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1.  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
2.  Using registries to identify type 2 diabetes patients 
Clinical Epidemiology  2014;7:1-3.
PMCID: PMC4274149  PMID: 25565888
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Use of corticosteroids during pregnancy and risk of asthma in offspring: a nationwide Danish cohort study 
BMJ Open  2014;4(6):e005053.
To examine whether in utero exposure to local and systemic corticosteroids is associated with asthma development in offspring.
Cohort study.
We included all singletons born alive in Denmark between 1996 and 2009. Data on maternal corticosteroid use, asthma in offspring and covariates were obtained from medical registries.
Main outcome measures
We compared asthma risks of children prenatally exposed to corticosteroids and of children of former corticosteroid users with that of unexposed children. We computed absolute risks and used proportional-hazards regression to compute adjusted HRs (aHRs). Using logistic regression we compared exposed children with unexposed siblings in a ‘within-mother-between-pregnancy’ analysis. Adjustment addressed varying length of follow-up.
We identified 877 778 children, 3.6% of whom were prenatally exposed to systemic (n=5327) or local (n=24 436) corticosteroids. A total of 105 677 children developed asthma during follow-up with a 10-year risk of 18.4% among the exposed and 13.5% among the unexposed. The aHR was 1.54 (95% CI 1.45 to 1.65) for systemic use, 1.45 (95% CI 1.40 to 1.50) for local use and 1.32 (95% CI 1.30 to 1.34) for former use. The adjusted OR of the ‘within-mother-between-pregnancy’ analysis was 1.11 (95% CI 0.98 to 1.25).
These population-based data do not support a strong causal association between maternal corticosteroid use during pregnancy and increased asthma risk in offspring.
PMCID: PMC4054622  PMID: 24902733
14.  Impact of comorbidity on risk of venous thromboembolism in patients with breast cancer: a Danish population-based cohort study 
BMJ Open  2014;4(6):e005082.
To assess the interaction between comorbidity and breast cancer (BC) on the rate of venous thromboembolism (VTE) beyond what can be explained by the independent effects of BC and comorbidity.
Population-based matched cohort study.
Danish patients with BC (n=62 376) diagnosed in 1995–2010 and a comparison cohort of women without BC (n=304 803) from the general population were matched to the patients with BC on year of birth in 5-year intervals and on the specific diseases included in the Charlson Comorbidity Index (CCI) and atrial fibrillation and obesity.
The rate ratios of VTE per 1000 person-years (PY) were computed by comorbidity levels using the CCI, and interaction contrasts (IC) were calculated as a measure of the excess or deficit VTE rate not explained by the independent effects of BC and comorbidity.
Among patients with BC with a CCI score of 1, the 0–1 year VTE rate was 12/1000 PY, and interaction accounted for 10% of the rate (IC=3.2, 95% CI 0.5 to 5.9). Among patients with BC with CCI ≥4, the VTE rate was 17, and interaction accounted for 8% of the rate (IC=1.2, 95% CI −1.8 to 4.2). There was no interaction during 2–5 years of follow-up.
There was only little interaction between BC and the CCI score on the rate of VTE.
PMCID: PMC4054647  PMID: 24902734
Epidemiology; Oncology
15.  Volitional Determinants and Age-related Decline in Fecundability: A General Population Prospective Cohort Study in Denmark 
Fertility and sterility  2013;99(7):1958-1964.
To quantify the natural decline in fecundability by age and assess the effect of selected volitional factors.
Prospective cohort study of women attempting conception.
General population cohort of Danish women aged 20–40 years.
2,820 women without infertility, trying to conceive for less than 3 cycles at study entry.
Outcome measure
Age had little effect on fecundability except for women 35–40 yrs, for whom it was 0.77 relative to women aged 20–24. Male age showed a similar but smaller drop, declining to 0.95 for men aged 35–39. The effect of age differed for parous and nulliparous women, with the latter experiencing much stronger age-related declines relative to fecundability at age 20. Frequency of intercourse, use of nonhormonal birth control as the last method, and timing of intercourse each had small effects on fecundability. Women who were in the high-fecundability categories for all three of these volitional factors had an estimated probability of conceiving of 88% (95% CI: 83%–93%). Unlike age, these factors represent individual choices that together can offset some of the age-related decline in fecundability.
Fecundability peaks around age 30, slightly earlier for nulliparous than for parous women, and then declines. The decline with age is more modest for males. Couples will experience a compounded effect of their separate age-related declines. At age 40, a couple’s fecundability would be approximately half of what it is at age 30, but some of this decline can be counteracted by volitional factors affecting conception.
PMCID: PMC3672329  PMID: 23517858
fecundability; fertility; age; behavioral factors; cohort study
16.  Next-Generation Stool DNA Test Accurately Detects Colorectal Cancer and Large Adenomas 
Gastroenterology  2011;142(2):248-e26.
Technical advances have led to stool DNA (sDNA) tests that might accurately detect neoplasms on both sides of the colorectum. We assessed colorectal neoplasm detection by a next-generation sDNA test and effects of covariates on test performance.
We performed a blinded, multicenter, case-control study using archived stool samples collected in preservative buffer from 252 patients with colorectal cancer (CRC), 133 with adenomas ≥1 cm, and 293 individuals with normal colonoscopy results (controls); two-thirds were randomly assigned to a training set and one-third to a test set. The sDNA test detects 4 methylated genes, a mutant form of KRAS, and the α-actin gene (as a reference value) using quantitative, allele-specific, real-time target and signal amplification; it also quantifies hemoglobin. We used a logistical model to analyze data.
The sDNA test identified 85% of patients with CRC and 54% of patients with adenomas ≥1 cm with 90% specificity. The test had a high rate of detection for all nonmetastatic stages of CRC (aggregate 87% detection rate for CRC stages I–III). Detection rates increased with adenoma size: 54% ≥1 cm, 63% >1 cm, 77% >2 cm, 86% >3 cm, and 92% >4 cm (P < .0001). Based on receiver operating characteristic analysis, the rate of CRC detection was slightly greater for the training than the test set (P = .04), whereas the rate of adenoma detection was comparable between sets. Sensitivities for detection of CRC and adenoma did not differ with lesion site.
Early-stage CRC and large adenomas can be detected throughout the colorectum and with high levels of accuracy by the sDNA test. Neoplasm size, but not anatomical site, affected detection rates. Further studies are needed to validate the findings in a larger population and optimize the sDNA test.
PMCID: PMC4017869  PMID: 22062357
QuARTS; Colorectal Cancer Screening; Stool Testing; Precancer Detection
17.  Autism spectrum disorders in children of parents with inflammatory bowel disease – a nationwide cohort study in Denmark 
Inflammatory bowel disease (IBD) and autism spectrum disorders (ASD) may share genetic and environmental risk factors. We examined whether parental IBD is associated with an increased risk of ASD in offspring.
We conducted a registry-based nationwide cohort study including children born alive in Denmark from January 1, 1994 to December 31, 2009, with follow-up throughout 2010. IBD in parents and ASD in offspring were identified using inpatient and outpatient hospital diagnoses. We computed risk of ASD and crude and adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CI) using Cox proportional-hazards regression. We evaluated the risk of ASD according to maternal and paternal IBD, and separately for maternal and paternal Crohn’s disease (CD) and ulcerative colitis (UC). Children with parents free of IBD were the comparison cohort.
We identified 1,005,330 children during the study period. Among them, 11,888 (1.2%) had a parent with IBD and 8,087 (0.8%) had a diagnosis of ASD during up to 17 years of follow-up. The 10-year risks of ASD were 0.7% among children of parents with IBD and 0.9% among children of parents without IBD. The aIRR for ASD among children with parental IBD was 0.8 (95% CI: 0.6–1.0), and results were similar regardless of parent of IBD origin or whether a parent had CD or UC. The estimates were similar for different ASD subtypes.
We found no evidence of an increased risk of ASD among children born to parents with IBD.
PMCID: PMC4019630  PMID: 24855384
autistic disorder; children; cohort study; epidemiology; inflammatory bowel disease; parents
18.  Pre-gravid oral contraceptive use and time to pregnancy: a Danish prospective cohort study 
Human Reproduction (Oxford, England)  2013;28(5):1398-1405.
Is there an association between oral contraceptive (OC) use (age at the start of use, duration of use, ethinylestradiol dose and generation) and time to pregnancy (TTP)?
Although OC use was associated with a transient delay in the return of fertility, we found no evidence that long-term OC use deleteriously affects fecundability.
Studies using retrospective data on TTP have reported a short-term delay in the return of fertility after OC use. However, little is known about the long-term OC use and TTP.
Data were derived from ‘Snart’, a prospective cohort study that enrolled participants from 1 June 2007 to 31 May 2010. The final study population consisted of 3727 women.
Eligible women were Danish pregnancy planners, aged 18–40 years, who completed a baseline questionnaire and bimonthly follow-up questionnaires until conception or for 12 months, whichever came first. Cohort retention was 80%. We used proportional probability regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), with adjustment for potential confounders.
Compared with barrier methods, the use of OCs as the last contraception method before attempting to conceive was associated with a short-term delay in return of fertility (FR = 0.87, 95% CI: 0.79–0.96). Longer term OC use was associated with higher fecundability: compared with OC use for less than 2 years; FRs were 0.98 (95% CI: 0.83–1.15) for 2–3 years, 1.16 (95% CI: 0.98–1.37) for 4–5 years, 1.10 (95% CI: 0.93–1.29) for 6–7 years, 1.17 (95% CI: 0.99–1.38) for 8–9 years, 1.23 (95% CI: 1.04–1.46) for 10–11 years and 1.28 (95% CI: 1.07–1.53) for ≥12 years of OC use.
Because this was a non-experimental study, where study volunteers provided information about their history of contraceptive use at baseline and were followed prospectively to assess their waiting times to pregnancy, there was some potential for error in the reporting of OC use and TTP. Nevertheless, participants reported data on OC use before the occurrence of pregnancy, thereby reducing the potential for systematic bias.
Women who have used OCs for many years should be reassured as there was no evidence that long-term OC use has a deleterious affects on fecundability. Both short- and long-term OC users are likely to experience a transient delay in conception compared with those discontinuing barrier methods.
This study was supported by the National Institute of Child Health and Human Development (R21050264) and the Danish Medical Research Council (271-07-0338). The authors declare that there are no conflicts of interest.
PMCID: PMC3627337  PMID: 23427234
oral contraceptives; fecundability; time to pregnancy
Training guidelines for novice runners are needed to reduce the risk of injury. The purpose of this study was to investigate whether the risk of injury varied in obese and non‐obese individuals initiating a running program at different weekly distances.
A volunteer sample of 749 of 1532 eligible healthy novice runners was included in a 3‐week observational explorative prospective cohort study. Runners were categorized into one of six strata based on their body mass index (BMI) (≤30=low; >30=high) and running distance after 1 week (<3 km = low; 3 to 6 km = medium; >6 km = high). Data was collected for three weeks for the six strata. The main outcome measure was running‐related injury.
Fifty‐six runners sustained a running‐related injury during the 3‐week data collection. A significantly greater number of individuals with BMI>30 sustained injuries if they ran between 3 to 6 km (cumulative risk difference (CRD) = 14.3% [95%CI: 3.3% to 25.3%], p<0.01) or more than 6 km (CRD = 16.2% [95%CI: 4.4% to 28.0%], p<0.01) the first week than individuals in the reference group (low distance and low BMI). The effect‐measure modification between high running distance and BMI on additive scale was positive (11.7% [‐3.6% to 27.0%], p=0.13). The number of obese individuals needed to change their running distance from high to low to avoid one injury was 8.5 [95%CI: 4.6 to 52].
Obese individuals were at greater risk of injury if they exceeded 3 km during the first week of their running program. Because of a considerable injury risk compared with their non‐obese peers, individuals with a BMI>30 may be well advised to begin running training with an initial running distance of less than 3 km (1.9 miles) the first week of their running regime. Large‐scale trials are needed to further describe and document this relationship.
Level of Evidence:
Level 2b
PMCID: PMC4060311  PMID: 24944852
Body mass index; distance; injury risk; Running
20.  Validity of the International Classification of Diseases, 10th revision discharge diagnosis codes for hyponatraemia in the Danish National Registry of Patients 
BMJ Open  2014;4(4):e004956.
To examine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes for hyponatraemia in the nationwide population-based Danish National Registry of Patients (DNRP) among inpatients of all ages.
Population-based validation study.
All somatic hospitals in the North and Central Denmark Regions from 2006 through 2011.
Patients of all ages admitted to hospital (n=819 701 individual patients) during the study period. The patient could be included in the study more than once, and our study did not restrict to patients with serum sodium measurements (total of n=2 186 642 hospitalisations).
Main outcome measure
We validated ICD-10 discharge diagnoses of hyponatraemia recorded in the DNRP, using serum sodium measurements obtained from the laboratory information systems (LABKA) research database as the gold standard. One sodium value <135 mmol/L measured at any time during hospitalisation confirmed the diagnosis. We estimated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ICD-10 codes for hyponatraemia overall and for cut-off points for increasing hyponatraemia severity.
An ICD-10 code for hyponatraemia was recorded in the DNRP in 5850 of the 2 186 642 hospitalisations identified. According to laboratory measurements, however, hyponatraemia was present in 306 418 (14%) hospitalisations. Sensitivity of hyponatraemia diagnoses was 1.8% (95% CI 1.7% to 1.8%). For sodium values <115 mmol/L, sensitivity was 34.3% (95% CI 32.6% to 35.9%). The overall PPV was 92.5% (95% CI 91.8% to 93.1%) and decreased with increasing hyponatraemia severity. Specificity and NPV were high for all cut-off points (≥99.8% and ≥86.2%, respectively). Patients with hyponatraemia without a corresponding ICD-10 discharge diagnosis were younger and had higher Charlson Comorbidity Index scores than patients with hyponatraemia with a hyponatraemia code in the DNRP.
ICD-10 codes for hyponatraemia in the DNRP have high specificity but very low sensitivity. Laboratory test results, not discharge diagnoses, should be used to ascertain hyponatraemia.
PMCID: PMC4010845  PMID: 24760354
Epidemiology; Statistics & Research Methods
21.  Weight at Birth and Subsequent Fecundability: A Prospective Cohort Study 
PLoS ONE  2014;9(4):e95257.
To examine the association between a woman's birth weight and her subsequent fecundability.
In this prospective cohort study, we included 2,773 Danish pregnancy planners enrolled in the internet-based cohort study “Snart-Gravid”, conducted during 2007–2012. Participants were 18–40 years old at study entry, attempting to conceive, and were not receiving fertility treatment. Data on weight at birth were obtained from the Danish Medical Birth Registry and categorized as <2,500 grams, 2,500–2,999 grams, 3,000–3,999 grams, and ≥4,000 grams. In additional analyses, birth weight was categorized according to z-scores for each gestational week at birth. Time-to-pregnancy measured in cycles was used to compute fecundability ratios (FR) and 95% confidence intervals (CI), using a proportional probabilities regression model.
Relative to women with a birth weight of 3,000–3,999 grams, FRs adjusted for gestational age, year of birth, and maternal socio-demographic and medical factors were 0.99 (95% CI: 0.73;1.34), 0.99 (95% CI: 0.87;1.12), and 1.08 (95% CI: 0.94;1.24) for birth weight <2,500 grams, 2,500–2,999 grams, and ≥4,000 grams, respectively. Estimates remained unchanged after further adjustment for markers of the participant's mother's fecundability. We obtained similar results when we restricted to women who were born at term, and to women who had attempted to conceive for a maximum of 6 cycles before study entry. Results remained similar when we estimated FRs according to z-scores of birth weight.
Our results indicate that birth weight appears not to be an important determinant of fecundability.
PMCID: PMC3988145  PMID: 24736472
22.  Manganese Superoxide Dismutase and Breast Cancer Recurrence: A Danish Clinical Registry-Based Case-Control Study, and a Meta-Analysis 
PLoS ONE  2014;9(1):e87450.
Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses.
We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990–2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR.
The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively.
Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.
PMCID: PMC3909115  PMID: 24498107
23.  A note on arterial to venous oxygen saturation as reference for NIRS-determined frontal lobe oxygen saturation in healthy humans 
PMCID: PMC3897873  PMID: 24478709
cerebral oxygenation; humans; hypocapnia; hypercapnia; hypoxia; jugular vein; NIRS
24.  Prenatal influenza exposure and cardiovascular events in adulthood 
This study examined the association between prenatal exposure to pandemic influenza and cardiovascular events in adulthood.
Using Danish surveillance data to identify months when influenza activity was highest during three previous pandemics (1918, 1957, and 1968), persons were defined as exposed/unexposed based on whether they were in utero during peak months of one of the pandemics. Episodes of acute myocardial infarction (MI) and stroke were identified in the Danish National Registry of Patients covering all Danish hospitals since 1977.
Information from Danish national registries on all persons with a Civil Personal Registry number and birthdates in 1915 through 1922, 1954 through 1960, and 1966 through 1972 was collected.
Main outcome measures
Crude incidence rate ratios (IRRs) were calculated per pandemic. Generalized linear models were fit to estimate IRRs adjusted for sex.
For acute MI, sex-adjusted IRRs for persons in utero during peaks of the 1918, 1957, and 1968 pandemics, compared with those born afterward, were 1·02 (95% confidence interval (CI): 0·99, 1·05), 0·96 (95% CI: 0·87, 1·05), and 1·18 (95% CI: 0·96, 1·45), respectively. For stroke, the corresponding IRRs were 0·99 (95% CI: 0·97, 1·02), 0·99 (95% CI: 0·92, 1·05), and 0·85 (95% CI: 0·77, 0·94), respectively.
There was generally no evidence of an association between prenatal influenza exposure and acute MI or stroke in adulthood. However, survivor bias and left truncation of outcomes for the 1918 pandemic are possible, and the current young ages of persons included in the analyses for the 1957 and 1968 pandemics may warrant later re-evaluation.
PMCID: PMC4177801  PMID: 24373293
Acute myocardial infarction; influenza; pandemic; stroke
25.  Elevated Plasma Vitamin B12 Levels as a Marker for Cancer: A Population-Based Cohort Study 
A substantial proportion of patients referred for plasma vitamin B12 (cobalamin [Cbl]) measurement present with high Cbl levels, which have been reported in patients with different cancer types. However, the cancer risk among patients with newly diagnosed high Cbl levels has not been adequately examined.
We conducted this cohort study using population-based Danish medical registries. Patients referred for Cbl measurement with levels greater than the lower reference limit (≥200 pmol/L) were identified from the population of Northern Denmark during the period of 1998 to 2009 using a database of laboratory test results covering the entire population. Data on cancer incidence (follow-up 1998–2010), Cbl treatment, and prior diagnoses were obtained from medical registries. Patients receiving Cbl treatment were excluded. Cancer risks were calculated as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs), stratified by plasma Cbl levels. All statistical tests were two-sided.
We identified 333 667 persons without prevalent cancer and not receiving Cbl treatment. Six percent had Cbl levels greater than the upper reference limit (≥601 pmol/L). Cancer risk increased with higher Cbl levels and was highest during the first year of follow-up (Cbl 601–800 pmol/L: SIR = 3.44, 95% CI = 3.14 to 3.76; Cbl >800 pmol/L: SIR = 6.27, 95% CI = 5.70 to 6.88; both P < .001). The risks were particularly elevated for hematological and smoking- and alcohol-related cancers for persons with high Cbl levels.
High Cbl levels were associated with the risk of subsequently diagnosed cancer, mostly within the first year of follow-up. This may have clinical implications for the interpretation of high Cbl levels.
PMCID: PMC3848986  PMID: 24249744

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