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2.  Population-based study of the association between asthma and pneumococcal disease in children 
Clinical Epidemiology  2015;7:325-334.
Although asthma has recently been established as a risk factor for pneumococcal disease (PD), few studies have specifically evaluated this association in children.
We conducted a nation-wide population-based cohort study of the effect of asthma on childhood PD among all singleton live births in Denmark from 1994 to 2007, before the introduction of the 7-valent pneumococcal conjugate vaccine. All data were abstracted from Danish medical registries. Because underlying comorbidity substantially increases the PD risk in children, standard methods were used to assess the evidence of biologic interaction between comorbidity and asthma on the risk of PD.
There were 2,253 cases of childhood PD among 888,655 children born in Denmark from 1994 to 2007. The adjusted incidence rate ratio of the effect of asthma on childhood PD was 2.2 (95% confidence interval [CI]: 2.0, 2.5). Age-stratified incidence rate ratios were 2.1 (95% CI: 1.8, 2.9) in children 6 months to <24 months, 4.1 (95% CI: 3.3, 5.1) in children 24 months to <60 months, and 2.3 (95% CI: 1.6, 3.2) in children ≥60 months. Evaluation of the biologic interaction between asthma and comorbidity in older children revealed that 55% (24 months to <60 months) to 73% (≥60 months) of cases among asthma-exposed children can be accounted for by the interaction between asthma and comorbidity.
These results confirm that asthma is an important risk factor for PD in children and suggest that children with underlying comorbidities are more sensitive to the effect of asthma on PD than children without comorbidities.
PMCID: PMC4507794  PMID: 26203278
pneumococcal disease; asthma; comorbidity; children
3.  Active and Passive Smoking and Fecundability in Danish Pregnancy Planners 
Fertility and sterility  2014;102(1):183-191.e2.
To investigate the extent to which fecundability is associated with active smoking, time since smoking cessation, and passive smoking.
Prospective cohort study.
Denmark, 2007–2011.
3,773 female pregnancy planners aged 18–40 years.
Main Outcome Measures
Self-reported pregnancy. Fecundability ratios (FR) and 95% confidence intervals (CI) were estimated using a proportional probabilities model that adjusted for menstrual cycle at risk and potential confounders.
Among current smokers, smoking duration ≥10 years was associated with reduced fecundability compared with never smokers (FR=0.85, 95% CI: 0.72–1.00). Former smokers who had smoked ≥10 pack-years had reduced fecundability regardless of when they quit smoking (1–1.9 years FR=0.83, 95% CI: 0.54–1.27; ≥2 years FR=0.73, 95% CI: 0.53–1.02). Among never smokers, the FRs were 1.04 (95% CI: 0.89–1.21) for passive smoking in early life and 0.92 (95% CI: 0.82–1.03) for passive smoking in adulthood.
Among Danish pregnancy planners, cumulative exposure to active cigarette smoking was associated with delayed conception among current and former smokers. Time since smoking cessation and passive smoking were not appreciably associated with fecundability.
PMCID: PMC4104516  PMID: 24746741
Fecundability; Fertility; Cigarette Smoking; Tobacco Smoke Pollution; Cohort Study
5.  Hyperemesis gravidarum and risk of cancer in offspring, a Scandinavian registry-based nested case–control study 
BMC Cancer  2015;15:398.
Hyperemesis gravidarum is a serious condition affecting 0.8–2.3 % of pregnant women and can be regarded as a restricted period of famine. Research concerning potential long-term consequences of the condition for the offspring, is limited, but lack of nutrition in-utero has been associated with chronic disease in adulthood, including some cancers. There is growing evidence that several forms of cancer may originate during fetal life. We conducted a large study linking the high-quality population-based medical birth- and cancer registries in Norway, Sweden and Denmark, to explore whether hyperemesis is associated with increased cancer risk in offspring.
A registry-based nested case–control study. Twelve types of childhood cancer were selected; leukemia, lymphoma, cancer of the central nervous system, testis, bone, ovary, breast, adrenal and thyroid gland, nephroblastoma, hepatoblastoma and retinoblastoma. Conditional logistic regression models were applied to study associations between hyperemesis and risk of childhood cancer, both all types combined and separately. Cancer types with five or more exposed cases were stratified by age at diagnosis. All analysis were adjusted for maternal age, ethnicity and smoking, in addition to the offspring’s Apgar score, placental weight and birth weight. Relative risks with 95 % confidence intervals were calculated.
In total 14,805 cases and approximately ten controls matched on time, country of birth, sex and year of birth per case (147,709) were identified. None of the cancer types, analyzed combined or separately, revealed significant association with hyperemesis. When stratified according to age at diagnosis, we observed a RR 2.13 for lymphoma among adolescents aged 11–20 years ((95 % CI 1.14–3.99), after adjustment for maternal ethnicity and maternal age, RR 2.08 (95 % CI 1.11–3.90)). The finding was not apparent when a stricter level of statistical significance was applied.
The main finding of this paper is that hyperemesis does not seem to increase cancer risk in offspring. The positive association to lymphoma may be by chance and needs confirmation.
PMCID: PMC4430929  PMID: 25963309
Hyperemesis; Cancer; Fetal programming
6.  The REporting of Studies Conducted Using Observational Routinely-Collected Health Data (RECORD) Statement: Methods for Arriving at Consensus and Developing Reporting Guidelines 
PLoS ONE  2015;10(5):e0125620.
Routinely collected health data, collected for administrative and clinical purposes, without specific a priori research questions, are increasingly used for observational, comparative effectiveness, health services research, and clinical trials. The rapid evolution and availability of routinely collected data for research has brought to light specific issues not addressed by existing reporting guidelines. The aim of the present project was to determine the priorities of stakeholders in order to guide the development of the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement.
Two modified electronic Delphi surveys were sent to stakeholders. The first determined themes deemed important to include in the RECORD statement, and was analyzed using qualitative methods. The second determined quantitative prioritization of the themes based on categorization of manuscript headings. The surveys were followed by a meeting of RECORD working committee, and re-engagement with stakeholders via an online commentary period.
The qualitative survey (76 responses of 123 surveys sent) generated 10 overarching themes and 13 themes derived from existing STROBE categories. Highest-rated overall items for inclusion were: Disease/exposure identification algorithms; Characteristics of the population included in databases; and Characteristics of the data. In the quantitative survey (71 responses of 135 sent), the importance assigned to each of the compiled themes varied depending on the manuscript section to which they were assigned. Following the working committee meeting, online ranking by stakeholders provided feedback and resulted in revision of the final checklist.
The RECORD statement incorporated the suggestions provided by a large, diverse group of stakeholders to create a reporting checklist specific to observational research using routinely collected health data. Our findings point to unique aspects of studies conducted with routinely collected health data and the perceived need for better reporting of methodological issues.
PMCID: PMC4428635  PMID: 25965407
7.  Effect of comorbidity on risk of venous thromboembolism in patients with renal cell carcinoma1 
Urologic oncology  2014;32(4):466-472.
Venous thromboembolism (VTE) is associated with renal cell carcinoma (RCC), but data on the effect of comorbidities are limited. Therefore, our purpose was to determine the effect of comorbidity on VTE risk among patients with RCC.
Materials and methods
A population-based cohort of all patients with RCC (n = 8,633) diagnosed in Denmark between 1995 and 2010 and a comparison cohort selected from the general population and matched on age, sex, and comorbidities (n = 83,055) were identified. Risk of subsequent VTE was estimated with 95% CI for the first 3 months, 1 year, and 5 years following cancer diagnosis. We stratified by Charlson comorbidity index (CCI) scores to estimate excess risk in patients with RCC vs. the comparison cohort within comorbidity strata. We also performed subanalyses for postoperative VTE and metastases.
VTE risk was higher in the RCC compared with comparison cohort, particularly during the initial year following diagnosis (risk difference = 9.9 per 1,000 persons [95% CI: 7.7–12.2]). After stratifying by CCI, excess risk declined with increasing comorbidities. The risk difference was 12.3 per 1,000 persons (95% CI: 9.1–15.5) for CCI = 0 and 0.5 (95% CI: 6.0–7.0) for CCI = 4. Excess risk also declined with increasing comorbidities among patients with postoperative VTE and among those with metastases.
RCC is associated with increased risk of VTE when compared with a matched general population cohort. Risk did not appear to increase with added comorbidity burden. Clinical attention to VTE risk in patients with RCC is appropriate regardless of the presence or absence of comorbidities.
PMCID: PMC4017852  PMID: 24767684
Carcinoma; Renal cell; Venous thromboembolism; Incidence; Epidemiology; Comorbidity
8.  Survival in patients with breast cancer with bone metastasis: a Danish population-based cohort study on the prognostic impact of initial stage of disease at breast cancer diagnosis and length of the bone metastasis-free interval 
BMJ Open  2015;5(4):e007702.
Since population-based data on prognostic factors affecting survival in patients with breast cancer with bone metastasis (BM) are currently limited, we conducted this nationwide retrospective cohort study to examine the prognostic role of disease stage at breast cancer diagnosis and length of BM-free interval (BMFI).
2427 women with a breast cancer diagnosis between 1997 and 2011 in the Danish Cancer Registry and a concurrent or subsequent BM diagnosis in the Danish National Registry of Patients.
Primary and secondary outcome measures
Survival (crude) based on Kaplan-Meier method and mortality risk (crude and adjusted for age, year of diagnosis, estrogen receptor status and comorbidity) based on Cox proportional hazards regression analyses by stage of disease at breast cancer diagnosis and by length of BMFI (time from breast cancer to BM diagnosis), following patients from BM diagnosis until death, emigration or until 31 December 2012, whichever came first.
Survival decreased with more advanced stage of disease at the time of breast cancer diagnosis; risk of mortality during the first year following a BM diagnosis was over two times higher for those presenting with metastatic versus localised disease (adjusted HR=2.12 (95% CI 1.71 to 2.62)). With respect to length of BMFI, survival was highest in women with a BMFI <1 year (ie, in those who presented with BM at the time of breast cancer diagnosis or were diagnosed within 1 year). However, among patients with a BMFI ≥1 year, survival increased with longer BMFI (1-year survival: 39.9% (95% CI 36.3% to 43.6%) for BMFI 1 to <3 years and 52.6% (95% CI 47.4% to 57.6%) for BMFI ≥5 years). This pattern was also observed in multivariate analyses.
Stage of disease at breast cancer diagnosis and length of BMFI appear to be important prognostic factors for survival following BM.
PMCID: PMC4420974  PMID: 25926150
9.  Impact of cardiovascular risk factors and medication use on the efficacy of remote ischaemic conditioning: post hoc subgroup analysis of a randomised controlled trial 
BMJ Open  2015;5(4):e006923.
Remote ischaemic conditioning (RIC) promotes cardioprotection in patients undergoing primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI). The effect of RIC may be modified by cardiovascular risk factors and their medications. We examined whether cardiovascular risk factors, lipid and glucose levels, and medication use influenced the efficacy of RIC in patients with STEMI treated with pPCI.
Post hoc subgroup analysis of a single-centre randomised controlled trial.
A total of 139 patients with STEMI, randomised during ambulance transport to hospital for pPCI with (n=71) or without (n=68) RIC, met the trial criteria and achieved data for a myocardial salvage index (MSI).
RIC was administered through intermittent arm ischaemia with four cycles of 5 min inflation and 5 min deflation of a blood pressure cuff.
Primary outcome measures
MSI, estimated by single-photon emission CT. We evaluated the efficacy of RIC on the MSI in patient subgroups of cardiovascular risk factors, lipid and glucose levels, and medication use.
We found no significant difference in the efficacy of RIC in subgroups of cardiovascular risk factors, lipid and glucose levels, and medication use. However, point estimates indicated a reduced effect of RIC among smokers (median difference in MSI between RIC and control groups: −0.02 (95% CI −0.32 to 0.28) in smokers vs 0.25 (95% CI 0.08 to 0.42) in non-smokers, p value for interaction=0.13) and an increased effect of RIC in statin users (median difference in MSI between RIC and control groups: 0.34 (95% CI 0.03 to 0.65) in statin users vs 0.09 (95% CI −0.11 to 0.29) in non-statin users, p value for interaction=0.19).
RIC as an adjunct to pPCI seems to improve MSI in our trial population of patients with STEMI regardless of most cardiovascular risk factors and their medications. Our post hoc finding on a limited sample size calls for further investigation in large-scale multicentre trials.
Trial registration number
PMCID: PMC4390720  PMID: 25838505
10.  Risk of Cancer in Patients with Inflammatory Bowel Diseases: a Nationwide Population-Based Cohort Study with 30 Years of Follow Up 
Background & Aims
Data regarding the risk of gastrointestinal and extra-intestinal cancers in Crohn’s disease (CD) and ulcerative colitis (UC) are needed to understand the clinical course of inflammatory bowel diseases (IBDs) and their treatments.
We performed a nationwide historical cohort study using Danish healthcare databases. We identified patients with a diagnosis of CD or UC, recorded from 1978 through 2010, and followed them until first occurrence of cancer, death, or emigration. We used standardized incidence ratios (SIRs) to compare cancer incidence in CD and UC patients to that expected in the general population.
Excluding cancers diagnosed within 1 year of IBD diagnosis, 772 cases of invasive cancer occurred among 13,756 patients with CD (SIR, 1.3; 95% confidence interval [CI], 1.2–1.4) and 2331 occurred among 35,152 patients with UC (SIR, 1.1; 95% CI, 1.0–1.1). CD was weakly associated with gastrointestinal cancers (SIR 1.2; 95% CI, 1.0–1.4) and extra-intestinal cancers (SIR, 1.3; 95% CI, 1.2–1.4), with the strongest associations for hematological malignancies (SIR, 1.9; 95% CI, 1.5–2.3), smoking-related cancers (SIR 1.5, 95% CI 1.3–1.8), and melanoma (SIR, 1.4; 95% CI, 1.0–1.9). Associations between UC and gastrointestinal and extra-intestinal cancers were weaker (SIR, 1.1; 95% CI, 1.0–1.2 and SIR, 1.1; 95% CI, 1.0–1.1, respectively). The relative risk of extra-intestinal cancers among patients with IBD was relatively stable over time, although the risk of gastrointestinal cancers decreased.
Patients with IBD, particularly CD, are at increased risk for gastrointestinal and extra-intestinal malignancies. The relative risk of gastrointestinal malignancy has deceased since 1978, without a concomitant increase in the risk of non-gastrointestinal malignancy.
PMCID: PMC4361949  PMID: 23602821
Epidemiology; Crohn’s disease; ulcerative colitis; colorectal cancer; GI tumor
11.  Body Size and Risk of Spontaneous Abortion among Danish Pregnancy Planners 
Several studies indicate that female obesity increases the risk of spontaneous abortion (SAB). Central adiposity, height, and location of typical weight gain have not been examined as risk factors for SAB.
We examined the associations between selected anthropometric factors and risk of SAB among 5132 women enrolled in a Danish Internet-based prospective cohort study of pregnancy planners. We used Cox proportional hazards regression models, with gestational weeks as the time scale, to compute hazard ratios (HRs) of SAB and 95% confidence intervals (CIs).
After adjustment for potential confounders, the HRs for SAB among underweight (body mass index (BMI, kg/m2) <20), overweight (BMI: 25–29) and obese (BMI ≥30) women were 1.00 [95% CI: 0.81, 1.24], 0.90 [95% CI: 0.73, 1.09] and 1.23 [95% CI: 0.98, 1.54], respectively, compared with normal weight women (BMI 20–24). The association between obesity and SAB was stronger for early SAB (<8 weeks gestation); HR: 1.34 95% CI: 1.01, 1.77. The HR for height ≥174 cm vs. <166 cm was 0.81 [95% CI: 0.66, 1.00]. Increased waist-to-hip ratio (WHR) was inversely associated with risk of SAB (HR: 0.81; 95% CI: 0.63, 1.05). Waist circumference and location of typical weight gain were not appreciably associated with SAB risk.
This study confirms previous studies that have shown a small positive association between obesity and SAB risk. Our results suggest that obesity is a stronger risk factor for early pregnancy losses, and that small stature and low WHR are associated with an increased risk of SAB.
PMCID: PMC4356022  PMID: 25225009
obesity; body size; spontaneous abortion
12.  Out-of-hours and weekend admissions to Danish medical departments: admission rates and 30-day mortality for 20 common medical conditions 
BMJ Open  2015;5(3):e006731.
Knowledge on timing of admissions and mortality for acute medical patients is limited. The aim of the study was to examine hospital admission rates and mortality rates for patients with common medical conditions according to time of admission.
Nationwide population-based cohort study.
Population of Denmark.
Using the Danish National Registry of Patients covering all Danish hospitals, we identified all adults with the first acute admission to a medical department in Denmark during 2010.
Primary and secondary outcome measures
Hourly admission rates and age-standardised and sex-standardised 30-day mortality rates comparing weekday office hours, weekday out of hours, weekend daytime hours and weekend night-time hours.
In total, 174 192 acute medical patients were included in the study. The admission rates (patients per hour) were 38.7 (95% CI 38.4 to 38.9) during weekday office hours, 13.3 (95% CI 13.2 to 13.5) during weekday out of hours, 19.8 (95% CI 19.6 to 20.1) during weekend daytime hours and 7.9 (95% CI 7.8 to 8.0) during weekend night-time hours. Admission rates varied between medical conditions. The proportion of patients admitted to an intensive care unit (ICU) increased outside of office hours. The age-standardised and sex-standardised 30-day mortality rate was 5.1% (95% CI 5.0% to 5.3%) after admission during weekday office hours, 5.7% (95% CI 5.5% to 6.0%) after admission during weekday out of hours, 6.4% (95% CI 6.1% to 6.7%) after admission during weekend daytime hours and 6.3% (95% CI 5.9% to 6.8%) after admission during weekend night-time hours. For the majority of the medical conditions examined, weekend admission was associated with highest mortality.
While admission rates decreased from office hours to weekend hours there was an observed increase in mortality. This may reflect differences in severity of illness as the proportion admitted to an ICU increased during the weekend.
PMCID: PMC4360838  PMID: 25762233
13.  Impact of preadmission treatment with calcium channel blockers or beta blockers on short-term mortality after stroke: a nationwide cohort study 
BMC Neurology  2015;15:24.
The prognostic impact of preadmission use of calcium channel blockers (CCBs) and beta blockers (BBs) on stroke mortality remains unclear. We aimed to examine whether preadmission use of CCBs or BBs was associated with improved short-term mortality following ischemic stroke, intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH).
We conducted a nationwide population-based cohort study using Danish medical registries. We identified all patients with a first-time inpatient diagnosis of stroke between 2004 and 2012 and their comorbidities. We defined CCB/BB use as current use, former use, or non-use. Current use was further classified as new or long-term use. We used Cox regression modeling to compute 30-day mortality rate ratios (MRRs) with 95% confidence intervals (CIs), controlling for potential confounders.
We identified 100,043 patients with a first-time stroke. Of these, 83,736 (83.7%) patients had ischemic stroke, 11,779 (11.8%) had ICH, and 4,528 (4.5%) had SAH. Comparing current users of CCBs or BBs with non-users, we found no association with mortality for ischemic stroke [adjusted 30-day MRR = 0.99 (95% CI: 0.94-1.05) for CCBs and 1.01 (95% CI: 0.96-1.07) for BBs], ICH [adjusted 30-day MRR = 1.05 (95% CI: 0.95-1.16) for CCBs and 0.95 (95% CI: 0.87-1.04) for BBs], or SAH [adjusted 30-day MRR = 1.05 (95% CI: 0.85-1.29) for CCBs and 0.89 (95% CI: 0.72-1.11) for BBs]. Former use of CCBs or BBs was not associated with mortality.
Preadmission use of CCBs or BBs was not associated with 30-day mortality following ischemic stroke, ICH, or SAH.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0279-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4365558  PMID: 25884780
Beta-blocker; Calcium channel blocker; Stroke; Ischemic stroke; Hemorrhagic stroke; Mortality
14.  The impact of exacerbation frequency on mortality following acute exacerbations of COPD: a registry-based cohort study 
BMJ Open  2014;4(12):e006720.
To examine the association between exacerbation frequency and mortality following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).
Cohort study using medical databases.
Northern Denmark.
On 1 January 2005, we identified all patients with prevalent hospital-diagnosed chronic obstructive pulmonary disease (COPD) who had at least one AECOPD during 1 January 2005 to 31 December 2009. We followed patients from the first AECOPD during this period until death, emigration or 31 December 2009, whichever came first. We flagged all AECOPD events during follow-up and characterised each by the exacerbation frequency (0, 1, 2 or 3+) in the prior 12-month period.
Main outcomes and measures
Using Cox regression, we computed 0–30-day and 31–365-day age-adjusted, sex-adjusted, and comorbidity-adjusted mortality rate ratios (MRRs) with 95% CIs entering exacerbation frequency as a time-varying exposure.
We identified 16 647 eligible patients with prevalent COPD, of whom 6664 (40%) developed an AECOPD and were thus included in the study cohort. The 0–30-day MRRs were 0.97 (95% CI 0.80 to 1.18), 0.90 (95% CI 0.70 to 1.15) and 1.03 (95% CI 0.81 to 1.32) among patients with AECOPD with 1, 2 and 3+ AECOPDs versus no AECOPD within the past 12 months, respectively. The corresponding MRRs were 1.47 (95% CI 1.30 to 1.66), 1.89 (95% CI 1.59 to 2.25) and 1.59 (95% CI 1.23 to 2.05) for days 31–365.
Among patients with AECOPD, one or more exacerbations in the previous year were not associated with 30-day mortality but were associated with an increased 31–365-day mortality.
PMCID: PMC4275660  PMID: 25526796
Cohort study; Registry study; Severe exacerbations; Time-varying exposure
15.  Using registries to identify type 2 diabetes patients 
Clinical Epidemiology  2014;7:1-3.
PMCID: PMC4274149  PMID: 25565888
16.  Joint kinematics and kinetics during walking and running in 32 patients with hip dysplasia 1 year after periacetabular osteotomy 
Acta Orthopaedica  2014;85(6):592-599.
Background and purpose —
Hip dysplasia can be treated with periacetabular osteotomy (PAO). We compared joint angles and joint moments during walking and running in young adults with hip dysplasia prior to and 6 and 12 months after PAO with those in healthy controls.
Patients and methods —
Joint kinematics and kinetics were recorded using a 3-D motion capture system. The pre- and postoperative gait characteristics quantified as the peak hip extension angle and the peak joint moment of hip flexion were compared in 23 patients with hip dysplasia (18–53 years old). Similarly, the gait patterns of the patients were compared with those of 32 controls (18–54 years old).
Results —
During walking, the peak hip extension angle and the peak hip flexion moment were significantly smaller at baseline in the patients than in the healthy controls. The peak hip flexion moment increased 6 and 12 months after PAO relative to baseline during walking, and 6 months after PAO relative to baseline during running. For running, the improvement did not reach statistical significance at 12 months. In addition, the peak hip extension angle during walking increased 12 months after PAO, though not statistically significantly. There were no statistically significant differences in peak hip extension angle and peak hip flexion moment between the patients and the healthy controls after 12 months.
Interpretation —
Walking and running characteristics improved after PAO in patients with symptomatic hip dysplasia, although gait modifications were still present 12 months postoperatively.
PMCID: PMC4259030  PMID: 25191933
17.  Fetal Growth and Childhood Cancer: A Population-Based Study 
Pediatrics  2013;132(5):e1265-e1275.
The etiology of childhood cancers is largely unknown. Studies have suggested that birth characteristics may be associated with risk. Our goal was to evaluate the risk of childhood cancers in relation to fetal growth.
We conducted a case-control study nested within Nordic birth registries. The study included cancer cases diagnosed in Denmark, Finland, Norway, and Sweden among children born from 1967 to 2010 and up to 10 matched controls per case, totaling 17 698 cases and 172 422 controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were derived from conditional logistic regression.
Risks of all childhood cancers increased with increasing birth weight (Ptrend ≤ .001). Risks of acute lymphoid leukemia and Wilms tumor were elevated when birth weight was >4000 g and of central nervous system tumors when birth weight was >4500 g. Newborns large for gestational age were at increased risk of Wilms tumor (OR: 2.1 [95% CI: 1.2–3.6]) and connective/soft tissue tumors (OR: 2.1 [95% CI: 1.1–4.4]). In contrast, the risk of acute myeloid leukemia was increased among children born small for gestational age (OR: 1.8 [95% CI: 1.1–3.1]). Children diagnosed with central nervous system tumors at <1 year of age had elevated risk with increasing head circumference (Ptrend < .001). Those with head circumference >39 cm had the highest risk (OR: 4.7 [95% CI: 2.5–8.7]).
In this large, Nordic population-based study, increased risks for several childhood tumors were associated with measures of fetal growth, supporting the hypothesis that tumorigenesis manifesting in childhood is initiated in utero.
PMCID: PMC3813399  PMID: 24167169
birth weight; childhood cancer; fetal growth; nested case-control study; Nordic countries
18.  Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target 
eLife  2014;3:e03711.
To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.
eLife digest
Pneumonia is a disease that is commonly caused by a bacterial infection and results in the lungs becoming inflamed. Pneumonia is a serious condition and can lead to hospitalization and sometimes death. However, women—and other female animals—are less likely than males to get pneumonia and are more likely to survive if they do. Understanding this sex-based difference may help to develop treatments or preventive actions that either reduce the number of people who get pneumonia or help infected patients to recover.
Bacteria from the nose—including those that cause pneumonia—frequently enter the lungs during sleep. Luckily, the body has very robust defense mechanisms against such invasions; the immune system immediately deploys cells called macrophages as a ‘first response’ to devour and kill invading bacteria in the lungs. However, this system is not perfect, particularly if an individual has a weakened immune system or if they are already suffering with a respiratory infection. Indeed, many individuals with severe influenza infections are hospitalized as a result of pneumonia.
Yang et al. studied why females are more able to fend off pneumonia and found that estrogen, the main female sex hormone, boosts the ability of the macrophages to kill bacteria. Treating male mice with estrogen also boosted their immune system's ability to kill off bacteria in the lungs.
Investigating further, Yang et al. found that the estrogen worked by increasing the number of proteins produced from one gene called NOS3. Female mice lacking NOS3 proteins lost their pneumonia-fighting advantage. A widely used class of drugs called statins, which are used to treat cardiovascular disease, boosts the activity of the NOS3 gene. Yang et al. therefore wondered whether treatment with either estrogen or statins might prevent pneumonia, or help patients with pneumonia fight off the infection.
Using a large database of information about healthcare in Denmark, Yang et al. assessed the relationship between taking these drugs and the risk of pneumonia. When several confounding factors (such as unrelated diseases that the patient was suffering from) are taken into account, the data show that the women were less likely to be hospitalized for pneumonia if they were taking statins or estrogens. Those taking both treatments had an even lower risk.
Yang et al. also found that treating mice with statins or an experimental drug that boosts NOS3 activity increased the ability of the animals to fight off pneumonia-causing bacteria—even if they also had influenza—and increased the likelihood that mice already infected with pneumonia would survive. Further studies will be needed to determine if statins or the experimental drug might also help to prevent pneumonia in human patients with influenza.
PMCID: PMC4215537  PMID: 25317947
macrophages; innate immunity; pneumonia; nitric oxide; bacteria; gender; human; mouse
19.  Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: a population-based cohort study 
Critical Care  2014;18(5):492.
Acute kidney injury (AKI) is common among intensive care unit (ICU) patients, but follow-up data on subsequent risk of cardiovascular disease remain sparse. We examined the impact of AKI on three-year risk of first-time heart failure, myocardial infarction (MI), and stroke among ICU patients surviving to hospital discharge, and whether this risk is modified by renal recovery before hospital discharge.
We used population-based medical registries to identify all adult patients admitted to an ICU in Northern Denmark between 2005 and 2010 who survived to hospital discharge and who had no previous or concurrent diagnosis of heart failure, MI, or stroke. AKI was defined according to the creatinine criteria in the Kidney Disease Improving Global Outcomes classification. We computed the three-year cumulative risk of hospitalization with heart failure, MI, and stroke for patients with and without AKI and the hazard ratios (HRs), using a Cox model adjusted for potential confounders.
Among 21,556 ICU patients surviving to hospital discharge, 4,792 (22.2%) had an AKI episode. Three-year cumulative risk of heart failure was 2.2% in patients without AKI, 5.0% for AKI stage 1, and 5.0% for stages 2 to 3. The corresponding adjusted HRs were 1.33 (95% confidence interval (CI), 1.06 to 1.66) for patients with AKI stage 1 and 1.45 (95% CI, 1.14 to 1.84) for AKI stages 2 to 3, compared to patients without AKI. The three-year cumulative MI risk was 1.0% for patients without AKI, 1.8% for patients with AKI stage 1 and 2.3% for patients with AKI stages 2 to 3. The adjusted HR for MI was 1.04 (95% CI, 0.71 to 1.51) for patients with AKI stage 1 and 1.51 (95% CI, 1.05 to 2.18) for patients with AKI stages 2 to 3, compared with patients without AKI. We found no association between AKI and stroke. The increased risk of heart failure and MI persisted in patients with renal recovery before discharge, although it was less pronounced than in patients without renal recovery.
ICU patients surviving any stage of AKI are at increased three-year risk of heart failure, but not stroke. Only AKI stages 2 to 3 are associated with increased MI risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0492-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4197334  PMID: 25601057
20.  Lifestyle and clinical factors associated with elevated C-reactive protein among newly diagnosed Type 2 diabetes mellitus patients: a cross-sectional study from the nationwide DD2 cohort 
We aimed to examine the prevalence of and modifiable factors associated with elevated C-reactive Protein (CRP), a marker of inflammation, in men and women with newly diagnosed Type 2 Diabetes mellitus (DM) in a population-based setting.
CRP was measured in 1,037 patients (57% male) with newly diagnosed Type 2 DM included in the prospective nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. We assessed the prevalence of elevated CRP and calculated relative risks (RR) examining the association of CRP with lifestyle and clinical factors by Poisson regression, stratified by gender. We used linear regression to examine the association of CRP with other biomarkers.
The median CRP value was 2.1 mg/L (interquartile range, 1.0 – 4.8 mg/L). In total, 405 out of the 1,037 Type 2 DM patients (40%) had elevated CRP levels (>3.0 mg/L). More women (46%) than men (34%) had elevated CRP. Among women, a lower risk of elevated CRP was observed in patients receiving statins (adjusted RR (aRR) 0.7 (95% confidence interval (CI) 0.6-0.9)), whereas a higher risk was seen in patients with central obesity (aRR 2.3 (95% CI 1.0-5.3)). For men, CRP was primarily elevated among patients with no regular physical activity (aRR 1.5 (95% CI 1.1-1.9)), previous cardiovascular disease (aRR1.5 (95% CI 1.2-1.9) and other comorbidity. For both genders, elevated CRP was 1.4-fold increased in those with weight gain >30 kg since age 20 years. Sensitivity analyses showed consistent results with the full analysis. The linear regression analysis conveyed an association between high CRP and increased fasting blood glucose.
Among newly diagnosed Type 2 DM patients, 40% had elevated CRP levels. Important modifiable risk factors for elevated CRP may vary by gender, and include low physical activity for men and central obesity and absence of statin use for women.
PMCID: PMC4161271  PMID: 25163828
C-reactive protein; Lifestyle factors; Obesity; Physical activity
21.  Ventilatory strategy during liver transplantation: implications for near-infrared spectroscopy-determined frontal lobe oxygenation 
Background: As measured by near infrared spectroscopy (NIRS), cerebral oxygenation (ScO2) may be reduced by hyperventilation in the anhepatic phase of liver transplantation surgery (LTx). Conversely, the brain may be subjected to hyperperfusion during reperfusion of the grafted liver. We investigated the relationship between ScO2 and end-tidal CO2 tension (EtCO2) during the various phases of LTx.
Methods: In this retrospective study, 49 patients undergoing LTx were studied. Forehead ScO2, EtCO2, minute ventilation (VE), and hemodynamic variables were recorded from the beginning of surgery through to the anhepatic and reperfusion phases during LTx.
Results: In the anhepatic phase, ScO2 was reduced by 4.3% (95% confidence interval: 2.5–6.0%; P < 0.0001), EtCO2 by 0.3 kPa (0.2–0.4 kPa; P < 0.0001), and VE by 0.4 L/min (0.1–0.7 L/min; P = 0.0018). Conversely, during reperfusion of the donated liver, ScO2 increased by 5.5% (3.8–7.3%), EtCO2 by 0.7 kPa (0.5–0.8 kPa), and VE by 0.6 L/min (0.3–0.9 L/min; all P < 0.0001). Changes in ScO2 were correlated to those in EtCO2 (Pearson r = 0.74; P < 0.0001).
Conclusion: During LTx, changes in ScO2 are closely correlated to those of EtCO2. Thus, this retrospective analysis suggests that attention to maintain a targeted EtCO2 would result in a more stable ScO2 during the operation.
PMCID: PMC4142416  PMID: 25202281
cerebral oxygenation; cerebral oximetry; end-tidal carbon dioxide; liver transplantation; monitoring; ventilation
22.  Atrial Fibrillation as a Marker of Occult Cancer 
PLoS ONE  2014;9(8):e102861.
Recent studies suggest that cancer increases risk of atrial fibrillation. Whether atrial fibrillation is a marker for underlying occult cancer is unknown.
We conducted a cohort study (1980–2011) of all Danish patients with new-onset atrial fibrillation. To examine cancer risk, we computed absolute risk at 3 months and standardized incidence ratios (SIRs) by comparing observed cancer incidence among patients newly diagnosed with atrial fibrillation with that expected based on national cancer incidence during the period.
Median follow-up time was 3.4 years among 269 742 atrial fibrillation patients. Within 3 months of follow-up, 6656 cancers occurred (absolute risk, 2.5%; 95% confidence intervals [CI], 2.4%–2.5%) versus 1302 expected, yielding a SIR of 5.11; 95% CI, 4.99–5.24. Associations were particularly strong for cancers of the lung, kidney, colon, ovary, and for non-Hodgkin's lymphoma. The SIR within 3 months of follow-up was 7.02; 95% CI, 6.76–7.28 for metastatic and 3.53; 95% CI, 3.38–3.68 for localized cancer. Beyond 3 months of follow-up, overall cancer risk was modestly increased (SIR, 1.13; 95% CI, 1.12–1.15).
Patients with new-onset atrial fibrillation had a markedly increased relative risk of a cancer diagnosis within the next three months, however, corresponding absolute risk was small.
PMCID: PMC4138009  PMID: 25119880
23.  Clopidogrel discontinuation within the first year after coronary drug-eluting stent implantation: an observational study 
The impact of adherence to the recommended duration of dual antiplatelet therapy after first generation drug-eluting stent implantation is difficult to assess in real-world settings and limited data are available.
We followed 4,154 patients treated with coronary drug-eluting stents in Western Denmark for 1 year and obtained data on redeemed clopidogrel prescriptions and major adverse cardiovascular events (MACE, i.e., cardiac death, myocardial infarction, or stent thrombosis) from medical databases.
Discontinuation of clopidogrel within the first 3 months after stent implantation was associated with a significantly increased rate of MACE at 1-year follow-up (hazard ratio (HR) 2.06; 95% confidence interval (CI): 1.08-3.93). Discontinuation 3-6 months (HR 1.29; 95% CI: 0.70-2.41) and 6-12 months (HR 1.29; 95% CI: 0.54-3.07) after stent implantation were associated with smaller, not statistically significant, increases in MACE rates. Among patients who discontinued clopidogrel, MACE rates were highest within the first 2 months after discontinuation.
Discontinuation of clopidogrel was associated with an increased rate of MACE among patients treated with drug-eluting stents. The increase was statistically significant within the first 3 months after drug-eluting stent implantation but not after 3 to 12 months.
PMCID: PMC4135343  PMID: 25125079
Percutaneous coronary intervention; Dual antiplatelet therapy; Drug-eluting stent; Clopidogrel
24.  The impact of chronic obstructive pulmonary disease on intensive care unit admission and 30-day mortality in patients undergoing colorectal cancer surgery: a Danish population-based cohort study 
BMJ Open Respiratory Research  2014;1(1):e000036.
Background and purpose
Chronic obstructive pulmonary disease (COPD) may increase the risk of postoperative complications and thus mortality after colorectal cancer (CRC) surgery, but the evidence is sparse.
We conducted this nationwide population-based cohort study in Denmark, including all patients undergoing CRC surgery in the period 2005–2011, identified through medical databases. We categorised the patients according to the history of COPD.
We assessed the rate of complications within 30 days. We computed 30-day mortality among patients with/without COPD using the Kaplan-Meier method. We used Cox regression to compute HRs for death, controlling for age, gender, type of admission, cancer stage, hospital volume, alcohol-related diseases, obesity and Charlson comorbidity score.
We identified 18 302 CRC surgery patients. Of these, 7.9% had a prior diagnosis of COPD. Among patients with COPD, 16.1% were admitted postoperatively to the intensive care unit, 1.9% were treated with mechanical ventilation, and 3.6% were treated with non-invasive ventilation. In patients without COPD, the corresponding proportions were 9.7%, 1.1% and 1.1%. The reoperation rate was 10.6% among patients with COPD and 8% among patients with cancer without COPD. 30-day mortality was 13% (95% CI 11.4% to 14.9%) among patients with COPD and 5.3% (95% CI 5.0% to 5.7%) among patients without COPD, corresponding to an adjusted HR of 1.7 (95% CI 1.5 to 2.0).
COPD is a strong predictor for intensive care unit admission and mortality after CRC surgery.
PMCID: PMC4212724  PMID: 25478184
COPD ÀÜ Mechanisms; Clinical Epidemiology
25.  Use of β-Blockers, Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Risk of Breast Cancer Recurrence: A Danish Nationwide Prospective Cohort Study 
Journal of Clinical Oncology  2013;31(18):2265-2272.
To estimate associations between use of β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) and breast cancer recurrence in a large Danish cohort.
Patients and Methods
We enrolled 18,733 women diagnosed with nonmetastatic breast cancer between 1996 and 2003. Patient, treatment, and 10-year recurrence data were ascertained from the Danish Breast Cancer Cooperative Group registry. Prescription and medical histories were ascertained by linkage to the National Prescription Registry and Registry of Patients, respectively. β-Blocker exposure was defined in aggregate and according to solubility, receptor selectivity, and individual drugs. ACE inhibitor and ARB exposures were defined in aggregate. Recurrence associations were estimated with multivariable Cox regression models in which time-varying drug exposures were lagged by 1 year.
Compared with never users, users of any β-blocker had a lower recurrence hazard in unadjusted models (unadjusted hazard ratio [HR] = 0.91; 95% CI, 0.81 to 1.0) and a slightly higher recurrence hazard in adjusted models (adjusted HR = 1.3; 95% CI, 1.1 to 1.5). Associations were similar for exposures defined by receptor selectivity and solubility. Although most individual β-blockers showed no association with recurrence, metoprolol and sotalol were associated with increased recurrence rates (adjusted metoprolol HR = 1.5, 95% CI, 1.2 to 1.8; adjusted sotalol HR = 2.0, 95% CI, 0.99 to 4.0). ACE inhibitors were associated with a slightly increased recurrence hazard, whereas ARBs were not associated with recurrence (adjusted ACE inhibitor HR = 1.2, 95% CI, 0.97 to 1.4; adjusted ARBs HR = 1.1, 95% CI, 0.85 to 1.3).
Our data do not support the hypothesis that β-blockers attenuate breast cancer recurrence risk.
PMCID: PMC3677839  PMID: 23650417

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