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1.  Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry 
European Heart Journal  2014;35(25):1657-1665.
The totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transvenous ICD system to minimize intravascular lead complications. There are limited data describing the long-term performance of the S-ICD. This paper presents the first large international patient population collected as part of the EFFORTLESS S-ICD Registry.
Methods and results
The EFFORTLESS S-ICD Registry is a non-randomized, standard of care, multicentre Registry designed to collect long-term, system-related, clinical, and patient reported outcome data from S-ICD implanted patients since June 2009. Follow-up data are systematically collected over 60-month post-implant including Quality of Life. The study population of 472 patients of which 241 (51%) were enrolled prospectively has a mean follow-up duration of 558 days (range 13–1342 days, median 498 days), 72% male, mean age of 49 ± 18 years (range 9–88 years), 42% mean left ventricular ejection fraction. Complication-free rates were 97 and 94%, at 30 and 360 days, respectively. Three hundred and seventeen spontaneous episodes were recorded in 85 patients during the follow-up period. Of these episodes, 169 (53%) received therapy, 93 being for Ventricular Tachycardia/Fibrillation (VT/VF). One patient died of recurrent VF and severe bradycardia. Regarding discrete VT/VF episodes, first shock conversion efficacy was 88% with 100% overall successful clinical conversion after a maximum of five shocks. The 360-day inappropriate shock rate was 7% with the vast majority occurring for oversensing (62/73 episodes), primarily of cardiac signals (94% of oversensed episodes).
The first large cohort of real-world data from an International patient S-ICD population demonstrates appropriate system performance with clinical event rates and inappropriate shock rates comparable with those reported for conventional ICDs. Clinical trial registration URL: Unique identifier NCT01085435.
PMCID: PMC4076663  PMID: 24670710
Subcutaneous ICD; Ventricular arrhythmias; Cardiac arrest; Primary prevention; Secondary prevention
2.  Do educational materials change knowledge and behaviour about crying and shaken baby syndrome? A randomized controlled trial 
Shaken baby syndrome often occurs after shaking in response to crying bouts. We questioned whether the use of the educational materials from the Period of PURPLE Crying program would change maternal knowledge and behaviour related to shaking.
We performed a randomized controlled trial in which 1279 mothers received materials from the Period of PURPLE Crying program or control materials during a home visit by a nurse by 2 weeks after the birth of their child. At 5 weeks, the mothers completed a diary to record their behaviour and their infants' behaviour. Two months after giving birth, the mothers completed a telephone survey to assess their knowledge and behaviour.
The mean score (range 0–100 points) for knowledge about infant crying was greater among mothers who received the PURPLE materials (63.8 points) than among mothers who received the control materials (58.4 points) (difference 5.4 points, 95% confidence interval [CI] 4.1 to 6.5 points). The mean scores were similar for both groups for shaking knowledge and reported maternal responses to crying, inconsolable crying and self-talk responses. Compared with mothers who received control materials, mothers who received the PURPLE materials reported sharing information about walking away if frustrated more often (51.5% v. 38.5%, difference 13.0%, 95% CI 6.9% to 19.2%), the dangers of shaking (49.3% v. 36.4%, difference 12.9%, 95% CI 6.8% to 19.0%), and infant crying (67.6% v. 60.0%, difference 7.6%, 95% CI 1.7% to 13.5%). Walking away during inconsolable crying was significantly higher among mothers who received the PURPLE materials than among those who received control materials (0.067 v. 0.039 events per day, rate ratio 1.7, 95% CI 1.1 to 2.6).
The receipt of the Period of PURPLE Crying materials led to higher maternal scores for knowledge about infant crying and for some behaviours considered to be important for the prevention of shaking. ( trial register no. NCT00175422.)
PMCID: PMC2659818  PMID: 19255065
3.  Human consumption of methyleugenol and its elimination from serum. 
Environmental Health Perspectives  2004;112(6):678-680.
Under a mandate from the U.S. Congress, the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services conducts animal bioassays for carcinogenicity of potentially toxic chemicals to which the U.S. population might be exposed. Methyleugenol, a natural as well as synthesized substance, was nominated for study because it is structurally similar to safrole, a known animal carcinogen. Methyleugenol was found to be a very potent multisite carcinogen in male and female F344/N rats and B6C3F1 mice at all doses tested in 2-year NTP bioassays using gavage dosing. For this reason, human toxicokinetic studies were added to the traditional NTP protocol. A commercial brand of gingersnaps was found by chemists at the Centers for Disease Control and Prevention to contain a relatively high concentration of methyleugenol. After thorough scientific and clinical review, and approval by a National Institutes of Health institutional review board for the protection of human subjects, a study was conducted with nine healthy adult male and female human volunteers. The volunteers were given 12 gingersnaps for breakfast. Blood was drawn immediately before the meal and at 15, 30, 60, and 120 min afterward. The mean +/- SD fasting level of methyleugenol in serum was 16.2 +/- 4.0 pg/g wet weight. Peak blood levels were found at 15 min (mean +/- SD, 53.9 +/- 7.3 pg/g wet weight), followed by a rapid decline; the half-life of elimination was about 90 min. The peak levels were within the range of methyleugenol blood levels in the U.S. population, as measured concurrently in a subset of nonfasting participants in the Third National Health and Nutrition Examination Survey (NHANES III).
PMCID: PMC1241961  PMID: 15121510
4.  Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. 
Environmental Health Perspectives  2003;111(5):749-756.
We have measured 29 pesticides in plasma samples collected at birth between 1998 and 2001 from 230 mother and newborn pairs enrolled in the Columbia Center for Children's Environmental Health prospective cohort study. Our prior research has shown widespread pesticide use during pregnancy among this urban minority cohort from New York City. We also measured eight pesticides in 48-hr personal air samples collected from the mothers during pregnancy. The following seven pesticides were detected in 48-83% of plasma samples (range, 1-270 pg/g): the organophosphates chlorpyrifos and diazinon, the carbamates bendiocarb and 2-isopropoxyphenol (metabolite of propoxur), and the fungicides dicloran, phthalimide (metabolite of folpet and captan), and tetrahydrophthalimide (metabolite of captan and captafol). Maternal and cord plasma levels were similar and, except for phthalimide, were highly correlated (p < 0.001). Chlorpyrifos, diazinon, and propoxur were detected in 100% of personal air samples (range, 0.7-6,010 ng/m(3)). Diazinon and propoxur levels were significantly higher in the personal air of women reporting use of an exterminator, can sprays, and/or pest bombs during pregnancy compared with women reporting no pesticide use or use of lower toxicity methods only. A significant correlation was seen between personal air level of chlorpyrifos, diazinon, and propoxur and levels of these insecticides or their metabolites in plasma samples (maternal and/or cord, p < 0.05). The fungicide ortho-phenylphenol was also detected in 100% of air samples but was not measured in plasma. The remaining 22 pesticides were detected in 0-45% of air or plasma samples. Chlorpyrifos, diazinon, propoxur, and bendiocarb levels in air and/or plasma decreased significantly between 1998 and 2001. Findings indicate that pesticide exposures are frequent but decreasing and that the pesticides are readily transferred to the developing fetus during pregnancy.
PMCID: PMC1241486  PMID: 12727605
5.  Measurement of p-nitrophenol in the urine of residents whose homes were contaminated with methyl parathion. 
Environmental Health Perspectives  2002;110(Suppl 6):1085-1091.
During the last several years, illegal commercial application of methyl parathion (MP) in domestic settings in several U.S. Southeastern and Midwestern States has affected largely inner-city residents. As part of a multiagency response involving the U.S. Environmental Protection Agency (U.S. EPA), the Agency for Toxic Substances and Disease Registry (ATSDR), and state and local health departments, our laboratory developed a rapid, high-throughput, selective method for quantifying p-nitrophenol (PNP), a biomarker of MP exposure, using isotope dilution high-performance liquid chromatography-tandem mass spectrometry. We measured PNP in approximately 16,000 samples collected from residents of seven different states. Using this method, we were able to receive sample batches from each state; prepare, analyze, and quantify the samples for PNP; verify the results; and report the data to the health departments and ATSDR in about 48 hr. These data indicate that many residents had urinary PNP concentrations well in excess of those of the general U.S. population. In fact, their urinary PNP concentrations were more consistent with those seen in occupational settings or in poisoning cases. Although these data, when coupled with other MP metabolite data, suggest that many residents with the highest concentrations of urinary PNP had significant exposure to MP, they do not unequivocally rule out exposure to PNP resulting from environmental degradation of MP. Even with their limitations, these data were used with the assumption that all PNP was derived from MP exposure, which enabled the U.S. EPA and ATSDR to develop a comprehensive, biologically driven response that was protective of human health, especially susceptible populations, and included clinical evaluations, outreach activities, community education, integrated pest management, and decontamination of homes.
PMCID: PMC1241298  PMID: 12634145
6.  Levels of methyleugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry. 
Environmental Health Perspectives  2000;108(4):323-328.
We developed a sensitive and accurate analytical method for quantifying methyleugenol (ME) in human serum. Our method uses a simple solid-phase extraction followed by a highly specific analysis using isotope dilution gas chromatography-high resolution mass spectrometry. Our method is very accurate; its limit of detection is 3.1 pg/g and its average coefficient of variation is 14% over a 200-pg/g range. We applied this method to measure serum ME concentrations in adults in the general U.S. population. ME was detected in 98% of our samples, with a mean ME concentration of 24 pg/g (range < 3.1-390 pg/g). Lipid adjustment of the data did not alter the distribution. Bivariate and multivariate analyses using selected demographic variables showed only marginal relationships between race/ethnicity and sex/fasting status with serum ME concentrations. Although no demographic variable was a good predictor of ME exposure or dose, our data indicate prevalent exposure of U.S. adults to ME. Detailed pharmacokinetic studies are required to determine the relationship between ME intake and human serum ME concentrations.
PMCID: PMC1638031  PMID: 10753090
7.  Localization of Hydrogen Ion and Chloride Ion Fluxes in Nitella 
The Journal of General Physiology  1969;54(3):397-414.
Alternating bands of acid and base formation have been detected along the length of the internodal cell of Nitella clavata when it is illuminated, while in the dark this phenomenon is minimal. Chloride influx occurs only or largely in the acid-extruding regions, and this is also a light-dependent ion movement. Chloride efflux is slightly dependent on illumination and is not localized as are H+ efflux and Cl- influx. The results obtained support Kitasato's (1968) proposal that a large passive H+ influx is balanced by an active efflux of this ion. Transport mechanisms suggested by the correlations of Cl- and HCO3- influxes with H+ extrusion are discussed.
PMCID: PMC2225932  PMID: 5806597
9.  Adaptive Quantification and Longitudinal Analysis of Pulmonary Emphysema with a Hidden Markov Measure Field Model 
IEEE transactions on medical imaging  2014;33(7):1527-1540.
The extent of pulmonary emphysema is commonly estimated from CT images by computing the proportional area of voxels below a predefined attenuation threshold. However, the reliability of this approach is limited by several factors that affect the CT intensity distributions in the lung.
This work presents a novel method for emphysema quantification, based on parametric modeling of intensity distributions in the lung and a hidden Markov measure field model to segment emphysematous regions. The framework adapts to the characteristics of an image to ensure a robust quantification of emphysema under varying CT imaging protocols and differences in parenchymal intensity distributions due to factors such as inspiration level. Compared to standard approaches, the present model involves a larger number of parameters, most of which can be estimated from data, to handle the variability encountered in lung CT scans.
The method was used to quantify emphysema on a cohort of 87 subjects, with repeated CT scans acquired over a time period of 8 years using different imaging protocols. The scans were acquired approximately annually, and the data set included a total of 365 scans. The results show that the emphysema estimates produced by the proposed method have very high intra-subject correlation values. By reducing sensitivity to changes in imaging protocol, the method provides a more robust estimate than standard approaches. In addition, the generated emphysema delineations promise great advantages for regional analysis of emphysema extent and progression, possibly advancing disease subtyping.
PMCID: PMC4104988  PMID: 24759984
Computed tomography; lung; image segmentation; Markov random fields; emphysema index
10.  Prion Transmission Prevented by Modifying the β2-α2 Loop Structure of Host PrPC 
The Journal of Neuroscience  2014;34(3):1022-1027.
Zoonotic prion transmission was reported after the bovine spongiform encephalopathy (BSE) epidemic, when >200 cases of prion disease in humans were diagnosed as variant Creutzfeldt-Jakob disease. Assessing the risk of cross-species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the β2-α2 loop region of the mouse prion protein (residues 165–175) markedly influences infection by sheep scrapie, BSE, mouse-adapted scrapie, deer chronic wasting disease, and hamster-adapted scrapie prions. The tyrosine residue at position 169 is strictly conserved among mammals and an aromatic side chain in this position is essential to maintain a 310-helical turn in the β2-α2 loop. Here we examined the impact of the Y169G substitution together with the previously described S170N, N174T “rigid loop” substitutions on cross-species prion transmission in vivo and in vitro. We found that transgenic mice expressing mouse PrP containing the triple-amino acid substitution completely resisted infection with two strains of mouse prions and with deer chronic wasting disease prions. These studies indicate that Y169 is important for prion formation, and they provide a strong indication that variation of the β2-α2 loop structure can modulate interspecies prion transmission.
PMCID: PMC3891945  PMID: 24431459
conversion; transmission; amyloid; TSE; prions
11.  A synthetic biology approach to the development of transcriptional regulatory models and custom enhancer design☆,☆☆ 
Methods (San Diego, Calif.)  2013;62(1):91-98.
Synthetic biology offers novel opportunities for elucidating transcriptional regulatory mechanisms and enhancer logic. Complex cis-regulatory sequences—like the ones driving expression of the Drosophila even-skipped gene—have proven difficult to design from existing knowledge, presumably due to the large number of protein-protein interactions needed to drive the correct expression patterns of genes in multicellular organisms. This work discusses two novel computational methods for the custom design of enhancers that employ a sophisticated, empirically validated transcriptional model, optimization algorithms, and synthetic biology. These synthetic elements have both utilitarian and academic value, including improving existing regulatory models as well as evolutionary questions. The first method involves the use of simulated annealing to explore the sequence space for synthetic enhancers whose expression output fit a given search criterion. The second method uses a novel optimization algorithm to find functionally accessible pathways between two enhancer sequences. These paths describe a set of mutations wherein the predicted expression pattern does not significantly vary at any point along the path. Both methods rely on a predictive mathematical framework that maps the enhancer sequence space to functional output.
PMCID: PMC3924567  PMID: 23732772
modeling; transcriptional regulation; synthetic biology
12.  Plasma sphingomyelin and longitudinal change in emphysema on computed tomography. The MESA Lung study 
Ceramide causes endothelial apoptosis and emphysema-like changes in animal models.
Test if plasma sphingomyelin, a major precursor of ceramide, would predict longitudinal increase in the percentage of emphysema-like lung on computed tomography (CT).
Materials and methods
3,840 participants had their plasma sphingomyelin measured at baseline examination and their pulmonary emphysema measured on cardiac CT scans at baseline and on follow-up visits. Mixed effects models were used to adjust for potential confounders.
one standard deviation increase in sphingomyelin predicted a 0.12 % per year (95% CI: 0.02 to 0.22; p = 0.019) greater increase of percent emphysema.
Discussion and conclusion
Higher plasma levels of sphingomyelin predicted greater annual increase in quantitatively measured percent emphysema.
PMCID: PMC4088962  PMID: 24649875
Sphingomyelin; Ceramide; Emphysema; Computed Tomography
13.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
14.  Examining the Moderating Role of Family Cohesion on the Relationship Between Witnessed Community Violence and Delinquency in a National Sample of Adolescents 
Journal of interpersonal violence  2011;27(2):239-262.
Witnessed community violence has been linked to a number of internalizing and externalizing problems in adolescents. Guided by Cicchetti and Lynch’s (1993) ecological-transactional model, this study aimed to examine the impact that family-level factors had on negative outcomes associated with witnessed community violence. Using a nationally representative sample, we explored the moderational role of family cohesion in the relationship between witnessing community violence and delinquent behavior while taking demographic variables into account. Results from the investigation suggested that low levels of family cohesion were predictive of delinquency after controlling for race, gender, past delinquency, and direct trauma. In addition, the findings suggested that family cohesion moderated the impact of witnessed community violence on future delinquent behavior. Future directions for research and implications for practice were also discussed.
PMCID: PMC4085745  PMID: 21920873
community violence; violence exposure; family issues and mediators; child abuse
15.  Are job strain and sleep disturbances prognostic factors for neck/shoulder/arm pain? A cohort study of a general population of working age in Sweden 
BMJ Open  2014;4(7):e005103.
To study whether job strain, that is, psychological job demands and decision latitude, and sleep disturbances among persons with occasional neck/shoulder/arm pain (NSAP) are prognostic factors for having experienced at least one episode of troublesome NSAP, and to determine whether sleep disturbances modify the association between job strain and troublesome NSAP.
Prospective cohort study.
Stockholm, Sweden.
A population-based cohort of individuals with occasional NSAP (n=6979) who answered surveys in 2006 and 2010.
Outcome measures
Report of at least one episode of troublesome NSAP in 2010.
The ORs for troublesome NSAP at follow-up were in individuals exposed to passive jobs 1.2 (95% CI 0.9 to 1.4); to active jobs 1.3 (95% CI 1.1 to 1.5); to high strain 1.5 (95% CI 1.0 to 2.4); to mild sleep disturbances 1.4 (95% CI 1.3 to 1.6) and to severe sleep disturbances 2.2 (95% CI 1.6 to 3.0). High strain and active jobs were associated with having experienced at least one episode of troublesome NSAP during the previous 6 months in persons with sleep disturbances, but not in individuals without sleep disturbances.
Our results indicate that high strain, active jobs and sleep disturbances are prognostic factors that should be taken into account when implementing preventive measures to minimise the risk of troublesome NSAP among people of working age. We suggest that sleep disturbances may modify the association between high strain and troublesome NSAP.
PMCID: PMC4091459  PMID: 25005596
musculoskeletal diseases; prevention; sleep; stress; work
16.  Receipt of Post-Rape Medical Care in a National Sample of Female Victims 
It is important for rape victims to receive medical care to prevent and treat rape-related diseases and injuries, access forensic exams, and connect to needed resources. Few victims seek care, and factors associated with post-rape medical care–seeking are poorly understood.
The current study examined prevalence and factors associated with post-rape medical care–seeking in a national sample of women who reported a most-recent or only incident of forcible rape, and drug- or alcohol-facilitated/incapacitated rape when they were aged ≥14 years.
A national sample of U.S. adult women (N=3001) completed structured telephone interviews in 2006, and data for this study were analyzed in 2011. Logistic regression analyses examined demographic variables, health, rape characteristics, and post-rape concerns in relation to post-rape medical care–seeking among 445 female rape victims.
A minority of rape victims (21%) sought post-rape medical attention following the incident. In the final multivariate model, correlates of medical care included black race, rape-related injury, concerns about sexually transmitted diseases, pregnancy concerns, and reporting the incident to police.
Women who experience rapes consistent with stereotypic scenarios, acknowledge the rape, report the rape, and harbor health concerns appear to be more likely to seek post-rape medical services. Education is needed to increase rape acknowledgment, awareness of post-rape services that do not require formal reporting, and recognition of the need to treat rape-related health problems.
PMCID: PMC4084754  PMID: 22813683
17.  Effects of transdermal nicotine on episodic memory in non-smokers with and without schizophrenia 
Psychopharmacology  2008;199(1):89-98.
Nicotinic agonists may improve attention and memory in humans and may ameliorate some cognitive deficits associated with neuropsychiatric disorders such as schizophrenia.
Materials and methods
We investigated the effects of a single dose of nicotine on episodic memory performance in 10 adults with schizophrenia and 12 healthy controls. Participants were nonsmokers in order to avoid confounding effects of nicotine withdrawal and reinstatement on memory. At each of two study visits, participants performed a test of episodic memory before and 4 h after application of a 14-mg transdermal nicotine (or identical placebo) patch in counterbalanced order.
Compared with placebo, nicotine treatment was associated with more rapid and accurate recognition of novel items. There was a trend for a treatment by diagnosis interaction, such that the effect of nicotine to reduce false alarms was stronger in the schizophrenia than the control group. There was no effect of nicotine on accuracy or reaction time for identification of previously viewed items.
These data suggest that nicotine improves novelty detection in non-smokers, an effect that may be more pronounced in non-smokers with schizophrenia. Because memory deficits are associated with functional impairment in schizophrenia and because impaired novelty detection has been linked to the positive symptoms of schizophrenia, study of the effects of chronic nicotinic agonist treatment on novelty detection may be warranted.
PMCID: PMC4078257  PMID: 18548234
Nicotine; Memory; Inhibitory control; Novelty detection; False alarm; Impulsivity; Schizophrenia; Acetylcholine
19.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
20.  Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function 
Tang, Wenbo | Kowgier, Matthew | Loth, Daan W. | Soler Artigas, María | Joubert, Bonnie R. | Hodge, Emily | Gharib, Sina A. | Smith, Albert V. | Ruczinski, Ingo | Gudnason, Vilmundur | Mathias, Rasika A. | Harris, Tamara B. | Hansel, Nadia N. | Launer, Lenore J. | Barnes, Kathleen C. | Hansen, Joyanna G. | Albrecht, Eva | Aldrich, Melinda C. | Allerhand, Michael | Barr, R. Graham | Brusselle, Guy G. | Couper, David J. | Curjuric, Ivan | Davies, Gail | Deary, Ian J. | Dupuis, Josée | Fall, Tove | Foy, Millennia | Franceschini, Nora | Gao, Wei | Gläser, Sven | Gu, Xiangjun | Hancock, Dana B. | Heinrich, Joachim | Hofman, Albert | Imboden, Medea | Ingelsson, Erik | James, Alan | Karrasch, Stefan | Koch, Beate | Kritchevsky, Stephen B. | Kumar, Ashish | Lahousse, Lies | Li, Guo | Lind, Lars | Lindgren, Cecilia | Liu, Yongmei | Lohman, Kurt | Lumley, Thomas | McArdle, Wendy L. | Meibohm, Bernd | Morris, Andrew P. | Morrison, Alanna C. | Musk, Bill | North, Kari E. | Palmer, Lyle J. | Probst-Hensch, Nicole M. | Psaty, Bruce M. | Rivadeneira, Fernando | Rotter, Jerome I. | Schulz, Holger | Smith, Lewis J. | Sood, Akshay | Starr, John M. | Strachan, David P. | Teumer, Alexander | Uitterlinden, André G. | Völzke, Henry | Voorman, Arend | Wain, Louise V. | Wells, Martin T. | Wilk, Jemma B. | Williams, O. Dale | Heckbert, Susan R. | Stricker, Bruno H. | London, Stephanie J. | Fornage, Myriam | Tobin, Martin D. | O′Connor, George T. | Hall, Ian P. | Cassano, Patricia A.
PLoS ONE  2014;9(7):e100776.
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
PMCID: PMC4077649  PMID: 24983941
21.  In Silico Analysis of Functional Single Nucleotide Polymorphisms in the Human TRIM22 Gene 
PLoS ONE  2014;9(7):e101436.
Tripartite motif protein 22 (TRIM22) is an evolutionarily ancient protein that plays an integral role in the host innate immune response to viruses. The antiviral TRIM22 protein has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 expression has also been associated with multiple sclerosis, cancer, and autoimmune disease. In this study, multiple in silico computational methods were used to identify non-synonymous or amino acid-changing SNPs (nsSNP) that are deleterious to TRIM22 structure and/or function. A sequence homology-based approach was adopted for screening nsSNPs in TRIM22, including six different in silico prediction algorithms and evolutionary conservation data from the ConSurf web server. In total, 14 high-risk nsSNPs were identified in TRIM22, most of which are located in a protein interaction module called the B30.2 domain. Additionally, 9 of the top high-risk nsSNPs altered the putative structure of TRIM22's B30.2 domain, particularly in the surface-exposed v2 and v3 regions. These same regions are critical for retroviral restriction by the closely-related TRIM5α protein. A number of putative structural and functional residues, including several sites that undergo post-translational modification, were also identified in TRIM22. This study is the first extensive in silico analysis of the highly polymorphic TRIM22 gene and will be a valuable resource for future targeted mechanistic and population-based studies.
PMCID: PMC4077803  PMID: 24983760
23.  Recruitment feasibility to a cohort study of endocrine and metabolic health among survivors of childhood brain tumours: a report from the Canadian study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE) 
BMJ Open  2014;4(6):e005295.
The aim of this study was to test the feasibility of recruitment and performance of study procedures of the Canadian Study of Determinants of Endometabolic Health in ChIlDrEn (CanDECIDE) study, which was designed to assess the determinants of endocrine and metabolic health in survivors of childhood brain tumours.
A single paediatric tertiary care centre in Hamilton, Ontario, Canada.
We included boys and girls, aged 5 years and older, who were lean (body mass index (BMI) below 85th centile for age and gender) or overweight/obese (BMI 85th centile or above for age and gender). We excluded children on steroids or immunosuppressant therapy, smokers and those who had an active infection for the 2 weeks prior to participation.
Feasibility targets included recruitment rate of at least 50%, the consenting of 80% of participants to provide biological samples, 90% questionnaire completion rate and the ability to process biological samples from at least 80% of participants.
We approached 210 potential participants, and of the 112 (53%) who agreed to participate, 30 (26.8%) completed the study visit over 7 months. All participants agreed to fast, provide biological samples and complete the questionnaires. Sample collection was successful in 97% (29/30) of participants and laboratory procedures were feasible in 100% of collected samples. We also tested resources required for the conduct of the full study including personnel, space, laboratory equipment and procedures and determined that they are all feasible.
Recruitment and consenting of patients for the CanDECIDE study may be feasible. However, we are considering prolonging recruitment duration and collaboration with other centres to meet recruitment targets due to lower than expected recruitment rate. Completion of questionnaires and implementation of sample processing protocols are feasible.
PMCID: PMC4078774  PMID: 24969784
24.  Bone Loss from High Repetitive High Force Loading is Prevented by Ibuprofen Treatment 
We examined roles of loading and inflammation on forearm bones in a rat model of upper extremity overuse. Trabecular structure in distal radius and ulna was examined in three groups of young adult rats: 1) 5% food-restricted that underwent an initial training period of 10 min/day for 5 weeks to learn the repetitive task (TRHF); 2) rats that underwent the same training before performing a high repetition high force task, 2 hours/day for 12 weeks (HRHF); and 3) food-restricted only (FRC). Subsets were treated with oral ibuprofen (IBU). TRHF rats had increased trabecular bone volume and numbers, osteoblasts, and serum osteocalcin, indicative of bone adaptation. HRHF rats had constant muscle pulling forces, showed limited signs of bone adaptation, but many signs of bone resorption, including decreased trabecular bone volume and bone mineral density, increased osteoclasts and bone inflammatory cytokines, and reduced median nerve conduction velocity (15%). HRHF+IBU rats showed no trabecular resorptive changes, no increased osteoclasts or bone inflammatory cytokines, no nerve inflammation, preserved nerve conduction, and increased muscle voluntary pulling forces. Ibuprofen treatment preserved trabecular bone quality by reducing osteoclasts and bone inflammatory cytokines, and improving muscle pulling forces on bones as a result of reduced nerve inflammation.
PMCID: PMC4067254  PMID: 24583543
repetitive loading; work-related musculoskeletal disorders; radius; ulna; inflammatory cytokines; carpal tunnel syndrome
25.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive

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