Venous thromboembolism and risk of cancer in patients with rheumatoid arthritis.

Essentials Can venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients be marker of cancer? RA patients with VTE and comparison cohorts from population-based registries were compared. Increased risk of cancer in RA patients with VTE during the first year of VTE was observed. Risk of cancer in RA patients was increased also during the longer period following VTE. SUMMARY: Background It is unknown whether venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients can be a marker of occult cancer. Objectives To examine risk of cancer subsequent to VTE among RA patients compared with risk of cancer in an RA cohort without VTE and in a general population without RA and without VTE. Patients/Methods All RA patients with a first-time diagnosis of VTE (index date) during 1978-2013 and comparison cohorts were identified from population-based registries in Denmark. Results We identified three cohorts: 2497 RA patients with VTE, 11 672 RA patients without VTE and 12 730 persons from the general population. The cumulative incidence of cancer within the first year of the index date was 3.2% among RA with VTE, 2.2% among RA without VTE, and 2.0% in the general population cohort. Incidence rate ratios (IRRs) were 1.79 (95% confidence interval [CI], 1.37-2.33) for RA patients with VTE vs. RA patients without VTE and 2.12 (95% CI, 1.63-2.76) for RA patients with VTE vs. the general population. The IRR of cancer at > 1 to 36 years from the index date among RA patients with VTE was 1.16 (95% CI, 1.00-1.34) compared with the RA patients without VTE and 1.33 (95% CI, 1.15-1.53) compared with the general population. Conclusions We found an increased risk of cancer in RA patients with VTE during the first year following VTE and also during the longer follow-up period. Thus, VTE may not only be a result of inflammation and immunological dysfunctions associated with RA, but may also be a marker for occult cancer.

Risk factors for extended-spectrum ß-lactamase-producing Escherichia coli urinary tract infection in the community in Denmark: a case-control study.

OBJECTIVE: To verify the role of proton pump inhibitors (PPI) and nitrofurantoin, which have appeared as novel risk factors for carriage of extended-spectrum ß-lactamase (ESBL) -producing Escherichia coli, as risk factors for ESBL E. coli urinary tract infection (UTI). We included known risk factors to ascertain whether our findings are comparable with those of previous studies. METHODS: Population-based case-control study including 339 cases with community-onset ESBL E. coli UTI in 2007-2012, 3390 non-ESBL E. coli UTI controls and 3390 population controls. We investigated potential risk factors by estimating ORs and 95% CIs adjusting for sex, age and co-morbidity. RESULTS: Comparing cases with non-ESBL E. coli UTI, PPI use yielded an OR of 1.6 (95% CI 1.2-2.0) and antibiotic exposure gave an OR of 1.4 (95% CI 1.1-1.8); these were driven by nitrofurantoin (OR 1.8; 95% CI 1.3-2.6) and macrolides (OR 1.7; 95% CI 1.2-2.3). Other risk factors included previous hospitalization with one or two and more than two hospitalizations versus none yielding ORs of 1.9 (95% CI 1.4-2.5) and 4.6 (95% CI 3.2-6.8), recent surgery (OR 2.0; 95% CI 1.5-2.8), renal disease (OR 2.2; 95% CI 1.4-3.4), chronic pulmonary disease (OR 1.4; 95% CI 1.0-2.0) and cancer (OR 1.5; 95% CI 1.1-2.1). Comparing cases with population controls, we found that most risk factors were also risk factors for non-ESBL UTI. CONCLUSIONS: ESBL E. coli UTI were associated with previous hospitalization and surgery. Nitrofurantoin and macrolides augmented the risk. PPIs had a moderate effect but may be important facilitators of ESBL carriage due to their widespread use.

[Snippets of past medical research: worth saving?]. / Snippers uit een medisch onderzoeksverleden.

Medical researchers and physicians are not trained in the care of their written or digital past. Here, a scientific historian and a clinical epidemiologist reflect on possibilities for archiving the records of medical research in order to safeguard scientific legacies. In addition to the use of so-called witness seminars, which may suffer from interpretation by 'hindsight', archival material is necessary to understand and interpret the past. A particular problem is how to establish archives of day-to-day scientific undertakings that rely almost entirely on digital media for measurements, communication and publication. The recently developed conviction that good scientific practice encompasses an obligation to store all relevant information about medical research projects at the time of publication - for future replication or verification - might dovetail with the goals of medical historians, and thus might become a rich source of historical data in the future.

[Stability of high-dose etoposide dilutions for use in hematopoietic stem cell transplantation conditioning regimens]. / Stabilité d'une dose élevée d'étoposide en dilution pour utilisation lors du conditionnement avant greffe de cellules souches.

High-dose etoposide is used in conditioning regimens for allogeneic stem cell transplantation. The limited stability of the drug induces barriers for its use for pharmacists, nurses and patients. When using a concentration of 10 mg/mL etoposide in physiologic saline, limitations can be overcome. This study provides stability data for etoposide in a high concentration that can be used in conditioning regimens. The solution was stable for 48h at 5°C, for 48h at 5°C followed by 8h at 25°C and for 24 h at 25°C.

Experience with multiple control groups in a large population-based case-control study on genetic and environmental risk factors.

We discuss the analytic and practical considerations in a large case-control study that had two control groups; the first control group consisting of partners of patients and the second obtained by random digit dialling (RDD). As an example of the evaluation of a general lifestyle factor, we present body mass index (BMI). Both control groups had lower BMIs than the patients. The distribution in the partner controls was closer to that of the patients, likely due to similar lifestyles. A statistical approach was used to pool the results of both analyses, wherein partners were analyzed with a matched analysis, while RDDs were analyzed without matching. Even with a matched analysis, the odds ratio with partner controls remained closer to unity than with RDD controls, which is probably due to unmeasured confounders in the comparison with the random controls as well as intermediary factors. However, when studying injuries as a risk factor, the odds ratio remained higher with partner control subjects than with RRD control subjects, even after taking the matching into account. Finally we used factor V Leiden as an example of a genetic risk factor. The frequencies of factor V Leiden were identical in both control groups, indicating that for the analyses of this genetic risk factor the two control groups could be combined in a single unmatched analysis. In conclusion, the effect measures with the two control groups were in the same direction, and of the same order of magnitude. Moreover, it was not always the same control group that produced the higher or lower estimates, and a matched analysis did not remedy the differences. Our experience with the intricacies of dealing with two control groups may be useful to others when thinking about an optimal research design or the best statistical approach.

The risk for breast cancer is not evidently increased in women with hyperprolactinemia.

The question has been raised whether hyperprolactinemia in humans is associated with an excess risk for breast cancer. We aimed to assess the risk of breast cancer in a previously defined large cohort of patients treated for idiopathic hyperprolactinemia or prolactinomas. Based on the pattern of drug prescriptions we identified 11,314 subjects in the PHARMO network with at least one dispensing of dopamine agonists between 1996 and 2006. Of these, 1,607 subjects were considered to have dopamine agonist-treated hyperprolactinemia based on the prescribing pattern. For the present analysis, we included only women (n = 1,342). Patients with breast cancer were identified by hospital discharge codes. Data on breast cancer incidence in the Netherlands were derived from the Dutch cancer registry. Standardized mortality ratio (SMR) was the measure of outcome to assess the association between hyperprolactinemia and breast cancer. The 1,342 patients accounted for a total of 6,576 person years. Eight patients with breast cancer during follow-up were identified. Indirect standardization with incidence proportions from the general Dutch population revealed a 7.47 expected cases. The calculated SMR for breast cancer risk in patients treated hyperprolactinemia was 1.07 (95% confidence interval 0.50-2.03). In conclusion, there is no clear evidence for increased breast cancer risk in female patients treated for either idiopathic hyperprolactinemia or prolactinomas. The uncertainty about the exact risk that is due to the relatively low number of breast cancer cases, should be overcome by pooling results in a future meta-analysis.

How to assess the external validity of therapeutic trials: a conceptual approach.

BACKGROUND: External validity of study results is an important issue from a clinical point of view. From a methodological point of view, however, the concept of external validity is more complex than it seems to be at first glance. METHODS: Methodological review to address the concept of external validity. RESULTS: External validity refers to the question whether results are generalizable to persons other than the population in the original study. The only formal way to establish the external validity would be to repeat the study for that specific target population. We propose a three-way approach for assessing the external validity for specified target populations. (i) The study population might not be representative for the eligibility criteria that were intended. It should be addressed whether the study population differs from the intended source population with respect to characteristics that influence outcome. (ii) The target population will, by definition, differ from the study population with respect to geographical, temporal and ethnical conditions. Pondering external validity means asking the question whether these differences may influence study results. (iii) It should be assessed whether the study's conclusions can be generalized to target populations that do not meet all the eligibility criteria. CONCLUSION: Judging the external validity of study results cannot be done by applying given eligibility criteria to a single target population. Rather, it is a complex reflection in which prior knowledge, statistical considerations, biological plausibility and eligibility criteria all have place.

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study.

OBJECTIVE: To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands. DESIGN: Population based case-control study. SETTING: Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). PARTICIPANTS: Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls. MAIN OUTCOME MEASURES: First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf's method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model. RESULTS: Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives. CONCLUSIONS: Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

Clinical outcomes after estimated versus calculated activity of radioiodine for the treatment of hyperthyroidism: systematic review and meta-analysis.

BACKGROUND: Despite the long experience with radioiodine for hyperthyroidism, controversy remains regarding the optimal method to determine the activity that is required to achieve long-term euthyroidism. OBJECTIVES: To compare the effect of estimated versus calculated activity of radioiodine in hyperthyroidism. Design Systematic review and meta-analysis. METHODS: We searched the databases Medline, EMBASE, Web of Science, and Cochrane Library for randomized and nonrandomized studies, comparing the effect of activity estimation methods with dosimetry for hyperthyroidism. The main outcome measure was the frequency of treatment success, defined as persistent euthyroidism after radioiodine treatment at the end of follow-up in the dose estimated and calculated dosimetry group. Furthermore, we assessed the cure rates of hyperthyroidism. RESULTS: Three randomized and five nonrandomized studies, comparing the effect of estimated versus calculated activity of radioiodine on clinical outcomes for the treatment of hyperthyroidism, were included. The weighted mean relative frequency of successful treatment outcome (euthyroidism) was 1.03 (95% confidence interval (CI) 0.91-1.16) for estimated versus calculated activity; the weighted mean relative frequency of cure of hyperthyroidism (eu- or hypothyroidism) was 1.03 (95% CI 0.96-1.10). Subgroup analysis showed a relative frequency of euthyroidism of 1.03 (95% CI 0.84-1.26) for Graves' disease and of 1.05 (95% CI 0.91-1.19) for toxic multinodular goiter. CONCLUSION: The two main methods used to determine the activity in the treatment of hyperthyroidism with radioiodine, estimated and calculated, resulted in an equally successful treatment outcome. However, the heterogeneity of the included studies is a strong limitation that prevents a definitive conclusion from this meta-analysis.

Estimated age- and sex-specific incidence and prevalence of dopamine agonist-treated hyperprolactinemia.

CONTEXT: Few data exist on sex- and age-specific incidence and prevalence of idiopathic hyperprolactinemia and prolactinomas. OBJECTIVES: Our objective was to assess incidence and prevalence of dopamine agonist-treated hyperprolactinemia by age and sex. DESIGN: From the PHARMO network, we identified an open cohort of patients who were ever dispensed dopamine agonists for hyperprolactinemia. The network includes complete medication histories for more than 2 million community-dwelling residents. Prolonged use of low-dose dopamine agonist is a reliable marker for hyperprolactinemia, provided that use for Parkinson's disease and lactation withdrawal is excluded. Diagnoses were verified by prolactin values in a random subsample using the same network. RESULTS: We identified 11,314 subjects with at least one dispensing of dopamine agonist in the period 1996-2006, of whom 1607 subjects were considered to have dopamine agonist-treated hyperprolactinemia based on the prescribing pattern. The majority of patients were women (n = 1342, 84%). The diagnosis proved to be incorrect in only 1.5% of a random subsample. The estimated incidence rate of dopamine agonist-treated hyperprolactinemia for women was 8.7/100,000 person-years and for men 1.4/100,000 person-years. The highest incidence rate was found in women 25-34 yr of age: 23.9/100,000 person-years. The mean prevalence of ever treated female patients was almost five times higher (93.9/100,000) compared with male patients (19.6/100,000). CONCLUSION: The incidence rates and the prevalence of dopamine agonist-treated hyperprolactinemia showed an overall preponderance in women, with a strong peak for women aged 25-34 yr. In men, no peak was found.

[The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting of observational studies]. / Das Strengthening the Reporting of Observational Studies in Epidemiology (STROBE-) Statement.

Much of biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

The James Lind Library: explaining and illustrating the evolution of fair tests of medical treatments.

The James Lind Library (www.jameslindlibrary.org) has been established to improve public and professional general knowledge about fair tests of treatments in healthcare and their history. Its foundation was laid ten years ago at the Royal College of Physicians of Edinburgh, and its administrative centre is in the College's Sibbald Library, one of the most important collections of historic medical manuscripts, papers and books in the world. The James Lind Library is a website that introduces visitors to the principles of fair tests of treatments, with a series of short, illustrated essays, which are currently available in English, Arabic, Chinese, French, Portuguese, Russian and Spanish. A 100-page book-- Testing Treatments--is now available free through the website, both in English and in Arabic and Spanish translations. To illustrate the evolution of ideas related to fair tests of treatments from 2000 BC to the present, the James Lind Library contains key passages and images from manuscripts, books and journal articles, many of them accompanied by commentaries, biographies, portraits and other relevant documents and images, including audio and video files. New material is being added to the website continuously, as relevant new records are identified and as methods for testing treatments evolve. A multinational, multilingual editorial team oversees the development of the website, which currently receives tens of thousands of visitors every month.

Microbiological challenge of four protective devices for the reconstitution of cytotoxic agents.

AIMS: To evaluate the susceptibility to microbial contamination that occurs during simulated handling of protective devices for the preparation of cytotoxic drug solutions. METHODS AND RESULTS: Four devices, i.e. Chemoprotect spike, Clave connector, PhaSeal and Securmix were challenged with low and high inocula of micro-organisms. The cells, transferred to the connected vials during repeated manipulations of the devices were counted by means of solid-phase cytometry. Of the four devices, PhaSeal afforded the lowest transfer of micro-organisms. Secondly, the efficiency of procedures for the disinfection of an artificially contaminated rubber stopper was compared prior to connection of the vial to the PhaSeal device. Spraying or swabbing alone was inadequate, as opposed to a combination of spraying [0.5% or 2.0% (w/v) chlorhexidine in isopropanol] and swabbing [70% (v/v) isopropanol]. CONCLUSIONS: Although Phaseal afforded the lowest transfer of micro-organisms, adequate disinfection of the vial prior to connection remains required. SIGNIFICANCE AND IMPACT OF THE STUDY: Unlike aspects of operator protection, which are well documented, the microbiological safety of protective devices for the preparation of cytotoxic drugs has not been addressed in the literature. This study estimates the susceptibility to microbial contamination during handling of four commonly used devices.

Mortality in acromegaly: a metaanalysis.

CONTEXT: Several studies have assessed mortality risk in patients treated for acromegaly. All studies found a mortality that was higher than expected for the general population, but most of these increases were not statistically significant. For this reason, it is not formally established whether mortality in acromegaly is different from the general population. OBJECTIVE: The objective of the study was to address the all-cause mortality risk in patients with acromegaly. DESIGN: The study was a metaanalysis. METHODS: Sixteen studies on mortality in patients with acromegaly were included. The principal outcome of the metaanalysis was the weighted average of the standardized mortality ratio (SMR) of all studies. In addition, we performed a subgroup analysis of studies in which more than 80% of the patients were treated by transsphenoidal approach. RESULTS: The weighted mean of the SMR from all 16 studies was 1.72 (95% confidence interval 1.62-1.83). In studies with transsphenoidal surgery as the primary therapy, the weighted mean of the SMR was 1.32 (95% confidence interval 1.12-1.56). CONCLUSIONS: This metaanalysis shows increased all-cause mortality in acromegalic patients, compared with the general population, even after transsphenoidal surgery.

[Generalizability of therapeutic trials]. / Generaliseerbaarheid van therapeutisch onderzoek.

The external validity of a therapeutic trial addresses whether the study results may be applicable to other patients beyond the original study population. The inclusion criteria of the original study are a good indicator of the extent to which new patients are comparable with the study population, based on key characteristics. If the patients included in the study are not representative of the target population, the external validity is limited. The external validity can also be limited by study aspects that are not related to the inclusion criteria, such as the treatment protocol, the treatment centre, or the country in which the original study was performed. In exceptional cases the external validity can involve patients that would have been excluded in the original study.

[The N-of-1 trial: the ideal study design that is underused]. / De N = 1-trial, de meest ideale onderzoeksopzet, die te weinig wordt gebruikt.

The randomised experiment in a single patient, the N-of-1 trial, is the best study design for demonstrating causality, for example between agent and effect. Despite this, this type of study is only encountered sporadically in medical journals. One reason for this is that even this type of design cannot definitively demonstrate causality, because different points in time are compared with one another. Moreover, the design is rather inefficient, since the results correspond with those from observation without randomisation, placebo control or blinding. Even so, the N-of-1 trial is the ultimate form of verification in, for example, the individualisation of treatment. For this reason, this form of study might be used more often.

Cardiovascular risk factors after bariatric surgery: Do patients gain more than expected from their substantial weight loss?

BACKGROUND: While it has been established that even limited weight loss (5-10%) improves obesity-associated cardiovascular risk factors, it is not known if considerable weight loss following laparoscopic adjustable silicone gastric banding (LASGB) results in a cardiovascular risk profile that is comparable, worse, or even better than that of matched control subjects. METHODS: Cardiovascular risk factors were compared in three groups of 24 women each: an index group that had lost considerable weight following LASGB for morbid obesity (BMI>40 kg/m(2)), a control group with the same BMI that the index group achieved after weight loss, and a pre-weight loss group of women with a BMI above 40 kg/m(2). Anthropometric measures, fasting serum glucose, insulin, lipids, C-reactive protein, and homocysteine levels were determined and insulin sensitivity was estimated using a homeostasis model assessment index (HOMA-IR). RESULTS: After bariatric surgery, the index group had a BMI of 32.0+/-0.8 kg/m(2). This resulted in a significantly better cardiovascular risk profile than that of the pre-weight loss group (BMI 42.8+/-0.6 kg/m(2)). Unexpectedly, after weight loss, the index group had significantly lower systolic blood pressure, fasting serum insulin, and HOMA-IR than the BMI-matched (32.8+/-0.9 kg/m(2)) control group. Although not significant, diastolic blood pressure, LDL-cholesterol, and CRP levels were also lower. CONCLUSION: Considerable weight loss following bariatric surgery leads to a greater improvement in cardiovascular risk factors than might be expected from the weight loss.

[Levels of evidence are insufficient]. / Niveaus van bewijskracht schieten tekort.

Medical knowledge is based on various types of research, each with its own 'indication' and 'contraindication'. Although the randomised controlled trial is highly useful to quantify small differences in treatment effects, it is not able to establish all medical knowledge needed at the bedside. In most instances of non-therapeutic research, observational data are more useful. Evaluating all medical knowledge on the basis of a single hierarchy of level of evidence is therefore seriously flawed.