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1.  Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study 
Bjog  2014;121(12):1471-1481.
Objective
To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions.
Design
Population-based cohort study.
Setting
Linked UK maternal–child primary care records.
Population
A total of 349 127 singletons liveborn between 1990 and 2009.
Methods
Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression.
Main outcome measures
Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups.
Results
Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80).
Conclusions
Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.
doi:10.1111/1471-0528.12682
PMCID: PMC4232879  PMID: 24612301
Antidepressants; congenital anomaly; depression; SSRIs; TCAs
2.  Variation in the risk of venous thromboembolism in people with colorectal cancer: a population-based cohort study from England 
Background
Patients with colorectal cancer are at high risk of developing venous thromboembolism (VTE), and recent international guidelines have advised extended prophylaxis for some of these patients following surgery or during chemotherapy. However, our understanding of which patients are at increased risk, and to what extent, is limited.
Objectives
To determine absolute and relative rates of VTE among patients with colorectal cancer according to Dukes stage, surgical intervention, and chemotherapy.
Methods
We analyzed data from four linked databases from 1997 to 2006: the Clinical Practice Research Datalink, linked to Hospital Episode Statistics, Cancer Registry data, and Office for National Statistics cause of death data, all from England. Rates were compared by the use of Cox regression.
Results
There were 10 309 patients with colorectal cancer, and 555 developed VTE (5.4%). The incidence varied by Dukes stage, being three-fold higher among Dukes D patients than among Dukes A patients (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.95–4.84), and 40% higher for those receiving chemotherapy than for those not receiving chemotherapy (HR 1.39, 95% CI 1.14–1.69). The risk following surgery varied by stage of disease and chemotherapy, with Dukes A patients having a low incidence of VTE (0.74%; 95% CI 0.28–1.95) at 6 months, with all events occurring within 28 days of surgery, as compared with Dukes B and Dukes C patients, whose risk at 6 months was ∼ 2%.
Conclusion
Twenty-eight days of prophylaxis following surgery for colorectal cancer is appropriate for Dukes A patients. However, Dukes B and Dukes C patients receiving postoperative chemotherapy have a longer duration of risk.
doi:10.1111/jth.12533
PMCID: PMC4230392  PMID: 24977288
chemotherapy; colorectal cancer; colorectal surgery; incidence; venous thromboembolism
3.  Splash dispersal of Phyllosticta citricarpa conidia from infected citrus fruit 
Scientific Reports  2014;4:6568.
Rain-splash dispersal of Phyllosticta citricarpa (syn. Guignardia citricarpa) conidia (pycnidiospores) from infected oranges was studied in still air and combined with wind. High power microscopy demonstrated the presence of conidia in splash droplets from diseased oranges, which exuded conidia for over one hour during repeated wetting. The largest (5 mm) incident drops produced the highest splashes (up to 41.0 cm). A linear-by-quadratic surface model predicted highest splashes to be 41.91 cm at a horizontal distance of 25.97 cm from the target orange. Large splash droplets contained most conidia (4–5.5 mm splashes averaged 308 conidia), but were splashed <30 cm horizontal distance. Most (80–90%) splashes were <1 mm diameter but carried only 0–4 conidia per droplet. In multiple splash experiments, splashes combined to reach higher maxima (up to 61.7 cm; linear-by-quadratic surface model prediction, 62.1 cm) than in the single splash experiments. In combination with wind, higher wind speeds carried an increasing proportion of splashes downwind travelling horizontally at least 8 m at the highest wind speed tested (7 m/s), due to a small proportion of droplets (<1 mm) being aerosolised. These experiments suggest that P. citricarpa conidia can be dispersed from infected oranges by splashes of water in rainfall events.
doi:10.1038/srep06568
PMCID: PMC4190508  PMID: 25298272
4.  The effect of grid resolution on estimates of the burden of ozone and fine particulate matter on premature mortality in the United States 
Air quality, atmosphere, & health  2013;6(3):10.1007/s11869-013-0197-8.
Assessments of human health impacts associated with outdoor air pollution often use air quality models to represent exposure, but involve uncertainties due to coarse model resolution. Here we quantify how estimates of mortality in the United States attributable to ozone (O3) and fine particulate matter (PM2.5) at coarse resolution differ from those at finer resolution. Using the finest modeled concentrations (12 km), we estimate that 66,000 (95% CI, 39,300 – 84,500) all-cause and 21,400 (5,600 – 34,200) respiratory deaths per year are attributable to PM2.5 and O3 concentrations above low-concentration thresholds, respectively. Using model results at 36 km resolution gives mortality burdens that are 11% higher for PM2.5 and 12% higher for O3 than the 12 km estimates, suggesting a modest positive bias. We also scale modeled concentrations at 12 km to coarser resolutions by simple averaging, and repeat the mortality assessment at multiple resolutions from 24 to 408 km, including the resolutions of global models; in doing so, we account for the effect of resolution on population exposure. Coarse grid resolutions produce mortality estimates that are substantially biased low for PM2.5 (30–40% lower than the 12 km estimate at >250 km resolution), but less than 6% higher for O3 at any resolution. Mortality estimates for primary PM2.5 species show greater bias at coarse resolution than secondary species. These results suggest that coarse resolution global models (>100 km) are likely biased low for PM2.5 health effects. For ozone, biases due to coarse resolution may be much smaller, and the effect on modeled chemistry likely dominates.
doi:10.1007/s11869-013-0197-8
PMCID: PMC3862082  PMID: 24348882
Air pollution; exposure assessment; grid resolution; human health; ozone; PM2.5
5.  Differences in socioeconomic position, lifestyle and health-related pregnancy characteristics between Pakistani and White British women in the Born in Bradford prospective cohort study: the influence of the woman's, her partner's and their parents’ place of birth 
BMJ Open  2014;4(6):e004805.
Objective
To examine differences between Pakistani and White British women in relation to socioeconomic position, lifestyle and health-related pregnancy characteristics, and to determine whether these differences vary depending on the woman's, her partner's and both of their parents’ place of birth.
Design
Prospective cohort study.
Setting
Bradford, UK
Participants
3656 Pakistani and 3503 White British women recruited to the Born in Bradford study.
Main outcome measures
Socioeconomic position (employment status; level of education; receipt of benefits; housing tenure), lifestyle characteristics (body mass index (BMI) at the start of pregnancy; smoking during pregnancy) and health-related pregnancy characteristics (hypertensive disorders of pregnancy; gestational diabetes; fasting glucose, postload glucose and fasting insulin at ∼27 weeks gestation).
Results
Fewer Pakistani women were employed (OR 0.17, 95% CI 0.15 to 0.19), the difference being markedly less for UK born women. UK born Pakistani women were more likely, and South Asian born less likely, to be educated post 16 than White British women. Smoking was uncommon among Pakistani women, though the difference comparing UK born Pakistani women to White British women was less than for other groups. BMI was lower among Pakistani compared to White British women (adjusted mean difference −1.12, 95% CI −1.43 to −0.81), the difference being greatest when partners were UK born irrespective of the woman’s place of birth. Pakistani women had higher fasting and postload glucose (mean difference 0.20 mmol/L, 95% CI 0.17 to 0.24; 0.37, 95% CI 0.28 to 0.45), higher fasting insulin and were more likely to have gestational diabetes (GDM).
Conclusions
Our results suggest that some socioeconomic, lifestyle and pregnancy characteristics could be beginning to change in response to migration to the UK, with generally beneficial changes, that is, improving education and employment prospects, lower BMI and no evidence that being UK born has further increased the risk of GDM, but some negative, that is, slight increases in smoking.
doi:10.1136/bmjopen-2014-004805
PMCID: PMC4067825  PMID: 24948746
Epidemiology; Ethnicity; Lifestyle
6.  Co-benefits of Global Greenhouse Gas Mitigation for Future Air Quality and Human Health 
Nature climate change  2013;3(10):885-889.
Actions to reduce greenhouse gas (GHG) emissions often reduce co-emitted air pollutants, bringing co-benefits for air quality and human health. Past studies1–6 typically evaluated near-term and local co-benefits, neglecting the long-range transport of air pollutants7–9, long-term demographic changes, and the influence of climate change on air quality10–12. Here we simulate the co-benefits of global GHG reductions on air quality and human health using a global atmospheric model and consistent future scenarios, via two mechanisms: a) reducing co-emitted air pollutants, and b) slowing climate change and its effect on air quality. We use new relationships between chronic mortality and exposure to fine particulate matter13 and ozone14, global modeling methods15, and new future scenarios16. Relative to a reference scenario, global GHG mitigation avoids 0.5±0.2, 1.3±0.5, and 2.2±0.8 million premature deaths in 2030, 2050, and 2100. Global average marginal co-benefits of avoided mortality are $50–380 (ton CO2)−1, which exceed previous estimates, exceed marginal abatement costs in 2030 and 2050, and are within the low range of costs in 2100. East Asian co-benefits are 10–70 times the marginal cost in 2030. Air quality and health co-benefits, especially as they are mainly local and near-term, provide strong additional motivation for transitioning to a low-carbon future.
doi:10.1038/NCLIMATE2009
PMCID: PMC4051351  PMID: 24926321
7.  Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females 
The European respiratory journal  2009;34(5):1093-1099.
Mutations in bone morphogenetic protein receptor type 2 (BMPR2) cause familial pulmonary arterial hypertension (FPAH), but the penetrance is reduced and females are significantly overrepresented. In addition, gene expression data implicating the oestrogen-metabolising enzyme CYP1B1 suggests a detrimental role of oestrogens or oestrogen metabolites. We examined genetic and metabolic markers of altered oestrogen metabolism in subjects with a BMPR2 mutation.
Genotypes for CYP1B1 Asn453Ser (N453S) were determined for 140 BMPR2 mutation carriers (86 females and 54 males). Nested from those subjects, a case–control study of urinary oestrogen metabolite levels (2-hydroxyoestrogen (2-OHE) and 16α-hydroxyoestrone (16α-OHE1)) was conducted in females (five affected mutation carriers versus six unaffected mutation carriers).
Among females, there was four-fold higher penetrance among subjects homozygous for the wild-type genotype (N/N) than those with N/S or S/S genotypes (p=0.005). Consistent with this finding, the 2-OHE/16α-OHE1 ratio was 2.3-fold lower in affected mutation carriers compared to unaffected mutation carriers (p=0.006).
Our findings suggest that variations in oestrogens and oestrogen metabolism modify FPAH risk. Further investigation of the role of oestrogens in this disease with profound sex bias may yield new insights and, perhaps, therapeutic interventions.
doi:10.1183/09031936.00010409
PMCID: PMC3742124  PMID: 19357154
Bone morphogenetic protein receptor 2; CYP1B1; genetic polymorphism; oestrogen; pulmonary hypertension; sex
8.  Effects of N-acetylcysteine on matrix metalloproteinase-9 secretion and cell migration of human corneal epithelial cells 
Eye  2012;26(8):1138-1144.
Background
Matrix metalloproteinase-9 (MMP-9) secreted by corneal epithelial cells has a role in the remodelling of extracellular matrix and migration of epithelial cells. Elevated levels of MMP-9 activity in the ocular surface may be involved in the pathogenesis of corneal diseases. N-acetylcysteine (NAC) has been used to treat corneal diseases, including recurrent epithelial erosions. In this study, its effects on the MMP-9 secretion and human corneal epithelial (HCE) cell migration were evaluated in vitro.
Methods
Confluent HCE cell cultures were treated with 0–20 mM NAC, and tested for MMP-9 secretion and epithelial cell migration by gelatin zymography and scratch wound assay, respectively. Comparisons between different treatment groups were made using analysis of variance, followed by multiple pairwise comparisons.
Results
Twenty mM NAC inhibited the secretion of MMP-9 significantly. Cell migration, assessed after 24 h of wounding, showed a highly significant dose-dependent inhibitory effect.
Conclusions
This study shows that NAC reduces MMP-9 production by HCE cells and inhibits cell migration in vitro. This information helps to elucidate the mechanisms by which NAC may be beneficial therapeutically and suggests that NAC may be useful for managing corneal erosions and related conditions.
doi:10.1038/eye.2012.135
PMCID: PMC3420048  PMID: 22766540
cornea; epithelium; healing; recurrent corneal erosions (RCE); N-acetylcysteine (NAC)
9.  Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI 
Neurology  2006;67(5):834-842.
Objective
To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI).
Methods
Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis.
Results
The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level.
Conclusions
Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.
doi:10.1212/01.wnl.0000234032.77541.a2
PMCID: PMC3488276  PMID: 16966547
10.  Global Air Quality and Health Co-benefits of Mitigating Near-Term Climate Change through Methane and Black Carbon Emission Controls 
Environmental Health Perspectives  2012;120(6):831-839.
Background: Tropospheric ozone and black carbon (BC), a component of fine particulate matter (PM ≤ 2.5 µm in aerodynamic diameter; PM2.5), are associated with premature mortality and they disrupt global and regional climate.
Objectives: We examined the air quality and health benefits of 14 specific emission control measures targeting BC and methane, an ozone precursor, that were selected because of their potential to reduce the rate of climate change over the next 20–40 years.
Methods: We simulated the impacts of mitigation measures on outdoor concentrations of PM2.5 and ozone using two composition-climate models, and calculated associated changes in premature PM2.5- and ozone-related deaths using epidemiologically derived concentration–response functions.
Results: We estimated that, for PM2.5 and ozone, respectively, fully implementing these measures could reduce global population-weighted average surface concentrations by 23–34% and 7–17% and avoid 0.6–4.4 and 0.04–0.52 million annual premature deaths globally in 2030. More than 80% of the health benefits are estimated to occur in Asia. We estimated that BC mitigation measures would achieve approximately 98% of the deaths that would be avoided if all BC and methane mitigation measures were implemented, due to reduced BC and associated reductions of nonmethane ozone precursor and organic carbon emissions as well as stronger mortality relationships for PM2.5 relative to ozone. Although subject to large uncertainty, these estimates and conclusions are not strongly dependent on assumptions for the concentration–response function.
Conclusions: In addition to climate benefits, our findings indicate that the methane and BC emission control measures would have substantial co-benefits for air quality and public health worldwide, potentially reversing trends of increasing air pollution concentrations and mortality in Africa and South, West, and Central Asia. These projected benefits are independent of carbon dioxide mitigation measures. Benefits of BC measures are underestimated because we did not account for benefits from reduced indoor exposures and because outdoor exposure estimates were limited by model spatial resolution.
doi:10.1289/ehp.1104301
PMCID: PMC3385429  PMID: 22418651
air quality; climate change; health impact analysis; outdoor air; particulate matter
11.  Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease 
Neuropsychology  2011;25(3):306-318.
Objective
Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance.
Method
Three groups of participants were recruited: 1) Imminent and early manifest HD (early HD, n=8); 2) premanifest (presymptomatic) CAG+ (preHD, n=10); and 3) CAG unexpanded (CAG−) controls (n=12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional magnetic resonance imaging during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis.
Results
Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG− group decreased progressively in a well-documented reward detection network that includes the pre-supplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG− group.
Conclusions
These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD.
doi:10.1037/a0021873
PMCID: PMC3086952  PMID: 21401260
Huntington disease; premanifest; saccades; functional MRI; error monitoring
12.  The Pathology of Bleomycin induced Fibrosis is Associated with Loss of Resident Lung Mesenchymal Stem cells which Regulate Effector T-cell Proliferation 
Stem Cells (Dayton, Ohio)  2011;29(4):725-735.
Tissue resident mesenchymal stem cells (MSC) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Here we define a population of resident lung mesenchymal stem cells (luMSC) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin induced loss of these endogenous luMSC and elicited fibrosis (PF), inflammation and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSC attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T cell proliferation in vitro. Global gene expression analysis indicated that the luMSC are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and pro-fibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity following injury however when endogenous MSC are lost this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury.
doi:10.1002/stem.604
PMCID: PMC3322548  PMID: 21312316
resident lung mesenchymal stem cells; pulmonary fibrosis; pulmonary hypertension; stem cells
15.  An Estimate of the Global Burden of Anthropogenic Ozone and Fine Particulate Matter on Premature Human Mortality Using Atmospheric Modeling 
Environmental Health Perspectives  2010;118(9):1189-1195.
Background
Ground-level concentrations of ozone (O3) and fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM2.5)] have increased since preindustrial times in urban and rural regions and are associated with cardiovascular and respiratory mortality.
Objectives
We estimated the global burden of mortality due to O3 and PM2.5 from anthropogenic emissions using global atmospheric chemical transport model simulations of preindustrial and present-day (2000) concentrations to derive exposure estimates.
Methods
Attributable mortalities were estimated using health impact functions based on long-term relative risk estimates for O3 and PM2.5 from the epidemiology literature. Using simulated concentrations rather than previous methods based on measurements allows the inclusion of rural areas where measurements are often unavailable and avoids making assumptions for background air pollution.
Results
Anthropogenic O3 was associated with an estimated 0.7 ± 0.3 million respiratory mortalities (6.3 ± 3.0 million years of life lost) annually. Anthropogenic PM2.5 was associated with 3.5 ± 0.9 million cardiopulmonary and 220,000 ± 80,000 lung cancer mortalities (30 ± 7.6 million years of life lost) annually. Mortality estimates were reduced approximately 30% when we assumed low-concentration thresholds of 33.3 ppb for O3 and 5.8 μg/m3 for PM2.5. These estimates were sensitive to concentration thresholds and concentration–mortality relationships, often by > 50%.
Conclusions
Anthropogenic O3 and PM2.5 contribute substantially to global premature mortality. PM2.5 mortality estimates are about 50% higher than previous measurement-based estimates based on common assumptions, mainly because of methodologic differences. Specifically, we included rural populations, suggesting higher estimates; however, the coarse resolution of the global atmospheric model may underestimate urban PM2.5 exposures.
doi:10.1289/ehp.0901220
PMCID: PMC2944076  PMID: 20382579
air pollution; atmospheric chemistry model; health effects of air pollution; health impact analysis; ozone; particulate matter
16.  Peroxisome Proliferator-Activated Receptor-γ Agonist Treatment Increases Septation and Angiogenesis and Decreases Airway Hyperresponsiveness in a Model of Experimental Neonatal Chronic Lung Disease 
Chronic lung disease (CLD) affects premature newborns requiring supplemental oxygen and results in impaired lung development and subsequent airway hyperreactivity. We hypothesized that the maintenance of peroxisome proliferator-activated receptor gamma (PPARγ) signaling is important for normal lung morphogenesis and treatment with PPARγ agonists could protect against CLD and airway hyperreactivity (AHR) following chronic hyperoxic exposure. This was tested in an established hyperoxic murine model of experimental CLD. Newborn mice and mothers were exposed to room air (RA) or moderate hyperoxia (70% oxygen) for 10 days and fed a standard diet or chow impregnated with the PPARγ agonist rosiglitazone (ROSI) for the duration of study. Following hyperoxic exposure (HE) animals were returned to RA until postnatal day (P) 13 or P41. The accumulation of ROSI in neonatal and adult tissue was confirmed by mass spectrometry. Analyses of body weight and lung histology were performed on P13 and P41 to localize and quantitate PPARγ expression, determine alveolar and microvessel density, proliferation and alpha-smooth muscle actin (α-SMA) levels as a measure of myofibroblast differentiation. Microarray analyses were conducted on P13 to examine transcriptional changes in whole lung. Pulmonary function and airway responsiveness were analyzed at P55. ROSI treatment during HE preserved septation and vascular density. Key array results revealed ontogeny groups differentially affected by hyperoxia including cell cycle, angiogenesis, matrix and muscle differentiation/contraction. These results were further confirmed by histological evaluation of myofibroblast and collagen accumulation. Late AHR to methacholine was present in mice following HE and attenuated with ROSI treatment. These findings suggest that rosiglitazone maintains downstream PPARγ effects and may be beneficial in the prevention of severe CLD with AHR.
doi:10.1002/ar.20921
PMCID: PMC2873208  PMID: 19484746
Chronic Lung Disease (CLD); Rosiglitazone; PPAR gamma; Lung simplification; airway hyperresonsiveness (AHR)
17.  Author's reply 
Gut  2007;56(2):310-311.
PMCID: PMC1856768
18.  The antecedents of biliary cancer: a primary care case–control study in the United Kingdom 
British Journal of Cancer  2008;100(1):178-180.
In a case–control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity.
doi:10.1038/sj.bjc.6604765
PMCID: PMC2634685  PMID: 19018260
cholangiocarcinoma; gall bladder cancer; risk factors; non-steroidal anti-inflammatory drugs; database study
19.  Coeliac disease and risk of tuberculosis: a population‐based cohort study 
Thorax  2007;62(1):1-2.
Are patients with coeliac disease at higher risk of tuberculosis?
doi:10.1136/thx.2006.062158
PMCID: PMC2111272  PMID: 17189527
20.  Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK 
Thorax  2006;61(11):980-985.
Background
Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are common diagnoses in patients attending chest clinics, but little is known about the epidemiology of these diseases. We used data from a general practice database to provide information on the current incidence of IPF and sarcoidosis in the UK.
Methods
Data were extracted for all patients with a diagnosis of IPF or sarcoidosis between 1991 and 2003. The whole population of the database was used to calculate disease incidence stratified by age, sex, region, and time period. Poisson regression was used to compare the incidence between populations and Cox regression was used to compare survival between populations.
Results
920 cases of IPF (mean age 71 years, 62% male) and 1019 cases of sarcoidosis (mean age 47 years, 47% male) were identified. The overall incidence rate per 100 000 person‐years was 4.6 for IPF and 5.0 for sarcoidosis. The incidence of IPF increased progressively between 1991 and 2003 (p<0.00001), and was highest in Northern England and Scotland (p<0.0001). The survival of patients with IPF was stable over time. In contrast, the incidence of sarcoidosis was highest in London, West Midlands and Northern Ireland and remained stable over time.
Conclusions
The incidence of IPF has more than doubled between 1990 and 2003; this is not due to the ageing of the UK population or an increased ascertainment of milder cases. The incidence of sarcoidosis has not changed during this time period. Our findings suggest that more than 4000 new cases of IPF and 3000 new cases of sarcoidosis are currently diagnosed each year in the UK.
doi:10.1136/thx.2006.062836
PMCID: PMC2121155  PMID: 16844727
idiopathic pulmonary fibrosis; sarcoidosis; epidemiology
21.  Vulnerability of pulmonary capillaries during severe exercise 
The pulmonary capillaries are vulnerable to mechanical failure during strenuous exercise
doi:10.1136/bjsm.2006.028886
PMCID: PMC2465077  PMID: 17021008
pulmonary capillaries; pulmonary haemorrhage; strenuous exercise
22.  Is an internal comparison better than using national data when estimating mortality in longitudinal studies? 
Background
Discrepancies between the results of different studies looking at mortality in similar disease cohorts led us to consider the impact of methodology upon outcome.
Methods
Cohort studies were carried out using age, sex, practice, and calendar time matched control groups in the general practice research database. Data were used on all subjects with inflammatory bowel disease, coeliac disease, or Barrett's oesophagus. Mortality data for the population of England and Wales were obtained from the UK Office for National Statistics. The study compared hazard ratios (HR) for mortality using the matched controls to those found when an indirect standardisation to the mortality experience of England and Wales was carried out.
Results
For all three conditions the mortality risk was slightly lower when the national population data were used compared with the internal comparison group (coeliac disease HR 1.33 v standardised mortality ratios (SMR) 1.25, Barrett's oesophagus HR 1.32 v SMR 1.32, inflammatory bowel disease HR 1.50 v SMR 1.34).
Conclusions
A bias was found towards underestimating mortality risk when cohort studies use national population death rates as a comparator. Estimates obtained when an internal comparison group has been used are probably more appropriate.
doi:10.1136/jech.2005.041202
PMCID: PMC2566035  PMID: 16905729
inflammatory bowel disease; Barrett's oesophagus; coeliac disease; cohort studies; standardised mortality ratio; Cox regression
23.  Recent advances in coeliac disease 
Gut  2006;55(7):1037-1046.
doi:10.1136/gut.2005.075119
PMCID: PMC1856316  PMID: 16766754
coeliac disease; recent advances
24.  Cardiac Cycle Dependent Left Atrial Dynamics: Implications for Catheter Ablation of Atrial Fibrillation 
Background
Left atrial volume (LAV) determines prognosis and response to therapy in atrial fibrillation. Integration of electro-anatomical maps with 3D-images rendered from CT and MRI is used to facilitate atrial fibrillation ablation.
Objectives
We measured LAV changes and regional motion during the cardiac cycle that might affect the accuracy of image integration and determined their relationship to standard LAV measurements.
Methods
MRI was performed in thirty patients with paroxysmal atrial fibrillation. Left atrial time-volume curves were generated and used to divide the left atrial function (LAEF) into pumping (PEF) and conduit (CEF) fractions and to determine the maximum LAV (LAMAX) and the pre-atrial contraction volume (PACV). LAV was measured using an MRI angiogram and traditional geometric models from echocardiography (area-length and ellipsoid). The in-plane displacement of the pulmonary veins, anterior left atrium, mitral annulus, and left atrial appendage was measured.
Results
LAMAX was 107±36ml and occurred at 42±5% of the RR interval. PACV was 86 ±34ml and occurred at 81±4% of the RR interval. LAEF was 45±10% and PEF was 31±10%. LAV measurements made from the MRI angiogram, area-length and ellipsoid models underestimated LAMAX by 21±25ml, 16±26ml, and 35±22ml, respectively. The anterior LA, mitral annulus, and left atrial appendage were significantly displaced during the cardiac cycle (8.8±2.0mm, 13.2±3.8mm, and 10.2±3.4mm, respectively); the pulmonary veins were not.
Conclusions
LAV changes significantly during the cardiac cycle and substantial regional variation in left atrial motion exists. Standard measurements of left atrial volume significantly underestimate LAMAX when compared to the gold standard measure of 3D-volumetrics.
doi:10.1016/j.hrthm.2008.03.003
PMCID: PMC2527027  PMID: 18486563
Atrial fibrillation; magnetic resonance imaging; MR imaging; atrial anatomy; atrial morphology; atrial mapping; atrial fibrillation ablation; left atrium
25.  Oral and inhaled corticosteroids and adrenal insufficiency: a case‐control study 
Thorax  2006;61(5):405-408.
Background
Adrenal insufficiency, a well recognised complication of treatment with oral corticosteroids, has been described in association with inhaled corticosteroid use in over 60 case reports. The risk of adrenal insufficiency in people prescribed an oral or inhaled corticosteroid in the general population is not known. A study was undertaken to quantify the association between adrenal insufficiency and oral and inhaled corticosteroid exposure.
Methods
A case‐control study was performed using computerised general practice data from The Health Improvement Network.
Results
From a cohort of 2.4 million people, 154 cases of adrenal insufficiency and 870 controls were identified. There was a dose related increased risk of adrenal insufficiency in people prescribed an oral corticosteroid with an odds ratio of 2.0 (95% CI 1.6 to 2.5) per course of treatment per year. Adrenal insufficiency was associated with a prescription for an inhaled corticosteroid during the 90 day period before the diagnosis with an odds ratio of 3.4 (95% CI 1.9 to 5.9) and this effect was dose related (p for trend <0.001). After adjusting for oral corticosteroid exposure, this odds ratio was reduced to 1.6 (95% CI 0.8 to 3.2) although the dose relation remained (p for trend 0.036).
Conclusion
People prescribed an oral or inhaled corticosteroid are at a dose related increased risk of adrenal insufficiency although the absolute risk is small. This analysis suggests that the increased risk in people prescribed an inhaled corticosteroid is largely due to oral corticosteroid exposure, but inhaled corticosteroids may have an effect when they are taken at higher doses.
doi:10.1136/thx.2005.052456
PMCID: PMC2111185  PMID: 16517576
inhaled corticosteroids; adrenal insufficiency

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