AIM: To develop and validate a case definition of eosinophilic esophagitis (EoE) in the linked Danish health registries.

METHODS: For case definition development, we queried the Danish medical registries from 2006-2007 to identify candidate cases of EoE in Northern Denmark. All International Classification of Diseases-10 (ICD-10) and prescription codes were obtained, and archived pathology slides were obtained and re-reviewed to determine case status. We used an iterative process to select inclusion/exclusion codes, refine the case definition, and optimize sensitivity and specificity. We then re-queried the registries from 2008-2009 to yield a validation set. The case definition algorithm was applied, and sensitivity and specificity were calculated.

RESULTS: Of the 51 and 49 candidate cases identified in both the development and validation sets, 21 and 24 had EoE, respectively. Characteristics of EoE cases in the development set [mean age 35 years; 76% male; 86% dysphagia; 103 eosinophils per high-power field (eos/hpf)] were similar to those in the validation set (mean age 42 years; 83% male; 67% dysphagia; 77 eos/hpf). Re-review of archived slides confirmed that the pathology coding for esophageal eosinophilia was correct in greater than 90% of cases. Two registry-based case algorithms based on pathology, ICD-10, and pharmacy codes were successfully generated in the development set, one that was sensitive (90%) and one that was specific (97%). When these algorithms were applied to the validation set, they remained sensitive (88%) and specific (96%).

CONCLUSION: Two registry-based definitions, one highly sensitive and one highly specific, were developed and validated for the linked Danish national health databases, making future population-based studies feasible.

Earlier studies suggest a protective association between vitamin K antagonist (VKA) anticoagulants and the incidence of cancer. The authors examined the associations between VKA therapy and incidence of 24 site-specific cancers with a Danish population-based cohort study, using heart valve replacement as an instrumental variable. The authors enrolled 9,727 Danish residents who received a replacement heart valve between 1989 and 2006. The heart valve recipients were matched with 95,481 unexposed individuals on age and sex. The authors used the heart valve replacement instrument to estimate rate ratios associating VKA therapy with incidence of the 24 site-specific cancers using Poisson regression models. Direct associations between VKA therapy and incidence of the 24 cancers were estimated in a prescription validation subset. The instrumental variable associations were plotted according to the inverse normal of rank percentile and subjected to semi-Bayes shrinkage adjustment for multiple comparisons. The pattern of associations was consistent with a null-centered Gaussian distribution. No individual cancer site showed a substantial positive or negative association with VKA therapy in the prescription validation subset, the instrumental variable analysis, or the analysis with semi-Bayes adjustment. These results do not support the existing hypothesis that VKA therapy is associated with reduced cancer risk.

OBJECTIVE

To examine the association between diabetes, glycemic control, and risk of tuberculosis (TB).

RESEARCH DESIGN AND METHODS

We conducted a population-based case-control study in Northern Denmark. Cases of active TB were all individuals with a first-time principal hospital diagnosis of TB between 1980 and 2008. Each case subject was matched with up to five population control subjects with similar age, sex, place and length of residence in Denmark, and country of emigration. We computed odds ratios (ORs) for a first-time TB diagnosis among people with and without diabetes using regression to control for other comorbidities, alcoholism, immunosuppressive medications, and socioeconomic markers.

RESULTS

We identified 2,950 patients, including 156 diabetic individuals (5.3%), with active TB, and 14,274 population control subjects, of which 539 had diabetes (3.8%). The adjusted OR for active TB among subjects with diabetes was 1.18 (95% CI 0.96–1.45) compared with nondiabetic individuals. We found a similar risk increase from diabetes in the 843 (29%) TB case subjects who were immigrants; adjusted OR = 1.23 (95% CI 0.78–1.93). In a subset with laboratory data, diabetic individuals with an HbA1c <7.0, 7–7.9, and ≥8.0% had ORs of 0.91 (0.51–1.63), 1.05 (0.41–2.66), and 1.19 (CI 0.61–2.30), respectively, compared with individuals without diabetes.

CONCLUSIONS

In the low TB–burden country of Denmark, the TB risk increase associated with diabetes is substantially lower than previously suggested. We found no evidence for any association between TB and dysglycemia.

The Danish health care system provides partial reimbursement of most prescription medications in Denmark. The dispensation of prescription medications is registered in administrative databases. Each time a prescription is redeemed at a pharmacy, an electronic record is generated with information related to the user, prescriber, the pharmacy, and the dispensed drug. The National Health Service gathers this information for administration of the drug reimbursement plan. Recently, this information became the basis for the establishment of a new research database, the Danish National Database of Reimbursed Prescriptions (DNDRP). In this paper, we review the content, coverage, quality, linkage, access, and research possibilities of this new database. The database encompasses the reimbursement records of all reimbursed drugs sold in community pharmacies and hospital-based outpatient pharmacies in Denmark since 2004. On average, approximately 3.5 million users are recorded in the database each year. During the coverage period, the number of annual prescription redemptions increased by 15%. Most dispensed prescriptions are in the categories “alimentary tract and metabolism”, “cardiovascular system”, “nervous system”, and “respiratory system”. Individuals are identified by the unique central personal registration (CPR) number assigned to all persons born in or immigrating to Denmark. The new database fully complies with Denmark’s Act on Processing of Personal Data, while avoiding additional restrictions imposed on data use at the Danish National Prescription Registry, administered by Statistics Denmark. Most importantly, CPR numbers are reversibly encrypted, which allows re-identification of drug users; furthermore, the data access is possible outside the servers of Statistics Denmark. These features open additional opportunities for international collaboration, validation studies, studies on adverse drug effects requiring review of medical records, studies involving contact to general practitioners, and linkage of prescription data to other clinical and research databases. The DNDRP thus is a valuable data source for pharmacoepidemiological research.

Introduction

Chronic diseases and their complications may increase breast cancer risk through known or still unknown mechanisms, or by shared causes. The association between morbidities and breast cancer risk has not been studied in depth.

Methods

Data on all Danish women aged 45 to 85 years, diagnosed with breast cancer between 1994 and 2008 and data on preceding morbidities were retrieved from nationwide medical registries. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression associating the Charlson comorbidity score (measured using both the original and an updated Charlson Comorbidity Index (CCI)) with incident breast cancer. Furthermore, we estimated associations between 202 morbidity categories and incident breast cancer, adjusting for multiple comparisons using empirical Bayes (EB) methods.

Results

The study included 46,324 cases and 463,240 population controls. Increasing CCI score, up to a score of six, was associated with slightly increased breast cancer risk. Among the Charlson diseases, preceding moderate to severe renal disease (OR = 1.25, 95% CI: 1.06, 1.48), any tumor (OR = 1.17, 95% CI: 1.10, 1.25), moderate to severe liver disease (OR = 1.86, 95% CI: 1.32, 2.62), and metastatic solid tumors (OR = 1.49, 95% CI: 1.17, 1.89), were most strongly associated with subsequent breast cancer. Preceding myocardial infarction (OR = 0.89, 95% CI: 0.81, 0.99), connective tissue disease (OR = 0.87, 95% CI: 0.80, 0.94), and ulcer disease (OR = 0.91, 95% CI: 0.83, 0.99) were most strongly inversely associated with subsequent breast cancer. A history of breast disorders was associated with breast cancer after EB adjustment. Anemias were inversely associated with breast cancer, but the association was near null after EB adjustment.

Conclusions

There was no substantial association between morbidity measured with the CCI and breast cancer risk.

Background

Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied.

Methods

We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I–III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided.

Results

Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = −0.10, 95% confidence interval = −0.11 to −0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = −0.01 to 0.11).

Conclusions

Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed.

Background

We evaluated the effectiveness and safety of a zotarolimus-eluting (ZES) versus a sirolimus-eluting (SES) coronary stent in a large cohort of patients treated with one of these stents in Western Denmark.

Methods

A total of 6,122 patients treated with ZES (n=2,282) or SES (n=3,840) were followed for up to 27 months. We ascertained clinical outcomes based on national medical databases.

Results

Incidence of target lesion revascularization (no. per 100 person-years) was 5.3 in the ZES group compared to 1.9 in the SES group (adjusted hazard ratio (HR)=2.19, 95% confidence intervals (CI): 1.39-3.47; p=0.001). All-cause mortality was also higher in the ZES group (ZES: 6.3; SES: 3.3; adjusted HR=1.34, 95% CI: 1.05-1.72; p=0.02), while stent thrombosis (ZES: 1.2; SES: 0.5; adjusted HR=1.98, 95% CI: 0.75-5.23; p=0.14) did not differ significantly.

Conclusions

In agreement with previously published randomised data, this observational study indicated that the ZES was associated with an increased risk of death and TLR in a large cohort of consecutive patients.

The authors examined the association between menstrual characteristics and time to pregnancy among 2,653 Danish women enrolled in a prospective cohort study (2007–2009). Menstrual characteristics were reported at baseline. Outcome data were updated bimonthly until pregnancy, fertility treatment, loss to follow-up, or end of observation (12 cycles). Adjusted fecundability ratios and 95% confidence intervals were estimated by using discrete-time Cox regression models. Relative to average cycle lengths (27–29 days), fecundability ratios for cycle lengths <25, 25–26, 30–31, 32–33, and ≥34 days were 0.64 (95% confidence interval (CI): 0.49, 0.84), 0.94 (95% CI: 0.77, 1.13), 1.10 (95% CI: 0.97, 1.25), 1.35 (95% CI: 1.06, 1.73), and 1.17 (95% CI: 0.91, 1.49), respectively. Compared with cycles that regularized within 2 years after menarche, fecundability ratios for cycles that regularized 2–3 and ≥4 years after menarche were 0.90 (95% CI: 0.80, 1.02) and 0.89 (95% CI: 0.77, 1.03), respectively. Fecundability ratios were 0.87 (95% CI: 0.72, 1.05) comparing <3 with 3–4 days of menstrual bleeding and 0.70 (95% CI: 0.43, 1.13) comparing very heavy with moderate flow. In the present study, shorter cycle length was associated with delayed time to pregnancy. Age at menarche, time to menstrual regularization, and duration or intensity of menstrual flow were not appreciably associated with fecundability.

Background

Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors.

Methods

We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype.

Results

No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype.

Conclusions

Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk.

Impact

Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy.

Introduction

The impact of statin use on pneumonia risk and outcome remains unclear. We therefore examined this risk in a population-based case-control study and did a 5-year update of our previous 30-day mortality analyses.

Methods

We identified 70,953 adults with a first-time hospitalization for pneumonia between 1997 and 2009 in Northern Denmark. Ten age- and sex-matched population controls were selected for each pneumonia patient. To control for potential confounders, we retrieved individual-level data on other medications, comorbidities, recent surgery, socioeconomic indicators, influenza vaccination, and other markers of frailty or health awareness from medical databases. We followed all pneumonia patients for 30 days after hospital admission.

Results

A total of 7,223 pneumonia cases (10.2%) and 64 523 controls (9.1%) were statin users before admission, corresponding to an age- and sex-matched odds ratio (OR) of 1.17 (95% confidence interval [CI]: 1.14-1.21). After controlling for higher comorbidity and a wide range of other potential confounders, the adjusted OR for pneumonia associated with current statin use dropped to 0.80 (95% CI: 0.77-0.83). Previous statin use was not associated with decreased pneumonia risk (adjusted OR = 0.97, 95% CI: 0.91-1.02). Decreased risk remained significant after further adjustment for frailty and health awareness markers.

The prevalence of statin use among Danish pneumonia patients increased from 1% in 1997 to 24% in 2009. Thirty-day mortality following pneumonia hospitalization was 11.3% among statin users versus 15.1% among nonusers. This corresponded to a 27% reduced mortality rate (adjusted hazard ratio = 0.73, 95% CI: 0.67-0.79), corroborating our earlier findings.

Conclusions

Current statin use was associated with both a decreased risk of hospitalization for pneumonia and lower 30-day mortality following pneumonia.

Introduction

There are few studies on long-term mortality among intensive care unit (ICU) patients with acute kidney injury (AKI). We assessed the prevalence of AKI at ICU admission, its impact on mortality during one year of follow-up, and whether the influence of AKI varied in subgroups of ICU patients.

Methods

We identified all adults admitted to any ICU in Northern Denmark (approximately 1.15 million inhabitants) from 2005 through 2010 using population-based medical registries. AKI was defined at ICU admission based on the risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) classification, using plasma creatinine changes. We included four severity levels: AKI-risk, AKI-injury, AKI-failure, and without AKI. We estimated cumulative mortality by the Kaplan-Meier method and hazard ratios (HRs) using a Cox model adjusted for potential confounders. We computed estimates for all ICU patients and for subgroups with different comorbidity levels, chronic kidney disease status, surgical status, primary hospital diagnosis, and treatment with mechanical ventilation or with inotropes/vasopressors.

Results

We identified 30,762 ICU patients, of which 4,793 (15.6%) had AKI at ICU admission. Thirty-day mortality was 35.5% for the AKI-risk group, 44.2% for the AKI-injury group, and 41.0% for the AKI-failure group, compared with 12.8% for patients without AKI. The corresponding adjusted HRs were 1.96 (95% confidence interval (CI) 1.80-2.13), 2.60 (95% CI 2.38 to 2.85) and 2.41 (95% CI 2.21 to 2.64), compared to patients without AKI. Among patients surviving 30 days (n = 25,539), 31- to 365 day mortality was 20.5% for the AKI-risk group, 23.8% for the AKI-injury group, and 23.2% for the AKI-failure group, compared with 10.7% for patients without AKI, corresponding to adjusted HRs of 1.33 (95% CI 1.17 to 1.51), 1.60 (95% CI 1.37 to1.87), and 1.64 (95% CI 1.42 to 1.90), respectively. The association between AKI and 30-day mortality was evident in subgroups of the ICU population, with associations persisting in most subgroups during the 31- to 365-day follow-up period, although to a lesser extent than for the 30-day period.

Conclusions

AKI at ICU admission is an important prognostic factor for mortality throughout the subsequent year.

Background

Cytochrome P450 2D6 (CYP2D6) inhibition reduces the concentration of 4-hydroxylated tamoxifen metabolites, but the clinical relevance remains uncertain.

Methods

We conducted a large case–control study nested in the population of 11 251 women aged 35–69 years at diagnosis of stage I–III breast cancer between 1985 and 2001 on Denmark’s Jutland Peninsula and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent or contralateral breast cancers among women with estrogen receptor–positive (ER+) disease treated with tamoxifen for at least 1 year and 300 cancers in women with ER-negative (ER−) disease never treated with tamoxifen. We matched one control subject per case patient on ER status, menopausal status, stage, calendar time, and county, genotyped the CYP2D6*4 allele to assess genetic inhibition, and ascertained prescription history to assess drug–drug inhibition. We estimated the odds ratio (OR), associating CYP2D6 inhibition with breast cancer recurrence and adjusted for potential confounding with logistic regression. To address bias from incomplete information on CYP2D6 function, we used Monte Carlo simulation to complete a record-level probabilistic bias analysis. All statistical tests were two-sided.

Results

The frequency of the CYP2D6*4 minor allele was 24% in case patients with ER+ tumors, 23% in case patients with ER− tumors, and 22% each in control subjects with ER+ and ER− tumors. In women with ER+ tumors, the associations of one functional allele with recurrence (OR = 0.99; 95% confidence interval = 0.76 to 1.3) and no functional allele with recurrence (OR = 1.4; 95% confidence interval = 0.84 to 2.3) were near null, as were those for women with ER− tumors. The near-null associations persisted when evaluated by intake of medications, by combining genotype with medication history, in the probabilistic bias analysis, or by restricting the analysis to women with ER expression confirmed by re-assay.

Conclusion

The association between CYP2D6 inhibition and recurrence in tamoxifen-treated patients is likely null or small.

Background

Early identification of persons with undiagnosed HIV infection is an important health care issue. We examined associations between diseases diagnosed in hospitals and risk of subsequent HIV diagnosis.

Methods

In this population-based case control study, cases were persons with incident HIV infection diagnosed in Denmark between 1 January 1995 and 1 June 2008. Risk-set sampling was used to identify 19 age- and gender-matched population controls for each HIV case, using the HIV diagnosis date as the index date for both cases and controls. Prior hospital diagnoses obtained from Danish medical databases were first categorized into 22 major disease categories (excluding AIDS-defining diseases except tuberculosis) and then subdivided into 161 subcategories, allowing us to examine specific diseases as potential HIV indicators by conditional logistic regression.

Results

The study included 2,036 HIV cases and 35,718 controls. Persons with the following disease categories had a high risk of HIV diagnosis during the subsequent 5-year period: sexually transmitted infections and viral hepatitis (adjusted odds ratio [aOR] = 12.3, 95% CI: 9.60–15.7), hematological diseases (aOR = 4.28, 3.13–5.85), lower respiratory tract infections (aOR = 3.98, 3.14–5.04)), CNS infections (aOR = 3.44, 1.74–6.80), skin infections (aOR = 3.05, 2.47–3.75), other infections (aOR = 4.64, 3.89–5.54), and substance abuse (aOR = 2.60, 2.06–3.29). Several specific diseases were associated with aORs >20 including syphilis, hepatitis A, non “A” viral hepatitis, herpes zoster, candida infection, endocarditis, thrombocytopenia, and opioid abuse.

Conclusions

Targeted testing for HIV in patients diagnosed with diseases associated with HIV may lead to earlier treatment and thereby reduced morbidity, mortality and HIV transmission.

Introduction

Glucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear.

Methods

We conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases.

Results

We found no effect on breast cancer risk in ever users (> 2 prescriptions) of any glucocorticoids (adjusted odds ratio (aOR) = 1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR = 1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR = 1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding two years) and former use (more than two years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (< 1, 1 to 5, 5+ years), was also not associated with breast cancer risk.

Conclusions

Overall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.

Background

Estrogen receptor (ER) expression predicts tamoxifen response, which halves the risk of breast cancer recurrence. We examined clinical factors associated with concordance between ER expression at diagnosis and centralized re-assay, and the association of concordance with breast cancer recurrence.

Materials and Methods

We used immunohistochemistry to assess ER expression on archived fixed, paraffin-embedded breast carcinoma tissue excised from women aged 35–69 years, diagnosed 1985–2001 in Jutland, Denmark. We calculated the percentage agreement, positive predictive value (PPV) and negative predictive value (NPV) of ER status at diagnosis and re-assay. We used logistic regression to investigate factors associated with concordance, and its association with recurrence (odds ratios (OR) and associated 95% confidence intervals (95%CI)).

Results

ER was re-assayed in 91% of patients (n=1530). Concordance was better in ER+ than ER− tumors (PPV=94% versus NPV=75%). Factors associated with concordance included menopausal status, tumor size, surgical procedure, diagnostic period, lymph node status and time to recurrence. ER+ women at diagnosis who re-assayed ER+ were less likely to have recurrent disease (OR=0.49, 95% CI=0.28, 0.86) than those who re-assayed ER−. In originally ER− women, concordance was not associated with recurrence (OR=0.97, 95% CI=0.66, 1.42).

Conclusions

Several clinical factors were associated with ER assay concordance. Some women were ineffectively treated with tamoxifen, or required but did not receive tamoxifen. We observed almost exactly the protective effect of endocrine therapy among tamoxifen-treated ER+ women whose tumors expressed the ER on re-assay, compared with those ER− on re-assay. Diagnostic pathology results for ER+ tumors appear a valid and useful resource for research studies. However, those for ER− tumors have lower validity. Study-specific considerations regarding the aims, diagnostic period, and consequences of including ER− patients with truly ER+ disease ought to be examined when using diagnostic pathology results for ER− tumors in research studies.

Purpose:

The purpose of this systematic review was to examine the link between training characteristics (volume, duration, frequency, and intensity) and running related injuries.

Methods:

A systematic search was performed in PubMed, Web of Science, Embase, and SportDiscus. Studies were included if they examined novice, recreational, or elite runners between the ages of 18 and 65. Exposure variables were training characteristics defined as volume, distance or mileage, time or duration, frequency, intensity, speed or pace, or similar terms. The outcome of interest was Running Related Injuries (RRI) in general or specific RRI in the lower extremity or lower back. Methodological quality was evaluated using quality assessment tools of 11 to 16 items.

Results:

After examining 4561 titles and abstracts, 63 articles were identified as potentially relevant. Finally, nine retrospective cohort studies, 13 prospective cohort studies, six case-control studies, and three randomized controlled trials were included. The mean quality score was 44.1%. Conflicting results were reported on the relationships between volume, duration, intensity, and frequency and RRI.

Conclusion:

It was not possible to identify which training errors were related to running related injuries. Still, well supported data on which training errors relate to or cause running related injuries is highly important for determining proper prevention strategies. If methodological limitations in measuring training variables can be resolved, more work can be conducted to define training and the interactions between different training variables, create several hypotheses, test the hypotheses in a large scale prospective study, and explore cause and effect relationships in randomized controlled trials.

Level of evidence:

2a

Background

Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.

Methodology/Principal Findings

To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.

Conclusions/Significance

Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.

Introduction

Alcoholic patients comprise a large proportion of patients in intensive care units (ICUs). However, data are limited on the impact of alcoholism on mortality after intensive care.

Methods

We conducted a cohort study among 16,848 first-time ICU patients between 2001 and 2007 to examine 30-day and 3-year mortality among alcoholic patients. Alcoholic patients with and without complications of alcohol misuse (for example, alcoholic liver disease) were identified from previous hospital contacts for alcoholism-related conditions or redemption of a prescription for alcohol deterrents. Data on medication use, demographics, hospital diagnoses, and comorbidity were obtained from medical databases. We computed 30-day and 3-year mortality and mortality rate ratios (MRRs) by using Cox regression analysis, controlling for covariates.

Results

In total, 1,229 (7.3%) ICU patients were current alcoholics. Among alcoholic patients without complications of alcoholism (n = 785, 4.7% of the cohort), 30-day mortality was 15.9% compared with 19.7% among nonalcoholic patients. Compared with nonalcoholic patients, the adjusted 30-day MRR was 1.04 (95% confidence interval (CI), 0.87 to 1.25). Three-year mortality was 36.2% compared with 40.9% among nonalcoholic patients, corresponding to an adjusted 3-year MRR of 1.16 (95% CI, 1.03 to 1.31). For alcoholic patients with complications (n = 444, 2.6% of the cohort), 30-day mortality was 33.6%, and 3-year mortality was 64.5%, corresponding to adjusted MRRs, with nonalcoholics as the comparator, of 1.64 (95% CI, 1.38 to 1.95) and 1.67 (95% CI, 1.48 to 1.90), respectively.

Conclusions

Alcoholic ICU patients with chronic complications of alcoholism have substantially increased 30-day and 3-year mortality. In contrast, alcoholics without complications have no increased 30-day and only slightly increased 3- year mortality.

Background

We determined the impact of three factors on mortality in HIV-infected patients who had been on highly active antiretroviral therapy (HAART) for at least one year: (1) insufficient response to (HAART) and presence of AIDS-defining diseases, (2) comorbidity, and (3) drug and alcohol abuse and compared the mortality to that of the general population.

Methodology/Principal Findings

In a Danish nationwide, population-based cohort study, we used population based registries to identify (1) all Danish HIV-infected patients who started HAART in the period 1 January 1998–1 July 2009, and (2) a comparison cohort of individuals matched on date of birth and gender (N = 2,267 and 9,068, respectively). Study inclusion began 1 year after start of HAART. Patients were categorised hierarchically in four groups according to the three risk factors, which were identified before study inclusion. The main outcome measure was probability of survival from age 25 to 65 years. The probability of survival from age 25 to age 65 was substantially lower in HIV patients [0.48 (95% confidence interval (CI) 0.42–0.55)] compared to the comparison cohort [0.88 (0.86 to 0.90)]. However, in HIV patients with no risk factors (N = 871) the probability of survival was equivalent to that of the general population [0.86 (95% CI 0.77–0.92)]. In contrast, the probability of survival was 0.58 in patients with HIV risk factors (N = 704), 0.30 in patients with comorbidities (N = 479), and 0.03 in patients with drug or alcohol abuse (N = 313).

Conclusions

The increased risk of death in HIV-infected individuals is mainly attributable to risk factors that can be identified prior to or in the initial period of antiretroviral treatment. Mortality in patients without risk factors on a successful HAART is almost identical to that of the non–HIV-infected population.

Background

The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity.

Methodology/Principal Findings

Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20–39 years or 40–69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40–69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%–97%), MRR: 1.3 (95% CI: 0.8–2.3)), whereas those aged 20–39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3–14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40–69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1–30.6)).

Conclusions

Mortality in patients aged 40–69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20–39 years without documented substance abuse or comorbidity.

Background

The search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.

Results

This study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2%) DBS samples failed whole-genome amplification. A total of 4,586 (98.8%) samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.

Conclusion

Our study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.