysis, but, unlike fusion, it did not depend on cross-over. Thus GTP hydrolysis initiates stable head-domain contact in trans to tether opposing membranes, whereas cross-over formation plays a more pivotal role in powering the lipid rearrangements for fusion.
doi:10.1091/mbc.E14-08-1284
PMCID: PMC4244202  PMID: 25253720
10.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
doi:10.1093/cid/cit747
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
11.  Stewardship to tackle global phosphorus inefficiency: The case of Europe 
Ambio  2015;44(Suppl 2):193-206.
The inefficient use of phosphorus (P) in the food chain is a threat to the global aquatic environment and the health and well-being of citizens, and it is depleting an essential finite natural resource critical for future food security and ecosystem function. We outline a strategic framework of 5R stewardship (Re-align P inputs, Reduce P losses, Recycle P in bioresources, Recover P in wastes, and Redefine P in food systems) to help identify and deliver a range of integrated, cost-effective, and feasible technological innovations to improve P use efficiency in society and reduce Europe’s dependence on P imports. Their combined adoption facilitated by interactive policies, co-operation between upstream and downstream stakeholders (researchers, investors, producers, distributors, and consumers), and more harmonized approaches to P accounting would maximize the resource and environmental benefits and help deliver a more competitive, circular, and sustainable European economy. The case of Europe provides a blueprint for global P stewardship.
doi:10.1007/s13280-014-0614-8
PMCID: PMC4329152  PMID: 25681977
Phosphorus; Europe; Inefficiency; Eutrophication; Human health; Resources; Sustainability
12.  Total Synthesis of Thiaplakortone A: Derivatives as Metabolically Stable Leads for the Treatment of Malaria 
ACS Medicinal Chemistry Letters  2013;5(2):178-182.
Thiaplakortone A (3a), an antimalarial natural product, was prepared by an operationally simple and scalable synthesis. In our efforts to deliver a lead compound with improved potency, metabolic stability, and selectivity, the synthesis was diverted to access a series of analogues. Compounds 3a–d showed nanomolar activity against the chloroquine-sensitive (3D7) Plasmodium falciparum line and were more active against the chloroquine- and mefloquine-resistant (Dd2) P. falciparum line. All compounds are “Rule-of-5” compliant, and we show that metabolic stability can be enhanced via modification at either the primary or pyrrole nitrogen. These promising results lay the foundation for the development of this structurally unprecedented natural product.
doi:10.1021/ml400447v
PMCID: PMC4027726  PMID: 24900794
Malaria; natural products; total synthesis
13.  Molecules and Morphology Reveal Overlooked Populations of Two Presumed Extinct Australian Sea Snakes (Aipysurus: Hydrophiinae) 
PLoS ONE  2015;10(2):e0115679.
The critically endangered leaf-scaled (Aipysurus foliosquamaI) and short-nosed (A. apraefrontalis) sea snakes are currently recognised only from Ashmore and Hibernia reefs ~600km off the northwest Australian coast. Steep population declines in both species were documented over 15 years and neither has been sighted on dedicated surveys of Ashmore and Hibernia since 2001. We examine specimens of these species that were collected from coastal northwest Australian habitats up until 2010 (A.foliosquama) and 2012 (A. apraefrontalis) and were either overlooked or treated as vagrants in conservation assessments. Morphological variation and mitochondrial sequence data confirm the assignment of these coastal specimens to A. foliosquama (Barrow Island, and offshore from Port Hedland) and A.apraefrontalis (Exmouth Gulf, and offshore from Roebourne and Broome). Collection dates, and molecular and morphological variation between coastal and offshore specimens, suggest that the coastal specimens are not vagrants as previously suspected, but instead represent separate breeding populations. The newly recognised populations present another chance for leaf-scaled and short-nosed sea snakes, but coastal habitats in northwest Australia are widely threatened by infrastructure developments and sea snakes are presently omitted from environmental impact assessments for industry. Further studies are urgently needed to assess these species’ remaining distributions, population structure, and extent of occurrence in protected areas.
doi:10.1371/journal.pone.0115679
PMCID: PMC4324969  PMID: 25671608
14.  Exposures to volatile organic compounds (VOCs) and associated health risks of socio-economically disadvantaged population in a “hot spot” in Camden, New Jersey 
To address disparities in health risks associated with ambient air pollution for racial/ethnic minority groups, this study characterized personal and ambient concentrations of volatile organic compounds (VOCs) in a suspected hot spot of air pollution – the Village of Waterfront South (WFS), and an urban reference community – the Copewood/Davis Streets (CDS) neighborhood in Camden, New Jersey. Both are minority-dominant, impoverished communities. We collected 24-h integrated personal air samples from 54 WFS residents and 53 CDS residents, with one sample on a weekday and one on a weekend day during the summer and winter seasons of 2004–2006. Ambient air samples from the center of each community were also collected simultaneously during personal air sampling. Toluene, ethylbenzene, and xylenes (TEX) presented higher (p < 0.05) ambient levels in WFS than in CDS, particularly during weekdays. A stronger association between personal and ambient concentrations of MTBE and TEX was found in WFS than in CDS. Fourteen to forty-two percent of the variation in personal MTBE, hexane, benzene, and TEX was explained by local outdoor air pollution. These observations indicated that local sources impacted the community air pollution and personal exposure in WFS. The estimated cancer risks resulting from two locally emitted VOCs, benzene and ethylbenzene, and non-cancer neurological and respiratory effects resulting from hexane, benzene, toluene, and xylenes exceeded the US EPA risk benchmarks in both communities. These findings emphasized the need to address disparity in health risks associated with ambient air pollution for the socio-economically disadvantaged groups. This study also demonstrated that air pollution hot spots similar to WFS can provide robust setting to investigate health effects of ambient air pollution.
doi:10.1016/j.atmosenv.2012.04.029
PMCID: PMC4321696
VOCs; Community air pollution; Hot spot; Personal exposure; Health risks; Socio-economically disadvantaged population
15.  Salmonella Osteomyelitis of the Hand in an Infant with Sickle Cell Disease 
Summary:
Salmonella osteomyelitis involving the hand is a rare, but potentially morbid, complication of sickle cell disease in children. This entity can be difficult to distinguish from the more frequent presentation of dactylitis, but accurate diagnosis is critical to direct proper treatment. We report on a 15-month-old patient with sickle cell disease who ultimately developed osteomyelitis of 1 hand after an acute vasoocclusive episode caused 4 extremity dactylitis. The case description illustrates the diagnostic and treatment challenges.
doi:10.1097/GOX.0000000000000267
PMCID: PMC4323402
16.  Update to the study protocol, including statistical analysis plan for a randomized clinical trial comparing comprehensive cardiac rehabilitation after heart valve surgery with control: the CopenHeartVR trial 
Trials  2015;16:38.
Background
Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising because of an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post-surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesize that a comprehensive cardiac rehabilitation program can improve physical capacity and self-assessed mental health and reduce hospitalization and healthcare costs after heart valve surgery.
Methods
This randomized clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients 1:1 to an intervention or a control group, using central randomization, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise and a psycho-educational intervention comprising five consultations. The primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. The secondary outcome is self-assessed mental health measured by the standardized questionnaire Short Form-36. Long-term healthcare utilization and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design will be used to evaluate qualitative and quantitative findings, encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study.
Conclusion
This randomized clinical trial will contribute with evidence of whether cardiac rehabilitation should be provided after heart valve surgery. The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015).
Trial registration
Trial registered 16 March 2012; ClinicalTrials.gov (NCT01558765).
doi:10.1186/s13063-015-0562-z
PMCID: PMC4326522  PMID: 25652891
Heart valve surgery; Rehabilitation; Physical exercise; Psycho-education
17.  Maternal stress exposures, reactions, and priorities for stress reduction among low-income urban women 
INTRODUCTION
Maternal psychosocial stress has been associated with adverse maternal-child outcomes. Vulnerable women’s experiences with stressors during pregnancy and their desires and priorities for appropriate and useful stress reduction interventions for pregnant women are not well-understood.
METHODS
Qualitative interviews with low-income, urban women explored their stress exposures and reactions during pregnancy, ways that stressors overlapped and interacted, and their priorities for stress reduction. Quantitative measures (Perceived Stress Scale, My Exposure to Violence Instrument Danger Assessment, Center for Epidemiologic Studies of Depression Scale, Revised, and Posttraumatic Stress Disorder Checklist-Civilian) supplemented qualitative descriptions of women’s stress exposures and reactions. Analyses explored relationships between stressors and women’s priorities for stress intervention. Lay advisors from the sample population reviewed qualitative interview guides for appropriateness, completeness, and language prior to interviews, and reviewed study findings for validity. Study findings were returned to the community in newsletter form.
RESULTS
Twenty-four low-income urban women participated in interviews. Women in the sample reported high stress, lifetime violence exposure, depression and posttraumatic stress disorder symptoms. The most common stressors reported were financial strain, violence exposure, and feelings of intense isolation and loneliness. Few participants reported having discussed psychosocial stressors with prenatal care providers. Participants in this study described connections with other women as desirable to relieve their stress and provided input on ways healthcare providers could facilitate such connections.
DISCUSSION
Clinical and research implications of findings are discussed, including approaches that health care providers may find useful to facilitate connections among vulnerable pregnant women.
doi:10.1111/j.1542-2011.2012.00197.x
PMCID: PMC4317357  PMID: 23278984
Stress; Psychological; Socioeconomic Factors; Depression; Posttraumatic Stress Disorder; Violence; Maternal Health; Prenatal Care
18.  Patient costs of breast cancer endocrine therapy agents under Medicare Part D vs with generic formulations 
SpringerPlus  2015;4:54.
Purpose
The high expense of newer, more effective adjuvant endocrine therapy agents (aromatase inhibitors [AIs]) for postmenopausal breast cancer contributes to socioeconomic disparities in breast cancer outcomes. This study compares endocrine therapy costs for breast cancer patients during the first five years of Medicare Part D implementation, and when generic alternatives became available.
Methods
The out of pocket patient costs for AIs and tamoxifen under Medicare Part D drug plans were determined for 2006–2011 from the CMS Website for the 50 US states and District of Columbia.
Results
Between 2006 and 2010, the mean annual patient drug cost under Medicare Part D in the median state rose 19% for tamoxifen, 113% for anastrozole, 89% for exemestane, and 129% for letrozole, resulting in median annual out of pocket costs in 2010 of $701, $3050, $2804, and $3664 respectively. However, the 2011 availability of generic AI preparations led to median annual costs in 2011 of $804, $872, $1837, and $2217 respectively. Not included in the reported patient costs, the mean monthly drug premiums in the median state increased 58% in 2011 compared to 2007.
Conclusions
The more effective AI agents became considerably more expensive during the first several years of the Medicare Part D program. Cost decreased with the introduction of generic agents, an intervention that was independent of the Part D program. It is unlikely that the Part D program ameliorated existing socioeconomic disparities in survival among breast cancer patients, but the availability of generic agents may do so.
doi:10.1186/s40064-015-0827-8
PMCID: PMC4320689
Breast cancer; Treatment; Hormonal therapy; Cost; Medicare
19.  Dopamine Increases CD14+CD16+ Monocyte Migration and Adhesion in the Context of Substance Abuse and HIV Neuropathogenesis 
PLoS ONE  2015;10(2):e0117450.
Drug abuse is a major comorbidity of HIV infection and cognitive disorders are often more severe in the drug abusing HIV infected population. CD14+CD16+ monocytes, a mature subpopulation of peripheral blood monocytes, are key mediators of HIV neuropathogenesis. Infected CD14+CD16+ monocyte transmigration across the blood brain barrier mediates HIV entry into the brain and establishes a viral reservoir within the CNS. Despite successful antiretroviral therapy, continued influx of CD14+CD16+ monocytes, both infected and uninfected, contributes to chronic neuroinflammation and the development of HIV associated neurocognitive disorders (HAND). Drug abuse increases extracellular dopamine in the CNS. Once in the brain, CD14+CD16+ monocytes can be exposed to extracellular dopamine due to drug abuse. The direct effects of dopamine on CD14+CD16+ monocytes and their contribution to HIV neuropathogenesis are not known. In this study, we showed that CD14+CD16+ monocytes express mRNA for all five dopamine receptors by qRT-PCR and D1R, D5R and D4R surface protein by flow cytometry. Dopamine and the D1-like dopamine receptor agonist, SKF38393, increased CD14+CD16+ monocyte migration that was characterized as chemokinesis. To determine whether dopamine affected cell motility and adhesion, live cell imaging was used to monitor the accumulation of CD14+CD16+ monocytes on the surface of a tissue culture dish. Dopamine increased the number and the rate at which CD14+CD16+ monocytes in suspension settled to the dish surface. In a spreading assay, dopamine increased the area of CD14+CD16+ monocytes during the early stages of cell adhesion. In addition, adhesion assays showed that the overall total number of adherent CD14+CD16+ monocytes increased in the presence of dopamine. These data suggest that elevated extracellular dopamine in the CNS of HIV infected drug abusers contributes to HIV neuropathogenesis by increasing the accumulation of CD14+CD16+ monocytes in dopamine rich brain regions.
doi:10.1371/journal.pone.0117450
PMCID: PMC4315499  PMID: 25647501
22.  Inflammatory Myofibroblastic Tumors harbor multiple potentially actionable kinase fusions 
Cancer discovery  2014;4(8):889-895.
Inflammatory myofibroblastic tumor (IMT) is a neoplasm which typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. While 50% of IMTs harbor ALK rearrangements, no therapeutic targets have been identified in ALK negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8 year old boy with treatment-refractory ALK negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor, crizotinib. This case prompted assessment of a larger series of IMTs. Next generation sequencing revealed that 85% of cases evaluated harbored kinase fusions, involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.
doi:10.1158/2159-8290.CD-14-0377
PMCID: PMC4125481  PMID: 24875859
Inflammatory myofibroblastic tumor; ALK; ROS1; PDGFRβ; tyrosine kinase; tyrosine kinase inhibitor; crizotinib; cancer; sarcoma; targeted therapeutics; next generation sequencing; gene rearrangement; gene fusion
23.  The Common Marmoset Genome Provides Insight into Primate Biology and Evolution 
Worley, Kim C. | Warren, Wesley C. | Rogers, Jeffrey | Locke, Devin | Muzny, Donna M. | Mardis, Elaine R. | Weinstock, George M. | Tardif, Suzette D. | Aagaard, Kjersti M. | Archidiacono, Nicoletta | Rayan, Nirmala Arul | Batzer, Mark A. | Beal, Kathryn | Brejova, Brona | Capozzi, Oronzo | Capuano, Saverio B. | Casola, Claudio | Chandrabose, Mimi M. | Cree, Andrew | Dao, Marvin Diep | de Jong, Pieter J. | del Rosario, Ricardo Cruz-Herrera | Delehaunty, Kim D. | Dinh, Huyen H. | Eichler, Evan | Fitzgerald, Stephen | Flicek, Paul | Fontenot, Catherine C. | Fowler, R. Gerald | Fronick, Catrina | Fulton, Lucinda A. | Fulton, Robert S. | Gabisi, Ramatu Ayiesha | Gerlach, Daniel | Graves, Tina A. | Gunaratne, Preethi H. | Hahn, Matthew W. | Haig, David | Han, Yi | Harris, R. Alan | Herrero, Javier M. | Hillier, LaDeana W. | Hubley, Robert | Hughes, Jennifer F. | Hume, Jennifer | Jhangiani, Shalini N. | Jorde, Lynn B. | Joshi, Vandita | Karakor, Emre | Konkel, Miriam K. | Kosiol, Carolin | Kovar, Christie L. | Kriventseva, Evgenia V. | Lee, Sandra L. | Lewis, Lora R. | Liu, Yih-shin | Lopez, John | Lopez-Otin, Carlos | Lorente-Galdos, Belen | Mansfield, Keith G. | Marques-Bonet, Tomas | Minx, Patrick | Misceo, Doriana | Moncrieff, J. Scott | Morgan, Margaret B. | Muthuswamy, Raveendran | Nazareth, Lynne V. | Newsham, Irene | Nguyen, Ngoc Bich | Okwuonu, Geoffrey O. | Prabhakar, Shyam | Perales, Lora | Pu, Ling-Ling | Puente, Xose S. | Quesada, Victor | Ranck, Megan C. | Raney, Brian J. | Deiros, David Rio | Rocchi, Mariano | Rodriguez, David | Ross, Corinna | Ruffier, Magali | Ruiz, San Juana | Sajjadian, S. | Santibanez, Jireh | Schrider, Daniel R. | Searle, Steve | Skaletsky, Helen | Soibam, Benjamin | Smit, Arian F. A. | Tennakoon, Jayantha B. | Tomaska, Lubomir | Ullmer, Brygg | Vejnar, Charles E. | Ventura, Mario | Vilella, Albert J. | Vinar, Tomas | Vogel, Jan-Hinnerk | Walker, Jerilyn A. | Wang, Qing | Warner, Crystal M. | Wildman, Derek E. | Witherspoon, David J. | Wright, Rita A. | Wu, Yuanqing | Xiao, Weimin | Xing, Jinchuan | Zdobnov, Evgeny M. | Zhu, Baoli | Gibbs, Richard A. | Wilson, Richard K.
Nature genetics  2014;46(8):850-857.
A first analysis of the genome sequence of the common marmoset (Callithrix jacchus), assembled using traditional Sanger methods and Ensembl annotation, has permitted genomic comparison with apes and that old world monkeys and the identification of specific molecular features a rapid reproductive capacity partly due to may contribute to the unique biology of diminutive The common marmoset has prevalence of this dizygotic primate. twins. Remarkably, these twins share placental circulation and exchange hematopoietic stem cells in utero, resulting in adults that are hematopoietic chimeras.
We observed positive selection or non-synonymous substitutions for genes encoding growth hormone / insulin-like growth factor (growth pathways), respiratory complex I (metabolic pathways), immunobiology, and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibit rapid sequence evolution. This New World monkey genome sequence enables significantly increased power for comparative analyses among available primate genomes and facilitates biomedical research application.
doi:10.1038/ng.3042
PMCID: PMC4138798  PMID: 25038751
24.  Accommodation in Astigmatic Children During Visual Task Performance 
Purpose.
To determine the accuracy and stability of accommodation in uncorrected children during visual task performance.
Methods.
Subjects were second- to seventh-grade children from a highly astigmatic population. Measurements of noncycloplegic right eye spherical equivalent (Mnc) were obtained while uncorrected subjects performed three visual tasks at near (40 cm) and distance (2 m). Tasks included reading sentences with stimulus letter size near acuity threshold and an age-appropriate letter size (high task demands) and viewing a video (low task demand). Repeated measures ANOVA assessed the influence of astigmatism, task demand, and accommodative demand on accuracy (mean Mnc) and variability (mean SD of Mnc) of accommodation.
Results.
For near and distance analyses, respectively, sample size was 321 and 247, mean age was 10.37 (SD 1.77) and 10.30 (SD 1.74) years, mean cycloplegic M was 0.48 (SD 1.10) and 0.79 diopters (D) (SD 1.00), and mean astigmatism was 0.99 (SD 1.15) and 0.75 D (SD 0.96). Poor accommodative accuracy was associated with high astigmatism, low task demand (video viewing), and high accommodative demand. The negative effect of accommodative demand on accuracy increased with increasing astigmatism, with the poorest accommodative accuracy observed in high astigmats (≥3.00 D) with high accommodative demand/high hyperopia (1.53 D and 2.05 D of underaccommodation for near and distant stimuli, respectively). Accommodative variability was greatest in high astigmats and was uniformly high across task condition. No/low and moderate astigmats showed higher variability for the video task than the reading tasks.
Conclusions.
Accuracy of accommodation is reduced in uncorrected children with high astigmatism and high accommodative demand/high hyperopia, but improves with increased visual task demand (reading). High astigmats showed the greatest variability in accommodation.
Poor accommodative accuracy was associated with high astigmatism, low task demand, and high accommodative demand. High astigmats vary accommodation more than low astigmats during visual task performance.
doi:10.1167/iovs.14-14400
PMCID: PMC4148923  PMID: 25103265
astigmatism; accommodation; children

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