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2.  Multimorbidity and cancer outcomes: a for more research 
Clinical Epidemiology  2013;5(Suppl 1):1-2.
PMCID: PMC3833011  PMID: 24265558
4.  Editor’s choice 
Clinical Epidemiology  2012;4:157-158.
PMCID: PMC3410687  PMID: 22866016
9.  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
10.  Using registries to identify type 2 diabetes patients 
Clinical Epidemiology  2014;7:1-3.
PMCID: PMC4274149  PMID: 25565888
11.  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
12.  Penicillin allergy 
PMCID: PMC2546099  PMID: 3135904
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
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.  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
22.  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
23.  The impact of comorbidity on cancer survival: a review 
Clinical Epidemiology  2013;5(Suppl 1):3-29.
A number of studies have shown poorer survival among cancer patients with comorbidity. Several mechanisms may underlie this finding. In this review we summarize the current literature on the association between patient comorbidity and cancer prognosis. Prognostic factors examined include tumor biology, diagnosis, treatment, clinical quality, and adherence.
All English-language articles published during 2002–2012 on the association between comorbidity and survival among patients with colon cancer, breast cancer, and lung cancer were identified from PubMed, MEDLINE and Embase. Titles and abstracts were reviewed to identify eligible studies and their main results were then extracted.
Our search yielded more than 2,500 articles related to comorbidity and cancer, but few investigated the prognostic impact of comorbidity as a primary aim. Most studies found that cancer patients with comorbidity had poorer survival than those without comorbidity, with 5-year mortality hazard ratios ranging from 1.1 to 5.8. Few studies examined the influence of specific chronic conditions. In general, comorbidity does not appear to be associated with more aggressive types of cancer or other differences in tumor biology. Presence of specific severe comorbidities or psychiatric disorders were found to be associated with delayed cancer diagnosis in some studies, while chronic diseases requiring regular medical visits were associated with earlier cancer detection in others. Another finding was that patients with comorbidity do not receive standard cancer treatments such as surgery, chemotherapy, and radiation therapy as often as patients without comorbidity, and their chance of completing a course of cancer treatment is lower. Postoperative complications and mortality are higher in patients with comorbidity. It is unclear from the literature whether the apparent undertreatment reflects appropriate consideration of greater toxicity risk, poorer clinical quality, patient preferences, or poor adherence among patients with comorbidity.
Despite increasing recognition of the importance of comorbid illnesses among cancer patients, major challenges remain. Both treatment effectiveness and compliance appear compromised among cancer patients with comorbidity. Data on clinical quality is limited.
PMCID: PMC3820483  PMID: 24227920
comorbidity; cancer; diagnosis; treatment; survival
24.  Comorbid Diseases Interact with Breast Cancer to Affect Mortality in the First Year after Diagnosis—A Danish Nationwide Matched Cohort Study 
PLoS ONE  2013;8(10):e76013.
Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied.
From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer.
The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up.
There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.
PMCID: PMC3794020  PMID: 24130755
25.  Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study 
Critical Care  2013;17(5):R192.
Metformin has anti-inflammatory and anti-thrombotic effects that may improve the outcome of critical illness, but clinical data are limited. We examined the impact of preadmission metformin use on mortality among intensive care unit (ICU) patients with type 2 diabetes.
We conducted this population-based cohort study among all persons admitted to the 17 ICUs in Northern Denmark (population approximately 1.8 million). We focused on all patients with type 2 diabetes who were admitted to the ICUs between January 2005 and December 2011. Through individual-level linkage of population-based medical databases, type 2 diabetes was identified using a previously validated algorithm including hospital diagnoses, filled prescriptions for anti-diabetic drugs, and elevated HbA1c levels. Metformin use was identified by filled prescriptions within 90 days before admission. Covariates included surgery, preadmission morbidity, diabetes duration, and concurrent drug use. We computed 30-day mortality and hazard ratios (HRs) of death using Cox regression adjusted for covariates, both overall and after propensity score matching.
We included 7,404 adult type 2 diabetes patients, representing 14.0% of 52,964 adult patients admitted to the ICUs. Among type 2 diabetes patients, 1,073 (14.5%) filled a prescription for metformin as monotherapy within 90 days before admission and 1,335 (18.0%) received metformin in combination with other anti-diabetic drugs. Thirty-day mortality was 17.6% among metformin monotherapy users, 17.9% among metformin combination therapy users, and 25.0% among metformin non-users. The adjusted HRs were 0.80 (95% confidence interval (CI): 0.69, 0.94) for metformin monotherapy users and 0.83 (95% CI: 0.71, 0.95) for metformin combination therapy users, compared to non-users. Propensity-score-matched analyses yielded the same results. The association was evident across most subgroups of medical and surgical ICU patients, but most pronounced in elderly patients and in patients with well-controlled diabetes. Former metformin use was not associated with decreased mortality.
Preadmission metformin use was associated with reduced 30-day mortality among medical and surgical intensive care patients with type 2 diabetes.
PMCID: PMC4057514  PMID: 24018017

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