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1.  Management of Fetal Malposition in the Second Stage of Labor: A Propensity Score Analysis 
Objective
To determine the factors associated with selection of rotational instrumental versus cesarean delivery to manage persistent fetal malposition, and to assess differences in adverse neonatal and maternal outcomes following delivery by rotational instruments versus cesarean section.
Study Design
We conducted a retrospective cohort study over a 5-year period in a tertiary UK obstetrics center. 868 women with vertex-presenting, single, live-born infants at term with persistent malposition in the second stage of labor were included. Propensity-score stratification was used to control for selection bias: the possibility that obstetricians may systematically select more difficult cases for cesarean section. Linear and logistic regression models were used to compare maternal and neonatal outcomes for delivery by rotational forceps or ventouse versus cesarean section, adjusting for propensity scores.
Results
Increased likelihood of rotational instrumental delivery was associated with lower maternal age (OR= 0.95 p<0.01), lower BMI (OR=0.94 p<0.001), lower birth-weight (OR=0.95 p<0.01), no evidence of fetal compromise at the time of delivery (OR=0.31 p<0.001), delivery during the daytime (OR= 1.45, P<0.05), and delivery by a more experienced obstetrician (OR=7.21 p<0.001). Following propensity score stratification, there was no difference by delivery method in the rates of delayed neonatal respiration, reported critical incidents, or low fetal arterial pH. Maternal blood loss was higher in the cesarean group (295.8± 48ml p<0.001).
Conclusions
Rotational instrumental delivery is often regarded as unsafe. However, we find that neonatal outcomes are no worse once selection bias is accounted for, and that the likelihood of severe obstetric hemorrhage is reduced. More widespread training of obstetricians in rotational instrumental delivery should be considered, particularly in light of rising cesarean section rates.
doi:10.1016/j.ajog.2014.10.023
PMCID: PMC4346422  PMID: 25446659
cesarean section; operative vaginal delivery; fetal malposition; delivery; intra-partum care
2.  Acknowledgement of manuscript reviewers 2015 
Contributing reviewers
The editors of Tobacco Induced Diseases would like to thank all our reviewers who have contributed to the journal in Volume 13 (2015).
doi:10.1186/s12971-016-0071-1
PMCID: PMC4766652  PMID: 26918005
3.  Wheeze in Infancy: Protection Associated with Yeasts in House Dust Contrasts with Increased Risk Associated with Yeasts in Indoor Air and Other Fungal Taxa 
Allergy  2013;68(11):1410-1418.
Background
While fungal exposures are assumed to provoke wheeze through irritant or allergenic mechanisms, little is known about the differential effects of indoor and outdoor fungi on early-life wheeze.
Methods
In a Boston prospective birth-cohort of 499 at-risk infants, culturable fungi in bedroom air and dust and outdoor air were measured at age 2–3 months. Wheeze was determined using bimonthly telephone-questionnaires. Odds ratios were estimated for an interquartile increase in fungal natural log-transformed concentrations, adjusting for predictors of wheeze and potential confounders.
Results
Increased odds of ‘any wheeze’ (≥1 versus 0 episodes) by age one were positively associated with indoor dust Alternaria [odds ratio (OR)=1.83; 95% confidence interval (CI), 1.07–3.14], Penicillium [OR=1.18; (0.98–1.43)] and Cladosporium [OR=1.47; (1.16–1.85)], indoor air Penicillium [OR=1.26; (0.92–1.74)], and outdoor air Cladosporium [OR=1.68; (1.04–2.72)]. In contrast, indoor dust yeasts were protective [OR=0.78; (0.66–0.93)]. ‘Frequent wheeze’ (≥2 versus <2 episodes) by age one was borderline associated with dust yeasts [OR=0.86; (0.70–1.04)] and indoor air yeasts [OR=1.53; (0.93–2.53)]. Alternaria concentration was associated with any wheeze for children with maternal mold sensitization [OR=9.16; (1.37–61.22)], but not for those without maternal mold sensitization [OR=1.32; (0.79–2.20)].
Conclusions
While wheeze rates were higher with exposures to fungal taxa considered to be irritant or allergenic in sensitive subjects, yeasts in the home had a strong protective association with wheeze in infancy. Molecular microbiologic studies may elucidate specific components of innate microbiologic stimulants that lead to contrasting effects on wheeze development.
doi:10.1111/all.12254
PMCID: PMC4761422  PMID: 24118031
Yeast; Fungi; Wheeze; Asthma; Infants; Housing
4.  Endotoxin in Concentrated Coarse and Fine Ambient Particles Induce Acute Systemic Inflammation in Controlled Human Exposures 
Background
Knowledge of the inhalable particulate matter components responsible for health effects is important for developing targeted regulation.
Objectives
In a double-blind randomized cross-over trial of controlled human exposures to concentrated ambient particles (CAPs) and their endotoxin and (1→3)-β-D-glucan components, we evaluated acute inflammatory responses.
Methods
Thirty-five healthy adults were exposed to five 130-minute exposures at rest: 1) fine CAPs (~250 μg/m3); 2) coarse CAPs (~200 μg/m3); 3) a second coarse CAPs (~200 μg/m3); 4) filtered air; and 5) medical air. Induced sputum cell counts were measured at screening and 24-hours post-exposure. Venous blood total leukocytes, neutrophils, interleukin-6 and high-sensitivity C-reactive protein (CRP) were measured pre-, 3 and 24-hours post-exposure.
Results
Relative to filtered air, an increase in blood leukocytes 24-hours (but not 3-hours) post-exposure was significantly associated with coarse [estimate = 0.44 × 109 cells/L (95% CI: 0.01, 0.88); n=132] and fine CAPs [0.68 × 109 cells/L (95% CI: 0.19, 1.17); n=132], but not medical air. Similar associations were found with neutrophil responses. An interquartile increase in endotoxin (5.4 ng/m3) was significantly associated with increased blood leukocytes 3-hours post-exposure [0.27 × 109 cells/L (95% CI: 0.03, 0.51); n=98] and 24-hours post-exposure [0.37 × 109 cells/L (95% CI: 0.12, 0.63); n=98]. This endotoxin effect did not differ by particle size. There were no associations with glucan concentrations or interleukin-6, CRP or sputum responses.
Conclusions
In healthy adults, controlled coarse and fine ambient particle exposures independently induced acute systemic inflammatory responses. Endotoxin contributes to the inflammatory role of particle air pollution.
doi:10.1136/oemed-2013-101498
PMCID: PMC4761440  PMID: 24143017
Endotoxin; Coarse Ambient Particles; Inflammation
5.  Quantum electric-dipole liquid on a triangular lattice 
Nature Communications  2016;7:10569.
Geometric frustration and quantum fluctuations may prohibit the formation of long-range ordering even at the lowest temperature, and therefore liquid-like ground states could be expected. A good example is the quantum spin liquid in frustrated magnets. Geometric frustration and quantum fluctuations can happen beyond magnetic systems. Here we propose that quantum electric-dipole liquids, analogues of quantum spin liquids, could emerge in frustrated dielectrics where antiferroelectrically coupled electric dipoles reside on a triangular lattice. The quantum paraelectric hexaferrite BaFe12O19 with geometric frustration represents a promising candidate for the proposed electric-dipole liquid. We present a series of experimental lines of evidence, including dielectric permittivity, heat capacity and thermal conductivity measured down to 66 mK, to reveal the existence of an unusual liquid-like quantum phase in BaFe12O19, characterized by itinerant low-energy excitations with a small gap. The possible quantum liquids of electric dipoles in frustrated dielectrics open up a fresh playground for fundamental physics.
In magnetic materials, geometry-defined competing interactions between spins combined with quantum fluctuations can present the possibility of quantum liquid states which do not order even as 0K is approached. Here, the authors present an analogue built from electric dipoles on a triangular lattice.
doi:10.1038/ncomms10569
PMCID: PMC4743005  PMID: 26843363
6.  A Vulnerability Assessment of Fish and Invertebrates to Climate Change on the Northeast U.S. Continental Shelf 
PLoS ONE  2016;11(2):e0146756.
Climate change and decadal variability are impacting marine fish and invertebrate species worldwide and these impacts will continue for the foreseeable future. Quantitative approaches have been developed to examine climate impacts on productivity, abundance, and distribution of various marine fish and invertebrate species. However, it is difficult to apply these approaches to large numbers of species owing to the lack of mechanistic understanding sufficient for quantitative analyses, as well as the lack of scientific infrastructure to support these more detailed studies. Vulnerability assessments provide a framework for evaluating climate impacts over a broad range of species with existing information. These methods combine the exposure of a species to a stressor (climate change and decadal variability) and the sensitivity of species to the stressor. These two components are then combined to estimate an overall vulnerability. Quantitative data are used when available, but qualitative information and expert opinion are used when quantitative data is lacking. Here we conduct a climate vulnerability assessment on 82 fish and invertebrate species in the Northeast U.S. Shelf including exploited, forage, and protected species. We define climate vulnerability as the extent to which abundance or productivity of a species in the region could be impacted by climate change and decadal variability. We find that the overall climate vulnerability is high to very high for approximately half the species assessed; diadromous and benthic invertebrate species exhibit the greatest vulnerability. In addition, the majority of species included in the assessment have a high potential for a change in distribution in response to projected changes in climate. Negative effects of climate change are expected for approximately half of the species assessed, but some species are expected to be positively affected (e.g., increase in productivity or move into the region). These results will inform research and management activities related to understanding and adapting marine fisheries management and conservation to climate change and decadal variability.
doi:10.1371/journal.pone.0146756
PMCID: PMC4739546  PMID: 26839967
7.  Asthma & Allergy Development: Contrasting Influences of Yeasts & Other Fungal Exposures 
Background
Infancy is a developmental stage with heightened susceptibility to environmental influences on the risk of chronic childhood disease. Few birth cohort studies have detailed measures of fungal diversity data in infants’ bedrooms, limiting the potential to measure long-term associations of these complex exposures with development of asthma or allergy.
Objective
We evaluated the relation of home fungal levels in infancy to repeated measures of wheeze and development of asthma and rhinitis by age 13, and sensitization by age 12 years.
Methods
In the Epidemiology of Home Allergens and Asthma prospective birth cohort study, we recruited 408 children with family history of allergic disease or asthma. When children were aged 2–3 months, we measured culturable fungi in bedroom air and dust, and in outdoor air. Main outcomes included ascertainment of symptoms/disease onset by questionnaire from birth through age 13. We estimated hazard ratios and, for wheeze and sensitization, odds ratios for an interquartile increase in log-transformed fungal concentrations, adjusting for other outcome predictors and potential confounders.
Results
Elevated levels of yeasts in bedroom floor dust were associated with reduced: i) wheeze at any age; ii) fungal sensitization; and iii) asthma development by age 13 (hazard ratio (HR) = 0.86; 95% confidence interval (CI), [0.75 to 0.98]). Outdoor airborne Cladosporium and dustborne Aspergillus predicted increased rhinitis. Risk of fungal sensitization by age 12, in response to environmental Alternaria and Aspergillus, was elevated in children with a maternal history of fungal sensitization.
Conclusions and Clinical Relevance
Despite the irritant and allergenic properties of fungi, early-life elevated dust yeast exposures or their components may be protective against allergy and asthma in children at risk for these outcomes. Ascertainment of fungal components associated with immunoprotective effects may have therapeutic relevance for asthma.
doi:10.1111/cea.12401
PMCID: PMC4733530  PMID: 25200568
Yeast; Mold; Fungi; Damp; Indoor; Outdoor; Wheeze; Asthma; Rhinitis; Allergy; Development; Infants; Children; Housing
8.  Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study 
Summary
Background
Indian Asians, who make up a quarter of the world’s population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes.
Methods
We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10−7. We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians.
Findings
1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8–3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1–2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07–1·11; p=1·3 × 10−17) for ABCG1, 0·94 (0·92–0·95; p=4·2 × 10−11) for PHOSPHO1, 0·94 (0·92–0·96; p=1·4 × 10−9) for SOCS3, 1·07 (1·04–1·09; p=2·1 × 10−10) for SREBF1, and 0·92 (0·90–0·94; p=1·2 × 10−17) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79–4·42; p=1·3 × 10−26), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10−34).
Interpretation
DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians.
Funding
The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.
doi:10.1016/S2213-8587(15)00127-8
PMCID: PMC4724884  PMID: 26095709
9.  Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation 
Kato, Norihiro | Loh, Marie | Takeuchi, Fumihiko | Verweij, Niek | Wang, Xu | Zhang, Weihua | Kelly, Tanika N | Saleheen, Danish | Lehne, Benjamin | Leach, Irene Mateo | Drong, Alexander W | Abbott, James | Wahl, Simone | Tan, Sian-Tsung | Scott, William R | Campanella, Gianluca | Chadeau-Hyam, Marc | Afzal, Uzma | Ahluwalia, Tarunveer S | Bonder, Marc Jan | Chen, Peng | Dehghan, Abbas | Edwards, Todd L | Esko, Tõnu | Go, Min Jin | Harris, Sarah E | Hartiala, Jaana | Kasela, Silva | Kasturiratne, Anuradhani | Khor, Chiea-Chuen | Kleber, Marcus E | Li, Huaixing | Yu Mok, Zuan | Nakatochi, Masahiro | Sapari, Nur Sabrina | Saxena, Richa | Stewart, Alexandre F R | Stolk, Lisette | Tabara, Yasuharu | Teh, Ai Ling | Wu, Ying | Wu, Jer-Yuarn | Zhang, Yi | Aits, Imke | Da Silva Couto Alves, Alexessander | Das, Shikta | Dorajoo, Rajkumar | Hopewell, Jemma C | Kim, Yun Kyoung | Koivula, Robert W | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Nguyen, Quang N | Pereira, Mark A | Postmus, Iris | Raitakari, Olli T | Bryan, Molly Scannell | Scott, Robert A | Sorice, Rossella | Tragante, Vinicius | Traglia, Michela | White, Jon | Yamamoto, Ken | Zhang, Yonghong | Adair, Linda S | Ahmed, Alauddin | Akiyama, Koichi | Asif, Rasheed | Aung, Tin | Barroso, Inês | Bjonnes, Andrew | Braun, Timothy R | Cai, Hui | Chang, Li-Ching | Chen, Chien-Hsiun | Cheng, Ching-Yu | Chong, Yap-Seng | Collins, Rory | Courtney, Regina | Davies, Gail | Delgado, Graciela | Do, Loi D | Doevendans, Pieter A | Gansevoort, Ron T | Gao, Yu-Tang | Grammer, Tanja B | Grarup, Niels | Grewal, Jagvir | Gu, Dongfeng | Wander, Gurpreet S | Hartikainen, Anna-Liisa | Hazen, Stanley L | He, Jing | Heng, Chew-Kiat | Hixson, James E | Hofman, Albert | Hsu, Chris | Huang, Wei | Husemoen, Lise L N | Hwang, Joo-Yeon | Ichihara, Sahoko | Igase, Michiya | Isono, Masato | Justesen, Johanne M | Katsuya, Tomohiro | Kibriya, Muhammad G | Kim, Young Jin | Kishimoto, Miyako | Koh, Woon-Puay | Kohara, Katsuhiko | Kumari, Meena | Kwek, Kenneth | Lee, Nanette R | Lee, Jeannette | Liao, Jiemin | Lieb, Wolfgang | Liewald, David C M | Matsubara, Tatsuaki | Matsushita, Yumi | Meitinger, Thomas | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Mononen, Nina | Müller-Nurasyid, Martina | Nabika, Toru | Nakashima, Eitaro | Ng, Hong Kiat | Nikus, Kjell | Nutile, Teresa | Ohkubo, Takayoshi | Ohnaka, Keizo | Parish, Sarah | Paternoster, Lavinia | Peng, Hao | Peters, Annette | Pham, Son T | Pinidiyapathirage, Mohitha J | Rahman, Mahfuzar | Rakugi, Hiromi | Rolandsson, Olov | Ann Rozario, Michelle | Ruggiero, Daniela | Sala, Cinzia F | Sarju, Ralhan | Shimokawa, Kazuro | Snieder, Harold | Sparsø, Thomas | Spiering, Wilko | Starr, John M | Stott, David J | Stram, Daniel O | Sugiyama, Takao | Szymczak, Silke | Tang, W H Wilson | Tong, Lin | Trompet, Stella | Turjanmaa, Väinö | Ueshima, Hirotsugu | Uitterlinden, André G | Umemura, Satoshi | Vaarasmaki, Marja | van Dam, Rob M | van Gilst, Wiek H | van Veldhuisen, Dirk J | Viikari, Jorma S | Waldenberger, Melanie | Wang, Yiqin | Wang, Aili | Wilson, Rory | Wong, Tien-Yin | Xiang, Yong-Bing | Yamaguchi, Shuhei | Ye, Xingwang | Young, Robin D | Young, Terri L | Yuan, Jian-Min | Zhou, Xueya | Asselbergs, Folkert W | Ciullo, Marina | Clarke, Robert | Deloukas, Panos | Franke, Andre | Franks, Paul W | Franks, Steve | Friedlander, Yechiel | Gross, Myron D | Guo, Zhirong | Hansen, Torben | Jarvelin, Marjo-Riitta | Jørgensen, Torben | Jukema, J Wouter | kähönen, Mika | Kajio, Hiroshi | Kivimaki, Mika | Lee, Jong-Young | Lehtimäki, Terho | Linneberg, Allan | Miki, Tetsuro | Pedersen, Oluf | Samani, Nilesh J | Sørensen, Thorkild I A | Takayanagi, Ryoichi | Toniolo, Daniela | Ahsan, Habibul | Allayee, Hooman | Chen, Yuan-Tsong | Danesh, John | Deary, Ian J | Franco, Oscar H | Franke, Lude | Heijman, Bastiaan T | Holbrook, Joanna D | Isaacs, Aaron | Kim, Bong-Jo | Lin, Xu | Liu, Jianjun | März, Winfried | Metspalu, Andres | Mohlke, Karen L | Sanghera, Dharambir K | Shu, Xiao-Ou | van Meurs, Joyce B J | Vithana, Eranga | Wickremasinghe, Ananda R | Wijmenga, Cisca | Wolffenbuttel, Bruce H W | Yokota, Mitsuhiro | Zheng, Wei | Zhu, Dingliang | Vineis, Paolo | Kyrtopoulos, Soterios A | Kleinjans, Jos C S | McCarthy, Mark I | Soong, Richie | Gieger, Christian | Scott, James | Teo, Yik-Ying | He, Jiang | Elliott, Paul | Tai, E Shyong | van der Harst, Pim | Kooner, Jaspal S | Chambers, John C
Nature genetics  2015;47(11):1282-1293.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
doi:10.1038/ng.3405
PMCID: PMC4719169  PMID: 26390057
10.  Effect of Atlas Vertebrae Realignment in Subjects with Migraine: An Observational Pilot Study 
BioMed Research International  2015;2015:630472.
Introduction. In a migraine case study, headache symptoms significantly decreased with an accompanying increase in intracranial compliance index following atlas vertebrae realignment. This observational pilot study followed eleven neurologist diagnosed migraine subjects to determine if the case findings were repeatable at baseline, week four, and week eight, following a National Upper Cervical Chiropractic Association intervention. Secondary outcomes consisted of migraine-specific quality of life measures. Methods. After examination by a neurologist, volunteers signed consent forms and completed baseline migraine-specific outcomes. Presence of atlas misalignment allowed study inclusion, permitting baseline MRI data collection. Chiropractic care continued for eight weeks. Postintervention reimaging occurred at week four and week eight concomitant with migraine-specific outcomes measurement. Results. Five of eleven subjects exhibited an increase in the primary outcome, intracranial compliance; however, mean overall change showed no statistical significance. End of study mean changes in migraine-specific outcome assessments, the secondary outcome, revealed clinically significant improvement in symptoms with a decrease in headache days. Discussion. The lack of robust increase in compliance may be understood by the logarithmic and dynamic nature of intracranial hemodynamic and hydrodynamic flow, allowing individual components comprising compliance to change while overall it did not. Study results suggest that the atlas realignment intervention may be associated with a reduction in migraine frequency and marked improvement in quality of life yielding significant reduction in headache-related disability as observed in this cohort. Future study with controls is necessary, however, to confirm these findings. Clinicaltrials.gov registration number is NCT01980927.
doi:10.1155/2015/630472
PMCID: PMC4689902  PMID: 26783523
11.  The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: assessment of environmental exposures 
The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set.
doi:10.1038/jes.2015.7
PMCID: PMC4611361  PMID: 25805254
environmental exposure assessment; longitudinal birth cohort; indoor air quality; etiology of asthma; biomarkers; CHILD study
12.  Giant Dielectric Permittivity in Ferroelectric Thin Films: Domain Wall Ping Pong 
Scientific Reports  2015;5:14618.
The dielectric permittivity in ferroelectric thin films is generally orders of magnitude smaller than in their bulk. Here, we discover a way of increasing dielectric constants in ferroelectric thin films by ca. 500% by synchronizing the pulsed switching fields with the intrinsic switching time (nucleation of domain plus forward growth from cathode to anode). In a 170-nm lead zirconate titanate thin film with an average grain size of 850 nm this produces a dielectric constant of 8200 with the maximum nucleus density of 3.8 μm−2, which is one to three orders of magnitude higher than in other dielectric thin films. This permits smaller capacitors in memory devices and is a step forward in making ferroelectric domain-engineered nano-electronics.
doi:10.1038/srep14618
PMCID: PMC4594126  PMID: 26440528
13.  Estimating Trait Heritability in Highly Fecund Species 
G3: Genes|Genomes|Genetics  2015;5(12):2639-2645.
Increasingly, researchers are interested in estimating the heritability of traits for nonmodel organisms. However, estimating the heritability of these traits presents both experimental and statistical challenges, which typically arise from logistical difficulties associated with rearing large numbers of families independently in the field, a lack of known pedigree, the need to account for group or batch effects, etc. Here we develop both an empirical and computational methodology for estimating the narrow-sense heritability of traits for highly fecund species. Our experimental approach controls for undesirable culturing effects while minimizing culture numbers, increasing feasibility in the field. Our statistical approach accounts for known issues with model-selection by using a permutation test to calculate significance values and includes both fitting and power calculation methods. We further demonstrate that even with moderately high sample-sizes, the p-values derived from asymptotic properties of the likelihood ratio test are overly conservative, thus reducing statistical power. We illustrate our methodology by estimating the narrow-sense heritability for larval settlement, a key life-history trait, in the reef-building coral Orbicella faveolata. The experimental, statistical, and computational methods, along with all of the data from this study, are available in the R package multiDimBio.
doi:10.1534/g3.115.020701
PMCID: PMC4683637  PMID: 26438295
heritability; nonmodel organisms; common garden; binary variable traits; coral settlement
15.  Earliest Pottery on New Guinea Mainland Reveals Austronesian Influences in Highland Environments 3000 Years Ago 
PLoS ONE  2015;10(9):e0134497.
Austronesian speaking peoples left Southeast Asia and entered the Western Pacific c.4000-3000 years ago, continuing on to colonise Remote Oceania for the first time, where they became the ancestral populations of Polynesians. Understanding the impact of these peoples on the mainland of New Guinea before they entered Remote Oceania has eluded archaeologists. New research from the archaeological site of Wañelek in the New Guinea Highlands has broken this silence. Petrographic and geochemical data from pottery and new radiocarbon dating demonstrates that Austronesian influences penetrated into the highland interior by 3000 years ago. One potsherd was manufactured along the northeast coast of New Guinea, whereas others were manufactured from inland materials. These findings represent the oldest securely dated pottery from an archaeological context on the island of New Guinea. Additionally, the pottery comes from the interior, suggesting the movements of people and technological practices, as well as objects at this time. The antiquity of the Wañelek pottery is coincident with the expansion of Lapita pottery in the Western Pacific. Such occupation also occurs at the same time that changes have been identified in subsistence strategies in the archaeological record at Kuk Swamp suggesting a possible link between the two.
doi:10.1371/journal.pone.0134497
PMCID: PMC4557931  PMID: 26331310
16.  Perinatal Exposure to Traffic-Related Air Pollution and Atopy at 1 Year of Age in a Multi-Center Canadian Birth Cohort Study 
Environmental Health Perspectives  2015;123(9):902-908.
Background
The role of traffic-related air pollution (TRAP) exposure in the development of allergic sensitization in children is unclear, and few birth cohort studies have incorporated spatiotemporal exposure assessment.
Objectives
We aimed to examine the association between TRAP and atopy in 1-year-old children from an ongoing national birth cohort study in four Canadian cities.
Methods
We identified 2,477 children of approximately 1 year of age with assessment of atopy for inhalant (Alternaria, Der p, Der f, cat, dog, cockroach) and food-related (milk, eggs, peanuts, soy) allergens. Exposure to nitrogen dioxide (NO2) was estimated from city-specific land use regression models accounting for residential mobility and temporal variability in ambient concentrations. We used mixed models to examine associations between atopy and exposure during pregnancy and the first year of life, including adjustment for covariates (maternal atopy, socioeconomic status, pets, mold, nutrition). We also conducted analyses stratified by time-location patterns, daycare attendance, and modeled home ventilation.
Results
Following spatiotemporal adjustment, TRAP exposure after birth increased the risk for development of atopy to any allergens [adjusted odds ratio (aOR) per 10 μg/m3 NO2 = 1.16; 95% CI: 1.00, 1.41], but not during pregnancy (aOR = 1.02; 95% CI: 0.86, 1.22). This association was stronger among children not attending daycare (aOR = 1.61; 95% CI: 1.28, 2.01) compared with daycare attendees (aOR = 1.05; 95% CI: 0.81, 1.28). Trends to increased risk were also found for food (aOR = 1.17; 95% CI: 0.95, 1.47) and inhalant allergens (aOR = 1.28; 95% CI: 0.93, 1.76).
Conclusion
Using refined exposure estimates that incorporated temporal variability and residential mobility, we found that traffic-related air pollution during the first year of life was associated with atopy.
Citation
Sbihi H, Allen RW, Becker A, Brook JR, Mandhane P, Scott JA, Sears MR, Subbarao P, Takaro TK, Turvey SE, Brauer M. 2015. Perinatal exposure to traffic-related air pollution and atopy at 1 year of age in a multi-center Canadian birth cohort study. Environ Health Perspect 123:902–908; http://dx.doi.org/10.1289/ehp.1408700
doi:10.1289/ehp.1408700
PMCID: PMC4559953  PMID: 25826816
17.  Cost Resulting from Anti-Tuberculosis Drug Shortages in the United States: A Hypothetical Cohort Study 
PLoS ONE  2015;10(8):e0134597.
Background
From 2012 through 2014, the United States experienced acute shortages and price escalations of several first-line anti-tuberculosis (TB) medications. Because secondary TB drug regimens are longer and adverse events occur more frequently with them, we sought to conservatively estimate the cost, to patients and the health care system, of TB treatment and medication adverse events from alternative regimens during drug shortages.
Methods
We assessed the cost of treatment for TB disease in the absence of isoniazid (INH), rifampin (RIF), or pyrazinamide (PZA), or both INH and RIF. We simulated adverse events based on published probabilities using a monthly discrete-time stochastic model. For total costs, we summed costs of medications, routine testing, and treatment of adverse events using procedural terminology codes. We report average cost ratios of TB treatment during drug shortages to standard TB treatment.
Results
The cost ratio of TB treatment without INH, RIF, or PZA to standard treatment was 1.7 (Range: 1.2, 2.3), 4.9 (Range: 3.2, 7.3), and 1.1 (Range: 0.7, 1.7) times higher, respectively. Without both INH and RIF, the cost ratio was 18.6 (Range: 10.0, 39.0) times higher. When the prices for INH, RIF and PZA were increased, the cost for standard treatment increased by a factor of 2.7 (Range: 1.9, 3.0). The percentage of patients experiencing at least one adverse event while taking standard therapy was 3.9% (Range: 1.3%, 11.8%). This percentage increased to 51.5% (Range: 20.1%, 83.8%) when RIF was unavailable, and increased to 82.5% (Range: 41.2%, 98.5%) when both INH and RIF were unavailable.
Conclusions
Our conservative model illustrates that an interruption in first-line anti-TB medications leads to appreciable additional costs and adverse events for patients. The availability of these drugs in the United States should be ensured. Models that incorporate the effectiveness of alternative regimens, delays in treatment initiation, and TB transmission can provide broader perspectives on the impact of drug shortages.
doi:10.1371/journal.pone.0134597
PMCID: PMC4540488  PMID: 26284924
18.  Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer’s disease 
Scientific Reports  2015;5:12393.
Previous studies have evaluated gene expression in Alzheimer’s disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD.
doi:10.1038/srep12393
PMCID: PMC4511863  PMID: 26202100
19.  CrEdit: CRISPR mediated multi-loci gene integration in Saccharomyces cerevisiae 
Background
One of the bottlenecks in production of biochemicals and pharmaceuticals in Saccharomyces cerevisiae is stable and homogeneous expression of pathway genes. Integration of genes into the genome of the production organism is often a preferred option when compared to expression from episomal vectors. Existing approaches for achieving stable simultaneous genome integrations of multiple DNA fragments often result in relatively low integration efficiencies and furthermore rely on the use of selection markers.
Results
Here, we have developed a novel method, CrEdit (CRISPR/Cas9 mediated genome Editing), which utilizes targeted double strand breaks caused by CRISPR/Cas9 to significantly increase the efficiency of homologous integration in order to edit and manipulate genomic DNA. Using CrEdit, the efficiency and locus specificity of targeted genome integrations reach close to 100% for single gene integration using short homology arms down to 60 base pairs both with and without selection. This enables direct and cost efficient inclusion of homology arms in PCR primers. As a proof of concept, a non-native β-carotene pathway was reconstructed in S. cerevisiae by simultaneous integration of three pathway genes into individual intergenic genomic sites. Using longer homology arms, we demonstrate highly efficient and locus-specific genome integration even without selection with up to 84% correct clones for simultaneous integration of three gene expression cassettes.
Conclusions
The CrEdit approach enables fast and cost effective genome integration for engineering of S. cerevisiae. Since the choice of the targeting sites is flexible, CrEdit is a powerful tool for diverse genome engineering applications.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-015-0288-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12934-015-0288-3
PMCID: PMC4492099  PMID: 26148499
Metabolic engineering; CRISPR/Cas9; Genome editing; Saccharomyces cerevisiae; Carotenoid production; Genome integrations
20.  Characterizing Social Interaction in Tobacco-Oriented Social Networks: An Empirical Analysis 
Scientific Reports  2015;5:10060.
Social media is becoming a new battlefield for tobacco “wars”. Evaluating the current situation is very crucial for the advocacy of tobacco control in the age of social media. To reveal the impact of tobacco-related user-generated content, this paper characterizes user interaction and social influence utilizing social network analysis and information theoretic approaches. Our empirical studies demonstrate that the exploding pro-tobacco content has long-lasting effects with more active users and broader influence, and reveal the shortage of social media resources in global tobacco control. It is found that the user interaction in the pro-tobacco group is more active, and user-generated content for tobacco promotion is more successful in obtaining user attention. Furthermore, we construct three tobacco-related social networks and investigate the topological patterns of these tobacco-related social networks. We find that the size of the pro-tobacco network overwhelms the others, which suggests a huge number of users are exposed to the pro-tobacco content. These results indicate that the gap between tobacco promotion and tobacco control is widening and tobacco control may be losing ground to tobacco promotion in social media.
doi:10.1038/srep10060
PMCID: PMC4473607  PMID: 26091553
21.  Mental Health Problems in Adolescence and the Interpretation of Unambiguous Threat 
PLoS ONE  2015;10(6):e0127167.
Aberrant threat perception has been linked to paranoia, anxiety and other mental health problems, and is widely considered to be a core, transdiagnostic feature of psychopathology. However, to date there has been only limited investigation of whether mental health problems are associated with a biased interpretation of stimuli that have explicit (as opposed to ambiguous) connotations of threat. In the present study, 41 adolescents diagnosed with a mental illness and 45 demographically matched controls were asked to provide danger ratings of stimuli normatively rated as being either low or high in potential threat. All participants were also asked to complete background measures of cognitive function, mental health and wellbeing. The results indicated that the two groups did not differ in their capacity to discriminate between low and high threat stimuli, nor did they differ in the absolute level of threat that they attributed to these stimuli. However, for the control group, the overall level of threat perceived in facial stimuli was correlated with two important indices of mental health (depression and anxiety). No associations emerged in the clinical group. These data are discussed in relation to their potential implications for the role of aberrant threat perception in transdiagnostic models of mental health.
doi:10.1371/journal.pone.0127167
PMCID: PMC4454485  PMID: 26039081
22.  Effects of Ambient Coarse, Fine, and Ultrafine Particles and Their Biological Constituents on Systemic Biomarkers: A Controlled Human Exposure Study 
Environmental Health Perspectives  2015;123(6):534-540.
Background
Ambient coarse, fine, and ultrafine particles have been associated with mortality and morbidity. Few studies have compared how various particle size fractions affect systemic biomarkers.
Objectives
We examined changes of blood and urinary biomarkers following exposures to three particle sizes.
Methods
Fifty healthy nonsmoking volunteers, mean age of 28 years, were exposed to coarse (2.5–10 μm; mean, 213 μg/m3) and fine (0.15–2.5 μm; mean, 238 μg/m3) concentrated ambient particles (CAPs), and filtered ambient and/or medical air. Twenty-five participants were exposed to ultrafine CAP (< 0.3 μm; mean, 136 μg/m3) and filtered medical air. Exposures lasted 130 min, separated by ≥ 2 weeks. Blood/urine samples were collected preexposure and 1 hr and 21 hr postexposure to determine blood interleukin-6 and C-reactive protein (inflammation), endothelin-1 and vascular endothelial growth factor (VEGF; vascular mediators), and malondialdehyde (lipid peroxidation); as well as urinary VEGF, 8-hydroxy-deoxy-guanosine (DNA oxidation), and malondialdehyde. Mixed-model regressions assessed pre- and postexposure differences.
Results
One hour postexposure, for every 100-μg/m3 increase, coarse CAP was associated with increased blood VEGF (2.41 pg/mL; 95% CI: 0.41, 4.40) in models adjusted for O3, fine CAP with increased urinary malondialdehyde in single- (0.31 nmol/mg creatinine; 95% CI: 0.02, 0.60) and two-pollutant models, and ultrafine CAP with increased urinary 8-hydroxydeoxyguanosine in single- (0.69 ng/mg creatinine; 95% CI: 0.09, 1.29) and two-pollutant models, lasting < 21 hr. Endotoxin was significantly associated with biomarker changes similar to those found with CAPs.
Conclusions
Ambient particles with various sizes/constituents may influence systemic biomarkers differently. Endotoxin in ambient particles may contribute to vascular mediator changes and oxidative stress.
Citation
Liu L, Urch B, Poon R, Szyszkowicz M, Speck M, Gold DR, Wheeler AJ, Scott JA, Brook JR, Thorne PS, Silverman FS. 2015. Effects of ambient coarse, fine, and ultrafine particles and their biological constituents on systemic biomarkers: a controlled human exposure study. Environ Health Perspect 123:534–540; http://dx.doi.org/10.1289/ehp.1408387
doi:10.1289/ehp.1408387
PMCID: PMC4455587  PMID: 25616223
23.  Multi-Service Highly Sensitive Rectifier for Enhanced RF Energy Scavenging 
Scientific Reports  2015;5:9655.
Due to the growing implications of energy costs and carbon footprints, the need to adopt inexpensive, green energy harvesting strategies are of paramount importance for the long-term conservation of the environment and the global economy. To address this, the feasibility of harvesting low power density ambient RF energy simultaneously from multiple sources is examined. A high efficiency multi-resonant rectifier is proposed, which operates at two frequency bands (478–496 and 852–869 MHz) and exhibits favorable impedance matching over a broad input power range (−40 to −10 dBm). Simulation and experimental results of input reflection coefficient and rectified output power are in excellent agreement, demonstrating the usefulness of this innovative low-power rectification technique. Measurement results indicate an effective efficiency of 54.3%, and an output DC voltage of 772.8 mV is achieved for a multi-tone input power of −10 dBm. Furthermore, the measured output DC power from harvesting RF energy from multiple services concurrently exhibits a 3.14 and 7.24 fold increase over single frequency rectification at 490 and 860 MHz respectively. Therefore, the proposed multi-service highly sensitive rectifier is a promising technique for providing a sustainable energy source for low power applications in urban environments.
doi:10.1038/srep09655
PMCID: PMC4423474  PMID: 25951137
24.  Factors Influencing the Likelihood of Instrumental Delivery Success 
Obstetrics and gynecology  2014;123(4):796-803.
Objective
To evaluate risk factors for unsuccessful instrumental delivery when variability between individual accoucheurs is taken into account.
Methods
We conducted a retrospective cohort study of attempted instrumental deliveries over a 5-year period (2008–2012 inclusive) in a tertiary U.K. center. To account for inter-accoucheur variability, we matched unsuccessful deliveries (cases) with successful deliveries (controls) by the same operators. Multivariate logistic regression was used to compare successful and unsuccessful instrumental deliveries.
Results
Three thousand seven hundred ninety-eight Instrumental deliveries of vertex-presenting, single, term infants were attempted, of which 246 were unsuccessful (6.5%). Increased birth weight (OR=1.11 p<0.001), second-stage duration (OR=1.01 p<0.001), rotational delivery (OR=1.52 p<0.05) and use of ventouse versus forceps (OR=1.33 p<0.05) were associated with unsuccessful outcome. When interaccoucheur variability was controlled for, instrument selection and decision to rotate were no longer associated with instrumental delivery success. More senior accoucheurs had higher rates of unsuccessful deliveries (12% v. 5%, p<0.05), but undertook more complicated cases. Cesarean delivery in the second stage without prior attempt at instrumental delivery was associated with higher birth weight (OR=1.07 p<0.001), increased maternal age (OR=1.03 p<0.01), and epidural analgesia (OR=1.46 p<0.001).
Conclusion
Results suggest that birth weight and head position are the most important factors in successful instrumental delivery, whereas the influence of instrument selection and rotational delivery appear to be operator-dependent. Risk factors for lack of instrumental delivery success are distinct from risk factors for requiring instrumental delivery, and these should not be conflated in clinical practice.
doi:10.1097/AOG.0000000000000188
PMCID: PMC4009507  PMID: 24785607
25.  A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies 
Genome Biology  2015;16(1):37.
DNA methylation plays a fundamental role in the regulation of the genome, but the optimal strategy for analysis of genome-wide DNA methylation data remains to be determined. We developed a comprehensive analysis pipeline for epigenome-wide association studies (EWAS) using the Illumina Infinium HumanMethylation450 BeadChip, based on 2,687 individuals, with 36 samples measured in duplicate. We propose new approaches to quality control, data normalisation and batch correction through control-probe adjustment and establish a null hypothesis for EWAS using permutation testing. Our analysis pipeline outperforms existing approaches, enabling accurate identification of methylation quantitative trait loci for hypothesis driven follow-up experiments.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0600-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-015-0600-x
PMCID: PMC4365767  PMID: 25853392

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