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Elisabeth Svensson,1 Timothy L Lash,1,2 Patricia A Resick,3 Jens Georg Hansen,1 Jaimie L Gradus4–61Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 3Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; 4National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA; 5Department of Psychiatry, 6Department of Epidemiology, Boston University, Boston, MA, USAAims: To assess the validity of reaction to severe stress and adjustment disorder diagnoses registered in the Danish Psychiatric Central Research Register (DPCRR), to examine the documentation of stressful and traumatic events in the medical records, and to investigate the occurrence of stress diagnoses among persons not registered in the DPCRR.Methods: Among 101,633 patients diagnosed with International Classification of Diseases, 10th Edition (ICD-10) F43 diagnoses between 1995 and 2011, we selected 50 patients from two hospitals (100 total), comprising one above and one below median age for each diagnosis for five time periods, and reviewed their medical records. We calculated the positive predictive value, comparing registration in the DPCRR with the original medical records, and captured data on stressful life events. Two general practitioners were queried about 50 patients without a stress diagnosis in the DPCRR, regarding whether they had ever received a stress diagnosis.Results: The positive predictive value was 58% for acute stress reaction, 83% for posttraumatic stress disorder, 94% for adjustment disorder, 71% for other reactions to severe stress, and 68% for reaction to severe stress, unspecified. In 80% of the records, a stressful or traumatic event was noted. Of 100 patients without an F43 diagnosis in the DPCRR, seven had a stress diagnosis.Conclusion: The DPCRR represents a valid and comprehensive resource for research on reaction to severe stress and adjustment disorders, particularly for posttraumatic stress disorder and adjustment disorder.Keywords: validity (epidemiology), stress disorders, traumatic, Denmark

Sigrun Alba Johannesdottir, Merete Lund Mægbæk, Jens Georg Hansen, Timothy L Lash, Lars Pedersen, Vera EhrensteinDepartment of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, DenmarkAbstract: Epidemiologic studies often rely on drug dispensation records to measure medication intake. We aimed to estimate correspondence between general practitioner (GP)-reported treatment and timing of prescription dispensation. From seven GPs in northern Denmark, we obtained 317 prescription records for 286 patients treated with ten commonly prescribed medication types for chronic diseases. We linked the GP-reported information to the regional prescription database to retrieve patients’ prescription records both prospectively and retrospectively in relation to the GP-reported date of treatment (index date, August 20, 2008 for all patients). We computed overall and medication-specific correspondence between GP-reported treatment and the timing of dispensation. We computed correspondence based on both exact medication and therapeutic subgroup agreement. The correspondence for dispensation within ±90 days of GP-reported treatment was 0.81 (95% confidence interval = 0.76–0.85) with variation by medication type, ranging from 0.55 for ACE-inhibitors to 1.00 for oral glucose-lowering agents. The correspondence was greater when analyzed within therapeutic groups than when analyzed for exact medications within these groups.Keywords: pharmacoepidemiology, predictive value, drug prescriptions, primary health care

Jens Georg HansenDepartment of Clinical Epidemiology, Aarhus University Hospital and Aalborg Hospital, Aalborg, DenmarkPurpose: To evaluate whether the ongoing debate over diagnostic problems and treatment choices for acute rhinosinusitis has had any influence on the management of the disease.Methods: We randomly selected 300 Danish general practitioners (GPs) from the files of the Research Unit for General Practice at Aarhus University. Invitations to participate and a questionnaire were sent to the GPs by mail.Results: A total of 149 (49%) GPs answered the questionnaire. When asked about symptoms, the highest priority was given to sinus pain and signs of tenderness. The most frequent examinations were objective examination of the ear-nose-throat (ENT), palpation of the maxillofacial area, and C-reactive protein point-of-care testing (or CRP rapid test). Nearly all GPs prescribed local vasoconstrictors, and in 70% of cases, antibiotics were prescribed. Phenoxymethylpenicillin was the preferred antibiotic. Use of the CRP rapid test, years in practice, or employment in an ENT department did not have a significant impact on the diagnostic certainty and antibiotic prescribing rate.Conclusion: The clinical diagnoses are based on a few symptoms, signs, and the CRP rapid test. Other examinations, including imaging techniques, are seldom used. Phenoxymethylpenicillin is the preferred antibiotic, and the GPs' diagnostic certainty was 70%.Keywords: general practice, acute rhinosinusitis, diagnosis, treatment, antibiotic

Background: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults. Methods: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts. Results: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P = 0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P = 0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P < 0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P = 0.09). Conclusions: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies. [ABSTRACT FROM AUTHOR]

Objective: This trial aimed to compare three low-energy diets (LEDs) with different amounts of carbohydrates (CHO) on ketosis and changes in hunger feelings in adults with obesity., Methods: A total of 101 adults (51 female) with obesity (BMI, mean [SEM], 34.7 [0.4] kg/m 2 ) were randomized to follow three isocaloric LEDs (1000 kcal/day) for 8 weeks, containing either low, medium, or high CHO (70, 100, and 130 g/day, respectively), and 4 weeks of refeeding and weight stabilization. Body weight (BW) and composition, hunger and other appetite ratings, concentrations of β-hydroxybutyrate (βHB), and appetite-related hormones were measured at baseline and at the end of weeks 8 and 12., Results: At week 8, weight loss and βHB concentrations were significantly different among groups: Low CHO group versus Medium CHO group (BW: 2.32 [0.95] kg, 95% CI: 0.44 to 4.21, p = 0.016; βHB: -0.40 [0.09] mM, 95% CI: -0.67 to -0.09, p < 0.001); Low CHO group versus High CHO group (BW: 2.29 [0.96] kg, 95% CI: 0.39 to 4.19, p = 0.016; βHB: -0.644 [0.10] mM, 95% CI: -0.84 to -0.44, p < 0.001); and Medium CHO group versus High CHO group (BW: -0.03 [0.94] kg, 95% CI: -1.89 to 1.84, p = 0.977; βHB: -0.15 [0.08] mM, 95% CI: -0.30 to 0.002, p = 0.054). No significant differences in hunger were found among groups: Low CHO group versus Medium CHO group (-10.87 [5.92] mm, 95% CI: -0.82 to 22.57, p = 0.068); Low CHO group versus Medium CHO group (7.74 [7.36] mm, 95% CI: -6.77 to 22.26, p = 0.294); and Medium CHO group versus High CHO group (-3.13 [7.48] mm, 95% CI: -17.89 to 11.63, p = 0.676)., Conclusions: Although the findings of this trial are not definitive, changes in hunger ratings with weight loss did not differ among groups. Additional studies with CHO intake of up to 130 g in 1000-kcal/day LEDs are warranted to replicate these findings., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

A pivotal animal model for development of anticancer molecules is mice with subcutaneous tumors, grown by injection of xenografted tumor cells, where micro-Computed Tomography (µCT) of the mice is used to analyze the efficacy of the anticancer molecule. Manual delineation of the tumor region is necessary for the analysis, which is time-consuming and inconsistent, highlighting the need for automatic segmentation (AS) tools. This study introduces a preclinical µCT database, comprising 452 whole-body scans from 223 individual mice with subcutaneous tumors, spanning ten diverse µCT datasets conducted between 2014 and 2020 on a preclinical PET/CT scanner, making it the hitherto largest dataset of its kind. Each tumor is annotated manually by three expert annotators, allowing for robust model development. Inter-annotator agreement was analyzed, and we report an overall annotation agreement of 0.903 ± 0.046 (mean ± std) Fleiss' Kappa and a mean deviation in volume estimation of 0.015 ± 0.010 cm 3 (6.9% ± 4.7), which establishes a human baseline accuracy for delineation of subcutaneous tumors, while showing good inter-annotator agreement., (© 2024. The Author(s).)

The increased emergence of cereal stem rust in southern and western Europe, caused by the pathogen Puccinia graminis , and the prevalence of alternate (sexual) host, Berberis species, have regained attention as the sexual host may serve as source of novel pathogen variability that may pose a threat to cereal supply. The main objective of the present study was to investigate the functional role of Berberis species in the current epidemiological situation of cereal stem rust in Europe. Surveys in 11 European countries were carried out from 2018 to 2020, where aecial infections from five barberry species were collected. Phylogenetic analysis of 121 single aecial clusters of diverse origin using the elongation factor 1-α gene indicated the presence of different special forms (aka formae speciales ) of P. graminis adapted to different cereal and grass species. Inoculation studies using aecial clusters from Spain, United Kingdom, and Switzerland resulted in 533 stem rust isolates sampled from wheat, barley, rye, and oat, which confirmed the presence of multiple special forms of P. graminis . Microsatellite marker analysis of a subset of 192 sexually-derived isolates recovered on wheat, barley and rye from the three populations confirmed the generation of novel genetic diversity revealed by the detection of 135 multilocus genotypes. Discriminant analysis of principal components resulted in four genetic clusters, which grouped at both local and country level. Here, we demonstrated that a variety of Berberis species may serve as functional alternate hosts for cereal stem rust fungi and highlights the increased risks that the sexual cycle may pose to cereal production in Europe, which calls for new initiatives within rust surveillance, epidemiological research and resistance breeding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodriguez-Algaba, Hovmøller, Schulz, Hansen, Lezáun, Joaquim, Randazzo, Czembor, Zemeca, Slikova, Hanzalová, Holdgate, Wilderspin, Mascher, Suffert, Leconte, Flath and Justesen.)

Understanding the level and type of resistance in potato varieties is relevant for integrating varietal resistance into the management of potato late blight. Accordingly, 54 potato varieties were tested for their level and type of resistance to late blight in 2019 and 2020 in Denmark. Spreader rows were artificially inoculated to ensure an even inoculum distribution in the trial. Disease severity was assessed once or twice per week. Cluster analysis (CA) was done based on the weighted mean absolute rate (WMAR), the relative area under the disease progress curve, the onset of disease (Xo), the severity of disease in the middle of the season, the time to reach 1% disease severity, the time to reach final disease severity, and the maximum disease severity. The resistance types were determined by comparing the tested varieties to Bintje (susceptible reference) for Xo and WMAR. The CA ranked the varieties as susceptible, moderately resistant, resistant, and very resistant based on their level of resistance. Except for a few varieties, the expressed resistance levels varied between the years. Several varieties that were susceptible in 2019 were moderately resistant in 2020. Also, the types of resistance that the varieties exhibited varied from year to year. In 2020, most varieties exhibited race-specific resistance, while in 2019 they mostly showed susceptible characteristics. The variation between years for the level and types of resistance of the varieties highlights the importance of regularly monitoring varietal resistance across time and space.

Background: Antibiotics are overused in patients with acute rhinosinusitis (ARS) as it is difficult to identify those who benefit from antibiotic treatment., Aim: To develop prediction models for computed tomography (CT)-confirmed ARS and culture-confirmed acute bacterial rhinosinusitis (ABRS) in adults presenting to primary care with symptoms suggestive of ARS., Design and Setting: This was a systematic review and individual participant data meta-analysis., Method: CT-confirmed ARS was defined as the presence of fluid level or total opacification in any maxillary sinuses, whereas culture-confirmed ABRS was defined by culture of fluid from antral puncture. Prediction models were derived using logistic regression modelling., Results: Among 426 patients from three studies, 140 patients (32.9%) had CT-confirmed ARS. A model consisting of seven variables: previous diagnosis of ARS, preceding upper respiratory tract infection, anosmia, double sickening, purulent nasal discharge on examination, need for antibiotics as judged by a physician, and C-reactive protein (CRP) showed an optimism-corrected c-statistic of 0.73 (95% confidence interval [CI] = 0.69 to 0.78) and a calibration slope of 0.99 (95% CI = 0.72 to 1.19). Among 225 patients from two studies, 68 patients (30.2%) had culture-confirmed ABRS. A model consisting of three variables: pain in teeth, purulent nasal discharge, and CRP showed an optimism-corrected c-statistic of 0.70 (95% CI = 0.63 to 0.77) and a calibration slope of 1.00 (95% CI = 0.66 to 1.52). Clinical utility analysis showed that both models could be useful to rule out the target condition., Conclusion: Simple prediction models for CT-confirmed ARS and culture-confirmed ABRS can be useful to safely reduce antibiotic use in adults with ARS in high-prescribing countries., (© The Authors.)

The objective of this study was to investigate the re-emergence of a previously important crop pathogen in Europe, Puccinia graminis f.sp. tritici, causing wheat stem rust. The pathogen has been insignificant in Europe for more than 60 years, but since 2016 it has caused epidemics on both durum wheat and bread wheat in local areas in southern Europe, and additional outbreaks in Central- and West Europe. The prevalence of three distinct genotypes/races in many areas, Clade III-B (TTRTF), Clade IV-B (TKTTF) and Clade IV-F (TKKTF), suggested clonal reproduction and evolution by mutation within these. None of these genetic groups and races, which likely originated from exotic incursions, were detected in Europe prior to 2016. A fourth genetic group, Clade VIII, detected in Germany (2013), was observed in several years in Central- and East Europe. Tests of representative European wheat varieties with prevalent races revealed high level of susceptibility. In contrast, high diversity with respect to virulence and Simple Sequence Repeat (SSR) markers were detected in local populations on cereals and grasses in proximity to Berberis species in Spain and Sweden, indicating that the alternate host may return as functional component of the epidemiology of wheat stem rust in Europe. A geographically distant population from Omsk and Novosibirsk in western Siberia (Russia) also revealed high genetic diversity, but clearly different from current European populations. The presence of Sr31 -virulence in multiple and highly diverse races in local populations in Spain and Siberia stress that virulence may emerge independently when large geographical areas and time spans are considered and that Sr31 -virulence is not unique to Ug99. All isolates of the Spanish populations, collected from wheat, rye and grass species, were succesfully recovered on wheat, which underline the plasticity of host barriers within P. graminis . The study demonstrated successful alignment of two genotyping approaches and race phenotyping methodologies employed by different laboratories, which also allowed us to line up with previous European and international studies of wheat stem rust. Our results suggest new initiatives within disease surveillance, epidemiological research and resistance breeding to meet current and future challenges by wheat stem rust in Europe and beyond., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Patpour, Hovmøller, Rodriguez-Algaba, Randazzo, Villegas, Shamanin, Berlin, Flath, Czembor, Hanzalova, Sliková, Skolotneva, Jin, Szabo, Meyer, Valade, Thach, Hansen and Justesen.)

Until recently, genotypes of Phytophthora infestans were regionally distributed in Europe, with populations in western Europe being dominated by clonal lineages and those in northern Europe being genetically diverse because of frequent sexual reproduction. However, since 2013 a new clonal lineage (EU&#95;41&#95;A2) has successfully established itself and expanded in the sexually recombining P. infestans populations of northern Europe. The objective of this study was to study phenotypic traits of the new clonal lineage of P. infestans , which may explain its successful establishment and expansion within sexually recombining populations. Fungicide sensitivity, aggressiveness, and virulence profiles of isolates of EU&#95;41&#95;A2 were analyzed and compared with those of the local sexual populations from Denmark, Norway, and Estonia. None of the phenotypic data obtained from the isolates collected from Denmark, Estonia, and Norway independently explained the invasive success of EU&#95;41&#95;A2 within sexual Nordic populations. Therefore, we hypothesize that the expansion of this new genotype could result from a combination of fitness traits and more favorable environmental conditions that have emerged in response to climate change.

Stygarctus keralensis sp. nov. (Arthrotardigrada: Stygarctidae), is described from the intertidal sandy sediments of Vadakara beach, Kerala, Southwest coast of India. To a certain extent, this new species shows morphological similarity with Stygarctus gourbaultae Renaud-Mornant, 1981, however it can be differentiated by some significant distinguishable characters like double looped seminal receptacle ducts and the presence of a bow shaped internal thickening in between the opening of seminal receptacles situated below the level of gonopore and above the anus; unsculptured body plates I-III; paired sub-cephalic pore/muscle attachment; shape and structure of caudal processes. Presence of minute spikes on third lateral processes in the new species is another unique character by which it can be easily differentiated from S. gourbaultae.

Objective: Increased infant birth weight and adiposity are associated with an altered risk of adult chronic diseases. The objective was to investigate the association between maternal dietary fat intake during pregnancy and newborn adiposity., Study Design: The study included 79 singleton pregnancies. Associations between maternal dietary fat intake during each trimester and infant adiposity at birth were assessed., Result: Average total grams of maternal total dietary fat and unsaturated fat intake during pregnancy correlated with infant percent body fat after adjusting for potential confounding variables (r = 0.23, p = 0.045; r = 0.24, p = 0.037). Maternal average daily intake of total fat, saturated fat, and unsaturated fat during the second trimester of pregnancy were each associated with infant percent body fat (r = 0.25, p = 0.029; r = 0.23, p = 0.046; r = 0.25, p = 0.031; respectively)., Conclusions: The second trimester of pregnancy is a key time period for fetal adipose tissue metabolic programming and therefore a target for nutritional intervention.

Introduction: This protocol outlines a diagnostic individual patient data (IPD) meta-analysis aimed at developing simple prediction models based on readily available signs, symptoms and blood tests to accurately predict acute bacterial rhinosinusitis and CT-confirmed (fluid level or total opacification in any sinus) acute rhinosinusitis (ARS) in adults presenting to primary care with clinically diagnosed ARS, target conditions associated with antibiotic benefit., Methods and Analysis: The systematic searches of PubMed and Embase of a review on the accuracy of signs and symptoms for diagnosing ARS in ambulatory care will be updated to April 2020 to identify relevant studies. Authors of eligible studies will be contacted and invited to provide IPD. Methodological quality of the studies will be assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Candidate predictor selection will be based on knowledge from existing literature, clinical reasoning and availability. Multivariable logistic regression analyses will be used to develop prediction models aimed at calculating absolute risk estimates. Large unexplained between-study heterogeneity in predictive accuracy of the models will be explored and may lead to either model adjustment or derivation of separate context-specific models. Calibration and discrimination will be evaluated to assess the models' performance. Bootstrap resampling techniques will be used to assess internal validation and to inform on possible adjustment for overfitting. In addition, we aim to perform internal-external cross-validation procedures., Ethics and Dissemination: In this IPD meta-analysis, no identifiable patient data will be used. As such, the Medical Research Involving Humans Subject Act does not apply, and official ethical approval is not required. Findings will be published in international peer-reviewed journals and presented at scientific conferences., Prospero Registration Number: PROSPERO CRD42020175659., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD) is the fourth in a series of web-based guidelines focusing on the diet treatment for inherited metabolic disorders and follows previous publication of guidelines for maple syrup urine disease (2014), phenylketonuria (2016) and propionic acidemia (2019). The purpose of this guideline is to establish harmonization in the treatment and monitoring of individuals with VLCAD of all ages in order to improve clinical outcomes. Six research questions were identified to support guideline development on: nutrition recommendations for the healthy individual, illness management, supplementation, monitoring, physical activity and management during pregnancy. This report describes the methodology used in its development including review, critical appraisal and abstraction of peer-reviewed studies and unpublished practice literature; expert input through two Delphi surveys and a nominal group process; and external review from metabolic physicians and dietitians. It includes the summary statements of the nutrition management recommendations for each research question, followed by a standardized rating based on the strength of the evidence. Online, open access of the full published guideline allows utilization by health care providers, researchers and collaborators who advise, advocate and care for individuals with VLCAD and their families and can be accessed from the Genetic Metabolic Dietitians International (https://GMDI.org) and Southeast Regional Genetics Network (https://southeastgenetics.org/ngp) websites., Competing Interests: Declaration of Competing Interest The authors do not report any conflicts of interest related to management of LC-FOADs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Marine tardigrades were sampled at three sites on Mexico's Caribbean coast. Eleven taxa were collected, one of which is described as a new species. Styraconyx robertoi sp. nov. is characterized by: asymmetric primary clavae; dorsal cuticle with a grid-like sculpture; claws with reduced accessory hooks; females with peduncles on only two digits (the external) of legs I-IV; males with peduncles only on the external digits of legs I-III and peduncles on all four digits of leg IV. Styraconyx robertoi sp. nov. is most similar to S. craticuliformis Chang Rho, 1998 and S. kristenseni Renaud-Mornant, 1981 by having asymmetric primary clavae but differs from S. craticuliformis mainly by the number of peduncles and from S. kristenseni mainly by the presence of a grid-like dorsal sculpture. Additionally, a comparison of material collected from the same region, but reported previously only as genus level records, was carried out in order to produce a refined list of the known Mexican marine tardigrade species.

Objectives The number of dinucleotide repeats (GT) n modulate expression of heme oxygenase 1 (HMOX1), a stress response gene. Multiple repeats might affect chronic obstructive pulmonary disease (COPD) susceptibility. We aimed to investigate the association of this polymorphism with COPD and its interaction with occupational exposures (vapor, gas, dust, or fumes). Methods This population-based cross-sectional study included 4703 Danes, aged 45-84 years. HMOX1 (GT) n was genotyped and grouped as short: ≤26, medium: 27-32 and long: ≥33 alleles. COPD was defined by the lower limit of normal (2.5 th FEV 1 /FVC and FEV 1 centiles). Occupational exposure was defined as ever exposed to vapor, gas, dust, or fume in expert-selected jobs. Associations were analyzed by adjusted mixed logistic regression. Results The population included 6% with COPD, 48% who had smoked ≥10 pack-years, and 46% with occupational exposure. HMOX1 was genotyped in 4423 participants. The adjusted odds ratio (OR) for the association between HMOX1 long allele and COPD was 1.75 [95% confidence interval (CI) 1.18-2.60]. An interaction was evident between HMOX1 long allele and occupational exposure, OR 2.38 (95% CI 1.04-5.46), versus HMOX1 short/medium without exposure. Analyses were replicated in another cohort, aged 20-44 years, N=1168, including 3% with COPD, 25% who had smoked ≥10 pack-years and 20% with occupational exposure. No associations were seen between COPD and HMOX1 long allele here. Conclusions Long alleles in HMOX1 alone and in interaction with occupational exposure seem to be associated with COPD. Failure to replicate data may be due to premature age for COPD development and low occupational exposure prevalence. We propose this long allele may be a genetic contributor to the COPD pathogenesis.

Background: In Denmark, the use of amoxicillin is widespread among children, despite phenoxymethylpenicillin being recommended as first-line therapy. The reason for this apparent discrepancy is not fully understood. We aimed at evaluating prescribing patterns of antibiotics among Danish children 0-4 years of age, with emphasis on incidence of treatment episodes, choice of initial antibiotic treatment and switching patterns between different types of antibiotics., Methods: We identified all children ≤4 years of age who filled a prescription of antibiotics from 2000 to 2015 according to the nationwide Danish National Prescription Registry. We estimated the incidence rate of episodes treated with antibiotics and the choice of initial antibiotic treatment over time. Further, we assessed the cumulative risk of switching within 0-3 days after initiating therapy., Results: We identified 3,481,684 antibiotic treatment episodes issued to 0- to 4-year-olds from 2000 to 2015. The incidence rate was stable until 2011 both among children 0-1 years of age (approximately 880/1000) and among children 2-4 years of age (approximately 610/1000), after which it dropped. Phenoxymethylpenicillin and, increasingly, amoxicillin were most frequently used as initial treatments (39% vs. 44%). Few switched from amoxicillin (1%) or phenoxymethylpenicillin (4.7%) within the first 3 days. Of those who switched from phenoxymethylpenicillin, 64% received amoxicillin as second-line treatment., Conclusions: The incidence of episodes treated with antibiotics among Danish children 0-4 years of age has decreased considerably since 2011. In contrast to guideline recommendations, amoxicillin is the most frequently used initial treatment. Early switching between antibiotics is uncommon. Initiatives should address the extensive use of amoxicillin.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classification separates the spirometric 1-4 staging from the ABCD groups defined by symptoms and exacerbations. Little is known about how this new classification predicts mortality in patients with chronic obstructive pulmonary disease (COPD). We aimed to establish the predictive ability of the GOLD 2017 classification, compared with earlier classifications, for all-cause and respiratory mortality, both when using its main ABCD groups and when further subdividing according to spirometric 1-4 staging., Methods: In this nationwide cohort study, we enrolled patients with COPD with data available in the Danish registry for COPD. To be included in this registry, individuals must have been outpatients in hospital-based pulmonary clinics in Denmark. Eligible patients were aged 30 years or older; had received a primary diagnosis of COPD (International Classification of Diseases [ICD]-10 J44.X) or acute respiratory failure (ICD-10 J96.X) in combination with COPD (ICD-10 J44.X) as a secondary diagnosis; and had complete data on FEV 1 , body-mass index, modified Medical Research Council dyspnoea scale score, and smoking status. We categorised eligible patients with complete data according to the 2007, 2011, and 2017 GOLD classifications at the first contact with an outpatient clinic. For the GOLD 2017 classification, we further subdivided the patients by spirometry into 16 subgroups (1A to 4D). We calculated adjusted hazard ratios (HRs) for all-cause and respiratory mortality and compared the predictive ability of the three GOLD classifications (2007, 2011, and 2017) using receiver operating curves., Findings: We enrolled 33 765 patients with COPD, who were outpatients in Danish hospitals between Jan 1, 2008, and Nov 30, 2013, in the main cohort assessed for all-cause mortality. 22 621 of these patients had data available on cause-specific mortality (respiratory) and were included in a subcohort followed from Jan 1, 2008, to Dec 31, 2011. For the GOLD 2017 classification, 3 year mortality increased with increasing exacerbations and dyspnoea from group A (all-cause mortality 10·0%, respiratory mortality 3·0%) to group D (all-cause mortality 36·9%, respiratory mortality 18·0%). However, 3 year mortality was higher for group B patients (all-cause mortality 23·8%, respiratory mortality 9·7%) than for group C patients (all-cause mortality 17·4%, respiratory mortality 6·4%). Compared with group A, adjusted HRs for all-cause mortality ranged from 2·05 (95% CI 1·87-2·26) for group B, to 1·47 (1·31-1·65) for group C, and to 3·01 (2·75-3·30) for group D. Area under the curve for all-cause mortality was 0·61 (95% CI 0·60-0·61) for GOLD 2007, 0·61 (0·60-0·62) for GOLD 2011, and 0·63 (0·53-0·73) for GOLD 2017. Area under the curve for respiratory mortality was 0·64 (0·62-0·65) for GOLD 2007, 0·63 (0·62-0·64) for GOLD 2011, and 0·65 (0·53-0·78) for GOLD 2017. The GOLD 2017 classification based on ABCD groups only did not predict mortality better than the earlier 2007 and 2011 GOLD classifications. However, when 16 subgroups (1A to 4D) were defined, the new classification predicted mortality more accurately than the previous systems (p<0·0001)., Interpretation: We showed that the new GOLD 2017 ABCD classification does not predict all-cause and respiratory mortality more accurately than the previous GOLD systems from 2007 and 2011., Funding: Danish Lung Association, Program for Clinical Research Infrastructure., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To reduce inappropriate antibiotic prescribing, we sought to develop a clinical decision rule for the diagnosis of acute rhinosinusitis and acute bacterial rhinosinusitis., Methods: Multivariate analysis and classification and regression tree (CART) analysis were used to develop clinical decision rules for the diagnosis of acute rhinosinusitis, defined using 3 different reference standards (purulent antral puncture fluid or abnormal finding on a computed tomographic (CT) scan; for acute bacterial rhinosinusitis, we used a positive bacterial culture of antral fluid). Signs, symptoms, C-reactive protein (CRP), and reference standard tests were prospectively recorded in 175 Danish patients aged 18 to 65 years seeking care for suspected acute rhinosinusitis. For each reference standard, we developed 2 clinical decision rules: a point score based on a logistic regression model and an algorithm based on a CART model. We identified low-, moderate-, and high-risk groups for acute rhinosinusitis or acute bacterial rhinosinusitis for each clinical decision rule., Results: The point scores each had between 5 and 6 predictors, and an area under the receiver operating characteristic curve (AUROCC) between 0.721 and 0.767. For positive bacterial culture as the reference standard, low-, moderate-, and high-risk groups had a 16%, 49%, and 73% likelihood of acute bacterial rhinosinusitis, respectively. CART models had an AUROCC ranging from 0.783 to 0.827. For positive bacterial culture as the reference standard, low-, moderate-, and high-risk groups had a likelihood of acute bacterial rhinosinusitis of 6%, 31%, and 59% respectively., Conclusions: We have developed a series of clinical decision rules integrating signs, symptoms, and CRP to diagnose acute rhinosinusitis and acute bacterial rhinosinusitis with good accuracy. They now require prospective validation and an assessment of their effect on clinical and process outcomes., Competing Interests: Conflicts of interest: authors report none., (© 2017 Annals of Family Medicine, Inc.)

We investigated whether the recent worldwide epidemics of wheat yellow rust were driven by races of few clonal lineage(s) or populations of divergent races. Race phenotyping of 887 genetically diverse Puccinia striiformis isolates sampled in 35 countries during 2009-2015 revealed that these epidemics were often driven by races from few but highly divergent genetic lineages. PstS1 was predominant in North America; PstS2 in West Asia and North Africa; and both PstS1 and PstS2 in East Africa. PstS4 was prevalent in Northern Europe on triticale; PstS5 and PstS9 were prevalent in Central Asia; whereas PstS6 was prevalent in epidemics in East Africa. PstS7, PstS8 and PstS10 represented three genetic lineages prevalent in Europe. Races from other lineages were in low frequencies. Virulence to Yr9 and Yr27 was common in epidemics in Africa and Asia, while virulence to Yr17 and Yr32 were prevalent in Europe, corresponding to widely deployed resistance genes. The highest diversity was observed in South Asian populations, where frequent recombination has been reported, and no particular race was predominant in this area. The results are discussed in light of the role of invasions in shaping pathogen population across geographical regions. The results emphasized the lack of predictability of emergence of new races with high epidemic potential, which stresses the need for additional investments in population biology and surveillance activities of pathogens on global food crops, and assessments of disease vulnerability of host varieties prior to their deployment at larger scales.

The PAF of occupational COPD among Danish women http://ow.ly/CEmy308XEgl., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Investigating the origin and dispersal pathways is instrumental to mitigate threats and economic and environmental consequences of invasive crop pathogens. In the case of Puccinia striiformis causing yellow rust on wheat, a number of economically important invasions have been reported, e.g., the spreading of two aggressive and high temperature adapted strains to three continents since 2000. The combination of sequence-characterized amplified region (SCAR) markers, which were developed from two specific AFLP fragments, differentiated the two invasive strains, PstS1 and PstS2 from all other P. striiformis strains investigated at a worldwide level. The application of the SCAR markers on 566 isolates showed that PstS1 was present in East Africa in the early 1980s and then detected in the Americas in 2000 and in Australia in 2002. PstS2 which evolved from PstS1 became widespread in the Middle East and Central Asia. In 2000, PstS2 was detected in Europe, where it never became prevalent. Additional SSR genotyping and virulence phenotyping revealed 10 and six variants, respectively, within PstS1 and PstS2, demonstrating the evolutionary potential of the pathogen. Overall, the results suggested East Africa as the most plausible origin of the two invasive strains. The SCAR markers developed in the present study provide a rapid, inexpensive, and efficient tool to track the distribution of P. striiformis invasive strains, PstS1 and PstS2.

Longitudinal outcomes following stress or trauma diagnoses are receiving attention, yet population-based studies are few. The aims of the present cohort study were to examine the cumulative incidence of traumatic events and psychiatric diagnoses following diagnoses of severe stress and adjustment disorders categorized using International Classification of Diseases, Tenth Revision, codes and to examine associations of these diagnoses with all-cause mortality and suicide. Data came from a longitudinal cohort of all Danes who received a diagnosis of reaction to severe stress or adjustment disorders (International Classification of Diseases, Tenth Revision, code F43.x) between 1995 and 2011, and they were compared with data from a general-population cohort. Cumulative incidence curves were plotted to examine traumatic experiences and psychiatric diagnoses during the study period. A Cox proportional hazards regression model was used to examine the associations of the disorders with mortality and suicide. Participants with stress diagnoses had a higher incidence of traumatic events and psychiatric diagnoses than did the comparison group. Each disorder was associated with a higher rate of all-cause mortality than that seen in the comparison cohort, and strong associations with suicide were found after adjustment. This study provides a comprehensive assessment of the associations of stress disorders with a variety of outcomes, and we found that stress diagnoses may have long-lasting and potentially severe consequences., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

The aim was to explore the impact of occupation on chronic obstructive pulmonary disease (COPD) in a cross-sectional population-based study among subjects aged 45 to 84 years. In a stratified sampling 89 general practitioners practices (GPP) in Denmark recruited 3106 males and 1636 females through the Danish Civil Registration System. COPD was defined by spirometry by the 2.5(th)-centile Lower Limit of Normal of FEV1 and FEV1/FVC. Information about smoking, occupational exposure and the respective occupations were obtained from questionnaires. Occupations followed the Danish adaptation of The International Standard Classification of Occupations, revision 1988 (DISCO-88). Exposure to vapour, gas, dust (organic and inorganic), and fume (VGDF) in each occupation (yes/no) was evaluated by two independent specialist in occupational medicine. Exposures were divided in no, low, medium, and high exposure as 0, < 5, 5-14, and ≥ 15 years in the job, respectively. Data was analysed by a mixed random effect logistic regression model. The age-standardised COPD study prevalence was 5.0%. Of 372 DISCO-88 codes 72 were identified with relevant exposure to VGDF. 46% of the participants reported at least one occupation with VGDF exposure. Adjusted for smoking, age, sex, and GPP a dose-dependent association of COPD was found among workers in jobs with high organic dust exposure, with OR 1.56 (95% CI 1.09-2.24). Restricted to agriculture the OR was 1.59 (95% CI: 1.08-2.33). No association was observed for workers in jobs with inorganic dust, fume/gas, or vapour exposures. In summary, occupational organic dust exposure was associated to the prevalence of COPD.

Background: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults., Methods: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts., Results: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09)., Conclusions: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

Occupational exposures have been shown to be risk factors for chronic obstructive pulmonary disease (COPD) among never-smokers. In a Danish population-based cohort, we analysed this association and the population attributable fraction. The study population (N=1575) was aged 45-84, COPD was defined by lung function measurements and the method of lower limit of normal (LLN), and occupational exposure was assessed by questionnaire and expert judgement. Furthermore, the estimates additionally were provided according to the Global Initiative for Chronic Obstructive Lung Diseases. More than a threefold increased risk (LLN OR=3.69 (95% CI 1.36 to 10.04) was found for occupational exposure to vapour, gas, dust and fumes (predominantly organic dust) in this never-smoking population, with a corresponding 48% (95% CI 30% to 65%) population attributable fraction among never-smokers., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations., Objective: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study., Methods: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort., Results: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-μg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences., Conclusions: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans., (© 2015 American Society for Nutrition.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

We created a registry of Danish-born citizens of Denmark with incident International Classification of Diseases (10th ed.; ICD-10) severe stress and adjustment disorder diagnoses between 1995 and 2011. A unique personal identifier was used to retrieve and merge data on demographic characteristics and diagnoses (ICD-10 codes F43.x). Here we report on the incidence of these disorders and the demographic characteristics of the subset of the Danish population who have received 1 of these diagnoses: 111,844 adults and children received a first diagnosis between 1995 and 2011. More women than men (60.1% vs. 39.9%) received a diagnosis. Diagnoses increased during the late teens through early 30s. Adjustment disorder was the most common diagnosis (65.7% of adults and 64% of children). Reaction to severe stress unspecified was the second most common (19.8% of adults and 23.8% of children), and there was a large increase in both, as well as acute stress reaction diagnoses, in 2007 (3,717-5,141, 1,248-2,520, and 348-1,024 in 2006 to 2007, respectively). Findings regarding gender and age of onset are similar to other westernized countries. This registry can be used for future research programs, contributing to the study of stress and trauma., (Published 2014. This article is a US Government work and is in the public domain in the USA.)

The idea behind this thesis is to present how ARS and especially acute maxillary sinusitis in adults is diagnosed and treated in general practice. The study extends over many years, beginning with the first survey in 1991. Based on doctors' answers, we then investigated the diagnostic values ​​of the symptoms, signs and examinations which the doctors reported using. All patients over 18 years suspected of acute maxillary sinusitis were included consecutively and only once and, after a clinical examination with the GP, they were offered the opportunity to enter into the prospective study referred to acute CT scan and by changes in the CT, immediately referred to sinus puncture. Both examinations were conducted at Aalborg Hospital. The disease was found most frequently in younger and 2/3 were women. The reason for this gender difference is unknown. We have assessed the diagnostic values of the symptoms, objective findings and investigations ​​using 3 different reference standards: sinus puncture, microbiological diagnosis and CT scan described in three articles. In all examinations, it appeared that the usual signs and symptoms of acute maxillary sinusitis occur almost equally often and with a few exceptions in patients, with and without pus in the sinus cavities. Pain in the sinus cavities occurring in 95% of patients, and only elevated levels of CRP and ESR are significantly and independently associated with pus in the sinus cavities. This finding is surprising, because they are two nonspecific markers. CRP tested by near-patient testing has, within the investigations period, been introduced in general practice, and from 1999 the doctors also get reimbursed for performing the test. We have on this background originally defined a clinical criterion with pain over the sinuses accompanied by elevated values ​​of CRP and/or ESR giving a sensitivity of 0.82, specificity 0.57, ppv 0.68 and npv 0.74. But looking at the ROC curve we suggest that a more clinical relevant diagnose will be based on use of CRP alone, as the test can be made easily and fast while the patient is in the clinic compared to the use of ESR. The disease is over-diagnosed in general practice. In only 53% of patients, who the GP suspected of having acute sinusitis, was there detected pus or mucopus at the sinus puncture, furthermore the patients' statements that they had had sinusitis was significantly negatively associated with current acute maxillary sinusitis. Almost all patients are prescribed topical treatment to the nose in the form of vasoconstrictor, and 50-70% also antibiotics. The most common bacteria that can be isolated are S. pneumoniae and H. influenzae. For many years the first drug of choice has been penicillin V, and treatment with penicillin V has followed Scandinavian recommendations. However, the resistance patterns in respect of H. influenzae have changed over the years and if the dominant flora is H. influenzae, then oral penicillin is not sufficient anymore, and should be replaced by amoxicillin with or without clavulanate. It is reported that the MIC of penicillin V is too high, such that oral dosage cannot provide sufficiently high concentrations. However, in daily clinical practice the doctor does not have the possibility to decide whether the infection is caused by either S. pneumoniae or H. influenzae, unless a sinus puncture is performed and it is not considered as a standard procedure. The recommended treatment is therefore starting with penicillin V, and at treatment failure switching to amoxicillin with or without clavulanate. It is well known that URTI's can exacerbate a chronic pulmonary disease - like asthma - in allergic patients, but this influence is also demonstrated as described in article 6 where ARS in adults without any sign of chronic lung disease or allergy is accompanied by a temporary reduction lung function. Future research should focus on the use of CRP in general practice, analysing cost-effectiveness of the use of CRP patient outcome in relation to antibiotic treatment, clarification of ARS as a female disease, and a detailed exploration of the relationship between URTI's and impaired lung function in lung-healthy patients.

Background: Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants., Methods: Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS)., Results: 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants., Conclusions: SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.

Antioxidant nutritional status is hypothesized to influence chronic obstructive pulmonary disease (COPD) susceptibility and progression. Although past studies relate antioxidants to gene expression, there are no data in patients with COPD. This study investigated the hypothesis that antioxidant status is compromised in patients with COPD, and antioxidant-responsive genes differentially express in a similar pattern. Lung tissue samples from patients with COPD were assayed for vitamin E and gene expression. Selenium and vitamin E were assayed in corresponding plasma samples. Discovery based genome-wide expression analysis compared moderate, severe, and very severe COPD (GOLD II-IV) patients to mild and at-risk/normal (GOLD 0-I). Hypotheses-driven analyses assessed differential gene expression by disease severity for vitamin E-responsive and selenium-responsive genes. GOLD II-IV COPD patients had 30% lower lung tissue vitamin E levels compared to GOLD 0-I participants (p = 0.0082). No statistically significant genome-wide differences in expression by disease severity were identified. Hypothesis-driven analyses of 109 genes found 16 genes differentially expressed (padjusted < 0.05) by disease severity including 6 selenium-responsive genes (range in fold-change -1.39 to 2.25), 6 vitamin E-responsive genes (fold-change -2.30 to 1.51), and 4 COPD-associated genes. Lung tissue vitamin E in patients with COPD was associated with disease severity and vitamin E-responsive genes were differentially expressed by disease severity. Although nutritional status is hypothesized to contribute to COPD risk, and is of therapeutic interest, evidence to date is mainly observational. The findings reported herein are novel, and support a role of vitamin E in COPD progression.

Introduction: The present study compared health care-related costs and the use of social benefits and transfer payments in participants with and without chronic obstructive pulmonary disease (COPD), and related the costs to the severity of the COPD., Material and Methods: Spirometry data from a cohort study performed in Denmark during 2004-2006 were linked with national register data that identified the costs of social benefits and health-care services. The cohort comprised 546 participants with COPD (forced expiratory volume in the first sec. (FEV1)/forced vital capacity (FVC) ratio<0.7 following bronchodilator administration) and 3,995 without COPD (in addition, 9,435 invited participants were non-responders and 331 were excluded). The costs were adjusted for gender, age, co-morbidity and educational level., Results: Health care-related costs were 4,779 (2,404-7,154) Danish kroner (DKK) higher for participants with COPD than for those without COPD, and 2,882 (556-5,208) DKK higher than for non-responders. The higher costs were mainly due to the cost of medicines and inpatient care. The health-care costs increased with disease severity Global Initiative for Chronic Obstructive Lung Disease (GOLD grade). In participants<65 years of age, the annual cost of social benefits and transfer payments was 15,901 (5,966-25,837) DKK higher and the total costs were 20,454 (7,559-33,350) DKK higher in those with COPD than in those without COPD; this was due mostly to the high cost of dis-ability pensions., Conclusion: Health care-related costs and costs for social benefits and transfer payments were higher for participants with COPD than for non-COPD participants and non-responders., Funding: This study was supported by The Obel Family Foundation, The Danish Lung Association and The Health Insurance Foundation., Trial Registration: Not relevant.

We examined rates of first hospitalization for COPD, rates of 5-year mortality among patients hospitalized for COPD, and comparisons of mortality between COPD patients and a matched cohort free of COPD. We computed standardized rates of first COPD hospitalization. Using Cox regression, we compared 180- and 181-day to 5-year mortality among COPD patients with the comparison cohort. We used medical databases in Denmark (population 5.4 million) from 1997 to 2006. We included patients 40 years or older with first hospitalization for COPD (64,499) and an age- and gender-matched comparison cohort of persons without COPD hospitalization (322,495). We examined the incidence of COPD hospitalization and risks and rates of mortality in the 5 years after hospitalization. Standardized rates of first hospitalization for COPD declined from 276 per 100,000 person-years in 1999 to 231 per 100,000 person-years in 2006. Within 180 days of hospitalization, 16% of COPD patients and 2.4% of persons in the matched cohort died (adjusted hazard ratio = 7.00, 95% CI = 6.79-7.22). Between 181 days and 5 years, 46% of COPD patients who survived the first 180 days and 19% of persons in the comparison cohort died (adjusted hazard ratio = 2.91, 95% CI = 2.86-2.95). COPD and comorbid diseases interacted to increase mortality in the first 180 days, but not thereafter. COPD continues to be a major public health problem causing substantial mortality in the 5 years after hospitalization, particularly in the first 180 days and in patients with comorbid diseases.

The objective of this study was to evaluate the association between changes revealed by computerized tomography scan (CT) and symptoms, signs, and bacteriological diagnoses in a general practice population who had been diagnosed with acute maxillary sinusitis (AMS). This study was designed as a prospective cohort study in Danish general practice in cooperation with the otorhinolaryngology and neuroradiology departments at Aalborg County Hospital. One hundred and seventy-four patients, aged 18-65 years, suspected of having AMS were included. The strongest associations were with purulent nasal discharge, preceding upper respiratory tract infection, maxillary toothache and oedema over the maxillary sinuses. Self-reported previous sinusitis was negatively associated with sinus infection. There was a strong association between increasing values of C-reactive protein (CRP) and erythrocyte sedimentation rate and changes on the CT scan. CT scans contributed only little to the final diagnosis, whereas increased CRP values and elevated erythrocyte sedimentation rates were more reliable indicators of inflammation in the sinuses., (© 2010 The Authors. APMIS © 2010 APMIS.)

Postembryonic development in the kinorhynch species Antygomonas incomitata was examined using scanning electron microscopy. The morphology of the six juvenile stages, J-1 to J-6, varies at numerous details, but they can also be distinguished by a few key characters. Juvenile stage 1 by its composition of only nine trunk segments; J-2 by the combination of possessing 10 trunk segments, but no cuspidate spines on segment 9; J-3 by the presence of cuspidate spines on segment 9, but only one pair of cuspidate spines on segment 8; J-4 by the combination of 10 trunk segments only, but having two pairs of cuspidate spines on segment 8; J-5 by possessing 11 trunk segments and same spine compositions as adults but is still maintaining postmarginal spiculae; J-6 specimens closely resemble adults and are most easily identified by their reduced trunk lengths. New segments are formed in a growth zone in the anterior part of the terminal segment. The complete number of segments is reached in J-5. Development of cuticular head and trunk structures are described through all postembryonic stages and following developmental patterns could be outlined: the mouth cone possesses outer oral styles from J-1, but in J-1 to J-3, the styles alternate in size. Scalids of the introvert are added after each molt, and scalids appear earliest in the anterior rings, whereas scalids in more posterior rings are added in older postembryonic stages. The early J-1 stage is poor in spines and sensory spots and both structures increase in number after each molt. The complete spine composition is reached in J-4, whereas new sensory spots appear after all molts, inclusive the final one from J-6 to adult. Sensory spots in the paraventral positions often appear as Type 3 sensory spots but are through development transformed to Type 2. This transformation happens earliest on the anterior segments.

Tardigrades are microscopic ecdysozoans with a worldwide distribution covering marine, limnic and terrestrial habitats. They are regarded as a neglected phylum with regard to studies of their phylogeny. During the last decade molecular data have been included in the investigation of tardigrades. However, the marine arthrotardigrades are still poorly sampled due to their relative rarity, difficult identification and minute size even for tardigrades. In the present study, we have sampled various arthrotardigrades and sequenced the 18S and partial 28S ribosomal subunits. The phylogenetic analyses based on Bayesian inference and maximum parsimony inferred Heterotardigrada (Arthrotardigrada+Echiniscoidea) and Eutardigrada to be monophyletic. Arthrotardigrada was inferred to be paraphyletic as the monophyletic Echiniscoidea is included within the arthrotardigrades. The phylogenetic positions of Stygarctidae and Batillipedidae are poorly resolved with low branch support. The Halechiniscidae is inferred to be polyphyletic as the currently recognized Styraconyxinae is not part of the family. Archechiniscus is the sister-group to the Halechiniscidae and Orzeliscus is placed as one of the basal halechiniscids. The phylogeny of the included eutardigrade taxa resembles the current molecular phylogenies. The genetic diversity within Arthrotardigrada is much larger (18S 15.1-26.5%, 28S 7.2-20.7%) than within Eutardigrada (18S 1.0-12.6%, 28S 1.3-8.2%). This can be explained by higher substitution rates in the arthrotardigrades or by a much younger evolutionary age of the sampled eutardigrades., (Copyright 2009 Elsevier Inc. All rights reserved.)

We investigated the prevalence of chronic obsctuctive pulmonary disease (COPD) and the proportion of affected patients receiving medical treatment. A total of 155 general practitioners examined 4,757 persons aged 45-84 years. All had a spirometry performed. Obstruction was defined as a forced expired volume in the first second (FEV 1 )/forced vital capacity (FVC) ratio < 0.70 after bronchodilation, and severity was defined according to Global Initiative for Obstructive Lung Disease (GOLD) guidelines. The determined prevalence was 12%. Standardized to the Danish population the true prevalence of COPD was 9% (95% confidence interval, 8-10%). The majority had mild or moderate COPD. Among persons with severe COPD, 42% did not receive medical treatment.

The objective of this study was to assess symptoms and signs in patients with maxillary sinusitis and a bacteriological diagnosis obtained by sinus aspiration or lavage. Designed as a prospective cohort study in general practice, the study included 174 patients, aged 18-65 years, suspected of having acute maxillary sinusitis by their general practitioner. The main outcome measures were the independent association of symptoms, signs, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) concentration and confirmed infection with the predominant bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae. The predominant organisms found in patients with acute maxillary sinusitis were S. pneumoniae and H. influenzae. Body temperature >38 degrees C and maxillary toothache were significantly associated with the presence of S. pneumoniae and H. influenzae. Positive bacteriological culture results were significantly associated with increasing ESR and CRP values. None of the symptoms and signs, with the exception of body temperature >38 degrees C and maxillary toothache, were particularly sensitive indicators of the specific aetiology in patients with acute maxillary sinusitis. Elevated ESR and CRP values were significantly associated with positive bacteriological culture results. On the other hand, absence of these symptoms and signs did not exclude the presence of acute maxillary sinusitis.

Objective: To evaluate the influence of acute rhinosinusitis on lung function as measured by spirometry., Method: An observational study in Danish general practice on 25 adult patients with a clinical diagnosis of acute rhinosinusitis and without any signs of chronic lung disease or allergy. Patients performed spirometry at the initial acute visit and then eight weeks later when the rhinosinusitis had resolved., Results: Eight weeks after the initial visit there was a significant increase in the maximum mid-expiratory flow (F25-75), and in peak flow., Conclusion: Acute rhinosinusitis in adults without any sign of chronic lung disease or allergy is accompanied by a temporary reduction in maximum mid-expiratory flow and peak flow. This may be caused by subclinical inflammation in the airways during acute rhinosinusitis. Further studies with extended lung function measurements are needed to evaluate and confirm this finding.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of disability and death in the world. Many people with disease are undiagnosed or untreated due to lack of consensus about the definition of COPD. The objective was to estimate the prevalence of COPD in the Danish population aged 45-84 years and to identify the proportion of persons not receiving appropriate medical treatment. A population-based study in the two Danish counties (population aged 45-84 years = 299,000 persons) based on data from 155 general practices in the 2004-2006 period. Stratified sampling was used to select 4,757 subjects from the Danish Civil Registration System and the National Health Service databases. The diagnosis of COPD was defined as FEV(1)/FVC < 0.70 after bronchodilator. The classification of disease severity was based on criteria developed by the Global Initiative for Chronic Obstructive Lung Diseases (GOLD) criteria. COPD prevalence was associated with sex, age, and smoking status. We found an overall COPD prevalence of 12% (95% CI 11%-13%). Standardized to the Danish population, the true prevalence of COPD is 9% (95% CI 8%-10%). The highest prevalence was observed among current smokers (23%) and former smokers (17%) as well as in the older age group (total = 18%; men = 21%; women = 15%). Most subjects with COPD had mild-to-moderate disease. Among subjects with severe and very severe COPD, 25% were not treated with bronchodilator or inhaled corticosteroids. In conclusion we found that the population prevalence of COPD is high among smokers. A large proportion of persons with COPD did not receive appropriate medical treatment.