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1.  Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study 
Objective To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections.
Design Nationwide register based propensity score matched cohort study.
Setting Denmark, 2002-12.
Participants The background cohort eligible for matching comprised 52 392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses.
Main outcome measures The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period.
Results Within the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12).
Conclusions This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment.
PMCID: PMC4456959  PMID: 26048617
2.  Incidence of Otitis Media in a Contemporary Danish National Birth Cohort 
PLoS ONE  2014;9(12):e111732.
In recent years welfare in Denmark has increased which might be expected to reduce otitis media (OM) incidence. We examined the age-specific incidence of OM in a nation-wide cohort of children aged 0–7 years born in 1996–2003 (Danish National Birth Cohort, DNBC). Only selection was ability to understand and speak Danish.
Information of OM and ventilation tubes (VT) was collected through three maternal interviews at 6-month, 18-month and 7-years of age and based on this age-specific and cumulative incidence of OM was calculated. As different numbers of the total population answered the different interviews, the calculations are done with different denominators. The information in DNBC was validated against two population based registries containing information of VT insertions.
Cumulative incidence of OM at 7 years was 60.6% (31,982/52,755). For children with OM, 16.2% (7143/44194) had their first OM episodes between 0–6 months of age, 44.3% (19579/44194) between 7–18 months, and 39.5% (17472/44194) between 19 months and 7 years. Four or more OM episodes before 7 years were reported by 39.5% (12620/31982) and by 64.0% (2482/3881) of those who had their OM debut between 0–6 months; by 48.2% (4998/10378) with debut between 7–18 months; and by 28.7% (4996/17344) with debut between 19 months and 7 years. These figures are essentially unchanged from earlier figures from Denmark. VT insertion at least once was reported by 26,1% in the 7-year interview. Assuming recordings in the Danish National Patient Registry to be gold standard, maternal self-reportings in DNBC of insertion of VT showed high sensitivity (96.4%), specificity (98.2%), and positive (94.8%) and negative predictive values (98.8%).
OM affects nearly 2/3 of preschool children in Denmark despite reduction in known OM risk factors.
PMCID: PMC4278672  PMID: 25545891
3.  Ten years of tuberculosis intervention in Greenland – has it prevented cases of childhood tuberculosis? 
International Journal of Circumpolar Health  2014;73:10.3402/ijch.v73.24843.
The incidence of tuberculosis (TB) disease in Greenland doubled in the 1990s. To combat the increase, national TB interventions were initiated in 2000 and strengthened in 2007.
To determine whether the effect of interventions could be detected, we estimated the TB disease risk among children≤15 years before and after interventions were implemented.
For a study cohort, we recruited all children ≤15 years of age included in the Greenlandic Civil Registration System (CRS) from 1990 to 2010. The CRS identifier was used to link cohort participants with TB cases identified based on the Greenlandic National TB registry. Bacille Calmette Guerin (BCG) vaccination status was identified through year of birth, as BCG was offered to newborns born either before 1991 or after 1996. Years with interventions were defined as 2000–2006 (primary interventions) and 2007–2010 (intensified interventions). Risk of TB was estimated using Poisson regression.
The study included 35,858 children, of whom 209 had TB disease. The TB disease incidence decreased after interventions were implemented (2007–2010: IRR [incidence rate ratios] 0.62, 95% CI: 0.39–0.95, p=0.03, compared with the 1995–1999 period). The TB disease risk was inversely associated with BCG vaccination (IRR: 0.54, 95% CI: 0.41–0.72, p<0.001).
Years with national TB interventions in Greenland, including neonate BCG vaccination, are associated with a lower TB disease incidence among children ≤15 years of age.
PMCID: PMC4095760  PMID: 25045654
epidemiological study; tuberculosis disease; tuberculosis control; children; Greenland
4.  Physical activity level and its clinical correlates in chronic obstructive pulmonary disease: a cross-sectional study 
Respiratory Research  2013;14(1):128.
Decreased physical activity is associated with higher mortality in subjects with COPD. The aim of this study was to assess clinical characteristics and physical activity levels (PALs) in subjects with COPD.
Seventy-three subjects with COPD (67 ± 7 yrs, 44 female) with one-second forced expiratory volume percentage (FEV1%) predicted values of 43 ± 16 were included. The ratio of total energy expenditure (TEE) and resting metabolic rate (RMR) was used to define the physical activity level (PAL) (PAL = TEE/RMR). TEE was assessed with an activity monitor (ActiReg), and RMR was measured by indirect calorimetry. Walking speed (measured over 30-meters), maximal quadriceps muscle strength, fat-free mass and systemic inflammation were measured as clinical characteristics. Hierarchical linear regression was applied to investigate the explanatory values of the clinical correlates to PAL.
The mean PAL was 1.47 ± 0.19, and 92% of subjects were classified as physically very inactive or sedentary. The walking speed was 1.02 ± 0.23 m/s, the quadriceps strength was 31.3 ± 11.2 kg, and the fat-free mass index (FFMI) was 15.7 ± 2.3 kg/m2, identifying 42% of subjects as slow walkers, 21% as muscle-weak and 49% as FFM-depleted. The regression model explained 45.5% (p < 0.001) of the variance in PAL. The FEV1% predicted explained the largest proportion (22.5%), with further improvements in the model from walking speed (10.1%), muscle strength (7.0%) and FFMI (3.0%). Neither age, gender nor systemic inflammation contributed to the model.
Apart from lung function, walking speed and muscle strength are important correlates of physical activity. Further explorations of the longitudinal effects of the factors characterizing the most inactive subjects are warranted.
PMCID: PMC3832683  PMID: 24237876
Physical activity; Activity monitor; COPD; Physical function; Body composition
5.  Living conditions, quality of life, adherence and treatment outcome in Greenlandic HIV patients 
International Journal of Circumpolar Health  2012;71:10.3402/ijch.v71i0.18639.
Despite a high level of sexually transmitted infections, HIV incidence has remained quite stable in Greenland with 5–6 new cases per year (approximately 10 per 100,000). However, disease control is suboptimal and mortality is relatively high. The aim of the present study was to determine associations between adherence to treatment and treatment outcome, living conditions and quality of life among HIV patients in Greenland.
Material and methods
Cross-sectional questionnaire-based cohort study of HIV patients in Greenland during 2008–2009. Data regarding treatment, viral load, CD4 count, etc. were obtained from a central HIV-database.
Forty-six persons, 17 women and 29 men, of the 60 registered HIV-positive patients (77%) were included. Eighty percent were heterosexually infected and 17% by men having sex with men (MSM) activity. Median age at the time of diagnosis was 48 years (range 20–63). Eighty-nine percent received highly active antiretroviral therapy (HAART). Sixty-seven percent were adherent as defined by a combination of adherence to appointments and to treatment. Ninety-seven percent of adherent and 17% non-adherent patients on HAART had HIV-RNA less than 200 copies per ml (RR=24.2, p<0.0001). Poor adherence was associated with younger age (<50 years) (adjusted RR=7.95, p=0.005) and living in remote areas with no direct contact with skilled personnel (adjusted RR=6.75, p=0.01). Unsafe sex was also more frequent among non-adherent patients (RR=4.12, p=0.026), but due to few answers this topic was not included in the multivariate model.
The HIV population in Greenland is peculiar since most patients are heterosexually infected and middle-aged at diagnosis. A relatively poor adherence and consequently inferior treatment outcome is related to young age and living in remote areas.
PMCID: PMC3417688  PMID: 22663939
HIV; Greenland; adherence; living conditions; quality of life
6.  Spatial and temporal patterns of malaria incidence in Mozambique 
Malaria Journal  2011;10:189.
The objective of this study is to analyze the spatial and temporal patterns of malaria incidence as to determine the means by which climatic factors such as temperature, rainfall and humidity affect its distribution in Maputo province, Mozambique.
This study presents a model of malaria that evolves in space and time in Maputo province-Mozambique, over a ten years period (1999-2008). The model incorporates malaria cases and their relation to environmental variables. Due to incompleteness of climatic data, a multiple imputation technique is employed. Additionally, the whole province is interpolated through a Gaussian process. This method overcomes the misalignment problem of environmental variables (available at meteorological stations - points) and malaria cases (available as aggregates for every district - area). Markov Chain Monte Carlo (MCMC) methods are used to obtain posterior inference and Deviance Information Criteria (DIC) to perform model comparison.
A Bayesian model with interaction terms was found to be the best fitted model. Malaria incidence was associated to humidity and maximum temperature. Malaria risk increased with maximum temperature over 28°C (relative risk (RR) of 0.0060 and 95% Bayesian credible interval (CI) of 0.00033-0.0095) and humidity (relative risk (RR) of 0.00741 and 95% Bayesian CI 0.005141-0.0093). The results would suggest that additional non-climatic factors including socio-economic status, elevation, etc. also influence malaria transmission in Mozambique.
These results demonstrate the potential of climate predictors particularly, humidity and maximum temperature in explaining malaria incidence risk for the studied period in Maputo province. Smoothed maps obtained as monthly average of malaria incidence allowed to visualize months of initial and peak transmission. They also illustrate a variation on malaria incidence risk that might not be related to climatic factors. However, these factors are still determinant for malaria transmission and intensity in the region.
PMCID: PMC3161914  PMID: 21752284
7.  Eye-Opening Approach to Norovirus Surveillance 
Emerging Infectious Diseases  2010;16(8):1319-1321.
PMCID: PMC3298324  PMID: 20678337
Viruses; surveillance; norovirus; enteric infections; food-borne infections; vomit; database searches; Sweden; letter
8.  Mapping malaria incidence distribution that accounts for environmental factors in Maputo Province - Mozambique 
Malaria Journal  2010;9:79.
The objective was to study if an association exists between the incidence of malaria and some weather parameters in tropical Maputo province, Mozambique.
A Bayesian hierarchical model to malaria count data aggregated at district level over a two years period is formulated. This model made it possible to account for spatial area variations. The model was extended to include environmental covariates temperature and rainfall. Study period was then divided into two climate conditions: rainy and dry seasons. The incidences of malaria between the two seasons were compared. Parameter estimation and inference were carried out using MCMC simulation techniques based on Poisson variation. Model comparisons are made using DIC.
For winter season, in 2001 the temperature covariate with estimated value of -8.88 shows no association to malaria incidence. In year 2002, the parameter estimation of the same covariate resulted in 5.498 of positive level of association. In both years rainfall covariate determines no dependency to malaria incidence. Malaria transmission is higher in wet season with both covariates positively related to malaria with posterior means 1.99 and 2.83 in year 2001. For 2002 only temperature is associated to malaria incidence with estimated value 2.23.
The incidence of malaria in year 2001, presents an independent spatial pattern for temperature in summer and for rainfall in winter seasons respectively. In year 2002 temperature determines the spatial pattern of malaria incidence in the region. Temperature influences the model in cases where both covariates are introduced in winter and summer season. Its influence is extended to the summer model with temperature covariate only. It is reasonable to state that with the occurrence of high temperatures, malaria incidence had certainly escalated in this year.
PMCID: PMC2853555  PMID: 20302674
9.  Spatial Point Pattern Analysis of Neurons Using Ripley's K-Function in 3D 
The aim of this paper is to apply a non-parametric statistical tool, Ripley's K-function, to analyze the 3-dimensional distribution of pyramidal neurons. Ripley's K-function is a widely used tool in spatial point pattern analysis. There are several approaches in 2D domains in which this function is executed and analyzed. Drawing consistent inferences on the underlying 3D point pattern distributions in various applications is of great importance as the acquisition of 3D biological data now poses lesser of a challenge due to technological progress. As of now, most of the applications of Ripley's K-function in 3D domains do not focus on the phenomenon of edge correction, which is discussed thoroughly in this paper. The main goal is to extend the theoretical and practical utilization of Ripley's K-function and corresponding tests based on bootstrap resampling from 2D to 3D domains.
PMCID: PMC2889688  PMID: 20577588
Ripley's K-function; edge correction in 3D; bootstrap resampling
10.  Impact of patient characteristics, education and knowledge on emergency room visits in patients with asthma and COPD: a descriptive and correlative study 
Asthma and COPD are major health problems and an extensive burden for the patient and the health care system. Patient education has been recommended, but the influence on knowledge and health outcomes is not fully examined. Our aims were to compare patient characteristics, education and knowledge in patients who had an emergency room (ER) visit, to explore factors related to disease knowledge, and to investigate patient characteristics, patient education and knowledge in relation to further ER visits over a 12 month period.
Eighty-four patients with asthma and 52 with COPD, who had had an ER visit, were included. They were interviewed by telephone 4 to 6 weeks after the ER visit and followed for a year.
Patients with COPD were older, more sedentary, had had more ER visits the previous year, and had more co morbidity than patients with asthma. About 80% of the patients had received information from health professionals or participated in education/rehabilitation, but a minority (< 20%) reported that their knowledge about how to handle the disease was good. Patients with "good knowledge" were younger, were more likely to have asthma diagnose, and had a higher educational background (p < 0.05). Sixty-seven percent of the patients with COPD had repeated ER visits during the following year versus 42% in asthma (p < 0.05) (adjusted HRR: 1.73 (1.03-2.90)). Patients who had had ER visits the year before inclusion had a higher risk of ER visits the following year (adjusted HRR: 3.83 (1.99-7.38)). There were no significant differences regarding patient education and knowledge between the group with and without further ER visits after adjusting for sex, diagnose, age, and educational background.
Patients with asthma had a better self reported knowledge of disease management and were less likely to have new exacerbations than patients with COPD. Reported level of knowledge was, however, in it self not a predictor of exacerbations. This indicates that information is not sufficient to reduce the burden of disease. Patient education focused on self-management and behavioral change should be emphasized.
PMCID: PMC2751756  PMID: 19735571
11.  EMBL Nucleotide Sequence Database in 2006 
Nucleic Acids Research  2006;35(Database issue):D16-D20.
The EMBL Nucleotide Sequence Database () at the EMBL European Bioinformatics Institute, UK, offers a large and freely accessible collection of nucleotide sequences and accompanying annotation. The database is maintained in collaboration with DDBJ and GenBank. Data are exchanged between the collaborating databases on a daily basis to achieve optimal synchrony. Webin is the preferred tool for individual submissions of nucleotide sequences, including Third Party Annotation, alignments and bulk data. Automated procedures are provided for submissions from large-scale sequencing projects and data from the European Patent Office. In 2006, the volume of data has continued to grow exponentially. Access to the data is provided via SRS, ftp and variety of other methods. Extensive external and internal cross-references enable users to search for related information across other databases and within the database. All available resources can be accessed via the EBI home page at . Changes over the past year include changes to the file format, further development of the EMBLCDS dataset and developments to the XML format.
PMCID: PMC1897316  PMID: 17148479
12.  How a Lateralized Brain Supports Symmetrical Bimanual Tasks 
PLoS Biology  2006;4(6):e158.
A large repertoire of natural object manipulation tasks require precisely coupled symmetrical opposing forces by both hands on a single object. We asked how the lateralized brain handles this basic problem of spatial and temporal coordination. We show that the brain consistently appoints one of the hands as prime actor while the other assists, but the choice of acting hand is flexible. When study participants control a cursor by manipulating a tool held freely between the hands, the left hand becomes prime actor if the cursor moves directionally with the left-hand forces, whereas the right hand primarily acts if it moves with the opposing right-hand forces. In neurophysiological (electromyography, transcranial magnetic brain stimulation) and functional magnetic resonance brain imaging experiments we demonstrate that changes in hand assignment parallels a midline shift of lateralized activity in distal hand muscles, corticospinal pathways, and primary sensorimotor and cerebellar cortical areas. We conclude that the two hands can readily exchange roles as dominant actor in bimanual tasks. Spatial relationships between hand forces and goal motions determine hand assignments rather than habitual handedness. Finally, flexible role assignment of the hands is manifest at multiple levels of the motor system, from cortical regions all the way down to particular muscles.
Johansson and colleagues combine the use of a novel bimanual task with neurophysiological and brain imaging experiments to examine the neural basis and dynamics of flexible hand coordination during object manipulation.
PMCID: PMC1457013  PMID: 16669700
13.  EMBL Nucleotide Sequence Database: developments in 2005 
Nucleic Acids Research  2005;34(Database issue):D10-D15.
The EMBL Nucleotide Sequence Database () at the EMBL European Bioinformatics Institute, UK, offers a comprehensive set of publicly available nucleotide sequence and annotation, freely accessible to all. Maintained in collaboration with partners DDBJ and GenBank, coverage includes whole genome sequencing project data, directly submitted sequence, sequence recorded in support of patent applications and much more. The database continues to offer submission tools, data retrieval facilities and user support. In 2005, the volume of data offered has continued to grow exponentially. In addition to the newly presented data, the database encompasses a range of new data types generated by novel technologies, offers enhanced presentation and searchability of the data and has greater integration with other data resources offered at the EBI and elsewhere. In stride with these developing data types, the database has continued to develop submission and retrieval tools to maximise the information content of submitted data and to offer the simplest possible submission routes for data producers. New developments, the submission process, data retrieval and access to support are presented in this paper, along with links to sources of further information.
PMCID: PMC1347492  PMID: 16381823
14.  Seroprevalence of pertussis antitoxin (anti-PT) in Sweden before and 10 years after the introduction of a universal childhood pertussis vaccination program 
Apmis  2009;117(12):912-922.
The prevalence of IgG ELISA antibodies against pertussis toxin (anti-PT) was studied in two Swedish seroepidemiological studies. One was performed in 1997 when the new pertussis vaccination program was 1 year old (n = 3420). In 2007, when Pa vaccines had been used countrywide for 10 years in the universal child vaccination program, this study was repeated to analyze the effect of vaccination on anti-PT prevalence (n = 2379). Before the statistical analysis of seroprevalence, children vaccinated within the last 2 years before the serosurveys were excluded. The results indicate a reduced exposure to Bordetella pertussis in the population. The proportion of sera without measurable anti-PT antibodies increased significantly, aggregated over all comparable age groups, from 3.8% in people sampled in 1997 to 16.3% in people sampled in 2007. For cord blood, 1% was without measurable anti-PT antibodies in 1997 compared to a significantly higher level, 12%, in 2007. With anti-PT concentrations of ≥50 and ≥100 EU/ml as cutoff points for ‘recent infection’ the proportion above the cutoff points for younger children was significantly higher in 1997 than in 2007 at both cutoff points. For all adults, 20 years of age and older, the difference in proportions above the lower cutoff point was close to statistically significant, comparing 1997 with 2007. This was not the case at 100 EU/ml. In the 1997 samples of children, there was a significant downward trend of ‘recent infections’ at both cutoff points for three sampled age groups between 5 and 15 years of age from 21% at 5.0–5.5 years of age to 7% at 14.7–15.7 years for the lowest cutoff. In the 2007 samples of children, on the contrary, there was a significant continuous upward trend of ‘recent infections’, at both cutoff points, for four sampled age groups between 4 and 18 years of age – from 4% at 4–5 years of age to 16% at 17–18 years at the lowest cutoff. The continuous increase, with age of children with high anti-PT concentrations, supports the recent change in the general Swedish childhood vaccination program to include a pre-school booster at 5–6 years and a school-leaving booster at 14–16 years of age.
PMCID: PMC3427879  PMID: 20078557
Pertussis; ELISA IgG anti-PT; seroepidemiology; Sweden

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